Olive leaf-derived PPAR agonist complex induces collagen IV synthesis in human skin models.

INTRODUCTION: Peroxisome proliferator-activated receptor (PPAR) agonists are known to modulate the synthesis of dermal lipids and proteins including collagens. Olive (Olea europaea) leaves have been reported to contain PPAR-binding ligands. Collagen IV, a major dermal-epidermal junction (DEJ) protein, degrades with both age and disease. Here, we report the formulation of a novel multi-ligand complex, Linefade, and its effects on collagen IV synthesis. METHODS: Linefade prepared from the leaves of Olea europaea contains 2% w/w plant extract solids dissolved in a mixture of glyceryl monoricinoleate and dimethyl isosorbide. In silico docking was performed with PPAR-α (PDB ID: 2P54). Linefade was evaluated for PPAR-α-dependent transcription in a luciferase reporter assay system. Cell viability and collagen IV levels in human dermal fibroblast cultures were measured using the MTT method and ELISA assay, respectively. Transcriptome analysis was conducted on a full-thickness reconstituted human skin (EpiDermFT) model. Ex vivo cell viability and collagen IV immunostaining were performed on human skin explants. RESULTS: In silico docking model of the major constituents (oleanolic acid and glyceryl monoricinoleate) produced a co-binding affinity of -6.7 Kcal/mole. Linefade significantly increased PPAR-α transcriptional activity in CHO cells and collagen IV synthesis in adult human dermal fibroblasts. Transcriptome analysis revealed that 1% Linefade modulated the expression of 280 genes with some related to epidermal differentiation, DEJ, PPAR, Nrf2 and retinoid pathways. An ex vivo human explant study showed that 1% Linefade, delivered via a triglycerides excipient, increased collagen IV levels along the dermal-epidermal junction by 52%. CONCLUSION: In silico modelling and in vitro and ex vivo analyses confirmed Linefade-mediated activation of PPAR-α and stimulation of collagen IV synthesis.

INTRODUCTION: Les agonistes du récepteur activé par les proliférateurs de peroxysomes (PPAR) sont connus pour moduler la synthèse des lipides cutanés et des protéines du derme, y compris des collagènes. Il a été signalé que les feuilles d'olivier (Olea europaea) contiennent des ligands de liaison aux PPAR. Le collagène IV, une protéine majeure de la jonction dermo-épidermique (DEJ), se dégrade avec l'âge et la maladie. Nous rapportons ici la formulation d'un nouveau complexe multi ligand, Linefade, et ses effets sur la synthèse du collagène IV. MÉTHODES: Le complexe Linefade préparé à partir des feuilles d'Olea europaea contient 2 % p/p de solides d'extraits végétaux dissous dans un mélange de monoricinoléate de glycéryle et d'isosorbide de diméthyle. Un docking in silico a été réalisé avec PPAR-α (PDB ID : 2P54). Linefade a été évalué pour la transcription dépendante du PPAR-α dans un système de test rapporteur à la luciférase. La viabilité cellulaire et les niveaux de collagène IV dans les cultures de fibroblastes dermiques humains ont été respectivement mesurés en utilisant la méthode MTT et le test ELISA. L'analyse du transcriptome a été réalisée sur un modèle de peau humaine reconstitué sur toute son épaisseur (EpiDermFT). La viabilité cellulaire ex vivo et l'immunomarquage du collagène IV ont été réalisés sur des explants de peau humaine. RÉSULTATS: Le modèle de docking in silico des principaux constituants (acide oléanolique et monoricinoléate de glycéryle) a produit une affinité de liaison conjointe de -6,7 Kcal/mole. Linefade a augmenté de manière significative l'activité transcriptionnelle du PPAR-α dans les cellules CHO et la synthèse du collagène IV dans les fibroblastes dermiques humains chez les personnes adultes. L'analyse du transcriptome a révélé que 1% de Linefade modulait l'expression de 280 gènes dont certains étaient liés à la différenciation épidermique, à la DEJ, au PPAR, à la voie Nrf2 et aux voies rétinoïdes. Une étude ex vivo sur des explants humains a montré que 1% de Linefade, délivré via un excipient de triglycérides, augmentait de 52% les niveaux de collagène IV le long de la jonction dermo-épidermique. CONCLUSION: La modélisation in silico et les analyses in vitro et ex vivo ont confirmé l'activation du PPAR-- α et la stimulation de la synthèse du collagène IV par Linefade.

