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Skin plays central roles in systemic physiology, and it undergoes significant functional changes during aging. Members of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) family (PGC-1s) are key regulators of the biology of numerous tissues, yet we know very little about their impact on skin functions. Global gene expression profiling and gene silencing in keratinocytes uncovered that PGC-1s control the expression of metabolic genes as well as that of terminal differentiation programs. Glutamine emerged as a key substrate promoting mitochondrial respiration, keratinocyte proliferation, and the expression of PGC-1s and terminal differentiation programs. Importantly, gene silencing of PGC-1s reduced the thickness of a reconstructed living human epidermal equivalent. Exposure of keratinocytes to a salicylic acid derivative potentiated the expression of PGC-1s and terminal differentiation genes and increased mitochondrial respiration. Overall, our results show that the PGC-1s are essential effectors of epidermal physiology, revealing an axis that could be targeted in skin conditions and aging.

The term probiotic has been defined by experts as live microorganisms, which when administered in adequate amounts, confer a health benefit on the host. Probiotics are, thus, by definition, live microorganisms, and the viability of probiotics is a prerequisite for certain benefits, such as the release of metabolites at the site or adhesion properties, for example. However, some semi-active or non-replicative bacterial preparations may retain a similar activity to the live forms. On cosmetic, lysates or fractions are generally used. Topically applied Vitreoscilla filiformis extract has shown to have some similar biological activity of probiotics in the gut, for example, regulating immunity by optimisation of regulatory cell function, protecting against infection, and helping skin barrier function for better recovery and resistance. Due to their mode of action and efficacy, V. filiformis extract (lysate including membrane and cytosol) may be considered as non-replicative probiotic fractions, and this review article presents all its properties.

Previous studies have shown that physicochemical properties of hair can be impacted by internal and environmental exposures ranging from chemical stressors to weather. Besides the effects on hair, these exposures, termed “exposome”, can act on specific organs including skin, as a synergistic damaging effect of UV exposure and pollution on human surfaces. The combination of several environmental factors such as sun exposure, temperature, relative humidity, air pollution and photo-oxidation caused by ground level ozone impacts hair properties such as melanin oxidation, protein content, surface quality and structural components. Therefore, exposome studies can reveal new hypotheses on how epithelia and hair could be affected by daily life environment and routine. The aim of this study was to evaluate the impact of several environmental aggressors on human surfaces, using portable and wearable devices for monitoring exposome. To better understand the underlying mechanisms associated with environmental factors, two subjects wore multiple sensors to capture the meteorological conditions biking through urban areas in summer and winter. Temperature, humidity, UV radiation and ozone concentration were recorded and hair swatches of different types, including natural, bleached/colored, colored and gray, were exposed on the helmets. Silicon wristbands were used on skin to identify main chemical aggressors. After exposure, hair swatches were analyzed by surface microscopy analysis, oxidation markers and more than 1,500 chemicals were evaluated on the bracelets. Correlated with GPS and monitoring data, all these results provide insights on how environmental stressors affect the quality of different hair types and body surface according to exposure routine. Our results suggest extreme climate conditions associated with hair damage and photo-oxidative marker linked to the environmental aggressors. Polycyclic aromatic hydrocarbons (PAH) indicate possible causes of hair damages. This is the first meteorotropic study of its kind, combining environmental aggressors related to hair damage, opening new research hypothesis further studies on exposome.

Background Polycyclic aromatic hydrocarbons (PAHs) are of environmental and public health concerns and contribute to adverse skin attributes such as premature skin aging and pigmentary disorder. However, little information is available on the potential roles of chronic urban PAH pollutant exposure on the cutaneous microbiota. Given the roles of the skin microbiota have on healthy and undesirable skin phenotypes and the relationships between PAHs and skin properties, we hypothesize that exposure of PAHs may be associated with changes in the cutaneous microbiota. In this study, the skin microbiota of over two hundred Chinese individuals from two cities in China with varying exposure levels of PAHs were characterized by bacterial and fungal amplicon and shotgun metagenomics sequencing. Results Skin site and city were strong parameters in changing microbial communities and their assembly processes. Reductions of bacterial-fungal microbial network structural integrity and stability were associated with skin conditions (acne and dandruff). Multivariate analysis revealed associations between abundances of Propionibacterium and Malassezia with host properties and pollutant exposure levels. Shannon diversity increase was correlated to exposure levels of PAHs in a dose-dependent manner. Shotgun metagenomics analysis of samples (n = 32) from individuals of the lowest and highest exposure levels of PAHs further highlighted associations between the PAHs quantified and decrease in abundances of skin commensals and increase in oral bacteria. Functional analysis identified associations between levels of PAHs and abundance of microbial genes of metabolic and other pathways with potential importance in host-microbe interactions as well as degradation of aromatic compounds. Conclusions The results in this study demonstrated the changes in composition and functional capacities of the cutaneous microbiota associated with chronic exposure levels of PAHs. Findings from this study will aid the development of strategies to harness the microbiota in protecting the skin against pollutants.

