A Proteome-Centric View of Ageing, including that of the Skin and Age-Related Diseases: Considerations of a Common Cause and Common Preventative and Curative Interventions.

The proteome comprises all proteins of a cell or organism. To carry their catalytic and structure-related functions, proteins must be correctly folded into their unique native three-dimensional structures. Common oxidative protein damage affects their functionality by impairing their catalytic and interactive specificities. Oxidative damage occurs preferentially to misfolded proteins and fixes the misfolded state. This review provides an overview of the mechanism and consequences of oxidative proteome damage - specifically irreversible protein carbonylation - in relation to ageing, including that of the skin as well as to age-related degeneration and diseases (ARDD) and their mitigation. A literature review of published manuscripts, available from PubMed, focusing on proteome, proteostasis, proteotoxicity, protein carbonylation, related inflammatory diseases, ARDD and the impact of the damaged proteome on ageing. During ageing, proteome damage, especially protein carbonylation, correlates with biological age. Carbonylated proteins form aggregates which can be considered as markers and accelerators of ageing and are common markers of most ARDD. Protein carbonylation leads to general ageing of the organism and organs including the skin and potentially to diseases including Alzheimer and Parkinson disease, diabetes, psoriasis, and skin cancer. Current research is promising and may open new therapeutic approaches and perspectives by targeting proteome protection as an age and ARDD management strategy.

Evaluation of a new connected portable camera for the analysis of skin microrelief and the assessment of the effect of skin moisturisers.

BACKGROUND: Silicone replicas and non-contact methods are effective methods to analyse the micrometric scale of the skin microrelief. Yet, they imply data capture in research facilities. The capabilities of a new connected portable camera were evaluated to analyse microrelief under nomadic conditions, also studying the effect of moisturisers. MATERIALS AND METHODS: 3D depth maps were constructed using shape-from-shading algorithms. Roughness heterogeneity (Spa) was computed, and skin profiles were extracted to calculate roughness amplitude (Ra, Rq), as well as furrows/plateaus characteristics. Validation of the connected camera was performed on tanned cowhide leather and on the inner forearm skin of a single subject. The forearms of 18 subjects (23-60 years old) were also evaluated. While living their regular life, they self-performed triplicate acquisitions at various times. The effects of a placebo and of cream containing moisturisers-saccharide isomerate, urea or xylitylglucoside-anhydroxylitol-xylitol-were investigated, using untreated control skin as a reference. RESULTS: Validation of the device on leather and forearm skin shows high repeatability. The 18 subjects show the known correlation between age and changes in microrelief. While testing formulas, 8 h after a single application, all decreased Spa (-1.6/-2.1 folds). Only saccharide isomerate and xylitylglucoside-anhydroxylitol-xylitol decreased Ra (-2.4/-2.8 folds). The sectional area of plateaus was reduced from -1.5 (urea) to -2.1 folds (xylitylglucoside-anhydroxylitol-xylitol). The height of plateaus is also decreased by all moisturisers, from -1.5 (urea) to -2.1 folds (xylitylglucoside-anhydroxylitol-xylitol). CONCLUSION: This novel camera device enables microrelief analysis under nomadic conditions, allowing monitoring its changes along the day and upon moisturisers' application.

Basal Cell Carcinoma in Gorlin's Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?

Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated ß-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings suggest that defects in dermo/epidermal interactions could contribute to BCC susceptibility in NBCCS patients.