Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma

The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (ROS). The aim of this study was to identify mechanisms generating ROS and apoptosis of neuroblastoma cells in response to fenretinide. Fenretinide-induced ROS or apoptosis of SH-SY5Y or HTLA 230 neuroblastoma cells were not blocked by Nitro l-argenine methyl ester (l-NAME), an inhibitor of nitric oxide synthase. Flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase were also not involved in fenretinide-induced apoptosis or ROS generation. Similarly, ketoconazole, a cytochrome P450 inhibitor, and inhibitors of cyclooxygenase (COX) were also ineffective. In contrast, inhibition of phospholipase A(2) or lipoxygenases (LOX) blocked the induction of ROS and apoptosis in response to fenretinide. Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis. The effects of eicosatriynoic acid, a specific 12-LOX inhibitor, were reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid and 12 (S)-hydroxyeicosatetraenoic acid. The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.     

Circadian Variation in the Uptake of Tryptophan by Cortical Synaptosomes of the Rat Brain

The kinetics of the high affinity uptake system for L-tryptophan (L-Try)have been measured over 24 hr in cortical synaptosome preparations of rat brain. Both the K_m and V_max, of the uptake process showed a statistically significant 24 hr variation. The highest K_m value, 6.71 ± 10^-5 M, was measured at the beginning of the light phase and the lowest value, 4.23 ± 10^-5 M, 6 hr into the dark phase. V_max was highest at the end of the dark phase (10.43 nmol/mg/5 min) and lowest (4.80 nmol/mg/5 min) 3 hr into the dark phase. In contrast, there was no variation over 24 hr in the V_max/K_m ratio. These results suggest that the high affinity uptake process serves to ensure a constant rate of L-tryptophan entry into the neuron in the face of circadian or ultradian variations in extracellular concentration of tryptophan.     

Guinea Pig Terminal 5-HT1D Autoreceptors Do Not Display a Circadian Variation in Their Responsiveness to Serotonin

Many of the components involved in the synthesis and release of serotonin (5-HT) display a circadian variation in their activity. Autoreceptors located on nerve terminals were recently suggested to underlie some of these circadian variations. The aim of this study was to examine whether terminal 5-HT_1D autoreceptors in the cerebral cortex of the guinea pig exhibit a circadian variation in their responsiveness. The responsiveness of these autoreceptors was assessed by the ability of exogenously applied 5-HT to inhibit the potassium-evoked release of [³H]5-HT from slices of guinea pig cortex. Identical experiments were conducted at four different, equally spaced time points during the light:dark cycle of the guinea pig. The results presented here demonstrate that terminal 5-HT_1D autoreceptors do not exhibit a circadian variation in their responsiveness. Therefore, terminal 5-HT_1D autoreceptors bear similarity to terminal 5-HT_1B autoreceptors identified in rat brain in being devoid of a significant rhythm in their responsiveness.     

A new approach to the study of Romanization in Britain: a regional perspective of cultural change in late iron age and roman dorset using the siler and gompertz-makeham models of mortality

This is the first study of health in the Roman Empire to use the Siler and Gompertz-Makeham models of mortality to investigate the health consequences of the 43 AD conquest of Britain. The study examined late Iron Age and Romano-British populations (N = 518) from Dorset, England, which is the only region of Britain to display continuity in inhumation burial practice and cemetery use throughout the two periods. Skeletal evidence for frailty was assessed using cribra orbitalia, porotic hyperostosis, periosteal lesions, enamel hypoplasia, dental caries, tuberculosis, and rickets. These health variables were chosen for analysis because they are reliable indicators of general health for diachronic comparison (Steckel and Rose: The backbone of history: health and nutrition in the western hemisphere (2002)) and are associated with the introduction of urbanism in Britain during the Roman period (Redfern: J Rom Archaeol Supp Series 64 (2007) 171-194; Redfern: Britannia 39 (2008a) 161-191; Roberts and Cox: Health and disease in Britain: from prehistory to the present day (2003)). The results show that levels of frailty and mortality were lower in the late Iron Age period, and no sex differences in mortality was present. However, post-conquest, mortality risk increased for children and the elderly, and particularly for men. The latter finding challenges received wisdom concerning the benefits of incorporation into the Empire and the higher status of the male body in the Roman world. Therefore, we conclude that the consequences of urbanism, changes in diet, and increased population heterogeneity negatively impacted health, to the extent that the enhanced cultural buffering of men did not outweigh underlying sex differences in biology that advantage women.