ORCID Profile
0000-0002-8072-4222
Current Organisation
University of South Australia
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Publisher: Public Library of Science (PLoS)
Date: 11-08-2015
Publisher: MDPI AG
Date: 04-04-2019
DOI: 10.3390/C5020017
Abstract: Advances in wearable, highly sensitive and multifunctional strain sensors open up new opportunities for the development of wearable human interface devices for various applications such as health monitoring, smart robotics and wearable therapy. Herein, we present a simple and cost-effective method to fabricate a multifunctional strain sensor consisting of a skin-mountable dry adhesive substrate, a robust sensing component and a transdermal drug delivery system. The sensor has high piezoresisitivity to monitor real-time signals from finger bending to ulnar pulse. A transdermal drug delivery system consisting of polylactic-co-glycolic acid nanoparticles and a chitosan matrix is integrated into the sensor and is able to release the nanoparticles into the stratum corneum at a depth of ~60 µm. Our approach to the design of multifunctional strain sensors will lead to the development of cost-effective and well-integrated multifunctional wearable devices.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.NANO.2022.102536
Abstract: Bacterial biofilm infections tolerate high concentrations of antibiotics and are insidiously challenging to treat. Liquid crystal nanoparticles (LCNPs) advance the efficacy of tobramycin in biofilm-related infections by increasing the penetration of antibiotics across the biofilm matrix. Herewith, we develop the LCNPs as a platform technology, demonstrating that the LCNPs can increase the efficacy of two antibiotic classes (i.e. aminoglycosides and colistin) in P. aeruginosa biofilm infections. In C. elegans, the LCNPs potentiated the antimicrobial effect and significantly improved the survival of the nematodes. In mice with a full-thickness excisional wound, LCNPs were non-toxic and did not impair wound repair. Compared to the unformulated antibiotic treatment, tobramycin-LCNPs reduced the chronic bacterial load by 100-fold in the wound. This was also emulated in an ex vivo P. aeruginosa porcine wound infection model. The LCNPs represent a versatile platform technology that improves the efficacy of cationic antibiotics against biofilm infections utilizing multiple administration routes.
Publisher: Frontiers Media SA
Date: 19-11-2021
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/808234
Publisher: Wiley
Date: 06-12-2007
DOI: 10.1002/PATH.2113
Abstract: Collagen type I serves as an abundant structural and signalling component of skin. It is also an established target gene of the transcription factor, c-Myb. When c-myb-/- embryos were examined it was observed that their skin was markedly thinner than normal. Importantly, immunohistochemical investigation showed complete absence of collagen type I. Although these homozygous knock-out embryos fail to develop beyond day 15, fibroblasts established from these embryos (mouse embryonic fibroblasts [MEFs]) show defective proliferative responses. Furthermore, in vitro scratch wound assays demonstrated that these c-myb-/- MEFs also exhibit slower closure than their wild-type counterparts. Embryonic lethality has meant that examination of the role of c-Myb in adult mouse skin has not been reported to date. However, in view of the abundance of collagen type I in normal skin, its role in skin integrity and the in vitro data showing proliferative and migration defects in c-myb-/- MEFs, we investigated the consequences of heterozygous c-myb loss in adult mice on the complex process of skin repair in response to injury. Our studies clearly demonstrate that heterozygous c-myb deficiency has a functional effect on wound repair, collagen type I levels and, in response to wounding, transforming growth factor-beta1 (an important collagen stimulating factor) induction expression is aberrantly high. Manipulation of c-Myb may therefore provide new therapeutic opportunities for improving wound repair while uncontrolled expression may underpin some fibrotic disorders.
Publisher: Public Library of Science (PLoS)
Date: 16-07-2018
Publisher: Wiley
Date: 23-08-2023
Abstract: Current treatment modalities of cutaneous wound infections are largely ineffective, attributed to the increasing burden of antimicrobial resistance. S. aureus , a commonly wound‐associated pathogen continues to pose a clinical challenge, suggesting that new alternative therapeutic materials are urgently required to provide optimal treatment. A layered allotrope of phosphorus termed Black Phosphorus nanoflakes (BPNFs) has emerged as a potential alternative antibacterial material. However, wider deployment of this material requires extensive biological validation using the latest pre‐clinical models to understand its role in wound management. Here, the antibacterial potential of BPNFs against wound pathogens demonstrates over 99% killing efficiency at ambient conditions, while remaining non‐toxic to mammalian skin cells. In addition, in vivo validation of BPNFs using a preclinical model of S. aureus acute wound infection demonstrates that daily topical application significantly reduces infection (3‐log reduction) comparable to ciprofloxacin antibiotic control. Furthermore, the application of BPNFs also accelerates wound closure, increases wound re‐epithelization, and reduces tissue inflammation compared to controls, suggesting a potential role in alleviating the current challenges of infected cutaneous wounds. For the first time, this study demonstrates the potential role of BPNFs in ambient light conditions for clearing a clinically relevant wound infection with favorable wound healing properties.
