A novel Ca2+ double cone vector system to treat compromised skin.

BACKGROUND: Stressed, damaged or very aged skin is predominantly characterized by a malfunctioning skin barrier. Underlying skin barrier malfunction is a reduced or defective calcium gradient in the epidermis. Consequently, replenishing the compromised skin's calcium stores with topical calcium could be a potential therapeutic approach. METHODS: We investigated the effect of our novel Ca2+ double cone vector system on improving the differentiation and barrier function of reconstructed human epidermis (RHE), cultured at low basal calcium (0.3 mM) to represent very aged skin. Furthermore, in a randomized placebo-controlled clinical study the skin barrier of 20 healthy volunteers was challenged with 2% sodium lauryl sulphate (SLS) for 24 h under occlusion, following and/or prior to treatment with a gel containing 2% of our calcium vector system. RESULTS: Culture in reduced basal calcium conditions (0.3 mM) strongly impeded the formation of a dense stratified epidermis. The apical treatment with 1.1 mM CaCl2 was not able to restore a functional differentiation. Treatment with 0.1% of the Ca2+ delivery system rescued the differentiation process and resulted in a normal stratified epidermis. Clinically, application of the Ca2+ vector system prior to and following SLS stress prevented increases in skin irritation and transepidermal water loss (TEWL) compared to placebo controls. Importantly, the treatment also significantly accelerated the recovery time following SLS stress. CONCLUSION: With our novel Ca2+ vector system, we highlight the delivery of bioavailable Ca2+ ions into the skin as a new and successful approach to treat a damaged barrier present in stressed, aged or atopic skin.

CONTEXTE: Les peaux stressées, lésées ou très âgées se caractérisent principalement par un dysfonctionnement de la barrière cutanée. Le dysfonctionnement de la barrière cutanée est sous­tendu par un gradient de calcium réduit ou défectueux dans l'épiderme. Par conséquent, la reconstitution des réserves de calcium de la peau fragilisées à l'aide de calcium topique pourrait constituer une approche thérapeutique potentielle. MÉTHODES: Nous avons étudié l'effet de notre nouveau système de vecteur à double cône Ca2+ sur l'amélioration de la différenciation et de la fonction de barrière de l'épiderme humain reconstitué (EHR), cultivé à un faible niveau de calcium basal (0,3 mM) pour représenter une peau très âgée. En outre, dans une étude clinique randomisée, contrôlée par placebo, la barrière cutanée de 20 volontaires en bonne santé a été exposée à 2 % de laurylsulfate de sodium (SLS) pendant 24 heures sous occlusion, après et/ou avant le traitement avec un gel contenant 2 % de notre système de vecteur de calcium. RÉSULTATS: La culture dans des conditions de calcium basal réduit (0,3 mM) a fortement empêché la formation d'un épiderme stratifié dense. Le traitement apical avec 1,1 mM de CaCl2 n'a pas permis de rétablir une différenciation fonctionnelle. Le traitement avec 0,1 % du système de libération de Ca2+ a permis de rétablir le processus de différenciation et d'obtenir un épiderme stratifié normal. Sur le plan clinique, l'application du système de vecteur Ca2+ avant et après l'exposition au SLS a empêché l'augmentation de l'irritation cutanée et de la perte d'eau transépidermique (Transepidermal Water Loss, TEWL) par rapport aux témoins sous placebo. Il est important de noter que le traitement a également accéléré de manière significative le temps de récupération après l'exposition au SLS. CONCLUSION: Grâce à notre nouveau système de vecteurs Ca2+, nous mettons en évidence l'apport d'ions Ca2+ biodisponibles dans la peau comme une approche nouvelle et efficace pour traiter la barrière endommagée présente dans une peau stressée, âgée ou atopique.

Youthful and age-related matreotypes predict drugs promoting longevity.

The identification and validation of drugs that promote health during aging ("geroprotectors") are key to the retardation or prevention of chronic age-related diseases. Here, we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach-employing extracellular matrix homeostasis-facilitates the discovery of pharmacological interventions promoting healthy aging.

Heptapeptide-loaded solid lipid nanoparticles for cosmetic anti-aging applications.

The cosmetic industry requires more and more expensive actives and ingredients such as retinol, coenzyme Q10, proteins, peptides and biotechnologically produced molecules. In this study, we demonstrate the development of a cost effective formulation of a nanostructured lipid carrier (NLC) or solid lipid nanoparticles (SLN) improving peptide delivery into skin. NLC or SLN are very suitable vehicles for the delivery of active ingredients into skin. The SLN, produced by using hot high pressure homogenization method combine advantages such as physical stability, protection of incorporated labile actives and controlled release. By the used method we dispersed the amorphous heptapeptide DEETGEF in shea butter and homogenized this pre-dispersion at 60°C together with the water phase using a Microfluidizer at 1000bar. The analysis of the obtained SLN-P7 showed a particle size of 173nm, incorporated peptide of 0.014%, entrapment efficiency of 90.8%, melting peak (DSC) of the core lipid of 27°C and a zeta potential of -54mV. By an ex vivo study with skin explants we could stimulate NQO1 (NAD(P)H quinone oxidoreductase), HMOX1 (Heme oxygenase-1) and PRDX1 (Peroxiredoxin-1) genes all of which are cell protecting enzymes. In a multicellular protection against UV induced stress study with skin explants we detected the formation of sun burn cells and the number and morphology of Langerhans cells. The application of our SLN-P7 formulation on skin explants led to a significant and dose dependent protection against UV irradiation. In the clinical suction blister study, irradiation with UVA light for two hours after final product application led to a statistically significant increase of the 8-OhdG (8-hydroxy-2'-deoxyguanosine) concentration in the human epidermis. The skin treated with our verum formulation showed a statistically significant 20% decrease in DNA damage compared to placebo. In conclusion, it was demonstrated that SLN technology enabled peptide delivery into skin allowing it to perform protective functions.