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Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop and rigorously validate QSAR models to predict skin permeability; and (iii) explore the complex relationships between skin sensitization and skin permeability. Based on the largest publicly available dataset compiled in this study, we found no overall correlation between skin permeability and skin sensitization. In addition, cross-species correlation coefficient between human and rodent permeability data was found to be as low as R(2)=0.44. Human skin permeability models based on the random forest method have been developed and validated using OECD-compliant QSAR modeling workflow. Their external accuracy was high (Q(2)ext=0.73 for 63% of external compounds inside the applicability domain). The extended analysis using both experimentally-measured and QSAR-imputed data still confirmed the absence of any overall concordance between skin permeability and skin sensitization. This observation suggests that chemical modifications that affect skin permeability should not be presumed a priori to modulate the sensitization potential of chemicals. The models reported herein as well as those developed in the companion paper on skin sensitization suggest that it may be possible to rationally design compounds with the desired high skin permeability but low sensitization potential.
Coronavirus disease (COVID-19) skin manifestations have been increasingly reported in medical literature. Recent discussions have identified a lack of images of skin of color (SOC) patients with COVID-19 related skin findings despite people with skin of color being disproportionately affected with the disease. There have been calls to prioritize the identification of COVID-19 skin manifestations in patients with SOC and disseminate these findings. The objective of this article is to review the existing literature on COVID-19 skin manifestations and, where possible, discuss how they may present differently in patients with SOC. Further research is needed to allow primary care physicians and dermatologists to be aware of and easily identify patients with cutaneous findings that may be secondary to COVID-19. Patients presenting with idiopathic dermatologic manifestations should be considered for COVID-19 testing and follow public health guidelines for self-isolation.
Nutritional and medicinal benefits have been attributed to the consumption of tissues from the black-boned chickens in oriental countries. Lueyang black-boned chicken is one of the native chicken breeds. However, some birds may instead have white or lighter skin, which directly causes economic losses every year. Previous studies of pigmentation have focused on a number of genes that may play important roles in coat color regulation. Illumina2000 sequencing technology was used to catalog the global gene expression profiles in the skin of the Lueyang chicken with white versus black skin. A total of 18,608 unigenes were assembled from the reads obtained from the skin of the white and black chickens. A total of 649 known genes were differentially expressed in the black versus white chickens, with 314 genes that were up regulated and 335 genes that were down-regulated, and a total of 162 novel genes were differentially expressed in the black versus white chickens, consisting of 73 genes that were up-regulated (including 4 highly expressed genes that were expressed exclusively in the skin of the black chickens) and 89 genes that were down-regulated. There were also a total of 8 known coat-color genes expressed in previous studies (ASIP, TYR, KIT, TYRP1, OCA2, KITLG, MITF and MC1R). In this study, 4 of which showed greater expression in the black chickens, and several were up-regulated, such as KIT, ASIP, TYR and OCA2. To our surprise, KITLG, MITF and MC1R showed no significant difference in expression between the black- and white-skinned chickens, and the expression of TYRP1 was not detected in either skin color. The expression of ASIP, TYR, KIT, TYRP1, OCA2, KITLG, MITF and MC1R was validated by real-time quantitative polymerase chain reaction (qPCR), and the results of the qPCR were consistent with the RNA-seq. This study provides several candidate genes that may be associated with the development of black versus white skin. More importantly, the fact that the MC1R gene showed no significant difference in expression between the black and white chickens is of particular interest for future studies that aim to elucidate its functional role in the regulation of skin color.
The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensal Staphylococcus epidermidis is protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. Here, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. While depletion of the skin microbiome via antibiotics delayed repair from damage, application of commensals-- including the mouse commensal Staphylococcus xylosus, three distinct isolates of S. epidermidis, and all other tested human skin commensals-- also significantly delayed barrier repair. Increased inflammation was observed within four hours of S. epidermidis exposure and persisted through day four, at which point the skin displayed a chronic-wound-like inflammatory state with increased neutrophil infiltration, increased fibroblast activity, and decreased monocyte differentiation. Transcriptomic analysis suggested that the prolonged upregulation of early canonical proliferative pathways inhibited the progression of barrier repair. These results highlight the nuanced role of members of the skin microbiome in modulating barrier integrity and indicate the need for caution in their development as probiotics.
