Cell Cycle Phase Regulates Glucocorticoid Receptor Function

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase

Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats

Purpose: Lipid-based formulations (LBF) have shown oral bioavailability enhancement of lipophilic drugs, but not necessarily in the case of hydrophobic drugs. This study explored the potential of lipid vehicles to improve the bioavailability of the hydrophobic drug nilotinib comparing a chase dosing approach and lipid suspensions. Methods: Nilotinib in vivo bioavailability in rats was determined after administering an aqueous suspension chase dosed with blank olive oil, Captex 1000, Peceol or Capmul MCM, respectively. Absolute bioavailability was determined (relative to an intravenous formulation). Pharmacokinetic parameters were compared to lipid suspensions. Results: Compared to the lipid suspensions, the chase dosed lipids showed a 2- to 7-fold higher bioavailability. Both long chain chase dosed excipients also significantly increased the bioavailability up to 2-fold compared to the aqueous suspension. Deconvolution of the pharmacokinetic data indicated that chase dosing of nilotinib resulted in prolonged absorption compared to the aqueous suspension. Conclusion: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for ‘brick dust’ molecules such as nilotinib

Permo-Carboniferous granitoids with Jurassic high temperature metamorphism in Central Pontides, Northern Turkey

In the northern part of the Central Pontides (N Turkey) there are different metamorphic rocks exposed, notably the Devrekani metamorphic rocks. Here, upper amphibolite-lower granulite facies metamorphic rocks contain predominantly paragneiss, orthogneiss and metacarbonate, and to a lesser extent, amphibolite and quartzite, with cross-cutting aplite, pegmatite and granite veins. This is the first report of these rocks and includes new data on the petrochemistry, geochronology and metamorphic evolution of the Devrekani orthogneisses from the Central Pontides. The orthogneisses show five different mineral parageneses with the characteristic mineral assemblage quartz + K-feldspar + plagioclase + biotite ± hornblende ± opaque (± ilmenite and ± magnetite), and accessory minerals (zircon, sphene and apatite). These metamorphic rocks exhibit generally granoblastic, lepidogranoblastic and nematolepidogranoblastic with locally migmatitic and relic micrographic textures. They have well-developed centimeter-spaced gneissic banding and display gneissose structure with symmetric, asymmetric and irregular folds. The petrographic features, mineralogical assemblages and weak migmatization reflect high temperature conditions. Thermometric calculations in the orthogneisses indicate metamorphic temperatures reached 744 ± 33 °C. Field relations, petrography and petrochemistry suggest that the orthogneisses have predominantly granodioritic and some granitic protoliths, that show features of I-type, medium to high-potassic calc-alkaline volcanic arc granitoids. The orthogneisses have high contents of LILEs and low contents of HFSEs with negative Nb and Ti anomalies, which are typical of subduction-related magmas. The orthogneisses also show significant LREE enrichment relative to HREE with negative Eu anomalies (EuN/Eu* = 0.33–1.07) with LaN/LuN = 6.98–20.47 values. Based on U-Pb zircon dating data, the protoliths are related to Permo-Carboniferous (316–252 Ma) magmatism. It is likely that peak metamorphism took place during the Jurassic as reflected by the U-Pb zircon ages (199–158 Ma) and also 40Ar/39Ar from hornblende/biotite (163–152 Ma). The four biotite 40Ar/39Ar average ages from the rock samples are ca. 156 Ma, suggesting that the metamorphic rocks cooled to 350–400 °C at ca. 156 Ma. Conclusively, the Devrekani metamorphic rocks can be ascribed as products of Permo-Carboniferous continental arc magmatism overprinted by Jurassic metamorphism in the northern Central Pontides