Recent skin metagenomic studies have investigated the harbored viral diversity and its possible influence on healthy skin microbial populations, and tried to establish global patterns of skin-phage evolution. However, the detail associated with the phages that potentially play a role in skin health has not been investigated. While skin metagenome and -metavirome studies have indicated that the skin virome is highly site specific and shows marked interpersonal variation, they have not assessed the presence/absence of individual phages. Here, we took a semi-culture independent approach (metaviromic) to better understand the composition of phage communities on skin from South African study participants. Our data set adds over 130 new phage species of the skin to existing databases. We demonstrated that identical phages were present on different individuals and in different body sites, and we conducted a detailed analysis of the structural organization of these phages. We further found that a bacteriophage related to the Staphylococcus capitis phage Stb20 may be a common skin commensal virus potentially regulating its host and its activities on the skin.

Neural crest stem cells (NCPCs) have been shown to differentiate into various cell types and tissues during embryonic development, including sensory neurons. The few studies addressing the generation of NCPCs and peripheral sensory neurons (PSNs) from human induced pluripotent stem cells (hiPSCs), generated sensory cells without displaying robust activity. Here, we describe an efficient strategy for hiPSCs differentiation into NCPCs and functional PSNs using chemically defined media and factors to achieve efficient differentiation, confirmed by the expression of specific markers. After 10 days hiPSCs differentiated into NCPCs, cells were then maintained in neural induction medium containing defined growth factors for PSNs differentiation, followed by 10 days in neonatal human epidermal keratinocytes- (HEKn-) conditioned medium (CM). We observed a further increase in PSN markers expression and neurites length after CM treatment. The resulting neurons elicited action potentials after current injection and released substance P (SP) in response to nociceptive agents such as anandamide and resiniferatoxin. Anandamide induced substance P release via activation of TRPV1 and not CB1. Transcriptomic analysis of the PSNs revealed the main dorsal root ganglia neuronal markers and a transcriptional profile compatible with C fiber-low threshold mechanoreceptors. TRPV1 was detected by immunofluorescence and RNA-Seq in multiple experiments. In conclusion, the developed strategy generated PSNs useful for drug screening that could be applied to patient-derived hiPSCs, consisting in a powerful tool to model human diseases in vitro. Made available in DSpace on 2019-02-07T23:37:27Z (GMT). No. of bitstreams: 1 APGenerationiPSCFelipe.pdf: 7505321 bytes, checksum: 135c87796cec61c67776b2a6e5db7f0f (MD5) Previous issue date: 2019-02-07 Article 277.

Vascularization of reconstructed tissues is one of the remaining hurdles to be considered to improve both the functionality and viability of skin grafts and the relevance of in vitro applications. Our study, therefore, sought to develop a perfusable vascularized full-thickness skin equivalent that comprises a more complex blood vasculature compared to existing models. We combined molding, auto-assembly and microfluidics techniques in order to create a vascularized skin equivalent representing (a) a differentiated epidermis with a physiological organization and correctly expressing K14, K10, Involucrin, TGM1 and Filaggrin, (b) three perfusable vascular channels with angiogenic sprouts stained with VE-Caderin and Collagen IV, (c) an adjacent microvascular network created via vasculogenesis and connected to the sprouting macrovessels. Histological analysis and immunostaining of CD31, Collagen IV, Perlecan and Laminin proved the integrity of vascular constructs. In order to validate the vascularized skin potential of topical and systemic applications, caffeine and minoxidil, two compounds with different chemical properties, were topically applied to measure skin permeability and benzo[a]pyrene pollutant was systemically applied to evaluate systemic delivery. Our results demonstrated that perfusion of skin reconstructs and the presence of a complex vascular plexus resulted in a more predictive and reliable model to assess respectively topical and systemic applications. This model is therefore aimed at furthering drug discovery and improving clinical translation in dermatology.