Keratins comprise the type I and type II intermediate filament-forming proteins and occur primarily in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type-, differentiation-, and context-dependent manner. Keratins serve multiple homeostatic and stress-enhanced mechanical and nonmechanical functions in epithelia, including the maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications as well as keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility and/or altered tissue homeostasis. Moreover, keratin mutation or misregulation represents risk factors or genetic modifiers for several acute and chronic diseases. This chapter focuses on keratins that are expressed in skin epithelia, and details a number of basic protocols and assays that have proven useful for analyses being carried out in skin.
Currently, engineered skin substitutes (ESS) are unable to regenerate cutaneous appendages. Recent studies have shown that skin-derived precursors (SKPs), which are extensively available, have the potential to induce hair follicle neogenesis. Here, we demonstrate that ESS consisting of culture-expanded SKPs and epidermal stem cells (Epi-SCs) reconstitute the skin with hair follicle regeneration after grafting into nude mice. SKPs seeded in a C-GAG matrix proliferated and expressed higher levels of hair induction signature genes-such as Akp2, Sox2, CD133 and Bmp6-compared to dermal fibroblasts. Moreover, when ESS prepared by seeding a mixture of culture-expanded murine SKPs and human adult Epi-SCs into a C-GAG matrix was grafted into full-thickness skin wounds in nude mice, black hairs were generated within 3 weeks. Immunofluorescence analysis showed that the SKPs were localized to the dermal papillae of the newly-formed hair follicle. Our results indicate that SKPs can serve as the hair-inductive cells in ESS to furnish it with hair genesis potential.
Telocytes (TCs), a particular interstitial cell type, have been recently described in a wide variety of mammalian organs (www.telocytes.com). The TCs are identified morphologically by a small cell body and extremely long (tens to hundreds of μm), thin prolongations (less than 100 nm in diameter, below the resolving power of light microscopy) called telopodes. Here, we demonstrated with electron microscopy and immunofluorescence that TCs were present in human dermis. In particular, TCs were found in the reticular dermis, around blood vessels, in the perifollicular sheath, outside the glassy membrane and surrounding sebaceous glands, arrector pili muscles and both the secretory and excretory portions of eccrine sweat glands. Immunofluorescence screening and laser scanning confocal microscopy showed two subpopulations of dermal TCs; one expressed c-kit/CD117 and the other was positive for CD34. Both subpopulations were also positive for vimentin. The TCs were connected to each other by homocellular junctions, and they formed an interstitial 3D network. We also found TCs adjoined to stem cells in the bulge region of hair follicles. Moreover, TCs established atypical heterocellular junctions with stem cells (clusters of undifferentiated cells). Given the frequency of allergic skin pathologies, we would like to emphasize the finding that close, planar junctions were frequently observed between TCs and mast cells. In conclusion, based on TC distribution and intercellular connections, our results suggested that TCs might be involved in skin homeostasis, skin remodelling, skin regeneration and skin repair.
Patients with chronic wounds often have associated cognitive dysfunction and depression with an as yet unknown mechanism for this association. To address the possible causality of skin wounding inducing these changes, behavior and cognitive functions of female C57BL/6 mice with an excisional skin wound were compared to unwounded animals. At six days post wounding, animals exhibited anxiety-like behaviors, impaired recognition memory, and impaired coping behavior. Wounded animals also had concomitant increased hippocampal expression of Tnfa, the pattern recognition receptor (PRR) Nod2, the glucocorticoid receptors GR/Nr3c1 and Nr3c2. Prefrontal cortex serotonin and dopamine turnover were increased on day six post-wounding. In contrast to the central nervous system (CNS) findings, day six post -wounding serum catecholamines did not differ between wounded and unwounded animals, nor did levels of the stress hormone corticosterone, TNFα, or TGFβ. Serum IL6 levels were, however elevated in the wounded animals. These findings provide evidence of skin-to-brain signaling, mediated either by elevated serum IL6 or a direct neuronal signaling from the periphery to the CNS, independent of systemic mediators. Wounding in the periphery is associated with an altered expression of inflammatory mediators and PRR genes in the hippocampus, which may be responsible for the observed behavioral deficits.
