Cosmetic retinoid use in photoaged skin: A review of the compounds, their use and mechanisms of action.

The inevitable attrition of skin due to ultraviolet radiation, termed photoaging, can be partially restored by treatment with retinoid compounds. Photoaged skin in lightly pigmented individuals, clinically presents with the appearance of wrinkles, increased laxity, and hyper- and hypopigmentation. Underlying these visible signs of ageing are histological features such as epidermal thinning, dermal-epidermal junction flattening, solar elastosis and loss of the dermal fibrillin microfibrillar network, fibrillar collagen and glycosaminoglycans. Retinoid compounds are comprised of three main generations with the first generation (all-trans retinoic acid, retinol, retinaldehyde and retinyl esters) primarily used for the clinical and cosmetic treatment of photoaging, with varying degrees of efficacy, tolerance and stability. All-trans retinoic acid is considered the 'gold standard' for skin rejuvenation; however, it is a prescription-only product largely confined to clinical use. Therefore, retinoid derivatives are readily incorporated into cosmeceutical formulations. The literature reported in this review suggests that retinol, retinyl esters and retinaldehyde that are used in many cosmeceutical products, are efficacious, safe and well-tolerated. Once in the skin, retinoids utilize a complex signalling pathway that promotes remodelling of photoaged epidermis and dermis and leads to the improvement of the cutaneous signs of photoaging.

L'altération inévitable de la peau due aux rayons ultraviolets, appelée photovieillissement, peut être partiellement restaurée par un traitement à base de composés rétinoïdes. Chez les personnes à la pigmentation claire, le photovieillissement de la peau se manifeste au plan clinique par l'apparition de rides, un relâchement accru et une hyperpigmentation ou hypopigmentation. Ces signes visibles du vieillissement sont sous­tendus par des caractéristiques histologiques telles que l'amincissement de l'épiderme, l'aplatissement de la jonction dermo­épidermique, l'élastose solaire et la perte du réseau microfibrillaire de fibrilline dermique, du collagène fibrillaire et des glycosaminoglycanes. Les composés rétinoïdes sont constitués de trois générations principales, la première génération (acide tout­trans rétinoïque, rétinol, rétinaldéhyde et esters de rétinyle) étant principalement utilisée pour le traitement clinique et cosmétique du photovieillissement, avec des degrés variables d'efficacité, de tolérance et de stabilité. L'acide tout­trans rétinoïque est considéré comme la référence en matière de rajeunissement de la peau; il s'agit toutefois d'un produit délivré uniquement sur ordonnance, dont l'utilisation est largement limitée au domaine clinique. Les dérivés rétinoïdes sont donc volontiers incorporés ds formulations cosméceutiques. La littérature citée dans cette synthèse bibliographique laisse penser que le rétinol, les esters de rétinyle et le rétinaldéhyde, utilisés dans de nombreux produits cosmétiques, sont efficaces, sûrs et bien tolérés. Une fois dans la peau, les rétinoïdes utilisent une voie de signalisation complexe qui favorise le remodelage de l'épiderme et du derme photovieillis, et conduit à l'amélioration des signes cutanés du photovieillissement.

The impact of irritant challenge on the skin barrier and myeloid resident immune cells in post-menopausal women is modulated by hormone replacement therapy.

BACKGROUND: Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. Therefore, we examined how menopause and HRT affect skin barrier and immune cell composition in post-menopausal women following irritant challenge. METHODS: Two cohorts of post-menopausal women were recruited to the study, one untreated (HRT-; n = 10; mean age 56.5 yrs [range 48-63 yrs]) and the other receiving HRT (n = 8; mean age 54 yrs [range 48-63 yrs]). Skin irritation was induced by applying 1.25% topical Sodium Lauryl Sulfate (SLS) to occluded buttock skin for 48 hours. Clinical assessment was conducted after 24 hours, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. RESULTS: Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in trans-epidermal water loss (p<0.05), filaggrin deposition and keratin-10-positive cell layers (p<0.01) was observed in individuals receiving HRT compared to the HRT- group. Following SLS challenge in individuals taking HRT, a significant (p<0.01) reduction of CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans' cells (LCs). Significantly fewer migrating LCs were observed in those not receiving HRT (p<0.01). Furthermore, the number of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (p<0.05) higher in those taking HRT following SLS challenge. CONCLUSION: Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased keratin-10-positive epidermal cell layers. Following challenge, HRT users exhibited elevated counts of LCs, inflammatory DCs, and macrophages in the dermis. These may render skin both, more prone to inflammation and more capable of resolving it, while also promoting skin repair.

