Validation of a predictive method for sunscreen formula evaluation using gene expression analysis in a Chinese reconstructed full-thickness skin model.

OBJECTIVE: This study aimed to establish a predictive in vitro method for assessing the photoprotective properties of sunscreens using a reconstructed full-thickness skin model. MATERIALS AND METHODS: A full-thickness skin model reconstructed with human fibroblasts and keratinocytes isolated from Chinese skin was exposed to daily UV radiation (DUVR). We examined the transcriptomic response, identifying genes for which expression was modulated by DUVR in a dose-dependent manner. We then validated the methodology for efficacy evaluation of different sunscreens formulas. RESULTS: The reconstructed skin model was histologically consistent with human skin, and upon DUVR exposure, the constituent fibroblasts and keratinocytes exhibited transcriptomic alterations in pathways associated with oxidative stress, inflammation and extracellular matrix remodelling. When used to evaluate sunscreen protection on the model, the observed level of protection from UV-induced gene expression was consistent with the corresponding protection factors determined clinically and allowed for statistical ranking of sunscreen efficacy. CONCLUSIONS: Within this study we show that quantification of gene modulation within the reconstructed skin model is a biologically relevant approach with sensitivity and predictability to evaluate photoprotection products.

OBJECTIF: Cette étude visait à établir une méthode prédictive in vitro permettant d'évaluer les propriétés photoprotectrices des écrans solaires à l'aide d'un modèle de peau reconstruite sur toute son épaisseur. MATÉRIELS ET MÉTHODES: Un modèle de peau reconstruite sur toute son épaisseur avec des fibroblastes et des kératinocytes humains isolés à partir de peaux chinoises a été exposé au rayonnement UV quotidien (DUVR). Nous avons examiné la réponse transcriptomique en identifiant les gènes dont l'expression était modulée par le DUVR de façon dépendante à la dose. Nous avons ensuite validé la méthodologie d'évaluation de l'efficacité des formules des différents écrans solaires. RÉSULTATS: Le modèle de peau reconstruite correspondait histologiquement à de la peau humaine, et lors de l'exposition à des DUVR, les fibroblastes et les kératinocytes qui la composaient présentaient des altérations transcriptomiques des voies associées au stress oxydatif, à l'inflammation et au remodelage de la matrice extracellulaire. Lorsque ce modèle a été utilisé pour évaluer la protection solaire, le niveau de protection observé de l'expression génique induite par les UV correspondait aux facteurs de protection cliniques déterminés correspondants et permettait un classement statistique de l'efficacité de la protection solaire. CONCLUSIONS: Dans cette étude, nous montrons que la quantification de la modulation génique dans le modèle de peau reconstruite est une approche biologiquement pertinente offrant une sensibilité et une prédictibilité pour évaluer les produits de photoprotection.

Crocin, a natural molecule with potentially beneficial effects against skin ageing.

OBJECTIVE: Oxidative stress and low-grade chronic inflammation stand out as key features of physiological skin ageing. The aim of this study was to examine in normal human epidermal keratinocytes (NHEK) and human dermal fibroblasts (HDF) grown in vitro, the antioxidant and anti-inflammatory properties of crocin, a carotenoid glycoside responsible for the colour of saffron. Moreover, considering the newly emerging field of skin glycobiology and the presence of two gentiobiosyl moieties in crocin, the effect of crocin on NHEK glycosylation pathways was for the first time investigated. METHODS: The anti-inflammatory and antioxidant activities of crocin were evaluated by in vitro assays of antioxidation activities, ELISA and microarray analysis. The effect of crocin on keratinocyte glycobiology was evaluated by proprietary GLYcoDiag lectin technologies and microarray analysis. RESULTS: Crocin is endowed with antioxidant potential against reactive oxygen species, protects squalene against UVA-induced peroxidation and prevents the release of inflammatory mediators. The expression of NF-kB-related genes and glycosylation-related genes is modulated in the presence of crocin. CONCLUSION: Results could designate this molecule as a promising skin ageing prevention cosmetic agent. Of note, some of these effects could be mediated by protein O-glycosylation and interaction of crocin with osidic receptors of keratinocytes.

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar.

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.

Hypothermia and Alzheimer's disease neuropathogenic pathways.

Alzheimer's disease (AD) remains a major health problem, and accounts for 50 to 60% of all cases of dementia. The two histopathological hallmarks of AD are senile plaques, composed of the ß-amyloid peptide (Aß), and intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. Only a small proportion of AD is due to mutations in the genome of patients, the large majority of cases being of late onset and sporadic in origin. The relative contribution of genetics and environment to the sporadic cases is unclear, but they are accepted to be of multifactorial origin. This means that genetic and environmental factors can interact together to induce or accelerate the disease. Among environmental factors, studies suggest that hypothermia may contribute to the development and exacerbation AD. Here, we review the preclinical data involving hypothermia with tau and Aß, as well as clinical evidence implicating hypothermia in the development of AD.

Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3 beta and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse.

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brain. Starvation of adult mice induces tau hyperphosphorylation at many paired helical filaments sites and with a similar regional selectivity as those in AD, suggesting that a common mechanism may be mobilized. Here we investigated the mechanism of starvation-induced tau hyperphosphorylation in terms of tau kinases and Ser/Thr protein phosphatases (PP), and the results were compared with those reported in AD brain. During starvation, tau hyperphosphorylation at specific epitopes was accompanied by decreases in tau protein kinase I/glycogen synthase kinase 3 beta (TPKI/GSK3 beta), cyclin-dependent kinase 5 (cdk5), and PP2A activities toward tau. These results demonstrate that the activation of TPKI/GSK3 beta and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that inhibition of PP2A is likely the dominant factor in inducing tau hyperphosphorylation in the starved mouse, overriding the inhibition of key tau kinases such as TPKI/GSK3 beta and cdk5. Furthermore, these data give strong support to the hypothesis that PP2A is important for the regulation of tau phosphorylation in the adult brain, and provide in vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD.

Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer's disease.

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of this disease. The objective of this study was to reproduce tau hyperphosphorylation in an animal model by inducing hypoglycemia. Food deprivation of mice for 1 to 3 days progressively enhanced tau hyperphosphorylation in the hippocampus, to a lesser extent in the cerebral cortex, but the effect was least in the cerebellum, in correspondence with the regional selectivity of tauopathy in Alzheimer's disease. This hyperphosphorylation was reversible by refeeding for 1 day. We discuss possible mechanisms of this phenomenon, and propose the starved mouse as a simple model to study in vivo tau phosphorylation and dephosphorylation which are altered in Alzheimer's disease.