The current treatments for hyperpigmentation are often associated with a lack of efficacy and adverse side effects. We hypothesized that microRNA (miRNA)-based treatments may offer an attractive alternative by specifically targeting key genes in melanogenesis. The aim of this study was to identify miRNAs interfering with the pigmentary process and to assess their functional role. miRNA profiling was performed on mouse melanocytes after three consecutive treatments involving forskolin and solar-simulated UV (ssUV) irradiation. Sixteen miRNAs were identified as differentially expressed in treated melan-a cells versus untreated cells. Remarkably, a 15-fold downregulation of miR-145 was detected. Overexpression or downregulation of miR-145 in melan-a cells revealed reduced or increased expression of Sox9, Mitf, Tyr, Trp1, Myo5a, Rab27a, and Fscn1, respectively. Moreover, a luciferase reporter assay demonstrated direct targeting of Myo5a by miR-145 in mouse and human melanocytes. Immunofluorescence tagging of melanosomes in miR-145-transfected human melanocytes displayed perinuclear accumulation of melanosomes with additional hypopigmentation of harvested cell pellets. In conclusion, this study has established an miRNA signature associated with forskolin and ssUV treatment. The significant down- or upregulation of major pigmentation genes, after modulating miR-145 expression, suggests a key role for miR-145 in regulating melanogenesis.
Many studies have revealed that the permeability of reconstructed skin models is much higher compared with human excised skin. This is in accordance with the incomplete barrier found in these models. Nevertheless, the reconstructed skin models available today are useful tools for estimating the rank order of percutaneous absorption of a series of compounds with different physicochemical properties. A major challenge in the further development of reconstructed skin models for drug delivery studies is to obtain a barrier function similar to in vivo skin. Whether this goal will be achieved in the near future is uncertain and will be, in the authors' opinion, a very difficult task.
The extent to which nanoscale‐engineered systems cross intact human skin and can exert pharmacological effects in viable epidermis is controversial. This research seeks to develop a new lipid‐based nanosome that enables the effective delivery of siRNA into human skin. The major finding is that an ultraflexible siRNA‐containing nanosome—prepared using DOTAP, cholesterol, sodium cholate, and 30% ethanol—penetrates into the epidermis of freshly excised intact human skin and is able to enter into the keratinocytes. The nanosomes, called surfactant‐ethanol‐cholesterol‐osomes (SECosomes), show excellent size, surface charge, morphology, deformability, transfection efficiency, stability, and skin penetration capacity after complexation with siRNA. Importantly, these nanosomes have ideal characteristics for siRNA encapsulation, in that the siRNA is stable for at least 4 weeks, they enable highly efficient transfection of in vitro cultured cells, and are shown to transport siRNA delivery through intact human skin where changes in the keratinocyte cell state are demonstrated. It is concluded that increasing flexibility in nanosomes greatly enhances their ability to cross the intact human epidermal membrane and to unload their payload into targeted epidermal cells.
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