Several scalp microbiome studies from different populations have revealed the association of dandruff with bacterial and fungal dysbiosis. However, the functional role of scalp microbiota in scalp disorders and health remains scarcely explored. Here, we examined the bacterial and fungal diversity of the scalp microbiome and their potential functional role in the healthy and dandruff scalp of 140 Indian women. Propionibacterium acnes and Staphylococcus epidermidis emerged as the core bacterial species, where the former was associated with a healthy scalp and the latter with dandruff scalp. Along with the commonly occurring Malassezia species (M. restricta and M. globosa) on the scalp, a strikingly high association of dandruff with yet uncharacterized Malassezia species was observed in the core mycobiome. Functional analysis showed that the fungal microbiome was enriched in pathways majorly implicated in cell-host adhesion in the dandruff scalp, while the bacterial microbiome showed a conspicuous enrichment of pathways related to the synthesis and metabolism of amino acids, biotin, and other B-vitamins, which are reported as essential nutrients for hair growth. A systematic measurement of scalp clinical and physiological parameters was also carried out, which showed significant correlations with the microbiome and their associated functional pathways. The results point toward a new potential role of bacterial commensals in maintaining the scalp nutrient homoeostasis and highlights an important and yet unknown role of the scalp microbiome, similar to the gut microbiome. This study, therefore, provides new perspectives on the better understanding of the pathophysiology of dandruff.

It is known that roughness-smoothness, hardness-softness, stickiness-slipperiness and warm-cold are predominant perceptual dimensions in macro-, micro- and nano- texture perception. However, it is not clear to what extent active tactile texture discrimination remains intact with age. The general decrease in tactile ability induces physical and emotional dysfunction in elderly, and has increasing significance for an aging population. We report a method to quantify tactile acuity based on blinded active exploration of systematically varying micro-textured surfaces and a same-different paradigm. It reveals that elderly participants show significantly reduced fine texture discrimination ability. The elderly group also displays statistically lower finger friction coefficient, moisture and elasticity, suggesting a link. However, a subpopulation of the elderly retains discrimination ability irrespective of cutaneous condition and this can be related to a higher density of somatosensory receptors on the finger pads. Skin tribology is thus not the primary reason for decline of tactile discrimination with age. The remediation of cutaneous properties through rehydration, however leads to a significantly improved tactile acuity. This indicates unambiguously that neurological tactile loss can be temporarily compensated by restoring the cutaneous contact mechanics. Such mechanical restoration of tactile ability has the potential to increase the quality of life in elderly.

Skin aging is associated with changes in cutaneous physiology including interactions with a skin microbial community. A striking alteration and diversification in the skin microbiome with aging was observed between two different age groups of 37 healthy Japanese women, i.e. younger adults of 21–37 years old and older adults of 60–76 years old, using bacterial 16S rRNA gene sequencing. The analyses revealed that the alpha diversity/species richness was significantly higher in the older than the younger group for the cheek and forehead microbiomes, while the beta diversity in the overall structure significantly differed particularly for the forearm and scalp microbiomes between the two age groups. Taxonomic profiling showed a striking reduction in the relative abundance of the majority skin genus Propionibacterium in the cheek, forearm and forehead microbiomes of the older adults, and identified 38 species including many oral bacteria that significantly differentiated the two age groups with a skin site dependency. Furthermore, we found chronological age-related and unrelated skin clinical parameters that correlate with the observed changes in the skin microbiome diversity. Thus, our data suggested that the diversification of skin microbiomes in adult women was largely affected by chronological and physiological skin aging in association with oral bacteria.