The investigation of nanoparticle interactions with tissues is complex. High levels of standardization, ideally testing of different material types in the same biological model, and combinations of sensitive imaging and detection methods are required. Here, we present our studies on nanoparticle interactions with skin, skin cells, and biological media. Silica, titanium dioxide and silver particles were chosen as representative examples for different types of skin exposure to nanomaterials, e.g., unintended environmental exposure (silica) versus intended exposure through application of sunscreen (titanium dioxide) or antiseptics (silver). Because each particle type exhibits specific physicochemical properties, we were able to apply different combinations of methods to examine skin penetration and cellular uptake, including optical microscopy, electron microscopy, X-ray microscopy on cells and tissue sections, flow cytometry of isolated skin cells as well as Raman microscopy on whole tissue blocks. In order to assess the biological relevance of such findings, cell viability and free radical production were monitored on cells and in whole tissue samples. The combination of technologies and the joint discussion of results enabled us to look at nanoparticle-skin interactions and the biological relevance of our findings from different angles.
Metallothionein-3 (MT-3) has been shown to be expressed in several malignancies and to have an impact on patients' survival in breast and urinary bladder cancer cases. However, its expression has not been determined in normal skin or in its malignant lesions. MT-3 expression was studied using immunohistochemistry in 17 cases of normal skin, 18 of actinic keratosis (AK), 39 of squamous cell carcinoma (SCC), and 23 of basal cell carcinoma (BCC). Low MT-3 expression was observed in normal skin epidermis with faint or no expression in the epidermis basal layer. Significantly higher MT-3 expression was noted in AK (P=0.007) and SCC (P<0.0001), as compared with normal skin epidermis. BCC cases were characterized by the lowest MT-3 expression of all the examined groups, which was significantly lower in comparison to normal skin epidermis, AK, and SCC (P=0.009;P<0.0001 and P<0.0001, respectively). In conclusion, MT-3 may be involved in the development of SCC.
Since the skin covers most surfaces of the body, it is susceptible to damage, which can be fatal depending on the degree of injury to the skin because it defends against external attack and protects internal structures. Various types of artificial skin are being studied for transplantation to repair damaged skin, and recently, the production of replaceable skin using three-dimensional (3D) bioprinting technology has also been investigated. In this study, skin tissue was produced using a 3D bioprinter with human skin cell lines and cells extracted from mouse skin, and the printing conditions were optimized. Gelatin was used as a bioink, and fibrinogen and alginate were used for tissue hardening after printing. Printed skin tissue maintained a survival rate of 90% or more when cultured for 14 days. Culture conditions were established using 8 mM calcium chloride treatment and the skin tissue was exposed to air to optimize epidermal cell differentiation. The skin tissue was cultured for 14 days after differentiation induction by this optimized culture method, and immunofluorescent staining was performed using epidermal cell differentiation markers to investigate whether the epidermal cells had differentiated. After differentiation, loricrin, which is normally found in terminally differentiated epidermal cells, was observed in the cells at the tip of the epidermal layer, and cytokeratin 14 was expressed in the lower cells of the epidermis layer. Collectively, this study may provide optimized conditions for bioprinting and keratinization for three-dimensional skin production.
The human intestine hosts diverse microbial communities that play a significant role in maintaining gut-skin homeostasis. When the relationship between gut microbiome and the immune system is impaired, subsequent effects can be triggered on the skin, potentially promoting the development of skin diseases. The mechanisms through which the gut microbiome affects skin health are still unclear. Enhancing our understanding on the connection between skin and gut microbiome is needed to find novel ways to treat human skin disorders. In this review, we systematically evaluate current data regarding microbial ecology of healthy skin and gut, diet, pre- and probiotics, and antibiotics, on gut microbiome and their effects on skin health. We discuss potential mechanisms of the gut-skin axis and the link between the gut and skin-associated diseases, such as psoriasis, atopic dermatitis, acne vulgaris, rosacea, alopecia areata, and hidradenitis suppurativa. This review will increase our understanding of the impacts of gut microbiome on skin conditions to aid in finding new medications for skin-associated diseases.
