Randomized double-blind placebo-controlled cosmetic trial of a topical first-in-class Neutraligand targeting the chemokine TARC/CCL17 in mild-to-moderate atopic dermatitis.

BACKGROUND: Atopic dermatitis has a marked economic impact and affects the quality of life. A cosmetic compound with an innovative strategy is proposed here as a small chemical neutraligand, GPN279 (previously identified as a theophylline derivative), that binds and potently neutralizes the TARC/CCL17 chemokine, activating the Th2 cell-expressed CCR4 receptor. OBJECTIVE: Our objective was to evaluate the safety and activity of topically applied GPN279 in mild-to-moderate atopic dermatitis patients in a randomized, double-blind, placebo-controlled, parallel group trial. Such cosmetic active ingredient targeting dry skin with an atopic tendency would open a parallel strategy to the pharmaceutical approach, in particular for mild to moderate subjects, as an alternative to reduce the evolution towards severe forms of atopy. METHODS: This 4-week trial included adults with mild-to-moderate atopic dermatitis, according to the SCORAD index. Patients were randomized into two groups treated by topical applications of either an emulsion containing 0.44% GPN279 in placebo on skin lesions or the placebo (4.56% glycerin). Clinical activity was evaluated with the SCORAD as the primary objective. As secondary objectives, POEM, erythema, skin moisturization, its barrier function (TEWL) and safety were evaluated. RESULTS: Twenty-one patients in each group completed the study. SCORAD was significantly improved in the GPN279 group vs. placebo. GPN279 also significantly improved POEM, induced a rapid and significant decrease of erythema, and improved skin moisture. GPN279 and placebo were well tolerated throughout the study. CONCLUSION: A cosmetic cream comprising the CCL17 neutraligand GPN279 improved the skin barrier and physiology criteria in patients with mild-to-moderate atopic dermatitis.

GÉNÉRALITÉS: La dermatite atopique a un impact économique marqué et affecte la qualité de vie. Un composé cosmétique dote d'une stratégie innovante est proposé ici sous la forme d'un petit neutraligand chimique, le GPN279 (précédemment identifié comme un dérivé de la théophylline), qui se lie et neutralise puissamment la chimiokine TARC/CCL17, activant le récepteur CCR4 exprimé par les cellules Th2. OBJECTIF: Notre objectif était d'évaluer l'innocuité et l'activité du GPN279 appliqué localement chez des patients atteints de dermatite atopique légère à modérée dans un essai randomisé, en double aveugle contre placebo et en groupes parallèles. Un tel actif cosmétique ciblant les peaux sèches à tendance atopique ouvrirait une stratégie parallèle à l'approche pharmaceutique, notamment pour les sujets atteints de forme légère à modérée, comme alternative visant à réduire l'évolution vers des formes sévères d'atopie. MÉTHODES: Cet essai de 4 semaines incluait des adultes atteints de dermatite atopique légère à modérée, selon l'indice SCORAD. Les patients ont été randomisés en deux groupes traités par application topique sur les lésions cutanées soit d'une émulsion contenant 0,44% de GPN279 dans un placebo, soit du placebo seul (4,56% de glycérine). L'activité clinique a été évaluée selon l'indice SCORAD comme objectif principal. Les objectifs secondaires évaluaient le POEM, l'érythème, l'hydratation de la peau, sa fonction barrière (TEWL) et la sécurité. RÉSULTATS: Vingt et un patients de chaque groupe ont terminé l'étude. L'indice SCORAD a été significativement amélioré dans le groupe GPN279 par rapport au placebo. Le GPN279 a également amélioré de manière significative le POEM, a induit une diminution rapide et significative de l'érythème et amélioré l'hydratation de la peau. Le GPN279 et le placebo ont été bien tolérés tout au long de l'étude. CONCLUSION: Une crème cosmétique contenant le neutraligand CCL17 GPN279 améliore la barrière cutanée et les critères physiologiques chez les patients atteints de dermatite atopique légère à modérée.

Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the Golgi apparatus.

It is well recognized that the world population is ageing rapidly. Therefore, it is important to understand ageing processes at the cellular and molecular levels to predict the onset of age-related diseases and prevent them. Recent research has focused on the identification of ageing biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi-mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro-inflammatory cytokines and extracellular matrix-degrading enzymes, is modified during ageing, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi-related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non-senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and ageing.

A new tool to test active ingredient using lactic acid in vitro, a help to understand cellular mechanism involved in stinging test: An example using a bacterial polysaccharide (Fucogel® ).

The stinging test is an in vivo protocol that evaluates sensitive skin using lactic acid (LA). A soothing sensation of cosmetics or ingredients can be also appreciated through a decrease in stinging score. To predict the soothing sensation of a product before in vivo testing, we developed a model based on an LA test and substance P (SP) release using a co-culture of human keratinocytes and NGF-differentiated PC12 cells. A bacterial fucose-rich polysaccharide present in Fucogel® was evaluated as the soothing molecule in the in vivo stinging test and our in vitro model. Excluding toxic concentrations, the release of SP was significant from 0.2% of lactic acid for the PC12 cells and from 0.1% of lactic acid for the keratinocytes. When the pH was adjusted to approximately 7.4, LA did not provoke SP release. At these concentrations of LA, 0.1% of polysaccharide showed a significant decrease in SP release from the two cellular types and in co-cultures without modifying the pH of the medium. In vivo, a stinging test using the polysaccharide showed a 30% decrease in prickling intensity vs the placebo in 19 women between the ages of 21 and 69. Our in vitro model is ethically interesting and is adapted for cosmetic ingredients screening because it does not use animal experimentation and limits human volunteers. Moreover, Fucogel® reduced prickling sensation as revealed by the in vivo stinging test and inhibits the neurogenic inflammation as showed by our new in vitro stinging test based on SP release.

Comparison of ultraviolet B-induced imbalance of antioxidant status in foreskin- and abdominal skin-derived human fibroblasts.

Ultraviolet B radiation (UVB) is involved in the development of deleterious cutaneous damage. Several changes could be attributed to UVB-induced reactive oxygen species attacks in fibroblasts. However dermal cells from young and adult skin could respond differently to oxidative stress. So antioxidant status and its consequences on cytotoxicity and apoptosis were compared in child foreskin fibroblasts (FF) and adult abdominal skin fibroblasts (AF) in response to UVB. Basal levels of lipid peroxidation tended to be higher in AF than in FF, which could be related to a reshaping of antioxidant defences (higher catalase and lower superoxide dismutase activities). AF and FF appeared to react similarly to high UVB doses as regards cytotoxicity and apoptosis which increased significantly 24h after exposure. The enhancement of cell death could be due to the inherent oxidative stress: glutathione appeared significantly decreased in both cell populations. As a consequence AF, but not FF, presented significantly increased levels of lipid peroxidation, which could be explained by the pre-cited differences of basal antioxidant defences. These results suggest that AF and FF do not respond to UVB by the same pathway.