Background Jasmonates are plant hormones that exhibit anti-cancer and anti-inflammatory properties and have therefore raised interest for human health applications. The molecular basis of these activities remains poorly understood, although increasing evidence suggests that a variety of mechanisms may be involved. Recently, we have reported that a jasmonate derivative (JAD) displayed anti-aging effects on human skin by inducing extracellular matrix (ECM) remodeling. Based on this observation, we have investigated here the effects of JAD on proteoglycans and glycosaminoglycan (GAG) polysaccharides, which are major cell-surface/ECM components and are involved in a multitude of biological processes. In parallel, we have examined the ability of JAD to promote growth factor activities and improve skin wound healing. Methods Proteoglycan expression was analyzed on epidermal primary keratinocytes and reconstituted skin epidermis, using electron/immunofluorescence microscopy, western blotting and flow cytometry. GAG composition was determined by disaccharide analysis. Finally, biological activities of JAD were assessed in cellulo, in FGF-7 induced migration/proliferation assays, as well as in vivo, using a suction blister model performed on 24 healthy volunteers. Results JAD was found to induce expression of major skin proteoglycans and to induce subtle changes in GAG structure. In parallel, we showed that JAD promoted FGF-7 and improved skin healing by accelerating epithelial repair in vivo. Conclusion This study highlights JAD as a promising compound for investigating GAG structure-function relationships and for applications in skin cosmetic /corrective strategies. General significance We propose here a novel mechanism, by which jasmonate derivatives may elicit biological activities in mammals.

Dandruff is a prevalent chronic inflammatory skin condition of the scalp that has been associated with Malassezia yeasts. However, the microbial role has not been elucidated yet, and the etiology of the disorder remains poorly understood. Using high-throughput 16S rDNA and ITS1 sequencing, we characterized cutaneous bacterial and fungal microbiotas from healthy and dandruff subjects, comparing scalp and forehead (lesional and non-lesional skin sites). Bacterial and fungal communities from dandruff analyzed at genus level differed in comparison with healthy ones, presenting higher diversity and greater intragroup variation. The microbial shift was observed also in non-lesional sites from dandruff subjects, suggesting that dandruff is related to a systemic process that is not restricted to the site exhibiting clinical symptoms. In contrast, Malassezia microbiota analyzed at species level did not differ according to health status. A 2-step OTU assignment using combined databases substantially increased fungal assigned sequences, and revealed the presence of highly prevalent uncharacterized Malassezia organisms (>37% of the reads). Although clinical symptoms of dandruff manifest locally, microbial dysbiosis beyond clinically affected skin sites suggests that subjects undergo systemic alterations, which could be considered for redefining therapeutic approaches.

We report on a functional human model to evaluate multi-organ toxicity in a 4-organ system under continuous flow conditions in a serum-free defined medium utilizing a pumpless platform for 14 days. Computer simulations of the platform established flow rates and resultant shear stress within accepted ranges. Viability of the system was demonstrated for 14 days as well as functional activity of cardiac, muscle, neuronal and liver modules. The pharmacological relevance of the integrated modules were evaluated for their response at 7 days to 5 drugs with known side effects after a 48 hour drug treatment regime. The results of all drug treatments were in general agreement with published toxicity results from human and animal data. The presented phenotypic culture model exhibits a multi-organ toxicity response, representing the next generation of in vitro systems and constitutes a step towards an in vitro “human-on-a-chip” assay for systemic toxicity screening.

UNLABELLED:We studied skin microbiota present in three skin sites (forearm, axilla, scalp) in men from six ethnic groups living in New York City. METHODS:Samples were obtained at baseline and after four days following use of neutral soap and stopping regular hygiene products, including shampoos and deodorants. DNA was extracted using the MoBio Power Lyzer kit and 16S rRNA gene sequences determined on the IIlumina MiSeq platform, using QIIME for analysis. RESULTS:Our analysis confirmed skin swabbing as a useful method for sampling different areas of the skin because DNA concentrations and number of sequences obtained across subject libraries were similar. We confirmed that skin location was the main factor determining the composition of bacterial communities. Alpha diversity, expressed as number of species observed, was greater in arm than on scalp or axilla in all studied groups. We observed an unexpected increase in α-diversity on arm, with similar tendency on scalp, in the South Asian group after subjects stopped using their regular shampoos and deodorants. Significant differences at phylum and genus levels were observed between subjects of the different ethnic origins at all skin sites. CONCLUSIONS:We conclude that ethnicity and particular soap and shampoo practices are secondary factors compared to the ecological zone of the human body in determining cutaneous microbiota composition.