For patients with extensive burns or donor site scarring, the limited availability of autologous and the inevitable rejection of allogeneic skin drive the need for new alternatives. Existing engineered biologic and synthetic skin analogs serve as temporary coverage until sufficient autologous skin is available. Here we report successful engraftment of a self-assembled bilayered skin construct derived from autologous skin punch biopsies in a porcine model. Dermal fibroblasts were stimulated to produce an extracellular matrix and were then seeded with epidermal progenitor cells to generate an epidermis. Autologous constructs were grafted onto partial- and full-thickness wounds. By gross examination and histology, skin construct vascularization and healing were comparable to autologous skin grafts and were superior to an autologous bilayered living cellular construct fabricated with fibroblasts cast in bovine collagen. This is the first demonstration of spontaneous vascularization and permanent engraftment of a self-assembled bilayered bioengineered skin that could supplement existing methods of reconstruction.
Although it is well-known that human skin aging is accompanied by an alteration in the skin microbiota, we know little about how the composition of these changes during the course of aging and the effects of age-related skin microbes on aging. Using 16S ribosomal DNA and internal transcribed spacer ribosomal DNA sequencing to profile the microbiomes of 160 skin samples from two anatomical sites, the cheek and the abdomen, on 80 individuals of varying ages, we developed age-related microbiota profiles for both intrinsic skin aging and photoaging to provide an improved understanding of the age-dependent variation in skin microbial composition. According to the landscape, the microbial composition in the Children group was significantly different from that in the other age groups. Further correlation analysis with clinical parameters and functional prediction in each group revealed that high enrichment of nine microbial communities (i.e., Cyanobacteria, Staphylococcus, Cutibacterium, Lactobacillus, Corynebacterium, Streptococcus, Neisseria, Candida, and Malassezia) and 18 pathways (such as biosynthesis of antibiotics) potentially affected skin aging, implying that skin microbiomes may perform key functions in skin aging by regulating the immune response, resistance to ultraviolet light, and biosynthesis and metabolism of age-related substances. Our work re-establishes that skin microbiomes play an important regulatory role in the aging process and opens a new approach for targeted microbial therapy for skin aging.
The skin microbiome provides vital contributions to human health. However, the spatial organization and viability of its bacterial components remain unclear. Here, we apply culturing, imaging, and molecular approaches to human and mouse skin samples, and find that the skin surface is colonized by fewer viable bacteria than predicted by bacterial DNA levels. Instead, viable skin-associated bacteria are predominantly located in hair follicles and other cutaneous invaginations. Furthermore, we show that the skin microbiome has a uniquely low fraction of viable bacteria compared to other human microbiome sites, indicating that most bacterial DNA on the skin surface is not associated with viable cells Additionally, a small number of bacterial families dominate each skin site and traditional sequencing methods overestimate both the richness and diversity of the skin microbiome. Finally, we performed an in vivo skin microbiome perturbation-recovery study using human volunteers. Bacterial 16S rRNA gene sequencing revealed that, while the skin microbiome is remarkably stable even in the wake of aggressive perturbation, repopulation of the skin surface is driven by the underlying viable population. Our findings help explain the dynamics of skin microbiome perturbation as bacterial DNA on the skin surface can be transiently perturbed but is replenished by a stable underlying viable population. These results address multiple outstanding questions in skin microbiome biology with significant implications for future efforts to study and manipulate it.