Prediction, screening and characterization of novel bioactive tetrapeptide matrikines for skin rejuvenation.

BACKGROUND: Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In skin, loss of dermal collagens and disorganization of elastic fibre components are key features of photoageing. Although the application of some small matrix-derived peptides to aged skin has been shown to beneficially affect in vitro cell behaviour and, in vivo, molecular architecture and clinical appearance, the discovery of new peptides has lacked a guiding hypothesis. OBJECTIVES: To identify, using protease cleavage site prediction, novel putative matrikines with beneficial activities for skin composition and structure. METHODS: Here, we present an in silico (peptide cleavage prediction) to in vitro (proteomic and transcriptomic activity testing in cultured human dermal fibroblasts) to in vivo (short-term patch test and longer-term split-face clinical study) discovery pipeline, which enables the identification and characterization of peptides with differential activities. RESULTS: Using this pipeline we showed that cultured fibroblasts were responsive to all applied peptides, but their associated bioactivity was sequence-dependent. Based on bioactivity, toxicity and protein source, we further characterized a combination of two novel peptides, GPKG (glycine-proline-lysine-glycine) and LSVD (leucine-serine-valine-aspartate), that acted in vitro to enhance the transcription of matrix -organization and cell proliferation genes and in vivo (in a short-term patch test) to promote processes associated with epithelial and dermal maintenance and remodelling. Prolonged use of a formulation containing these peptides in a split-face clinical study led to significantly improved measures of crow's feet and firmness in a mixed population. CONCLUSIONS: This approach to peptide discovery and testing can identify new synthetic matrikines, providing insights into biological mechanisms of tissue homeostasis and repair and new pathways to clinical intervention.

Like other organs and tissues, the skin is composed of both cells and a complex network of molecules and proteins called an extracellular matrix. This matrix contains proteins such as collagen and elastin and undergoes many changes when the skin is damaged by the sun. We know from previous studies that small parts of matrix proteins (called peptide 'matrikines') can help to treat the signs of sun-related skin ageing. In this UK study, we show that new beneficial peptides (with matrikine activity) can be identified using machine learning (artificial intelligence) techniques that predict where common matrix proteins might be 'cut' by skin enzymes. Candidate peptides were first made in the laboratory and then applied to skin cells in culture. These cell culture screens demonstrated that, while all the peptides showed some matrikine activity, two were particularly promising. These two peptides were then tested in a short-term study on the forearm skin of volunteers and, in a longer-term study, on the face. We found that the combination of these two peptides can prompt forearm skin cells to express genes that are involved in many different aspect of skin health and, over the longer 6-month period, produce visible benefits in the appearance of fine lines and wrinkles and firmness on the face. Our findings suggest that this approach may be able to identify beneficial peptide treatments for not only skin ageing and diseases, but also unwanted changes in the extracellular matrix of other tissues and organs.

Skin ageing and topical rejuvenation strategies.

Skin ageing is a complex process involving the additive effects of skin's interaction with its external environment, predominantly chronic sun exposure, upon a background of time-dependent intrinsic ageing. Skin health and beauty is considered one of the principal factors perceived to represent overall 'health and wellbeing'; thus, the demand for skin rejuvenation strategies has rapidly increased, with a worldwide annual expenditure expected to grow from $US24.6 billion to around $US44.5 billion by 2030 (https://www.databridgemarketresearch.com/reports/global-facial-rejuvenation-market). Skin rejuvenation can be achieved in several ways, ranging from laser and device-based treatments to chemical peels and injectables; however, topical skin care regimes are a mainstay treatment for ageing skin and all patients seeking skin rejuvenation can benefit from this relatively low-risk intervention. While the most efficacious topical rejuvenation treatment is application of tretinoin (all-trans retinoic acid) - a prescription-only medicine considered to be the clinical 'gold standard' - a hybrid category of 'cosmeceutical' products at the midpoint of the spectrum of cosmetics and pharmaceutical has emerged. This article reviews the clinical manifestations of skin ageing and the available topical treatments for skin rejuvenation, including retinoids, peptides and antioxidants.

Behaviour and sun exposure in holidaymakers alters skin microbiota composition and diversity.

