Plant-derived compounds and other natural substances are a rich potential source of compounds that kill or attenuate pathogens that are resistant to current antibiotics. Medieval societies used a range of these natural substances to treat conditions clearly recognizable to the modern eye as microbial infections, and there has been much debate over the likely efficacy of these treatments. Our interdisciplinary team, comprising researchers from both sciences and humanities, identified and reconstructed a potential remedy for Staphylococcus aureus infection from a 10th century Anglo-Saxon leechbook. The remedy repeatedly killed established S. aureus biofilms in an in vitro model of soft tissue infection and killed methicillin-resistant S. aureus (MRSA) in a mouse chronic wound model. While the remedy contained several ingredients that are individually known to have some antibacterial activity, full efficacy required the combined action of several ingredients, highlighting the scholarship of premodern doctors and the potential of ancient texts as a source of new antimicrobial agents.
Multipotent mesenchymal stem cells (MSCs) are found in various tissues and can proliferate extensively in vitro. MSCs have been used in preclinical animal studies and clinical trials in many fields. Adipose derived stem cells (ASCs) have several advantages compared to other MSCs for use in cell-based treatments because they are easy to isolate with relative abundance. However, quantitative approaches for wound repair using ASCs have been limited because of lack of animal models which allow for quantification. Here, we addressed the effect of topically delivered ASCs in wound repair by quantitative analysis using the rabbit ear model. We characterized rabbit ASCs, and analyzed their multipotency in comparison to bone marrow derived-MSCs (BM-MSCs) and dermal fibroblasts (DFs) in vitro. Topically delivered ASCs increased granulation tissue formation in wounds when compared to saline controls, whereas BM-MSCs or DFs did not. These studies suggest that ASCs and BM-MSCs are not identical, though they have similar surface markers. We found that topically delivered ASCs are engrafted and proliferate in the wounds. We showed that transplanted ASCs exhibited activated fibroblast phenotype, increased endothelial cell recruitment, and enhanced macrophage recruitment in vivo.
St. John’s wort (Hypericum perforatum) has been intensively investigated for its antidepressive activity, but dermatological applications also have a long tradition. Topical St. John’s wort preparations such as oils or tinctures are used for the treatment of minor wounds and burns, sunburns, abrasions, bruises, contusions, ulcers, myalgia, and many others. Pharmacological research supports the use in these fields. Of the constituents, naphthodianthrones (e.g., hypericin) and phloroglucinols (e.g., hyperforin) have interesting pharmacological profiles, including antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. In addition, hyperforin stimulates growth and differentiation of keratinocytes, and hypericin is a photosensitizer which can be used for selective treatment of nonmelanoma skin cancer. However, clinical research in this field is still scarce. Recently, sporadic trials have been conducted in wound healing, atopic dermatitis, psoriasis, and herpes simplex infections, partly with purified single constituents and modern dermatological formulations. St. John’s wort also has a potential for use in medical skin care. Composition and stability of pharmaceutical formulations vary greatly depending on origin of the plant material, production method, lipophilicity of solvents, and storage conditions, and this must be regarded with respect to practical as well as scientific purposes.
After injury to the animal epidermis, a variety of genes are transcriptionally activated in nearby cells to regenerate the missing cells and facilitate barrier repair. The range and types of diffusible wound signals that are produced by damaged epidermis and function to activate repair genes during epidermal regeneration remains a subject of very active study in many animals. In Drosophila embryos, we have discovered that serine protease function is locally activated around wound sites, and is also required for localized activation of epidermal repair genes. The serine protease trypsin is sufficient to induce a striking global epidermal wound response without inflicting cell death or compromising the integrity of the epithelial barrier. We developed a trypsin wounding treatment as an amplification tool to more fully understand the changes in the Drosophila transcriptome that occur after epidermal injury. By comparing our array results with similar results on mammalian skin wounding we can see which evolutionarily conserved pathways are activated after epidermal wounding in very diverse animals. Our innovative serine protease-mediated wounding protocol allowed us to identify 8 additional genes that are activated in epidermal cells in the immediate vicinity of puncture wounds, and the functions of many of these genes suggest novel genetic pathways that may control epidermal wound repair. Additionally, our data augments the evidence that clean puncture wounding can mount a powerful innate immune transcriptional response, with different innate immune genes being activated in an interesting variety of ways. These include puncture-induced activation only in epidermal cells in the immediate vicinity of wounds, or in all epidermal cells, or specifically in the fat body, or in multiple tissues.