Publisher: American Chemical Society (ACS)
Date: 25-08-2020
Publisher: Mary Ann Liebert Inc
Date: 04-2020
Publisher: MDPI AG
Date: 08-09-2021
DOI: 10.3390/BIOMEDICINES9091182
Abstract: Biofilm-associated infections are a major cause of impaired wound healing. Despite the broad spectrum of anti-bacterial benefits provided by silver nanoparticles (AgNPs), these materials still cause controversy due to cytotoxicity and a lack of efficacy against mature biofilms. Herein, highly potent ultrasmall AgNPs were combined with a biocompatible hydrogel with integrated synergistic functionalities to facilitate elimination of clinically relevant mature biofilms in-vivo combined with improved wound healing capacity. The delivery platform showed a superior release mechanism, reflected by high biocompatibility, hemocompatibility, and extended antibacterial efficacy. In vivo studies using the S. aureus wound biofilm model showed that the AgNP hydrogel (200 µg/g) was highly effective in eliminating biofilm infection and promoting wound repair compared to the controls, including silver sulfadiazine (Ag SD). Treatment of infected wounds with the AgNP hydrogel resulted in faster wound closure (46% closure compared to 20% for Ag SD) and accelerated wound re-epithelization (60% for AgNP), as well as improved early collagen deposition. The AgNP hydrogel did not show any toxicity to tissue and/or organs. These findings suggest that the developed AgNP hydrogel has the potential to be a safe wound treatment capable of eliminating infection and providing a safe yet effective strategy for the treatment of infected wounds.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2015
DOI: 10.1007/S10735-015-9645-0
Abstract: We have recently shown that Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) has a single high-affinity binding site for fibroblast growth factor-2 (FGF-2) and that LTBP-2 blocks FGF-2 induced cell proliferation. Both proteins showed strong co-localisation within keloid skin from a single patient. In the current study, using confocal microscopy, we have investigated the distribution of the two proteins in normal and fibrotic skin s les including normal scar tissue, hypertrophic scars and keloids from multiple patients. Consistently, little staining for either protein was detected in normal adult skin and normal scar s les but extensive co-localisation of the two proteins was observed in multiple ex les of hypertrophic scars and keloids. LTBP-2 and FGF-2 were co-localised to fine fibrous elements within the extracellular matrix identified as elastic fibres by immunostaining with anti-fibrillin-1 and anti-elastin antibodies. Furthermore, qPCR analysis of RNA s les from multiple patients confirmed dramatically increased expression of LTBP-2 and FGF-2, similar TGF-beta 1, in hypertrophic scar compared to normal skin and scar tissue. Overall the results suggest that elevated LTBP-2 may bind and sequester FGF-2 on elastic fibres in fibrotic tissues and modulate FGF-2's influence on the repair and healing processes.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2020
DOI: 10.1186/S13018-020-01889-Y
Abstract: Surgical repair of tendons is common, but function is often limited due to the formation of flexor tendon adhesions which reduce the mobility and use of the affected digit and hand. The severity of adhesion formation is dependent on numerous cellular processes many of which involve the actin cytoskeleton. Flightless I (Flii) is a highly conserved cytoskeletal protein, which has previously been identified as a potential target for improved healing of tendon injuries. Using human in vitro cell studies in conjunction with a murine model of partial laceration of the digital flexor tendon, we investigated the effect of modulating Flii levels on tenocyte function and formation of adhesions. Human tenocyte proliferation and migration was determined using WST-1 and scratch wound assays following Flii knockdown by siRNA in vitro. Additionally, mice with normal and increased levels of Flii were subjected to a partial laceration of the digital flexor tendon in conjunction with a full tenotomy to immobilise the paw. Resulting adhesions were assessed using histology and immunohistochemistry for collagen I, III, TGF-β1and -β3 Flii knockdown significantly reduced human tenocyte proliferation and migration in vitro. Increasing the expression of Flii significantly reduced digital tendon adhesion formation in vivo which was confirmed through significantly smaller adhesion scores based on collagen fibre orientation, thickness, proximity to other fibres and crimping. Reduced adhesion formation was accompanied with significantly decreased deposition of type I collagen and increased expression of TGF-β1 in vivo. These findings suggest that increasing the level of Flii in an injured tendon may be beneficial for decreasing tendon adhesion formation.
Publisher: Cambridge Media
Date: 12-2019
Publisher: Oxford University Press (OUP)
Date: 10-12-2017
DOI: 10.1111/BJD.14842
Abstract: Psoriasis is a common chronic skin condition characterized by excessive inflammation and aberrant epidermal proliferation. Flightless I (Flii) is an actin-remodelling protein that regulates these processes, suggesting a possible role in psoriasis. We sought to determine whether a benefit in psoriasiform dermatitis might occur after modulating Flii gene expression or reducing its levels using neutralizing antibodies. Biopsies of psoriatic skin lesions from patients were assessed for Flii levels. Psoriasis-like lesions were induced in Flii heterozygous (Flii Flii was elevated in psoriatic lesions from patients with psoriasis compared with normal human skin. Reducing Flii decreased erythema, inflammatory cell infiltrate, proinflammatory cytokines and the thickness of the epidermis. Topical application of Flii neutralizing antibodies to wild-type mice treated with imiquimod resulted in significantly reduced psoriasiform dermatitis. Flii is a novel target involved in psoriasiform dermatitis and reducing cutaneous Flii could potentially be a new approach for treating patients with psoriasis.
Publisher: MDPI AG
Date: 08-12-2021
Abstract: Cutaneous squamous cell carcinoma (cSCC) accounts for 25% of cutaneous malignancies diagnosed in Caucasian populations. Surgical removal in combination with radiation and chemotherapy are effective treatments for cSCC. Nevertheless, the aggressive metastatic forms of cSCC still have a relatively poor patient outcome. Studies have linked actin cytoskeletal dynamics and the Wnt/β-catenin signaling pathway as important modulators of cSCC pathogenesis. Previous studies have also shown that the actin-remodeling protein Flightless (Flii) is a negative regulator of cSCC. The aim of this study was to investigate if the functional effects of Flii on cSCC involve the Wnt/β-catenin signaling pathway. Flii knockdown was performed using siRNA in a human late stage aggressive metastatic cSCC cell line (MET-1) alongside analysis of Flii genetic murine models of 3-methylcholanthrene induced cSCC. Flii was increased in a MET-1 cSCC cell line and reducing Flii expression led to fewer PCNA positive cells and a concomitant reduction in cellular proliferation and symmetrical ision. Knockdown of Flii led to decreased β-catenin and a decrease in the expression of the downstream effector of β-catenin signaling protein SOX9. 3-Methylcholanthrene (MCA)-induced cSCC in Flii overexpressing mice showed increased markers of cancer metastasis including talin and keratin-14 and a significant increase in SOX9 alongside a reduction in Flii associated protein (Flap-1). Taken together, this study demonstrates a role for Flii in regulating proteins involved in cSCC proliferation and tumor progression and suggests a potential role for Flii in aggressive metastatic cSCC.
Publisher: MDPI AG
Date: 09-11-2022
DOI: 10.20944/PREPRINTS202211.0160.V1
Abstract: Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified. The aim of this review has been to collate the information available from functional studies and recent transcriptome analysis to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.
Publisher: Frontiers Media SA
Date: 10-08-2018
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/168321
Abstract: Psoriasis is a common chronic inflammatory skin condition in which patients suffer from mild to chronic plaque skin plaques. The disease manifests through an excessive inflammatory response in the skin due to complex interactions between different genetic and environmental factors. Psoriasis can affect the physical, emotional, and psychosocial well-being of patients, and currently there is no cure with treatments focusing primarily on the use of anti-inflammatory agents to control disease symptoms. Traditional anti-inflammatory agents can cause immunosuppression and adverse systemic effects. Further understanding of the disease has led to current areas of research aiming at the development of selective molecular targets to suppress the pathogenic immune responses.
Publisher: CSIRO Publishing
Date: 19-05-2023
DOI: 10.1071/MA23029
Abstract: The recalcitrance of bacterial biofilms to current antimicrobials has presented a major cause of clinical recurrence of wound infections. These biofilm-associated infections are often present in polymicrobial nature associated with the presence of Pseudomonas aeruginosa and Staphylococcus aureus creating a large heterogeneity that shares a common resistance to current antimicrobials making pathogen eradication extremely challenging. In this study, we overcome the intrinsic biofilm barriers by delivering ultrasmall-sized silver nanoparticles (AgNP) using a smart hydrogel system that allows slow and sustained release of silver ions mediating successful accumulation and penetration of bacterial biofilms. The antibiofilm efficacy of the AgNP hydrogel was assessed using ex vivo porcine wound polymicrobial biofilms. Treatment with AgNP hydrogel resulted in significant dispersion of early to mature biofilms, 2–5-log reduction of bacteria compared to untreated controls. This approach overcomes the enhanced tolerance and resistance of polymicrobial biofilms by using the combined benefits of smart delivery system and the antibiofilm properties of ultrasmall AgNPs to ensure biofilm complete destruction and elimination.
Publisher: Wiley
Date: 18-03-2022
DOI: 10.1111/ANS.17598
Abstract: Antimicrobial silver has had a role in wound antisepsis throughout history and, with the rise in acquired antibiotic resistance, silver dressings are once again commonly used. Issues with silver dressings include the important environmental consideration of nanoparticle manufacture, and the significant financial cost of these products. One solution to these problems may be to adopt an opened‐but‐unused model of wound care whereby dressing materials are used in piecemeal fashion and excess stored in between dressing changes. Due to a lack of literature on the topic, this project was designed with the aim of testing the antimicrobial efficacy of available silver dressings during storage after opening. Four commonly used silver dressings were tested for antimicrobial activity using a zone of inhibition assay against clinically important pathogens. The assay was performed on opening of dressings and repeated over 3 months in storage at 4, 25 or 37°C. Analysis was performed using repeated measures ANOVA. Swab cultures were taken at each simulated dressing change to detect microbial contamination of the dressings during storage. There was no effect of time or storage temperature on the zone of inhibition over the 12 week test period. No swabs taken returned culture consistent with microbial contamination of stored dressings. Opened silver dressings maintain antimicrobial activity for at least 12 weeks in storage and are resistant to contamination. An opened‐but‐unused model for wound care is likely to improve cost‐effectiveness while preserving effectiveness and safety.
Publisher: Wiley
Date: 07-06-2012
Publisher: MDPI AG
Date: 13-07-2016
DOI: 10.3390/IJMS17071116
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.BIOCEL.2007.04.011
Abstract: Flightless I (FliI) is a member of the gelsolin family of actin-remodelling proteins, and has been identified as having two functional protein family domains: a leucine rich repeat (LRR) domain and a gelsolin-like domain. This unique structure allows FliI to act as an actin-remodelling protein as well as a nuclear receptor co-activator with ability to interact with various other proteins important in cellular signaling. The actin cytoskeleton is an integral component of all cells and the effect of FliI protein on actin remodelling is a vital part of cellular motility, contraction and adhesion. The product of the FliI gene is expected to provide a vital link between the molecules of yet unidentified signal transduction pathways and the actin cytoskeleton. Exact signaling pathways and mechanisms underpinning FliI effects in wound healing are yet to be fully identified however strong research evidence clearly identifies this molecule as a possible new therapeutic target whose manipulation may greatly improve wound healing and could lead to potential innovative medical applications.
Publisher: Wiley
Date: 03-12-2014
DOI: 10.1111/IWJ.12394
Publisher: InTech
Date: 12-10-2016
DOI: 10.5772/64673
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1186/S13018-020-01692-9
Abstract: Healing of tendons after injury involves the proliferation of tenocytes and the production of extracellular matrix however, their capacity to heal is limited by poor cell density and limited growth factor activity. Flightless I (Flii) has previously been identified as an important regulator of cellular proliferation and migration, and the purpose of this study was to evaluate the effect of differential Flii gene expression on tenocyte function in vitro. The role of Flii on tenocyte proliferation, migration, and contraction was assessed using established assays. Tenocytes from Flii +/− , wild-type, and Flii overexpressing mice were obtained and the effect of differential Flii expression on migration, proliferation, contraction, and collagen synthesis determined in vitro . Statistical differences were determined using unpaired Student’s t test and statistical outliers were identified using the Grubbs’ test. Flii overexpressing tenocytes showed significantly improved migration and proliferation as well as increased collagen I secretion. Explanted tendons from Flii overexpressing mice also showed significantly elevated tenocyte outgrowth compared to Flii +/− mice. In contrast to its role in dermal wound repair, Flii positively affects cellular processes in tendons. These findings suggest that Flii could be a novel target for modulating tenocyte activity and improving tendon repair. This could have significant clinical implications as novel therapeutic targets for improved healing of tendon injuries are urgently needed.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1038/JID.2011.69
Abstract: Flightless I (Flii) is an actin-remodeling protein that influences erse processes including cell migration and gene transcription and links signal transduction with cytoskeletal regulation. Here, we show that Flii modulation of focal adhesions and filamentous actin stress fibers is Rac1-dependent. Using primary skin fibroblasts from Flii overexpressing (Flii(Tg/Tg)), wild-type, and Flii deficient (Flii(+/-)) mice, we show that elevated expression of Flii increases stress fiber formation by impaired focal adhesion turnover and enhanced formation of fibrillar adhesions. Conversely, Flii knockdown increases the percentage of focal complex positive cells. We further show that a functional effect of Flii at both the cellular level and in in vivo mouse wounds is through inhibiting paxillin tyrosine phosphorylation and suppression of signaling proteins Src and p130Cas, both of which regulate adhesion signaling pathways. Flii is upregulated in response to wounding, and overexpression of Flii inhibits paxillin activity and reduces adhesion signaling by modulating the activity of the Rho family GTPases. Overexpression of constitutively active Rac1 GTPase restores the spreading ability of Flii(Tg/Tg) fibroblasts and may explain the reduced adhesion, migration, and proliferation observed in Flii(Tg/Tg) mice and their impaired wound healing, a process dependent on effective cellular motility and adhesion.
Publisher: American Chemical Society (ACS)
Date: 07-03-2022
DOI: 10.1021/ACSINFECDIS.1C00606
Abstract: Chronic
Publisher: Cambridge Media
Date: 12-2020
Publisher: Springer Science and Business Media LLC
Date: 05-08-2014
Publisher: Springer Science and Business Media LLC
Date: 05-09-2019
DOI: 10.1038/S41598-019-49129-6
Abstract: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by cytokine driven inflammation that disrupts the mucosa and impedes intestinal structure and functions. Flightless I (Flii) is an immuno-modulatory protein is a member of the gelsolin family of actin-remodelling proteins that regulates cellular and inflammatory processes critical in tissue repair. Here we investigated its involvement in UC and show that Flii is significantly elevated in colonic tissues of patients with inflammatory bowel disease. Using an acute murine model of colitis, we characterised the contribution of Flii to UC using mice with low ( Flii +/− ), normal ( Flii +/+ ) and high Flii ( Flii Tg/Tg ). High levels of Flii resulted in significantly elevated disease severity index scores, increased rectal bleeding and degree of colon shortening whereas, low Flii expression decreased disease severity, reduced tissue inflammation and improved clinical indicators of UC. Mice with high levels of Flii had significantly increased histological disease severity and elevated mucosal damage with significantly increased inflammatory cell infiltrate and significantly higher levels of TNF-α, IFN-γ, IL-5 and IL-13 pro-inflammatory cytokines. Additionally, Flii overexpression resulted in decreased β-catenin levels, inhibited Wnt/β-catenin signalling and impaired regeneration of colonic crypts. These studies suggest that high levels of Flii, as is observed in patients with UC, may adversely affect mucosal healing via mechanisms involving Th 1 and Th 2 mediated tissue inflammation and Wnt/β-catenin signalling pathway.