Introduction: The skin microbiota plays a crucial role in maintaining epidermal homeostasis. Ultraviolet radiation (UVR) and other environmental challenges can impact the skin microbiota through direct and indirect mechanisms. This study aimed to investigate the effects of sun exposure on the skin microbiota and its relationship with individual skin phototypes. Methods: Healthy volunteers (n = 21 [4M, 17 F], mean age 33.2 years) holidayed in a sunny destination for a minimum of 7 days with swabs taken pre-holiday and up to 84 days post-holiday. Participant group was categorised by individual typology angle (ITA) classification and the composition of the skin microbiota was examined using 16S rRNA gene sequencing. Results: In the entire cohort and at all time points, the major bacterial phyla were Actinobacteria, Proteobacteria and Firmicutes. There was a significant change in microbial beta diversity at day 28 post-holiday, compared to baseline, for all participants. However, when participants were segregated into three cohorts dependent on the degree of skin tanning response between baseline (pre-holiday) and immediately one-day post-holiday, there was a reduction in Proteobacteria in the sun-seeking participants 1 day after the holiday, which recovered over time. Discussion: These findings suggest that sun exposure can affect the diversity and composition of the skin microbiota, which may have downstream effects on skin health.

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy.

The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production.

Multifaceted amelioration of cutaneous photoageing by (0.3%) retinol.

BACKGROUND: Although retinol skin care products improve the appearance of photoaged skin, there is a need for an effective retinol concentration that provides skin benefits without irritation. OBJECTIVE: To compare the efficacy of topical 0.1%, 0.3% and 1% retinol in remodelling the cutaneous architecture in an in vivo experimental patch test study, and to determine tolerance of the most effective formulations when used in a daily in-use escalation study. METHODS: For the patch test study, retinol products were applied under occlusion, to the extensor forearm of photoaged volunteers (n = 5; age range 66-84 years), and 3 mm skin biopsies obtained after 12 days. Effects of different retinol concentrations, and a vehicle control, on key epidermal and dermal biomarkers of cellular proliferation and dermal remodelling were compared to untreated baseline. Separately, participants (n = 218) recorded their tolerance to 0.3% or 1% retinol over a six-week, approved regimen, which gradually increased the facial applications to once nightly. RESULTS: Retinol treatment induced a stepwise increase in epidermal thickness and induced the expression of stratum corneum proteins, filaggrin and KPRP. 0.3% retinol and 1% retinol were comparably effective at inducing keratinocyte proliferation in the epidermis, whilst reducing e-cadherin expression. Fibrillin-rich microfibril deposition was increased following treatment with 0.3% and 1% retinol (p < 0.01); other dermal components remained unaltered (e.g., fibronectin, collagen fibrils, elastin), and no evidence of local inflammation was detected. The in-use study found that 0.3% retinol was better tolerated than 1% retinol, with fewer and milder adverse events reported (χ2 (1) = 23.97; p < 0.001). CONCLUSIONS: This study suggests that 1% and 0.3% retinol concentrations were similarly effective at remodelling photodamaged skin in an in vivo model of long-term use. Use of 0.3% retinol in the escalation study was associated with fewer adverse reactions when applied daily. Hence, 0.3% retinol may be better tolerated than 1% retinol, thereby allowing longer-term topical application.

