Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability

Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 microM) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (<10 microM) the inhibition of Akt phosphorylation was transient and eventually returned to basal levels. Lower levels of quercetin also induced strong activation of the pro-survival transcription factor cAMP-responsive element-binding protein, although this did not prevent neuronal damage. O-Methylated quercetin metabolites inhibited Akt/PKB to lesser extent and did not induce such strong activation of caspase-3, which was reflected in the lower amount of damage they inflicted on neurons. In contrast, neither quercetin nor its O-methylated metabolites had any measurable effect on c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was not toxic and did not evoke any alterations in neuronal signaling, probably reflecting its inability to enter neurons. Together these data suggest that quercetin and to a lesser extent its O-methylated metabolites may induce neuronal death via a mechanism involving an inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK rather than by an activation of the c-Jun N-terminal kinase-mediated death pathway.

Local environmental action in Japan: the transfer of the groundwork approach

This paper is the basis for a report on the transfer of the UK Groundwork approach to Japan. It details the background and history of Groundwork in the UK and sets out some of the relevant context in Japan. A Japanese case study (plus two further secondary cases) is detailed and conclusions and recommendations are drawn from the work to help suggest future directions for GW and environmental action in Japan in the future.

Return of the 'Angry Woman': authenticating female physical action in contemporary cinema

In 1999, Elizabeth Hills pointed up the challenges that physically active women on film still posed, in cultural terms, and in relation to certain branches of feminist theory . Since then, a remarkable number of emphatically active female heroes have appeared on screen, from 'Charlie’s Angels' to 'Resident Evil', 'Aeon Flux', and the 'Matrix' and 'X-Men' trilogies. Nevertheless, in a contemporary Western culture frequently characterised as postfeminist, these seem to be the ‘acceptable face’ – and body – of female empowerment: predominantly white, heterosexual, often scantily clad, with the traditional hero’s toughness and resolve re-imagined in terms of gender-biased notions of decorum: grace and dignity alongside perfect hair and make-up, and a body that does not display unsightly markers of physical exertion. The homogeneity of these representations is worth investigating in relation to critical claims that valorise such air-brushed, high-kicking 'action babes' for their combination of sexiness and strength, and the feminist and postfeminist discourses that are refracted through such readings. Indeed, this arguably ‘safe’ set of depictions, dovetailing so neatly with certain postfeminist notions of ‘having it all’, suppresses particular kinds of spectacles in relation to the active female body: images of physical stress and extension, biological consequences of violence and dangerous motivations are all absent. I argue that the untidy female exertions refused in popular “action babe” representations are now erupting into view in a number of other contemporaneous movies – 'Kill Bill' Vols 1 & 2, 'Monster', and 'Hard Candy' – that mark the return of that which is repressed in the mainstream vision of female power – that is, a more viscerally realistic physicality, rage and aggression. As such, these films engage directly with the issue of how to represent violent female agency. This chapter explores what is at stake at a representational level and in terms of spectatorial processes of identification in the return of this particularly visceral rendering of the female avenger.

The effects of age, enactment, and cue-action relatedness on memory for intentions in the Virtual Week task

The current study investigated the influence of encoding modality and cue-action relatedness on prospective memory (PM) performance in young and older adults using a modified version of the Virtual Week task. Participants encoded regular and irregular intentions either verbally or by physically performing the action during encoding. For half of the intentions there was a close semantic relation between the retrieval cue and the intended action, while for the remaining intentions the cue and action were semantically unrelated. For irregular tasks, both age groups showed superior PM for related intentions compared to unrelated intentions in both encoding conditions. While older adults retrieved fewer irregular intentions than young adults after verbal encoding, there was no age difference following enactment. Possible mechanisms of enactment and relatedness effects are discussed in the context of current theories of event-based PM.

Adjuvant chemotherapy in older women (ACTION) study - what did we learn from the pilot phase?

Despite widespread support at several public meetings, input from patient groups including representation on the Trial Management Group, the trial failed to recruit due to the inability to convince patients to accept randomisation. It would therefore seem that randomising the patients to receive chemotherapy vs observation is not a viable design in the current era for this patient population.

The potential mechanisms involved in the anti-carcinogenic action of probiotics

Probiotic bacteria are live microbial food ingredients that provide a health benefit to the consumer. In the past it was suggested that they served to benefit the host primarily through the prevention of intestinal infections. More recent studies have implicated probiotic bacteria in a number of other beneficial effects within the host including: *The suppression of allergies. *Control of blood cholesterol levels. *Modulation of immune function. *And the prevention of cancers of the colon. The reputed anti-carcinogenic effect of probiotics arises from in vivo studies in both animals and to a limited extent in man; this evidence is supported by in vitro studies with carcinoma cell lines and anti-mutagenicity assays. However, the mechanisms involved in any effect have thus far been difficult to elucidate; studies offer evidence for a variety of mechanisms; we have reviewed these and come to the opinion that, the anti-carcinogenic effect may not be attributable to a single mechanism but rather to a combination of events not yet fully elucidated or understood.

Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells.