Sustained effect of two antioxidants (oxothiazolidine and δ-tocopheryl glucoside) for immediate and long-term sun protection in a sunscreen emulsion based on their different penetrating properties.

OBJECTIVE: We investigated the dermal bioavailability and antioxidative properties of a sunscreen formulation containing two antioxidants, oxothiazolidine (OTZ) and δ-tocopheryl glucoside (DTG). OTZ reacts directly with reactive oxygen species to form taurine, while DTG is metabolized in δ-tocopherol to achieve antioxidative activities. METHODS: After topical application to a hair follicle-derived reconstructed human epidermis (RHE) model, followed by solar-simulated radiation, kinetics of bioavailability and antioxidative responses were measured over 24 h. Markers for oxidative stress were malondialdehyde (MDA), superoxide dismutase (SOD) and catalase activities. RESULTS: The two antioxidants had different bioavailability profiles: OTZ was rapidly and extensively absorbed, whereas DTG was slowly absorbed and converted to δ-tocopherol. Compared to OTZ alone, the protection against effects on MDA levels and SOD and catalase activities was higher when DTG was used alone or in combination with OTZ. When used in combination, the degree of protection increased over time and remained constant over 24 h with maximal protection 2 h post-irradiation. DTG slowly penetrated into the skin and was present in the skin at all post-irradiation timepoints, thus allowing a slow but constant supply of δ-tocopherol over at least 24 h. By contrast, the oxidative protection by OTZ was immediate but short-lived due to its rapid penetration through the RHE and into the receptor fluid. CONCLUSION: These results indicate a complementary sunlight protective action of OTZ and DTG with an immediate delivery of OTZ just after topical application of the formulation, and a prolonged skin delivery of δ-tocopherol from the slower penetration and metabolism of DTG.

OBJECTIF: Nous avons étudié la cinétique de pénétration cutanée et les propriétés antioxydantes d'une formulation solaire contenant deux antioxydants, l'oxothiazolidine (OTZ) et le δ-tocophéryl glucoside (DTG). L'OTZ se transforme directement en taurine en présence de stress oxydant sans l'action des enzymes cutanées, tandis que le DTG est métabolisé par les enzymes cutanées pour libérer le δ-tocophérol qui est la molécule ayant les propriétés antioxydantes. MÉTHODES: Après application topique sur un modèle d'épiderme humain reconstruit dérivé de follicules pileux (RHE), suivi d'une irradiation solaire, la cinétique de biodisponibilité et les réponses antioxydantes de ces deux composés ont été mesurées sur 24 h. Les marqueurs du stress oxydatif étaient la production de malondialdéhyde (MDA), l'activité de la superoxyde dismutase (SOD) et de la catalase. RÉSULTATS: Les deux antioxydants ont des profils de biodisponibilité différents. L'OTZ pénètre rapidement dans la peau, tandis que le DTG pénètre lentement et est biotransformé par les enzymes cutanés pour libérer le δ-tocophérol. Par rapport à l'OTZ seul, la protection oxydante sur les niveaux de MDA et les activités SOD et catalase était plus élevée lorsque le DTG était utilisé seul ou en association avec OTZ. Lorsqu'il est utilisé en combinaison, le degré de protection augmente au cours du temps et atteint son maximum 2h post-irradiation et reste constant durant 24 h. Le DTG pénètre lentement dans la peau et est présent dans la peau durant 24h post-irradiation, permettant ainsi un apport lent mais constant de δ-tocophérol. En revanche, la protection oxydante via l'OTZ est immédiate mais de courte durée en raison de sa pénétration rapide à travers le RHE. CONCLUSION: Ces résultats indiquent une action de protection solaire complémentaire de l'OTZ et du DTG avec une absorption immédiate d'OTZ juste après l'application topique de la formulation, et une libération cutanée prolongée de δ-tocophérol grâce à la pénétration et la métabolisation plus lentes du DTG.

Efficacy of a Dermocosmetic Serum Combining Bakuchiol and Vanilla Tahitensis Extract to Prevent Skin Photoaging in vitro and to Improve Clinical Outcomes for Naturally Aged Skin.

BACKGROUND: Skin aging is characterized by slacking and loss of density, especially under ultraviolet (UV) radiation exposure. OBJECTIVE: To investigate the beneficial effects of a combination containing bakuchiol (BK) and vanilla tahitensis extract (VTE) to prevent skin photoaging in vitro and to improve clinical outcomes for naturally aged skin. MATERIALS AND METHODS: Human dermal fibroblasts were treated with active compounds, exposed to an acute dose of UVA and analyzed by confocal microscopy: actin network for morphology, interleukin-8 (IL-8) for inflammation and p16 for senescence. Human skin was used to evaluate chronic UVA-induced glycosaminoglycan (GAG) loss and to assess the benefit of topical application of a BK+VTE serum (Alcian blue staining). An open-label clinical trial was conducted in women applying the serum twice daily for 56 days (n=43). Skin remodeling was assessed by FaceScan®. Firmness was evaluated through Dynaskin® and clinical scoring. Skin radiance was also rated on standardized full-face photographs. RESULTS: UVA induced a significant increase in IL-8 and p16 expression and marked morphological changes in fibroblasts. Treatment with BK or VTE alone prevented both actin network alteration and IL-8 upregulation. Interestingly, BK+VTE demonstrated synergistic protection against IL-8 and p16 overexpression. Serum application prevented GAG loss at the dermo-epidermal junction and increased dermal GAG in UVA-exposed skin explants. In the clinical trial, face ptosis was reduced by 11% on average for 26 responsive subjects and up to 23%. Depth of skin deformation was also reduced by 24% on average for 30 responsive subjects and up to 30%. This firming effect was confirmed by clinical scoring. Radiance was significantly improved by 29% on average for 33 responsive subjects. The serum demonstrated good tolerance/safety. CONCLUSION: BK+VTE combination demonstrated anti-aging efficacy and might provide a substantial benefit in the daily care of naturally aged skin in women, through their synergistic effect on inflammaging and senescence.

LRP5 regulates the expression of STK40, a new potential target in triple-negative breast cancers.

Triple-negative breast cancers (TNBCs) account for a large proportion of breast cancer deaths, due to the high rate of recurrence from residual, resistant tumor cells. New treatments are needed, to bypass chemoresistance and improve survival. The WNT pathway, which is activated in TNBCs, has been identified as an attractive pathway for treatment targeting. We analyzed expression of the WNT coreceptors LRP5 and LRP6 in human breast cancer samples. As previously described, LRP6 was overexpressed in TNBCs. However, we also showed, for the first time, that LRP5 was overexpressed in TNBCs too. The knockdown of LRP5 or LRP6 decreased tumorigenesis in vitro and in vivo, identifying both receptors as potential treatment targets in TNBC. The apoptotic effect of LRP5 knockdown was more robust than that of LRP6 depletion. We analyzed and compared the transcriptomes of cells depleted of LRP5 or LRP6, to identify genes specifically deregulated by LRP5 potentially implicated in cell death. We identified serine/threonine kinase 40 (STK40) as one of two genes specifically downregulated soon after LRP5 depletion. STK40 was found to be overexpressed in TNBCs, relative to other breast cancer subtypes, and in various other tumor types. STK40 depletion decreased cell viability and colony formation, and induced the apoptosis of TNBC cells. In addition, STK40 knockdown impaired growth in an anchorage-independent manner in vitro and slowed tumor growth in vivo. These findings identify the largely uncharacterized putative protein kinase STK40 as a novel candidate treatment target for TNBC.

Master regulators in primary skin fibroblast fate reprogramming in a human ex vivo model of chronic wounds.

Fibroblasts are important players in regulating tissue homeostasis. In the dermis, they are involved in wound healing where they differentiate into contractile myofibroblasts leading to wound closure. In nonhealing chronic wounds, fibroblasts fail to undertake differentiation. We established and used a human ex vivo model of chronic wounds where fibroblasts can undergo normal myofibroblast differentiation, or take on a nondifferentiable pathological state. At the whole genome scale, we identified the genes that are differentially regulated in these two cell fates. By coupling the search of evolutionary conserved regulatory elements with global gene network expression changes, we identified transcription factors (TF) potentially involved in myofibroblast differentiation, and constructed a network of relationship between these key factors. Among these, we found that TCF4, SOX9, EGR2, and FOXS1 are major regulators of fibroblast to myofibroblast differentiation. Conversely, down-regulation of MEOX2, SIX2, and MAF causes reprogramming of fibroblasts to myofibroblasts even in absence of TGF-ß, the natural inducer of myofibroblast differentiation. These results provide insight into the fibroblast differentiation program and reveal a TF network essential for cellular reprogramming. They could lead to the development of new therapeutics to treat fibroblast-related human pathologies.