CONTEXTE: Même si les produits de soins pour la peau à base de rétinol améliorent l'apparence de la peau photovieillie, il est nécessaire d'obtenir une concentration efficace de rétinol procurant des bénéfices cutanés sans irritation. OBJECTIF: Comparer l'efficacité du rétinol à 0.1%, 0.3% et 1% en application locale dans le remodelage de l'architecture cutanée dans une étude d'irritation cutanée in vivo expérimental, et déterminer la tolérance des formulations les plus efficaces lorsqu'elles sont utilisées dans une étude à doses progressives quotidiennes en cours d'utilisation. MÉTHODES: Pour l'étude d'irritation cutanée, des produits à base de rétinol ont été appliqués sous occlusion, sur le muscle extenseur de l'avant-bras de volontaires présentant des signes de photovieillissement (n = 5; tranche d'âge: 66 à 84 ans), et des biopsies cutanées de 3 mm ont été obtenues après 12 jours. Les effets des différentes concentrations de rétinol, et d'un véhicule témoin sur les principaux biomarqueurs épidermiques et dermiques de la prolifération cellulaire et du remodelage dermique ont été comparés à ceux observés à une région non traitée. Séparément, les participants (n = 218) ont enregistré leur tolérance au rétinol à 0.3% ou 1% au cours d'un schéma posologique approuvé de six semaines, qui a progressivement augmenté les applications faciales à une fois par nuit. RÉSULTATS: Le traitement par rétinol a induit une augmentation progressive de l'épaisseur épidermique, et a induit l'expression des protéines de la couche cornée, la filaggrine et le KPRP. Le rétinol à 0.3% et le rétinol à 1% étaient aussi efficaces pour induire la prolifération des kératinocytes dans l'épiderme, tout en réduisant l'expression de la cadhérine E. Le dépôt de microfibrilles riches en fibrilline a augmenté après un traitement par rétinol à 0.3% et 1% (p < 0.001). CONCLUSIONS: Cette étude suggère que les concentrations de rétinol de 1% et 0.3% étaient aussi efficaces pour remodeler la peau photolésée dans un modèle in vivo lors d'une utilisation à long terme. L'utilisation de rétinol à 0.3% dans l'étude à doses progressives a été associée à moins d'effets indésirables lorsqu'il est appliqué quotidiennement. Par conséquent, le rétinol à 0.3% peut être mieux toléré que le rétinol à 1%, permettant ainsi une application topique à plus long terme.

Wound fluid sampling methods for proteomic studies: A scoping review.

Understanding why some wounds are hard to heal is important for improving care and developing more effective treatments. The method of sample collection used is an integral step in the research process and thus may affect the results obtained. The primary objective of this study was to summarise and map the methods currently used to sample wound fluid for protein profiling and analysis. Eligible studies were those that used a sampling method to collect wound fluid from any human wound for analysis of proteins. A search for eligible studies was performed using MEDLINE, Embase and CINAHL Plus in May 2020. All references were screened for eligibility by one reviewer, followed by discussion and consensus with a second reviewer. Quantitative data were mapped and visualised using appropriate software and summarised via a narrative summary. After screening, 280 studies were included in this review. The most commonly used group of wound fluid collection methods were vacuum, drainage or use of other external devices, with surgical wounds being the most common sample source. Other frequently used collection methods were extraction from absorbent materials, collection beneath an occlusive dressing and direct collection of wound fluid. This scoping review highlights the variety of methods used for wound fluid collection. Many studies had small sample sizes and short sample collection periods; these weaknesses have hampered the discovery and validation of novel biomarkers. Future research should aim to assess the reproducibility and feasibility of sampling and analytical methods for use in larger longitudinal studies.

Ultraviolet radiation-induced degradation of dermal extracellular matrix and protection by green tea catechins: a randomized controlled trial.

BACKGROUND: Loss and remodelling of the dermal extracellular matrix (ECM) are key features of photodamaged human skin. Green tea catechins (GTCs) have been explored for their anti-inflammatory and chemopreventive properties, but data on the impact of GTCs on ultraviolet radiation (UVR)-induced changes to the dermal ECM are lacking. AIM: To investigate the effect of an inflammatory dose of solar-simulated UVR on human dermal ECM and potential for protection by GTCs in a double-blind randomized controlled trial. METHODS: In total, 50 healthy white (Fitzpatrick skin type I-II) adults aged 18-65 years were randomized to a combination of GTCs 540 mg plus vitamin C 50 mg or to placebo twice daily for 12 weeks. The impact of solar-simulated UVR at 3 × minimal erythema dose on the dermal collagen and elastic fibre networks was assessed by histology and immunohistochemistry in all participants at baseline. The impact of GTC supplementation on UVR-induced effects was compared between the groups post-supplementation. RESULTS: The area of papillary dermis covered by collagen and elastic fibres was significantly lower (P < 0.001) in UVR-exposed skin than in unexposed skin. Significantly lower levels of fibrillin-rich microfibrils (P = 0.02), fibulin-2 (P < 0.001) and fibulin-5 (P < 0.001) were seen in UVR-exposed than unexposed skin, while procollagen-1 deposition was significantly higher in UVR-exposed skin (P = 0.01). Following GTC supplementation, the UVR-induced change in fibulin-5 was abrogated in the active group but not the placebo group, with no difference between the two groups for other components. CONCLUSIONS: Acute UVR induced significant changes in the human dermal collagen and elastic fibre networks, whereas oral GTCs conferred specific UVR protection to fibulin-5. Future studies could explore the impact of GTCs on the effects of repeated suberythemal UVR exposure of human skin.

Predicting Proteolysis in Complex Proteomes Using Deep Learning.

Both protease- and reactive oxygen species (ROS)-mediated proteolysis are thought to be key effectors of tissue remodeling. We have previously shown that comparison of amino acid composition can predict the differential susceptibilities of proteins to photo-oxidation. However, predicting protein susceptibility to endogenous proteases remains challenging. Here, we aim to develop bioinformatics tools to (i) predict cleavage site locations (and hence putative protein susceptibilities) and (ii) compare the predicted vulnerabilities of skin proteins to protease- and ROS-mediated proteolysis. The first goal of this study was to experimentally evaluate the ability of existing protease cleavage site prediction models (PROSPER and DeepCleave) to identify experimentally determined MMP9 cleavage sites in two purified proteins and in a complex human dermal fibroblast-derived extracellular matrix (ECM) proteome. We subsequently developed deep bidirectional recurrent neural network (BRNN) models to predict cleavage sites for 14 tissue proteases. The predictions of the new models were tested against experimental datasets and combined with amino acid composition analysis (to predict ultraviolet radiation (UVR)/ROS susceptibility) in a new web app: the Manchester proteome susceptibility calculator (MPSC). The BRNN models performed better in predicting cleavage sites in native dermal ECM proteins than existing models (DeepCleave and PROSPER), and application of MPSC to the skin proteome suggests that: compared with the elastic fiber network, fibrillar collagens may be susceptible primarily to protease-mediated proteolysis. We also identify additional putative targets of oxidative damage (dermatopontin, fibulins and defensins) and protease action (laminins and nidogen). MPSC has the potential to identify potential targets of proteolysis in disparate tissues and disease states.

Peptide location fingerprinting reveals modification-associated biomarker candidates of ageing in human tissue proteomes.

Although dysfunctional protein homeostasis (proteostasis) is a key factor in many age-related diseases, the untargeted identification of structurally modified proteins remains challenging. Peptide location fingerprinting is a proteomic analysis technique capable of identifying structural modification-associated differences in mass spectrometry (MS) data sets of complex biological samples. A new webtool (Manchester Peptide Location Fingerprinter), applied to photoaged and intrinsically aged skin proteomes, can relatively quantify peptides and map statistically significant differences to regions within protein structures. New photoageing biomarker candidates were identified in multiple pathways including extracellular matrix organisation (collagens and proteoglycans), protein synthesis and folding (ribosomal proteins and TRiC complex subunits), cornification (keratins) and hemidesmosome assembly (plectin and integrin α6ß4). Crucially, peptide location fingerprinting uniquely identified 120 protein biomarker candidates in the dermis and 71 in the epidermis which were modified as a consequence of photoageing but did not differ significantly in relative abundance (measured by MS1 ion intensity). By applying peptide location fingerprinting to published MS data sets, (identifying biomarker candidates including collagen V and versican in ageing tendon) we demonstrate the potential of the MPLF webtool for biomarker discovery.

Systemic sclerosis skin is a primed microenvironment for soft tissue calcification-a hypothesis.

Calcinosis cutis, defined as sub-epidermal deposition of calcium salts, is a major clinical problem in patients with SSc, affecting 20-40% of patients. A number of recognized factors associated with calcinosis have been identified, including disease duration, digital ischaemia and acro-osteolysis. Yet, to date, the pathogenesis of SSc-related calcinosis remains unknown, and currently there is no effective disease-modifying pharmacotherapy. Following onset of SSc, there are marked changes in the extracellular matrix (ECM) of the skin, notably a breakdown in the microfibrillar network and accumulation of type I collagen. Our hypothesis is that these pathological changes reflect a changing cellular phenotype and result in a primed microenvironment for soft tissue calcification, with SSc fibroblasts adopting a pro-osteogenic profile, and specific driving forces promoting tissue mineralization. Considering the role of the ECM in disease progression may help elucidate the mechanism(s) behind SSc-related calcinosis and inform the development of future therapeutic interventions.

Inflammaging and the Skin.

