Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aß uptake in astrocytes.

The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid ß (Aß)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aß uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aß production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.

Nutrient intake and blood iron status of male collegiate soccer players.

The purpose of this study was: 1) to collect baseline data on nutrient intake in order to advise athletes about nutrition practices that might enhance performance, and 2) to evaluate the dietary iron intake and blood iron status of Japanese collegiate soccer players. The subjects were 31 soccer players and 15 controls. Dietary information was obtained with a food frequency questionnaire. The mean carbohydrate (6.9 g.kg-1 BW) and protein (1.3 g/kg) intakes of the soccer players were marginal in comparisons with recommended targets. The mean intakes of calcium, magnesium, vitamin A, B1, B2, and C were lower than the respective Japanese recommended dietary allowances (RDAs) or adequate dietary intakes in the soccer players. The mean intakes of green and other vegetables, milk and dairy products, fruits, and eggs were lower than the recommended targets. Thus, we recommended athletes to increase the intake of these foodstuffs along with slight increase in carbohydrate and lean meat. The mean intake of iron was higher than the respective RDA in the soccer players. A high prevalence of hemolysis (71%) in the soccer players was found. None of the soccer players and controls had anemia. Two soccer players had iron depletion, while none was found in the controls. In those players who had iron deficiency, the training load need to be lowered and/or iron intake may be increased.

ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation.

The p53 tumor suppressor protein preserves genome integrity by regulating growth arrest and apoptosis in response to DNA damage. In response to ionizing radiation (IR), ATM, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of Ser(15) and (indirectly) Ser(20). Here we show that phosphorylation of p53 on Ser(46), a residue important for p53 apoptotic activity, as well as on Ser(9), in response to IR also is dependent on the ATM protein kinase. IR-induced phosphorylation at Ser(46) was inhibited by wortmannin, a phosphatidylinositol 3-kinase inhibitor, but not PD169316, a p38 MAPK inhibitor. p53 C-terminal acetylation at Lys(320) and Lys(382), which may stabilize p53 and activate sequence-specific DNA binding, required Ser(15) phosphorylation by ATM and was enhanced by phosphorylation at nearby residues including Ser(6), Ser(9), and Thr(18). These observations, together with the proposed role of Ser(46) phosphorylation in mediating apoptosis, suggest that ATM is involved in the initiation of p53-dependent apoptosis after IR in human lymphoblastoid cells.