Accelerated Barrier Repair in Human Skin Explants Induced with a Plant-Derived PPAR-α Activating Complex via Cooperative Interactions.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) govern epidermal lipid synthesis and metabolism. In skin, PPAR activation has been shown to regulate genes responsible for permeability barrier homeostasis, epidermal differentiation, lipid biosynthesis, and inflammation. OBJECTIVE: Given the known dermatologic benefits of PPARs, we set out to discover a naturally derived, multi-molecule complex that would be superior to the more commonly formulated conjugated linoleic acids (CLAs). We hypothesized that a complex may be capable of modulating PPAR-α by cooperative or multi-ligand binding interactions to accelerate skin barrier repair. METHODS: To achieve this, we assembled a novel PPAR-α agonist complex, referred to as RFV3, from a combination of small molecules routinely used in Ayurvedic medicine and accepted in cosmetic and topical over-the-counter dermatologic products. We tested RFV3's potential as a PPAR-α agonist by evaluating its transcriptional response, ligand binding affinity to PPAR-α, gene expression profiles and barrier repair properties in human skin explant models. RESULTS: We assembled RFV3 by solubilizing two standardized plant extracts in a suitable solvent and induced a significant transcriptional response in PPAR-α luciferase reporter assay. Furthermore, transcriptome profiling of RFV3-treated epidermal substitutes revealed expressed genes consistent with known targets of PPAR-α, including those involved in epidermal barrier repair. In addition, in silico modeling demonstrated differential co-binding affinities of RFV3 to PPAR-α compared with those of the endogenous ligands (CLAs) and a synthetic PPAR-α agonist. Lastly, delipidated skin explant models confirmed accelerated barrier repair activity with significant increases in ceramides, filaggrin and transglutaminase-1 after treatment. CONCLUSION: These findings suggest that the RFV3 complex successfully mimics a PPAR-α agonist and induces synthesis of skin barrier lipids and proteins consistent with known PPAR pathways.

Characterization of bound water in skin hydrators prepared with and without a 3D3P interpenetrating polymer network.

BACKGROUND: Hyaluronic acid (HA) has been considered the gold standard ingredient for improving skin hydration and combating age-related effects, however it is an inefficient polymer with inconsistent results partially due to its poor skin penetration, surface deposition, and rapid degradation. Herein we report the synthesis and in vitro characterization of a newly developed, topical super-humectant with the goal of attracting and binding water molecules more efficiently than traditional, cosmetic-grade forms of HA. METHODS: A modified interpenetrating polymer network (IPN) was developed using three polymers into a three-dimensional formation (3D3P) for entrapping HA and water. This 3D3P-IPN functions as a super-humectant, attracting and binding water molecules more efficiently than the traditional cosmetic-grade forms of HA. We compare 3D3P-IPN serum samples to a traditional commercial benchmark product of similar ingredients using microscopic analysis, rheology, Karl Fischer (KF) titration, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and dynamic vapor sorption (DVS) techniques. RESULTS: The 3D3P-IPN samples appeared to bind water tighter than the benchmark sample as evidenced by maximum endpoints of endotherms occurring at significantly higher temperatures. The DVS results further confirm this speculation as the 3D3P-IPN samples lost approximately 10% less water up to 35% RH than the benchmark. The 3D3P-IPN samples also absorbed more water as the humidity level increased,demonstrating superior humectant properties. KF titration indicated that all three samples had similar water concentrations; however, TGA results demonstrated that the benchmark (a viscous, humectant-rich hydrating masque) did not have much bound water. CONCLUSION: Through the synthesis of a 3D3P-IPN using simplified methods, we were able to increase the water-binding and HA-delivery capabilities of a thin serum. This 3D3P-IPN serum has potential to deliver more hydration to the skin's surface compared to traditional HA formulations.

Skincare Bootcamp: The Evolving Role of Skincare.

BACKGROUND: Although cosmetic procedures have a significant impact on certain aspects of aging, such as deep, wrinkling, sagging, and volume loss, they fail to address the overall quality of the skin. METHODS: Daily skincare routines potentially can have a significant long-term impact on the overall quality of a person's complexion. RESULTS: By expanding our product knowledge, we can help our patients individualize their at-home skincare routine using effective products and ingredients designed to address their specific skin concern and support the professional care we deliver. CONCLUSIONS: Here, we discuss the types of products and ingredients suitable for the most common dermatologic concerns, from wrinkling to skin sensitivity, acne to sun damage.