p63, a recently identified member of the p53 gene family, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. We show that in normal human epidermis, in hair follicles, and in stratified epidermal cultures, p63 protein is principally restricted to cells with high proliferative potential and is absent from the cells that are undergoing terminal differentiation. In normal human epidermis and in hair follicles, basal cells with abundant p63 are interspersed with cells with little or no p63. Whenever p63 mRNA is present, it encodes mainly truncated, potentially dominant-negative isotypes. In squamous cell carcinomas, the number of cells containing p63 and their distribution depends on the degree of anaplasia. In highly differentiated tumors, p63 is confined to a ring of basal-like cells surrounding, but at a distance from, centers of terminal differentiation. In less differentiated tumors, most cells contain p63 and their distribution is chaotic with respect to centers of terminal differentiation. p63 appears to be a valuable diagnostic marker for anaplastic keratinocytes.

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Skin Aging manifests primarily with wrinkles, dyspigmentations, texture changes, and loss of elasticity. During the skin aging process, there is a loss of moisture and elasticity in skin resulting in loss of firmness finally leading to skin sagging. The key molecule involved in skin moisture is hyaluronic acid (HA), which has a significant water-binding capacity. HA levels in skin decline with age resulting in decrease in skin moisture, which may contribute to loss of firmness. Clinical trials have shown that topically applied ROL effectively reduces wrinkles and helps retain youthful appearance. In the current study, ROL was shown to induce HA production and stimulates the gene expression of all three forms of hyaluronic acid synthases (HAS) in normal human epidermal keratinocytes monolayer cultures. Moreover, in human skin equivalent tissues and in human skin explants, topical treatment of tissues with a stabilized-ROL formulation significantly induced the gene expression of HAS mRNA concomitant with an increased HA production. Finally, in a vehicle-controlled human clinical study, histochemical analysis confirmed increased HA accumulation in the epidermis in ROL-treated human skin as compared to vehicle. These results show that ROL increases skin expression of HA, a significant contributing factor responsible for wrinkle formation and skin moisture, which decrease during aging. Taken together with the activity to increase collagen, elastin, and cell proliferation, these studies establish that retinol provides multi-functional activity for photodamaged skin.

Glucokinase first appears in the liver of the rat 2 weeks after birth and its activity rapidly increases after weaning on to a high-carbohydrate diet. The appearance of glucokinase is principally due to the increase of plasma insulin and to the decrease of plasma glucagon concentrations. Oral glucose administration to 1-or 10-day-old suckling rats induced an increase in plasma insulin and a fall in plasma glucagon and allowed a rapid accumulation of liver glucokinase mRNA, secondarily to a stimulation of gene transcription. When unrestrained late pregnant rats were infused with glucose during 36 h to induce an increase in fetal plasma insulin and a decrease in fetal plasma glucagon concentrations, glucokinase mRNA was detectable in fetal liver but the level was 100-fold lower than that observed in 1-or 10-day-old suckling rats. It is suggested that the hormonal environment did not allow glucokinase gene expression to be induced in fetal liver and that the absence of expression of glucokinase in suckling rat liver is due to the presence of low plasma insulin and high plasma glucagon levels.The chromatin structure of the glucokinase gene was examined during development by identification of DNase-I-hypersensitive sites from the region comprised between -8 kb upstream and +4 kb downstream of the cap site, Five hypersensitive sites were found: four liver-specific sites upstream of the cap site and one non-specific site in the first intron. These sites are already present in term fetus but the intensity of the two proximal sites located upstream of the cap site increase markedly after birth. This suggests that these sites could be implicated in the regulation of glucokinase gene expression by insulin and glucagon. Full DNase-I-hypersensitivity of these two proximal sites seems necessary for the mature response of glucokinase gene in response to changes in pancreatic hormones concentrations.Glucokinase plays a predominant role in the regulation of glucose homeostasis by catalyzing the first step of liver glycolysis [l]. It belongs to the mammalian hexokinase family and differs from the others by three characteristics: (a) a low affinity for glucose, (b) a lack of product inhibition by glucose 6-phosphate [2], (c) a molecular mass of about 50 kDa compared to 100kDa for the other hexokinases. Moreover, this enzyme is only expressed in liver and pancreatic p cells [3, 41. In the adult rat liver, the rate of glucokinase gene transcription as well as the level of mRNA and the activity of glucokinase fluctuate with the nutritional and hormonal status. They are decreased by fasting and by diabetes and increased after refeeding a high-carbohydrate diet to fasted

Acne vulgaris is a disease of pilosebaceous units with multifactorial pathogenesis, including hyperkeratinization, increased sebum secretion, and inflammation. Recently, it was suggested that acne subjects may have also impaired skin barrier. We hypothesized that excess unsaturated free fatty acids (UFFA) present in the sebum may cause barrier impairment associated with increased follicular stratum corneum (SC) thickening and inflammation seen in acne. Therefore, epidermal and sebaceous lipid profiles from acne and healthy subjects were analyzed and an in vitro epidermal tissue model was developed to validate this hypothesis. Significantly increased levels of free fatty acids (p < 0.05) were observed in skin lipids of human acne vs. healthy subjects. Exposure of human epidermal equivalents (HEEs) to the UFFA oleic acid (OA), also present in sebum, led to barrier impairment associated with increased SC lipid disorder, increased secretion of interleukin-1α (IL-1α), and excessive SC thickening. Furthermore, the expression of genes encoding for inflammatory cytokines and epidermal differentiation proteins was also increased both in acne lesions and in OA-treated HEEs. Taken together, these data are in agreement with the hypothesis that excess UFFAs in sebum of acne subjects may contribute to impaired skin barrier associated with the increased follicular SC thickness and inflammation seen in acne. Moreover, OA induces similar molecular and phenotypic changes in HEEs as those seen in acne lesions and suggests that an UFFA-treated epidermal tissue model can be used to study the UFFA-mediated pathways involved in the pathogenesis of inflammatory acne and for the development of appropriate therapies.