A Potent Inhibitor of SIK2, 3, 3′, 7-Trihydroxy-4′-Methoxyflavon (4′-O-Methylfisetin), Promotes Melanogenesis in B16F10 Melanoma Cells

Flavonoids, which are plant polyphenols, are now widely used in supplements and cosmetics. Here, we report that 4′-methylflavonoids are potent inducers of melanogenesis in B16F10 melanoma cells and in mice. We recently identified salt inducible kinase 2 (SIK2) as an inhibitor of melanogenesis via the suppression of the cAMP-response element binding protein (CREB)-specific coactivator 1 (TORC1). Using an in vitro kinase assay targeting SIK2, we identified fisetin as a candidate inhibitor, possibly being capable of promoting melanogenesis. However, fisetin neither inhibited the CREB-inhibitory activity of SIK2 nor promoted melanogenesis in B16F10 melanoma cells. Conversely, mono-methyl-flavonoids, such as diosmetin (4′-O-metlylluteolin), efficiently inhibited SIK2 and promoted melanogenesis in this cell line. The cAMP-CREB system is impaired in Ay/a mice and these mice have yellow hair as a result of pheomelanogenesis, while Sik2+/−; Ay/a mice also have yellow hair, but activate eumelanogenesis when they are exposed to CREB stimulators. Feeding Sik2+/−; Ay/a mice with diets supplemented with fisetin resulted in their hair color changing to brown, and metabolite analysis suggested the presence of mono-methylfisetin in their feces. Thus, we decided to synthesize 4′-O-methylfisetin (4′MF) and found that 4′MF strongly induced melanogenesis in B16F10 melanoma cells, which was accompanied by the nuclear translocation of TORC1, and the 4′-O-methylfisetin-induced melanogenic programs were inhibited by the overexpression of dominant negative TORC1. In conclusion, compounds that modulate SIK2 cascades are helpful to regulate melanogenesis via TORC1 without affecting cAMP levels, and the combined analysis of Sik2+/− mice and metabolites from these mice is an effective strategy to identify beneficial compounds to regulate CREB activity in vivo

Validity and reliability of a computerized cognitive function evaluation battery (CogEvo) as a screening tool

Abstract Aim The aim of this study was to determine the validity and reliability of cognitive function evaluation battery, CogEvo, a recently developed computerized cognitive function evaluation battery, as a screening tool for decreased cognitive function. Methods The study sample comprised 123 (age: 57–97 years) community‐dwelling elderly people. They were required to perform five CogEvo tasks and complete two questions‐based neuropsychological tests, including the Mini‐Mental State Examination, so that the correlations could be analyzed. The validity and reliability of CogEvo were examined using factor analysis, MacDonald's omega reliability coefficient, logistic regression analysis, and receiver operating characteristic curve analysis. Results Exploratory factor analysis revealed the orientation/spatial cognitive function (orientation and spatial cognition) and attention/executive function (attention, memory, and execution) factors. Structural validity was supported by confirmatory factor analysis. All two‐factor‐based subtasks showed adequate internal consistency (MacDonald's omega ≥0.6). The total CogEvo score and two‐factor scores were significantly correlated with neuropsychological test results. Based on the total CogEvo score, the cognitively normal and cognitive decline groups were identified by receiver operating characteristic curve analysis with a moderate predictive performance. The cognitive decline group was well identified using the orientation/spatial cognitive function factor. Conclusions CogEvo is a valid and reliable screening tool for cognitive function evaluation. It proved useful in the early identification of cognitive decline in our study sample