Genes of the S100 fused-type protein (SFTP) family are clustered within the epidermal differentiation complex and encode essential components that maintain epithelial homeostasis and barrier functions. Recent genetic studies have shown that mutations within the gene encoding the SFTP filaggrin cause ichthyosis vulgaris and are major predisposing factors for atopic dermatitis. As a vital component of healthy skin, filaggrin is also a precursor of natural moisturizing factors. Here we present the discovery of a member of this family, designated as filaggrin-2 (FLG2) that is expressed in human skin. The FLG2 gene encodes a histidine- and glutamine-rich protein of approximately 248 kDa, which shares common structural features with other SFTP members, in particular filaggrin. We found that FLG2 transcripts are present in skin, thymus, tonsils, stomach, testis and placenta. In cultured primary keratinocytes, FLG2 mRNA expression displayed almost the same kinetics as that of filaggrin following Ca2+ stimulation, suggesting an important role in molecular regulation of epidermal terminal differentiation. We provide evidences that like filaggrin, FLG2 is initially expressed by upper granular cells, proteolytically processed and deposited in the stratum granulosum and stratum corneum (SC) layers of normal epidermis. Thus, FLG2 and filaggrin may have overlapping and perhaps synergistic roles in the formation of the epidermal barrier, protecting the skin from environmental insults and the escape of moisture by offering precursors of natural moisturizing factors.

We investigated whether inhalation of green odor (a mixture of equal amounts of trans-2-hexenal and cis-3-hexenol) prevents the skin-barrier disruption induced by chronic restraint stress in rats. To this end, transepidermal water loss (TEWL) was measured as an index of the disruption of skin-barrier function, whereas light- and electron-microscope examinations were performed to observe histological changes in the skin of the stressed animals. In addition, the effects on TEWL induced by chronic administration of a glucocorticoid, dexamethasone (DEX), were examined. Chronic restraint stress (8 h per day for 14 days) increased TEWL (vehicle + stress group). This effect (and the chronic stress–induced increase in adrenal weight) was prevented in rats that inhaled green odor at the beginning of each day’s restraint (2 h each day for 14 days; green odor + stress group). Electronmicroscope studies revealed that rats in the green odor + stress group possessed sufficient intercorneocyte lipids to create an effective skin barrier, although these had apparently been decreased in the vehicle + stress group. Daily administration of DEX for 14 days increased TEWL. The present results suggest that chronic stress–induced disruption of the skin barrier in rats can be reduced or prevented by green odor (possibly at least in part through an inhibitory effect on the stress-induced activation of the hypothalamo-pituitary-adrenocortical axis). Key words: adrenal gland, dexamethasone, hypothalamo-pituitary-adrenocortical axis, stratum corneum, transepidermal

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The stratum corneum (SC) provides a permeability barrier that limits the inflow and outflow of water. The permeability barrier is continuously and dynamically formed, maintained, and degraded along the depth, from the bottom to the top, of the SC. Naturally, its functioning and structure also change dynamically in a depth-dependent manner. While transepidermal water loss is typically used to assess the function of the SC barrier, it fails to provide any in-formation about the dynamic mechanisms that are responsible for the depth-dependent characteristics of the permeability barrier. This paper aims to quantitatively characterize the depth-dependency of the permeability barrier using in vivo non-invasive measurement data for understanding the underlying mechanisms for barrier formation, maintenance, and deg-radation. As a framework to combine existing experimental data, we propose a mathemati-cal model of the SC, consisting of multiple compartments, to explicitly address and investigate the depth-dependency of the SC permeability barrier. Using this mathematical model, we derive a measure of the water permeability barrier, i.e. resistance to water diffu-sion in the SC, from the measurement data on transepidermal water loss and water concen-tration profiles measured non-invasively by Raman spectroscopy. The derived resistance profiles effectively characterize the depth-dependency of the permeability barrier, with three distinct regions corresponding to formation, maintenance, and degradation of the barrier. Quantitative characterization of the obtained resistance profiles allows us to compare and evaluate the permeability barrier of skin with different morphology and physiology (infants vs adults, different skin sites, before and after application of oils) and elucidates differences in underlying mechanisms of processing barriers. The resistance profiles were further used to predict the spatial-temporal effects of skin treatments by in silico experiments, in terms of spatial-temporal dynamics of percutaneous water penetration.

In stressed animals, several brain regions (e.g., hypothalamic paraventricular nucleus [PVN]) exhibit neuronal activation, which increases plasma adrenocorticotropic hormone (ACTH) and glucocorticoids. We previously reported that so-called ‘‘green odor’’ inhibits stress-induced activation of the hypothalamo–pituitary–adrenocortical axis (HPA axis) and thereby prevents the chronic stress-induced disruption of the skin barrier. Here, we investigated whether rose essential oil, another sedative odorant, inhibits the stress-induced 1) increases in PVN neuronal activity in rats and plasma glucocorticoids (corticosterone [CORT] in rats and cortisol in humans) and 2) skin-barrier disruption in rats and humans. The results showed that in rats subjected to acute restraint stress, rose essential oil inhalation significantly inhibited the increase in plasma CORTand reduced the increases in the number of c-Fos-positive cells in PVN. Inhalation of rose essential oil significantly inhibited the following effects of chronic stress: 1) the elevation of transepidermal water loss (TEWL), an index of the disruption of skin-barrier function, in both rats and humans and 2) the increase in the salivary concentration of cortisol in humans. These results suggest that in rats and humans, chronic stress-induced disruption of the skin barrier can be limited or prevented by rose essential oil inhalation, possibly

staff at the Centre for Integrated Genomic Medical Research, University of Manchester and