As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation associated with aging, termed inflammaging. This is characterized by increased levels of circulating proinflammatory cytokines and a shift toward cellular senescence, changes that are believed to drive many age-associated conditions, including dementia, arthritis, and type 2 diabetes. As with other organs, the skin undergoes functional decline during aging, becoming more fragile and susceptible to infection; however, the contribution of inflammaging is not well-understood. This review article describes the evidence for inflammaging in the skin, its relationship with senescence, and how this relates to declining skin structure and function.

Frontiers in translational systemic sclerosis research: A focus on the unmet 'cutaneous' clinical needs (Viewpoint).

This viewpoint considers four cutaneous unmet clinical needs of patients with systemic sclerosis (SSc), namely the rapidly progressive skin thickening (scleroderma) which occurs early on in diffuse cutaneous disease; digital (finger and toe) ulcers; calcinosis; and cutaneous telangiectases. All four problems cause pain, disability and/or disfigurement, all impact on quality of life, and for each, we require effective treatments. For each unmet need, we give a brief description of the clinical problem (including clinical burden), pathophysiology and current treatment, followed by a personal viewpoint of the key questions which research must address. For the painful, debilitating skin thickening of early diffuse cutaneous SSc, studies are required to decide whether corticosteroids are effective and safe (current opinion is divided) and whether phototherapy approaches have a role. Also, we need to develop and validate reliable outcome measures for clinical trials of promising new therapies: these could be composite indices, novel non-invasive imaging methods and patient-reported outcome measures, possibly in combination as they provide complementary information. For digital ulcers, again we require validated outcome measures for clinical trials. We also need to explore local (including topical) treatments, which are free from systemic adverse effects, and preventative strategies for high-risk patients. For calcinosis, we need to better understand pathophysiology, to validate outcome measures and to develop topical treatments. For telangiectases, we need to "use" these highly accessible lesions to help unravel the vascular pathophysiology of SSc and explore their different properties as potential biomarkers.

Remodelling of fibrillin-rich microfibrils by solar-simulated radiation: impact of skin ethnicity.

Fibrillin-rich microfibrils (FRMs) constitute integral components of the dermal elastic fibre network with a distinctive ultrastructural 'beads-on-a-string' appearance that can be visualised using atomic force microscopy and characterised by measurement of their length and inter-bead periodicity. Their deposition within the dermis in photoprotected skin appears to be contingent on skin ethnicity, and influences the ultrastructure of papillary - but not reticular - dermal FRMs. Truncation and depletion of FRMs at the dermal-epidermal junction of skin occurs early in photoageing in people with lightly pigmented skin; a process of accelerated skin ageing that arises due to chronic sun exposure. Accumulation of ultraviolet radiation (UVR)-induced damage, either by the action of enzymes, oxidation or direct photon absorption, results in FRM remodelling and changes to ultrastructure. In the current study, the direct effect of UVR exposure on FRM ultrastructure was assayed by isolating FRMs from the papillary and reticular dermis of photoprotected buttock skin of individuals of either black African or white Northern European ancestry and exposing them to solar-simulated radiation (SSR). Exposure to SSR resulted in significant reduction in inter-bead periodicity for reticular dermis-derived FRMs across both cohorts. In contrast, papillary dermal FRMs exhibited significantly increased inter-bead periodicity, with the magnitude of damage greater for African FRMs, as compared to Northern European FRMs. Our data suggest that FRMs of the dermis should be considered as two distinct populations that differentially accrue damage in response to SSR. Furthermore, papillary dermal FRMs derived from black African subjects show greater change following UVR challenge, when extracted from skin. Future studies should focus on understanding the consequences of UVR exposure in vivo, regardless of skin ethnicity, on the molecular composition of FRMs and how this UVR-induced remodelling may affect the role FRMs play in skin homeostasis.

Protease activity as a prognostic factor for wound healing in complex wounds.

