Boosting of retinol activity using novel lecithin: Retinol acyltransferase inhibitors.

Lecithin:retinol acyltransferase (LRAT) is the main enzyme catalysing the esterification of retinol to retinyl esters and, hence, is of central importance for retinol homeostasis. As retinol, by its metabolite retinoic acid, stimulates fibroblasts to synthesize collagen fibres and inhibits collagen-degrading enzymes, the inhibition of LRAT presents an intriguing strategy for anti-ageing ingredients by increasing the available retinol in the skin. Here, we synthesized several derivatives mimicking natural lecithin substrates as potential LRAT inhibitors. By exploring various chemical modifications of the core scaffold consisting of a central amino acid and an N-terminal acylsulfone, we explored 10 different compounds in a biochemical assay, resulting in two compounds with IC50 values of 21.1 and 32.7 µM (compounds 1 and 2), along with a simpler arginine derivative with comparative inhibitory potency. Supported by computational methods, we investigated their structure-activity relationship, resulting in the identification of several structural features associated with high inhibition of LRAT. Ultimately, we conducted an ex vivo study with human skin, demonstrating an increase of collagen III associated with a reduction of the skin ageing process. In conclusion, the reported compounds offer a promising approach to boost retinol abundance in human skin and might present a new generation of anti-ageing ingredients for cosmetic application.

La lécithine/rétinol acyltransférase (LRAT) est la principale enzyme qui catalyse l'estérification du rétinol en esters de rétinyle et, par conséquent, est d'une importance centrale pour l'homéostasie du rétinol. Étant donné que le rétinol, par son métabolite l'acide rétinoïque, stimule les fibroblastes pour synthétiser les fibres de collagène et inhibe les enzymes de dégradation du collagène, l'inhibition de la LRAT constitue une stratégie intéressante pour les ingrédients anti­âge en augmentant le rétinol disponible dans la peau. Ici, nous avons synthétisé plusieurs dérivés imitant les substrats naturels de la lécithine comme inhibiteurs de LRAT potentiels. En étudiant différentes modifications chimiques du noyau composé d'un acide aminé central et d'un acylsulfone N­terminal, nous avons étudié dix composés différents dans le cadre d'un essai biochimique; il en est résulté deux composés avec des valeurs de CI50 de 21.1 et 32.7 µm (composés 1 et 2), ainsi qu'un dérivé d'arginine plus simple avec une puissance inhibitrice comparative. Avec le soutien de méthodes computationnelles, nous avons étudié leur relation structure­activité, ce qui a permis d'identifier plusieurs caractéristiques structurelles associées à une inhibition élevée de la LRAT. Enfin, nous avons mené une étude ex vivo sur la peau humaine, démontrant une augmentation du collagène III associée à une réduction du processus de vieillissement de la peau. En conclusion, les composés rapportés offrent une approche prometteuse pour stimuler l'abondance du rétinol dans la peau humaine et pourraient aboutir à une nouvelle génération d'ingrédients anti­âge pour des applications cosmétiques.

Synergistic action of a triple peptide complex on an essential extra-cellular matrix protein exhibits significant anti-aging benefits.

Basement membranes are thin structures present in the extracellular matrix that provide a supporting framework on which epithelial and endothelial cells reside. Type IV collagen is present ubiquitously in all basement membranes and plays an important role in cell adhesion, migration differentiation, and growth. These are especially important at the dermoepidermal junction (DEJ) in skin. A reduction in the levels of DEJ proteins occurs in photodamaged skin and especially Type IV collagen at the base of a wrinkle. In these studies, the ability of a triple peptide complex (TPC) to stimulate the production of collagen IV in human skin fibroblasts and its effects on photoaged skin was investigated. Fibroblasts, matured to represent "aged" cells, were stimulated for 72 h with the TPC as well as the three individual peptides constituting the complex, and collagen IV production by the fibroblasts was determined immunochemically. The results show that stimulation with the individual peptides at doses found in 1% (v/v) of the TPC did not result in soluble collagen IV production above levels detected by the non-stimulated cells. However, after stimulation with 1% (v/v) of the TPC, collagen IV was produced by the cells (1.4 ng/ng total protein +/- 0.4 SD, n = 5) when compared to control un-stimulated cells (0.32 ng/ng total protein +/- 0.1 SD, n = 5). This indicates that the combination of the individual peptides is necessary to synergistically stimulate collagen IV production. These findings suggest that the TPC could play a role in the strengthening of the DEJ through its ability to produce collagen IV. In order to determine whether these results translated into significant effects in vivo, we performed two studies. In the first four-week study, a double blind, placebo-controlled and fully randomized clinical study on 22 healthy Caucasian volunteers displaying moderate periorbital wrinkles, a significant reduction in wrinkle parameters determined by profilometry was observed over the 4-week period in comparison to the placebo. This result was reproduced in a 12-week monadic study which also showed improvements in expertly graded wrinkle scores. Collectively, these results effectively demonstrate the anti-aging applications of the TPC.

Consumption of functional fermented milk containing borage oil, green tea and vitamin E enhances skin barrier function.

As emerging studies show that skin functioning can be improved with orally imbibed ingredients, we decided to investigate a mixture of borage oil, catechins, vitamin E and probiotics, all known for their reported effects on epidermal function, in a fermented dairy product, for the first time. Gamma-linolenic acid (GLA) and catechins bioavailability and their effects on skin functionality have not been previously investigated from a fermented dairy product. Firstly, we assessed the bioavailability of GLA and catechins mixed in a fermented dairy matrix by measuring their levels in chylomicrons and plasma samples respectively. For the GLA contained in the dairy matrix, the area under the curve and time for maximal absorption were significantly different to the same kinetic parameters compared with absorption from the free oil indicating improved oral bioavailability. However, the overall absorption of catechins over the 6-h period was identical for both product forms. These results were sufficiently promising to warrant a 24 week skin nutrition intervention study in female volunteers having dry and sensitive skin. The product improved stratum corneum barrier function compared with a control product as early as 6 weeks after the consumption which continued throughout the rest of the study. The reduction in transepidermal water loss relative to control was maintained throughout the trial despite seasonal changes. Moreover, as a result of the enhanced bioavailability, a much greater effect on skin barrier function occurred than reported previously for the individual ingredients. Nevertheless, body mass index significantly influenced various outcome measurements of this study.