Publisher: Oxford University Press (OUP)
Date: 04-09-2019
DOI: 10.1111/BJD.18419
Publisher: Elsevier BV
Date: 07-2021
Publisher: American Chemical Society (ACS)
Date: 10-11-2022
Abstract: Antibacterial treatment that provides on-demand release of therapeutics that can kill a broad spectrum of pathogens while maintaining long-term efficacy and without developing resistance or causing side effects is urgently required in clinical practice. Here, we demonstrate the development of a multistimuli-responsive hydrogel, prepared by cross-linking
Publisher: Portland Press Ltd.
Date: 02-2021
DOI: 10.1042/BSR20203404
Abstract: Infection of burn wounds often leads to poor healing, sepsis, disability, or even death. Traditional care focuses on early debridement, fluid resuscitation, and intravenous antibiotics but these are often inadequate due to compromised vasculature limiting systemic antibiotics effectiveness. Biofilms in burn wounds are barriers to treatment and are associated with the transition of wounds from acute to chronic non-healing state. Current topical treatments for burn wounds include skin substitutes impregnated with skin or stem cells that promote healing or hydrogels delivering an antibiotic, silver, or synthetic antimicrobial peptides. The success of currently available products is varied and, in some cases, very limited due to associated cytotoxicity to mammalian cells, the ability to only fight extracellular biofilm infections, and the ever-increasing development of antimicrobial resistance (AMR). There is, therefore, a high clinical need for the development of next-generation hydrogel wound dressings, to combat bacterial burn wound infection. A recent paper by Khan et al. (Bioscience Reports (2020) 39, 0.1042/BSR20190504) highlights the development of a catechol cross-linked antimicrobial peptide hydrogel, adding to the body of literature describing innovative solutions with better delivery systems for antimicrobial peptides, and identifying a promising future biomaterial for development of novel hydrogel dressing to combat multi-drug resistant bacterial infections in burn wounds.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1038/JID.2012.457
Abstract: Epidermolysis bullosa (EB) is a chronic inheritable disease that leads to severe blistering and fibrosis. Previous studies have shown that the actin cytoskeletal protein flightless I (Flii) impairs wound healing associated with EB. Using a mouse model of EB acquisita (EBA), the effect of "mopping up" Flii using Flii-neutralizing antibodies (FnAbs) before, during, and after blister formation was determined. FnAbs, incorporated into a cream vehicle and applied topically to the skin, penetrated into the basal epidermis and upper papillary dermis but were not detected in serum or other organs and did not alter neutrophil or macrophage infiltration into the blistered skin. Histological assessment of blister severity showed that treatment of early-stage blisters with FnAb cream reduced their severity and improved their rate of healing. Treatment of established blisters with FnAb cream also improved healing and restored the skin's tensile strength toward that of normal skin. Repeated application of FnAbs to EBA skin before the onset of blistering reduced the severity of skin blistering. Independent of when the FnAbs were applied, skin barrier function and wound healing were improved and skin fragility was reduced, suggesting that FnAbs could potentially improve healing of patients with EB.
Publisher: IntechOpen
Date: 18-03-2019
Publisher: MDPI AG
Date: 13-11-2022
Abstract: Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.
Publisher: MDPI AG
Date: 05-01-2021
DOI: 10.3390/ANTIBIOTICS10010049
Abstract: Persistent wound infections have been a therapeutic challenge for a long time. Current treatment approaches are mostly based on the delivery of antibiotics, but these are not effective for all infections. Here, we report the development of a sensitive pH-responsive hydrogel that can provide controlled, pH-triggered release of silver nanoparticles (AgNPs). This delivery system was designed to sense the environmental pH and trigger the release of AgNPs when the pH changes from acidic to alkaline, as occurs due to the presence of pathogenic bacteria in the wound. Our results show that the prepared hydrogel restricts the release of AgNPs at acidic pH (pH = 4) but substantially lifies it at alkaline pH (pH = 7.4 and pH = 10). This indicates the potential use of the hydrogel for the on-demand release of Ag+ depending on the environmental pH. In vitro antibacterial studies demonstrated effective elimination of both Gram-negative and positive bacteria. Additionally, the effective antibacterial dose of Ag+ showed no toxicity towards mammalian skin cells. Collectively, this pH-responsive hydrogel presents potential as a promising new material for the treatment of infected wounds.
Publisher: Informa UK Limited
Date: 11-2012
DOI: 10.4161/CIB.21928
Publisher: MDPI AG
Date: 10-07-2018
DOI: 10.3390/IJMS19072014
Publisher: Wiley
Date: 26-09-2011
DOI: 10.1002/PATH.2973
Abstract: Epidermolysis bullosa (EB) is a severe genetic skin fragility syndrome characterized by blister formation. The molecular basis of EB is still largely unknown and wound healing in patients suffering from EB remains a major challenge to their survival. Our previous studies have identified the actin remodelling protein Flightless I (Flii) as an important mediator of wound repair. Here we identify Flii as a novel target involved in skin blistering. Flii expression was significantly elevated in 30 patients with EB, most prominently in patients with recessive dystrophic EB (RDEB) who have defects in production of type VII collagen (ColVII). Using an autoimmune ColVII murine model of EB acquisita (EBA) and an immunocompetent-ColVII-hypomorphic genetic mouse model of RDEB together with murine Flii alleles, we investigated the contribution of Flii to EB. Overexpression of Flii produced severe blistering post-induction of EBA, while decreased Flii reduced blister severity, elevated integrin expression, and improved ColVII production. Flii(+/-) blistered skin showed reduced α-SMA, TGF-β1, and Smad 2/3 expression, suggesting that decreasing Flii may affect fibrosis. In support of this, Flii-deficient fibroblasts from EBA mice were less able to contract collagen gels in vitro however, addition of TGF-β1 restored collagen contraction, suggesting an interplay between Flii and TGF-β1. Elevated Flii gene and protein expression was further observed in the blisters of ColVII hypomorphic mice, a murine model of RDEB, suggesting that reducing Flii in blistered skin could be a potential new approach for treating patients with EB.