Malassezia spp. are saprophyte yeasts involved in skin diseases with different degrees of severity. The aim of our study was to analyze the response of human epidermal keratinocytes to Malassezia globosa and restricta strains evaluating the host defence mechanisms induced by Malassezia spp. colonization. Our results showed a different modulation of the inflammatory and immunomodulatory cytokine pathways obtained with the different strains of Malassezia tested. In addition, this expression is altered by blocking the TLR2 receptor. In comparison with M. furfur, M. globosa and restricta displayed an unexpected and striking cytotoxicity on keratinocytes. The differences observed could be related to the different modalities of interaction between keratinocytes and Malassezia strains, but also to their growth condition. Taken together, these results indicate that M. globosa or M. restricta colonization exert a different control on the cytokine inflammatory response activated in the human keratinocyte in which TLR2 might be involved. M. globosa and M. restricta may play a synergistic role in the exacerbation of skin diseases in which both are found.

International audience; The bacterial and fungal communities associated with dandruff were investigated using culture-independent methodologies in the French subjects. The major bacterial and fungal species inhabiting the scalp subject's were identified by cloning and sequencing of the conserved ribosomal unit regions (16S for bacterial and 28S-ITS for fungal) and were further quantified by quantitative PCR. The two main bacterial species found on the scalp surface were Propionibacterium acnes and Staphylococcus epidermidis, while Malassezia restricta was the main fungal inhabitant. Dandruff was correlated with a higher incidence of M. restricta and S. epidermidis and a lower incidence of P. acnes compared to the control population (p

The functional existence of the emerging endocannabinoid system (ECS), one of the new neuroendocrine players in cutaneous biology, is recently described in the human skin. In this study, using human eccrine sweat gland–derived immortalized NCL-SG3 model cells and a wide array of cellular and molecular assays, we investigated the effects of prototypic endocannabinoids (anandamide, 2-arachidonoylglycerol) on cellular functions. We show here that both endocannabinoids dose-dependently suppressed proliferation, induced apoptosis, altered expressions of various cytoskeleton proteins (e.g., cytokeratins), and upregulated lipid synthesis. Interestingly, as revealed by specific agonists and antagonists as well as by RNA interference, neither the metabotropic cannabinoid receptors (CB) nor the “ionotropic” CB transient receptor potential ion channels, expressed by these cells, mediated the cellular actions of the endocannabinoids. However, the endocannabinoids selectively activated the mitogen-activated protein kinase signaling pathway. Finally, other elements of the ECS (i.e., enzymes involved in the synthesis and degradation of endocannabinoids) were also identified on NCL-SG3 cells. These results collectively suggest that cannabinoids exert a profound regulatory role in the biology of the appendage. Therefore, from a therapeutic point of view, upregulation of endocannabinoid levels might help to manage certain sweat gland–derived disorders (e.g., tumors) characterized by unwanted growth.

BACKGROUND: Resveratrol is a plant-derived polyphenol with purported protecting action on various disorders associated with aging. It has been suggested that resveratrol could exert its protective action by acting on specific plasma membrane polyphenol binding sites (Han Y.S., et al. (2006) J Pharmacol Exp Ther 318:238-245). The purpose of this study was to investigate, in human skin, the possible existence of specific binding sites that mediate the protective action of resveratrol. METHODS AND FINDINGS: Using human skin tissue, we report here the presence of specific [(3)H]-resveratrol binding sites (K(D) = 180 nM) that are mainly located in the epidermis. Exposure of HaCaT cells to the nitric oxide free radical donor sodium nitroprusside (SNP; 0.3-3 mM) resulted in cell death which was reduced by resveratrol (EC(50) = 14.7 µM), and to a much lesser extent by the resveratrol analogue piceatannol (EC(50) = 95 µM) and epigallocatechin gallate (EC(50) = 200 µM), a green-tea derived polyphenol. The protective action of resveratrol likely relates to its anti-apoptotic effect since at the same range of concentration it was able to reduce both the number of apoptotic cells as well as mitochondrial apoptotic events triggered by SNP. CONCLUSION: Taken together, these findings suggest that resveratrol, by acting on specific polyphenol binding sites in epidermis, may be useful to prevent skin disorders associated with aging.