Healing mechanisms are disrupted in complex wounds. Proteases may persist longer in nonhealing wounds. We sought to investigate whether protease activity, protease inhibitor activity, or their combinations are independent prognostic factors for healing of complex wounds. We searched MEDLINE, EMBASE, CINAHL, and The Cochrane Library to March 2019. Study selection comprised longitudinal studies assessing the independent effect of proteases, their inhibitors or ratios of the two, on healing of complex wounds, while controlling for confounding factors. Two reviewers independently extracted data and assessed risk of bias. We conducted meta-analyses separately for proteases, inhibitors, and ratios. We graded the evidence certainty (quality). We identified eight eligible studies in 10 cohorts involving 343 participants. Risk of bias was moderate or high. Elevated protease activity may be associated with less wound healing (standardized mean difference [SMD]: -0.41, 95% CI -0.72 to -0.11; nine cohorts); and elevated protease inhibitor activity with more healing (SMD: 0.37, 95% CI 0.06-0.68; five cohorts), this is low certainty evidence. Increased protease: inhibitor ratios may be associated with less healing (SMD -0.47, 95% CI -0.94 to -0.01; four cohorts), but this evidence is of very low certainty. Heterogeneity in protease activity was unexplained by prespecified subgroup analyses for wound type or protease activity status, but partially explained by protease class. Posthoc analysis suggested elevated levels of a particular protease, MMP-1, may be associated with more healing and other proteases with less healing. This is low/very low certainty evidence. Limitations were small included studies at moderate or high risk of bias, and the use of posthoc analyses. Elevated protease activity and protease: inhibitor ratios may be associated with less healing, and elevated inhibitor levels with more healing. There may be important differences between MMP-1 and other proteases. High quality research is needed to explore these new findings further.

Heterogeneity of fibrillin-rich microfibrils extracted from human skin of diverse ethnicity.

The dermal elastic fibre network is the primary effector of skin elasticity, enabling it to extend and recoil many times over the lifetime of the individual. Fibrillin-rich microfibrils (FRMs) constitute integral components of the elastic fibre network, with their distribution showing differential deposition in the papillary dermis across individuals of diverse skin ethnicity. Despite these differential findings in histological presentation, it is not known if skin ethnicity influences FRM ultrastructure. FRMs are evolutionarily highly conserved from jellyfish to man and, regardless of tissue type or species, isolated FRMs have a characteristic 'beads-on-a-string' ultrastructural appearance, with an average inter-bead distance (or periodicity) of 56 nm. Here, skin biopsies were obtained from the photoprotected buttock of healthy volunteers (18-27 years; African: n = 5; European: n = 5), and FRMs were isolated from the superficial papillary dermis and deeper reticular dermis and imaged by atomic force microscopy. In the reticular dermis, there was no significant difference in FRM ultrastructure between European and African participants. In contrast, in the more superficial papillary dermis, inter-bead periodicity was significantly larger for FRMs extracted from European participants than from African participants by 2.20 nm (p < .001). We next assessed whether these differences in FRM ultrastructure were present during early postnatal development by characterizing FRMs from full-thickness neonatal foreskin. Analysis of FRM periodicity identified no significant difference between neonatal cohorts (p = .865). These data suggest that at birth, FRMs are developmentally invariant. However, in adults of diverse skin ethnicity, there is a deviation in ultrastructure for the papillary dermal FRMs that may be acquired during the passage of time from child to adulthood. Understanding the mechanism by which this difference in papillary dermal FRMs arises warrants further study.

Osmolyte transporter expression is reduced in photoaged human skin: Implications for skin hydration in aging.

Aging is characterized by the deterioration of tissue structure and function. In skin, environmental factors, for example, ultraviolet radiation (UVR), can accelerate the effects of aging such as decline in barrier function and subsequent loss of hydration. Water homeostasis is vital for all cellular functions and it is known that organic osmolyte transport is critical to this process. Therefore, we hypothesized that as we age, these tightly controlled physiological mechanisms become disrupted, possibly due to loss of transporter expression. We investigated this in vivo, using human skin samples from photoprotected and photoexposed sites of young and aged volunteers. We show a reduction in keratinocyte cell size with age and a downregulation of osmolyte transporters SMIT and TAUT with both chronic and acute UVR exposure. Single-cell live imaging demonstrated that aged keratinocytes lack efficient cell volume recovery mechanisms possessed by young keratinocytes following physiological stress. However, addition of exogenous taurine significantly rescued cell volume; this was corroborated by a reduction in TAUT mRNA and protein in aged, as compared to young, keratinocytes. Collectively, these novel data demonstrate that human epidermal keratinocytes possess osmolyte-mediated cell volume regulatory mechanisms, which may be compromised in aging. Therefore, this suggests that organic osmolytes-especially taurine-play a critical role in cutaneous age-related xerosis and highlights a fundamental mechanism, vital to our understanding of the pathophysiology of skin aging.