OBJECTIVESSternal wound complications following median sternotomy remain a challenge in cardiac surgery. Changes in both patient profile and type of operations have been observed in recent years. Therefore, we analysed current wound healing complications after median sternotomy at our centre.METHODSAll adult patients undergoing a median sternotomy between January 2009 and April 2011 were included in this retrospective analysis. Transplants and assist devices implantations were omitted. We assessed outcome, prognostic factors and microbiological results of standardized wound swabs.RESULTSIn total, 1297 patients with an average age of 67.0 ± 12.7 years were analysed. Operation types included 598 solitary coronary artery bypass grafts (CABGs), 213 solitary valve procedures, 105 CABGs with aortic valve replacement and 116 solitary aortic operations or conduit implantations. Furthermore, 255 of the remaining 265 were combined or otherwise complex procedures. Superficial healing disorders occurred in 43 patients (3.3%), while 33 (2.5%) developed deep wound complications. Six patients with sternal wound complications (7.9%) died in-hospital. In 7 patients, no pathogen was identified and the wound appeared uninfected (21% of all deep complications or 0.05% of all patients). These healing disorders were considered deep dehiscences. Patients with insulin-dependent diabetes mellitus, BMI of >40 kg/m(2) and who underwent reoperation were prone to superficial infections. Risk factors for all deep sternal wound complications were insulin-dependent diabetes mellitus, COPD and reoperation. Moreover, multivariate analysis revealed ‘emergency’ as an independent prognostic factor for all sternal wound complications. Microbial swabs of the sternal wound were taken in 82 of the 1297 patients (6.6%). Pathogens of the normal skin flora represented the majority of pathogens in both superficial and deep wound complications. Eight patients with deep, but only 2 patients with superficial complications suffered from polymicrobial infections. All deep polymicrobial infections involved coagulase-negative Staphylococci.CONCLUSIONSWound complications following median sternotomy remain a challenge to cardiac surgery. Redo and emergency operations are the most important risk factors in this contemporary series. More efforts seem mandatory to decrease this arduous morbidity and the costs of prolonged treatment.
Terahertz (THz) technology has emerged for biomedical applications such as scanning, molecular spectroscopy, and medical imaging. Although a thorough assessment to predict potential concerns has to precede before practical utilization of THz source, the biological effect of THz radiation is not yet fully understood with scant related investigations. Here, we applied a femtosecond-terahertz (fs-THz) pulse to mouse skin to evaluate non-thermal effects of THz radiation. Analysis of the genome-wide expression profile in fs-THz-irradiated skin indicated that wound responses were predominantly mediated by transforming growth factor-beta (TGF-β) signaling pathways. We validated NFκB1- and Smad3/4-mediated transcriptional activation in fs-THz-irradiated skin by chromatin immunoprecipitation assay. Repeated fs-THz radiation delayed the closure of mouse skin punch wounds due to up-regulation of TGF-β. These findings suggest that fs-THz radiation initiate a wound-like signal in skin with increased expression of TGF-β and activation of its downstream target genes, which perturbs the wound healing process in vivo.
Inositol kinase and its product accelerate wound healing by modulating calcium levels, Rho GTPases, and F-actin assembly
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 6 years ago
Wound healing is essential for survival. We took advantage of the Xenopus embryo, which exhibits remarkable capacities to repair wounds quickly and efficiently, to investigate the mechanisms responsible for wound healing. Previous work has shown that injury triggers a rapid calcium response, followed by the activation of Ras homolog (Rho) family guanosine triphosphatases (GTPases), which regulate the formation and contraction of an F-actin purse string around the wound margin. How these processes are coordinated following wounding remained unclear. Here we show that inositol-trisphosphate 3-kinase B (Itpkb) via its enzymatic product inositol 1,3,4,5-tetrakisphosphate (InsP4) plays an essential role during wound healing by modulating the activity of Rho family GTPases and F-actin ring assembly. Furthermore, we show that Itpkb and InsP4 modulate the speed of the calcium wave, which propagates from the site of injury into neighboring uninjured cells. Strikingly, both overexpression of itpkb and exogenous application of InsP4 accelerate the speed of wound closure, a finding that has potential implications in our quest to find treatments that improve wound healing in patients with acute or chronic wounds.
BackgroundLess invasive percutaneous acute Achilles tendon rupture repair techniques gain popularity because of lower risk of surgical wound complications. But these approaches have an increased risk of sural nerve iatrogenic injury as this sensory nerve is usually not visualized during minimally invasive operative procedures. We compared standard percutaneous Bunnell type and our proposed modified-medialized percutaneous technique in a cadaver study to evaluate potential advantages. Methods10 pairs of fresh frozen specimens were divided into two groups for comparative anatomical study. Tenotomies of Achilles tendons were made and wounds sutured. 10 standard and 10 modified-medialized repairs were applied for artificially performed ruptures. All sutured tendons were dissected meticulously. We carefully looked at repaired Achilles tendon end-to-end contact and adaptation, distance from Achilles insertion in calcaneal tubercle to place where sural nerve crosses lateral border of the Achilles tendon and possible sural nerve and vein entrapment. Groups were compared using Fisher’s exact and Student-T tests.ResultsAll ends of sharply dissected tendons in both groups were in sufficient contact. No measurable diastasis between tendon ends was found in all cases. No entrapment of sural nerve or vein was found in modified percutaneous Bunnell suture technique group. Whereas 7 of 10 sural nerves and 9 small saphenous veins were entrapped when using standard percutaneous Bunnell type technique. Average distance from Achilles tendon insertion in tuber calcanei to sural nerve crossing the lateral border of Achilles was 93 mm.ConclusionMedialization of percutaneous suture in acute Achilles tendon rupture repair show clear advantages compared to standard non medialized technique ensuring a possible lower incidence of sural nerve entrapment injury. Our modified percutaneous Bunnell type technique allows sufficient adaptation of ruptured Achilles tendon.
Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-β-Slug signaling
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 3 years ago
Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-β1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM(-/-)) wounds. Correspondingly, VIM(-/-) wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM(-/-) wounds. Vimentin reconstitution in VIM(-/-) fibroblasts restored both their proliferation and TGF-β1 production. Similarly, restoring paracrine TGF-β-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-β1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.
The present study investigated whether MSCs derived microvesicles (MVs) or (Exosomes) can exert therapeutic effects on an experimental model of cutaneous injury and explored the underlying involving mechanisms.