Dry electrodes offer an accessible continuous acquisition of biopotential signals as part of current in-home monitoring systems but often face challenges of high-contact impedance that results in poor signal quality. The performance of dry electrodes could be affected by electrode material and skin hydration. Herein, we investigate these dependencies using a circuit skin-electrode interface model, varying material and hydration in controlled benchtop experiments on a biomimetic skin phantom simulating dry and hydrated skin. Results of the model demonstrate the contribution of the individual components in the circuit to total impedance and assist in understanding the role of electrode material in the mechanistic principle of dry electrodes. Validation was performed by conducting in vivo skin-electrode contact impedance measurements across ten normative human subjects. Further, the impact of the electrode on biopotential signal quality was evaluated by demonstrating an ability to capture clinically relevant electrocardiogram signals by using dry electrodes integrated into a toilet seat cardiovascular monitoring system. Titanium electrodes resulted in better signal quality than stainless steel electrodes. Results suggest that relative permittivity of native oxide of electrode material come into contact with the skin contributes to the interface impedance, and can lead to enhancement in the capacitive coupling of biopotential signals, especially in dry skin individuals.
Early detection of several skin-related neglected tropical diseases (skin NTDs)-including leprosy, Buruli ulcer, yaws, and scabies- may be achieved through school surveys, but such an approach has seldom been tested systematically on a large scale in endemic countries. Additionally, a better understanding of the spectrum of skin diseases and the at-risk populations to be encountered during such surveys is necessary to facilitate the process.
Atopic dermatitis (AD) lesional skin is often colonized with S. aureus, and the load of S. aureus correlates with disease severity. However, a causative and mechanistic link between S. aureus skin colonization and severity of AD is not well established. We made use of well-established mouse model of AD elicited by epicutaneous sensitization of tape stripped skin with ovalbumin to investigate the relationship between allergic skin inflammation and cutaneous S. aureus colonization. Topical application of S aureus exacerbated allergic skin inflammation induced by epicutaneous sensitization with ovalbumin, whereas allergic skin inflammation generated a permissive environment for S. aureus persistence. Our results establish a mutually reinforcing role of allergic skin inflammation and S. aureus skin colonization.
One of the most important surgical approaches for restoring cutaneous abnormalities caused by tumor resection is the insertion of a skin flap. Flap transplantation has been used to cover and fill different deficiencies after tumor removal. However, distal necrosis is among the most prevalent postsurgical consequences for skin flaps, particularly when treating large regions. Blood circulation failure causes flap necrosis, which may lead to serious problems, particularly in patients undergoing body cavity reconstruction following tumor excision. ADSCs (adipose-derived stem cells) are a kind of stem cell separated from the adipose tissue that has multilineage differentiation, simple availability, high proliferation capability, and self-renewal capabilities. This paper uses human adipose-derived stem cell (ADSC) therapy for skin flap transplantation in skin malignant tumor resection. ADSC-based therapy is an applicable technique for assisting flap transplantation. The isolation of ADSC is performed using different trypsin concentrations, and then, the population doubling time is determined. The isolated ADSCs are differentiated and then employed for the skin flap model. The performance of the suggested method is analyzed using various assays. The usage of adipose-derived stem cells to boost the vitality of the skin flaps proved successful.
Emulsion systems are widely used in various industries, including the cosmetic, pharmaceutical, and food industries, because they require emulsifiers to stabilize the inherently unstable contact between oil and water. Although emulsifiers are included in many products, excessive use of emulsifiers destroys skin barriers and causes contact dermatitis. Accordingly, the consumer demand for cosmetic products made from natural ingredients with biocompatibility and biodegradability has increased. Starch in the form of solid nanosized particles is considered an attractive emulsifier that forms and stabilizes Pickering emulsion. Chemical modification of nanosized starch via acid hydrolysis can effectively provide higher emulsion stability. However, typical acid hydrolysis limits the industrial application of starch due to its high time consumption and low recovery. In previous studies, the effects of starch nanoparticles (SNPs) prepared by treatment with acidic dry heat, which overcomes these limitations, on the formation and stability of Pickering emulsions were reported. In this study, we evaluated the safety of SNPs in skin cell lines, 3D cultured skin, and human skin. We found that the cytotoxicity of SNPs in both HaCaT cells and HDF cells could be controlled by neutralization. We also observed that SNPs did not induce structural abnormalities on 3D cultured skin and did not permeate across micropig skin tissue or human skin membranes. Furthermore, patches loaded with SNPs were found to belong in the "No irritation" category because they did not cause any irritation when placed on human skin. Overall, the study results suggest that SNPs can be used as a safe emulsifier in various industries, including in cosmetics.
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