SynopsisThe process leading to the loss of corneocytes form the skin surface is termed desquamation. In healthy skin it is an orderly and essentially invisible process whereby individual or small groups of corneocytes detach from neighbouring cells to be lost to the environment and replaced by younger cells from the deeper layers. Desquamation is carefully controlled to ensure that corneum cohesion and integrity, and hence tissue thickness, is maintained.The most important components of the corneocytes contributing towards intercellular cohesion are the corneodesmosomes and lipids. Corneodesmosomes are proteinaceous complexes which effectively rivet corneocytes together. The intercellular lipids, primarily responsible for the water barrier, also provide part of the extracellular cement. In addition, the shape of the corneocyte itself plays a role in stratum corneum cohesion. Through interdigitation along their peripheral edges, adjacent corneocytes become physically locked together, a process which reinforces the integrity of the tissue.For effective desquamation to occur corneodesmosomes must be degraded: a process catalysed by serine proteases present within the intercellular space and facilitated by subtle changes in lipid composition and phase behaviour. Ultimately, it is the availability of free water which controls corneodesmolysis. In healthy skin this proteolytic process leaves relatively few corneodesmosomes intact in the most superficial layers.By contrast, in chronic and acute dry skin conditions, corneodesmosomal degradation and hence the final stages of desquamation are perturbed, leading to the characteristic formation of visible, powdery flakes on the skin surface. The inability to degrade these structures ultimately reflects a decreased hydrolytic activity of the desquamatory enzymes, either through reduced synthesis of the enzymes, inherent loss of activity, leaching from the surface layers of the corneum or changes in the surrounding lipid-rich microenvironment, which may indirectly reduce enzyme functionality.Increased understanding of the desquamation process is providing new insights into the mode of action of current moisturizing ingredients and is offering opportunities to develop novel therapies for preventing and correcting dry skin. Re sumeÂLe processus conduisant aÁ la perte des corne ocytes aÁ la surface de la peau est appele desquamation. Sur une peau saine c'est un processus normal et quasiment invisible par lequel des corne ocytes individuels ou par petits groupes se de tachent des cellules voisines pour se perdre dans l'environnement et eà tre remplace s par des cellules plus jeunes *To whom correspondence should be addressed. Les composants les plus importants des corne ocytes contribuant aÁ la cohe sion intercellulaire sont les corne odesmosomes et les lipides. Les corne odesmosomes sont des complexes prote ine s qui fixent efficacement les corne ocytes entre eux. Les lipides intercellulaires, principalement responsables de la barrieÁ re aqueuse, apportent aussi une...

Moisturizers are known to have occlusive, emollient and humectant properties, all of which help to alleviate the symptoms of skin xerosis. Although the biological mode of action of moisturizers is poorly understood, the recent observation that skin xerosis is associated with incomplete desmosome digestion suggests that moisturizers improve the desquamation process in such conditions. To examine the possibility that certain moisturizers act by facilitating desmosomal digestion, we investigated the ability of glycerol, a common humectant, to influence this process in stratum corneum in vitro. Examining desmosome morphology in isolated stratum corneum by electron microscopy, it was observed that the desmosomes were in more advanced stages of degradation in glycerol-treated tissue compared with control tissue. This enhanced desmosomal degradation in glycerol-treated tissue was confirmed by significant decreases in the levels of immunoreactive desmoglein 1, a marker of desmosome integrity. Desmosomal degradation was also shown to be a humidity-dependent event, being significantly reduced at low relative humidity. The effect of glycerol on desmosome digestion was emphasized further in two in vitro model systems. Firstly, glycerol increased the rate of corneocyte loss from the superficial surface of human skin biopsies in a simple desquamation assay. Secondly, measurement of the mechanical strength of sheets of stratum corneum, using an extensiometer, indicated a dramatic reduction in the intercorneocyte forces following glycerol treatment. These studies demonstrated the ability of glycerol to facilitate desmosome digestion in vitro. Extrapolating from these results, we believe that one of the major actions of moisturizers in vivo is to aid the digestion of desmosomes which are abnormally retained in the superficial layers of xerotic stratum corneum.

In humans peripheral administration of a cannabinoid receptor agonist attenuates histamine-induced itch. The observation that protein extravasation was not decreased demonstrates that the alleviation of itch is not due to an anti-histaminergic property of HU210. The reduced neurogenic flare reaction indicates an attenuated antidromic nerve fibre activation and neuropeptide release.

We have tested the hypothesis that changes in the levels and cellular location of protein kinase C (PKC) isozymes might be associated with the development of insulin resistance in skeletal muscles from the high-fat-fed rat. Lipid measurements showed that triglyceride and diacylglycerol, an activator of PKC, were elevated four- and twofold, respectively. PKC activity assays indicated that the proportion of membrane-associated calcium-independent PKC was also increased. As determined by immunoblotting, total (particulate plus cytosolic) PKC alpha, epsilon, and zeta levels were not different between control and fat-fed rats. However, the ratio of particulate to cytosolic PKC epsilon in red muscles from fat-fed rats was increased nearly sixfold, suggesting chronic activation. In contrast, the amount of cytosolic PKC theta was downregulated to 45% of control, while the ratio of particulate to cytosolic levels increased, suggesting a combination of chronic activation and downregulation. Interestingly, while insulin infusion in glucose-clamped rats increased the proportion of PKC theta in the particulate fraction of red muscle, this was potentiated by fat-feeding, suggesting that the translocation is a consequence of altered lipid flux rather than a proximal event in insulin signaling. PKC epsilon and theta measurements from individual rats correlated with triglyceride content of red gastrocnemius muscle; they did not correlate with plasma glucose, which was not elevated in fat-fed rats, suggesting that they were not simply a consequence of hyperglycemia. Our results suggest that these specific alterations in PKC epsilon and PKC theta might contribute to the link between increased lipid availability and muscle insulin resistance previously described using high-fat-fed rats.

The induction of hyperalgesia upon capsaicin administration requires activation of specific sub-classes of nociceptive afferent C-fibres providing nociceptive input to the central nervous system. It has been demonstrated in animal models that the endocannabinoid anandamide has anti-hyperalgesic properties upon capsaicin stimulation, albeit it also binds to vanilloid receptors. In the present study we topically administered the cannabinoid receptor ligand HU210 to human skin and investigated its effects on capsaicin-induced pain and hyperalgesia.We demonstrated that pre-treatment with HU210 significantly reduced the perception of pain following the administration of capsaicin. Heat pain thresholds were significantly reduced by capsaicin application measured 5 and 30min after administration. In contrast, at the HU210 pre-treated skin sites capsaicin failed to induce heat hyperalgesia during the fifth minute of administration. Secondary mechanical hyperalgesia to touch (allodynia) was measured during the fifth, 15th and 30th minute after capsaicin administration. In comparison to the ethanol control site, the area of touch-evoked allodynia was significantly reduced at the HU210 skin site during the first two measures. However, 30min after the administration of capsaicin no significant differences of allodynia were observed between the HU210 and ethanol pre-treated skin. The present study provided evidence for analgesic and anti-hyperalgesic properties of a topically applied cannabinoid receptor ligand, which might have important therapeutic implications in humans.