Publisher: Mary Ann Liebert Inc
Date: 15-05-2016
Abstract: Cutaneous stem cells (CSCs) orchestrate the homeostasis and regeneration of mammalian skin. Epithelial CSCs have been isolated and characterized from the skin and hold great potential for tissue engineering and clinical applications. The actin cytoskeleton is known to regulate cell adhesion and motility through its intricate participation in signal transduction and structural modifications. The dynamics of actin cytoskeleton can directly influence CSCs behaviors including tissue morphogenesis, homeostasis, niche maintenance, activation, and wound repair. Various regulators of the actin cytoskeleton including kinases, actin-remodeling proteins, paracrine signals, and micro-RNAs collaborate and contribute to epithelial CSC proliferation, adhesion, and differentiation. This review brings together the latest mechanistic insights into how the actin cytoskeleton participates in the regulation of epithelial CSCs during development, homeostasis, and wound repair.
Publisher: American Physiological Society
Date: 2023
DOI: 10.1152/AJPCELL.00080.2022
Abstract: Healing of cutaneous wounds is a fundamental process required to re-establish tissue integrity, repair skin barrier function, and restore skin homeostasis. Chronic wound infection, exacerbated by the growing development of resistance to conventional therapies, hinders the skin repair process and is a serious clinical problem affecting millions of people worldwide. In the past decade, the use of antimicrobial peptides (AMPs) has attracted increasing attention as a potential novel strategy for the treatment of chronic wound infections due to their unique multifaceted mechanisms of action, and AMPs have been demonstrated to function as potent host-defense molecules that can control microbial proliferation, modulate host-immune responses, and act as endogenous mediators of wound healing. To date over 3,200 AMPs have been discovered either from living organisms or through synthetic derivation, some of which have progressed to clinical trials for the treatment of burn and wound injuries. However, progress to routine clinical use has been hindered due to AMPs’ susceptibility to wound and environmental factors including changes in pH, proteolysis, hydrolysis, oxidation, and photolysis. This review will discuss the latest research focused on the development and applications of AMPs for wound infections using the latest nanotechnological approaches to improve AMP delivery, and stability to present effective combinatorial treatment for clinical applications.
Publisher: American Chemical Society (ACS)
Date: 22-12-2021
Abstract: Silver-based nano-antibiotics are rapidly developing as promising alternatives to conventional antibiotics. Ideally, to remain potent against a wide range of drug-resistant and anaerobic bacteria, silver-based nano-antibiotics should easily penetrate through the bacterial cell walls and actively release silver ions. In this study, highly monodispersed, ultrasmall (<3 nm), polycationic silver nanoclusters (pAgNCs) are designed and synthesized for the elimination of a range of common Gram-negative and Gram-positive pathogens and their corresponding established and matured biofilms, including those composed of multiple species. The pAgNCs also show greatly enhanced antibacterial efficacy against anaerobic bacteria such as
Publisher: Wiley
Date: 22-10-2021
DOI: 10.1111/SRT.12971
Publisher: MDPI AG
Date: 30-09-2020
DOI: 10.3390/IJMS21197228
Abstract: Psoriasis is a common chronic inflammatory skin condition manifested by T cell responses and characterized by preferential recurrence at previously inflamed sites upon withdrawal of treatment. The site-specific disease memory in psoriasis has been linked to CD8+CD103+ tissue-resident memory T cells (Trm) in the epidermis which were previously thought to only provide “frontline” protection against pathogens and immunosurveillance during cancer development. In this study, we correlated the presence of a subset of the Trm cells which are also CD49a+ with disease severity in human psoriatic lesions with acute and chronic disease. Using an imiquimod (IMQ)-induced murine model of psoriasiform dermatitis, we also investigated the level of CD49a+ Trm cells in acute, chronic and resolved psoriatic lesions. Investigation of clinical human s les showed that patient disease severity highly correlated with the numbers of epidermal CD49a+ Trm cells. Additionally, this subset of Trm cells was shown to persist in resolved lesions of murine psoriasiform dermatitis once clinical disease features had subsided. Importantly, these CD49a+ Trm cells showed significantly higher levels of granzyme B (GzmB) production compared to acute disease, suggesting a potential role of CD49a+ Trm cells for psoriatic re-occurrence in resolved patients. Better understanding of epidermal CD49a+ Trm cell activity is necessary for development of advanced treatment strategies for psoriasis to permit long-term, continuous disease control.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9NA00017H
Abstract: The interplay between size and valence state in ∼3 nm silver nanoparticles resulted in the highest antibacterial effect against multi-drug resistant bacteria.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1038/JID.2008.461
Abstract: Flightless I (Flii), a highly conserved member of the gelsolin family of actin-remodelling proteins associates with actin structures and is involved in cellular motility and adhesion. Our previous studies have shown that Flii is an important negative regulator of wound repair. Here, we show that Flii affects hemidesmosome formation and integrin-mediated keratinocyte adhesion and migration. Impaired hemidesmosome formation and sparse arrangements of keratin cytoskeleton tonofilaments and actin cytoskeleton anchoring fibrils were observed in Flii(Tg/+) and Flii(Tg/Tg) mice with their skin being significantly more fragile than Flii(+/-) and WT mice. Flii(+/-) primary keratinocytes showed increased adhesion on laminin and collagen I than WT and Flii(Tg/Tg) primary keratinocytes. Decreased expression of CD151 and laminin-binding integrins alpha3, beta1, alpha6 and beta4 were observed in Flii overexpressing wounds, which could contribute to the impaired wound re-epithelialization observed in these mice. Flii interacts with proteins directly linked to the cytoplasmic domain of integrin receptors suggesting that it may be a mechanical link between ligand-bound integrin receptors and the actin cytoskeleton driving adhesion-signaling pathways. Therefore Flii may regulate wound repair through its effect on hemidesmosome formation and integrin-mediated cellular adhesion and migration.
Publisher: Frontiers Media SA
Date: 14-05-2019
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.XPHS.2017.03.012
Abstract: Flightless I (Flii) is an actin remodeling protein important for cytoskeletal regulation and cellular processes including migration, proliferation, and adhesion. Previous studies have clearly identified Flii as a novel therapeutical target for improved wound repair and have demonstrated Flii regulation using Flii neutralizing antibodies (FnAb) in different models of wound healing in vivo. Here we describe the development of an optimized topical delivery system that can neutralize Flii activity in the epidermis. Topical delivery of FnAb is an attractive approach as it provides a convenient application, sustained release, localized effect, and reduced dosage. Three successful formulations were developed, and their physical and chemical stability examined. The in vitro release revealed prolonged and sustained release of FnAb in all the tested formulations. Additionally, penetration studies using intact porcine skin showed that FnAb penetrated the epidermis and upper papillary dermis. The penetrated FnAb significantly reduced Flii expression compared to dosed matched IgG controls. This study has successfully developed a topical delivery system for FnAb that could serve as a potential platform for future localized wound treatments.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2013
DOI: 10.1007/S00125-013-3107-6
Abstract: Skin lesions and ulcerations are severe complications of diabetes that often result in leg utations. In this study we investigated the function of the cytoskeletal protein flightless I (FLII) in diabetic wound healing. We hypothesised that overexpression of FLII would have a negative effect on diabetic wound closure and modulation of this protein using specific FLII-neutralising antibodies (FnAb) would enhance cellular proliferation, migration and angiogenesis within the diabetic wound. Using a streptozotocin-induced model of diabetes we investigated the effect of altered FLII levels through Flii genetic knockdown, overexpression or treatment with FnAb on wound healing. Diabetic wounds were assessed using histology, immunohistochemistry and biochemical analysis. In vitro and in vivo assays of angiogenesis were used to assess the angiogenic response. FLII levels were elevated in the wounds of both diabetic mice and humans. Reduction in the level of FLII improved healing of murine diabetic wounds and promoted a robust pro-angiogenic response with significantly elevated von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)-positive endothelial cell infiltration. Diabetic mouse wounds treated intradermally with FnAb showed improved healing and a significantly increased rate of re-epithelialisation. FnAb improved the angiogenic response through enhanced formation of capillary tubes and functional neovasculature. Reducing the level of FLII led to increased numbers of mature blood vessels, increased recruitment of smooth muscle actin-α-positive cells and improved tight junction formation. Reducing the level of FLII in a wound may be a potential therapeutic approach for the treatment of diabetic foot ulcers.
Publisher: Wiley
Date: 05-02-2014
DOI: 10.1002/PATH.4323
Abstract: Development of an intact epidermis is critical for maintaining the integrity of the skin. Patients with epidermolysis bullosa (EB) experience multiple erosions, which breach the epidermal barrier and lead to increased microbial colocalization of wounds, infections and sepsis. The cytoskeletal protein Flightless I (Flii) is a known regulator of both development and wound healing. Using Flii(+/-), WT and Flii(Tg/Tg) mice, we investigated the effect of altering Flii levels in embryos and adult mice on the development of the epidermal barrier and, consequently, how this affects the integrity of the skin in EB. Flii over-expression resulted in delayed formation of the epidermal barrier in embryos and decreased expression of tight junction (TJ) proteins Claudin-1 and ZO-2. Increased intercellular space and transepidermal water loss was observed in Flii(Tg)(/Tg) adult mouse skin, while Flii(Tg/Tg) keratinocytes showed altered TJ protein localization and reduced transepithelial resistance. Flii is increased in the blistered skin of patients with EB, and over-expression of Flii in experimental EBA showed impaired Claudin-1 and -4 TJ protein expression and delayed recovery of functional barrier post-blistering. Immunoprecipitation confirmed Flii associated with TJ proteins and in vivo actin assays showed that the effect of Flii on actin polymerization underpinned the impaired barrier function observed in Flii(Tg/Tg) mice. These results therefore demonstrate an important role for Flii in the development and regulation of the epidermal barrier, which may contribute to the impaired healing and skin fragility of EB patients.
Publisher: MDPI AG
Date: 30-07-2021
DOI: 10.3390/IJMS22158235
Abstract: Epidermal progenitor cells ide symmetrically and asymmetrically to form stratified epidermis and hair follicles during late embryonic development. Flightless I (Flii), an actin remodelling protein, is implicated in Wnt/β-cat and integrin signalling pathways that govern cell ision. This study investigated the effect of altering Flii on the isional orientation of epidermal progenitor cells (EpSCs) in the basal layer during late murine embryonic development and early adolescence. The effect of altering Flii expression on asymmetric vs. symmetric ision was assessed in vitro in adult human primary keratinocytes and in vivo at late embryonic development stages (E16, E17 and E19) as well as adolescence (P21 day-old) in mice with altered Flii expression (Flii knockdown: Flii+/−, wild type: WT, transgenic Flii overexpressing: FliiTg/Tg) using Western blot and immunohistochemistry. Flii+/− embryonic skin showed increased asymmetrical cell ision of EpSCs with an increase in epidermal stratification and elevated talin, activated-Itgb1 and Par3 expression. FliiTg/Tg led to increased symmetrical cell ision of EpSCs with increased cell proliferation rate, an elevated epidermal SOX9, Flap1 and β-cat expression, a thinner epidermis, but increased hair follicle number and depth. Flii promotes symmetric ision of epidermal progenitor cells during murine embryonic development.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Impact Journals, LLC
Date: 19-10-2015
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.BIOCEL.2007.11.024
Abstract: Impaired wound healing in the elderly presents a major clinical challenge. Understanding the cellular mechanisms behind age-related impaired healing is vital for developing new wound therapies. Here we show that the actin-remodelling protein, Flightless I (FliI) is a contributing factor to the poor healing observed in elderly skin and that gender plays a major role in this process. Using young and aged, wild-type and FliI overexpressing mice we found that aging significantly elevated FliI expression in the epidermis and wound matrix. Aging exacerbated the negative effect of FliI on wound repair and wounds in aged FliI transgenic mice were larger with delayed reepithelialisation. When the effect of gender was further analysed, despite increased FliI expression in young and aged male and female mice, female FliI transgenic mice had the most severe wound healing phenotype suggesting that male mice were refractory to FliI gene expression. Of potential importance, males, but not females, up-regulated transforming growth factor-beta1 and this was most pronounced in aged male FliI overexpressing wounds. As FliI also functions as a co-activator of the estrogen nuclear receptor, increasing concentrations of beta-estradiol were added to skin fibroblasts and keratinocytes and significantly enhanced FliI expression and translocation of FliI from the cytoplasm to the nucleus was observed. FliI further inhibited estrogen-mediated collagen I secretion suggesting a mechanism via which FliI may directly affect provisional matrix synthesis. In summary, FliI is a contributing factor to impaired healing and strategies aimed at decreasing FliI levels in elderly skin may improve wound repair.
Publisher: Wiley
Date: 06-11-2019
DOI: 10.1111/CUP.13597
Publisher: MDPI AG
Date: 17-01-2023
DOI: 10.3390/PHARMACEUTICS15020305
Abstract: Cutaneous chronic wounds impose a silent pandemic that affects the lives of millions worldwide. The delayed healing process is usually complicated by opportunistic bacteria that infect wounds. Staphylococcus aureus is one of the most prevalent bacteria in infected cutaneous wounds, with the ability to form antibiotic-resistant biofilms. Recently, we have demonstrated the potential of gallium protoporphyrin lipid liquid crystalline nanoparticles (GaPP-LCNP) as a photosensitizer against S. aureus biofilms in vitro. Herein, we investigate the potential of GaPP-LCNP using a pre-clinical model of infected cutaneous wounds. GaPP-LCNP showed superior antibacterial activity compared to unformulated GaPP, reducing biofilm bacterial viability by 5.5 log10 compared to 2.5 log10 in an ex vivo model, and reducing bacterial viability by 1 log10 in vivo, while unformulated GaPP failed to reduce bacterial burden. Furthermore, GaPP-LCNP significantly promoted wound healing through reduction in the bacterial burden and improved early collagen deposition. These findings pave the way for future pre-clinical investigation and treatment optimizations to translate GaPP-LCNP towards clinical application.
Publisher: Wiley
Date: 21-11-2021
DOI: 10.1111/ANS.17382
Abstract: Skin is an important barrier to pathogenic microorganisms and plays a critical role in a ctivation of innate immune responses. When the skin barrier is breached following wounding or burn injury, pathogens can invade and complicate healing with infection resulting in delayed healing and symptomatic scarring. Wound infection is a significant problem after burn injury and in patients with chronic wounds. Antimicrobial silver has had a significant role in wound antisepsis throughout history and, given the rise in community acquired antibiotic resistance, silver dressings are now commonly used to combat wound infection. The multi‐modal mechanism of action, low potential for toxicity and formation of microbial resistance makes silver dressings suitable tools against a wide array of clinically important microbes. There are, however, a number of issues with silver dressings including a conflicting evidence base, the important environmental consideration of nanoparticle manufacture, and the significant cost of these products. One solution may be to adopt an ‘opened‐but‐unused’ means of wound care whereby bulk dressing materials are used piecemeal and stored in between dressing changes to increase the cost‐effectiveness and reduced wastage. There is, however, little literature on this topic and so in vitro and clinical research must be performed to consider the efficacy of active ingredient dressings in wound care including silver dressings once opened and stored.
No related grants have been discovered for Zlatko Kopecki.