The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

Loss of adipose tissue in cancer cachexia in mice bearing the MAC16 tumour arises from an increased lipid mobilisation through increased expression of zinc-α2-glycoprotein (ZAG) in white (WAT) and brown (BAT) adipose tissue. Glucocorticoids have been suggested to increase ZAG expression, and this study examines their role in cachexia and the mechanisms involved. In mice bearing the MAC16 tumour, serum cortisol concentrations increased in parallel with weight loss, and the glucocorticoid receptor antagonist RU38486 (25 mg kg-1) attenuated both the loss of body weight and ZAG expression in WAT. Dexamethasone (66 μg kg-1) administration to normal mice produced a six-fold increase in ZAG expression in both WAT and BAT, which was also attenuated by RU38486. In vitro studies using 3T3-L1 adipocytes showed dexamethasone (1.68 μM) to stimulate lipolysis and increase ZAG expression, and both were attenuated by RU38486 (10 μM), anti-ZAG antibody (1 μ gml-1), and the β3-adrenoreceptor (β3-AR) antagonist SR59230A (10 μM). Zinc-α2-glycoprotein also increased its own expression and this was attenuated by SR59230A, suggesting that it was mediated through the β3-AR. This suggests that glucocorticoids stimulate lipolysis through an increase in ZAG expression, and that they are responsible for the increase in ZAG expression seen in adipose tissue of cachectic mice. © 2005 Cancer Research UK.

Antioxidants, reactive oxygen and nitrogen species, gene induction and mitochondrial function

Redox-sensitive cell signalling Thiol groups and the regulation of gene expression Redox-sensitive signal transduction pathways Protein kinases Protein phosphatases Lipids and phospholipases Antioxidant (electrophile) response element Intracellular calcium signalling Transcription factors NF-?B AP-1 p53 Cellular responses to oxidative stress Cellular responses to change in redox state Proliferation Cell death Immune cell function Reactive oxygen and nitrogen species – good or bad? Reactive oxygen species and cell death Reactive oxygen species and inflammation Are specific reactive oxygen species and antioxidants involved in modulating cellular responses? Specific effects of dietary antioxidants in cell regulation Carotenoids Vitamin E Flavonoids Inducers of phase II enzymes Disease states affected Oxidants, antioxidants and mitochondria Introduction Mitochondrial generation of reactive oxygen and nitrogen species Mitochondria and apoptosis Mitochondria and antioxidant defences Key role of mitochondrial GSH in the defence against oxidative damage Mitochondrial oxidative damage Direct oxidative damage to the mitochondrial electron transport chain Nitric oxide and damage to mitochondria Effects of nutrients on mitochondria Caloric restriction and antioxidants Lipids Antioxidants Techniques and approaches Mitochondrial techniques cDNA microarray approaches Proteomics approaches Transgenic mice as tools in antioxidant research Gene knockout and over expression Transgenic reporter mice Conclusions Future research needs

Deoxycytidine glyoxal:Lesion induction and evidence of repair following vitamin C supplementation in vivo

Oxidative DNA damage is postulated to be involved in carcinogenesis, and as a consequence, dietary antioxidants have received much interest. A recent report indicates that vitamin C facilitates the decomposition of hydroperoxides in vitro, generating reactive aldehydes. We present evidence for the in vivo generation of glyoxal, an established product of lipid peroxidation, glucose/ascorbate autoxidation, or free radical attack of deoxyribose, following supplementation of volunteers with 400 mg/d vitamin C. Utilizing a monoclonal antibody to a deoxycytidine-glyoxal adduct (gdC), we measured DNA lesion levels in peripheral blood mononuclear cells. Supplementation resulted in significant (p = .001) increases in gdC levels at weeks 11, 16, and 21, with corresponding increases in plasma malondialdehyde levels and, coupled with previous findings, is strongly suggestive of a pro-oxidative effect. However, continued supplementation revealed a highly significant (p = .0001) reduction in gdC levels. Simultaneous analysis of cyclobutane thymine dimers revealed no increase upon supplementation but, as with gdC, levels decreased. Although no single mechanism is identified, our data demonstrate a pro-oxidant event in the generation of reactive aldehydes following vitamin C supplementation in vivo. These results are also consistent with our hypothesis for a role of vitamin C in an adaptive/repair response and indicate that nucleotide excision repair specifically may be affected. © 2003 Elsevier Science Inc.

Rule induction for data exploration

This paper describes how the statistical technique of cluster analysis and the machine learning technique of rule induction can be combined to explore a database. The ways in which such an approach alleviates the problems associated with other techniques for data analysis are discussed. We report the results of experiments carried out on a database from the medical diagnosis domain. Finally we describe the future developments which we plan to carry out to build on our current work.

An investigation into children’s inductive reasoning strategies:What drives the development of category induction?

In a series of studies, I investigated the developmental changes in children’s inductive reasoning strategy, methodological manipulations affecting the trajectory, and driving mechanisms behind the development of category induction. I systematically controlled the nature of the stimuli used, and employed a triad paradigm in which perceptual cues were directly pitted against category membership, to explore under which circumstances children used perceptual or category induction. My induction tasks were designed for children aged 3-9 years old using biologically plausible novel items. In Study 1, I tested 264 children. Using a wide age range allowed me to systematically investigate the developmental trajectory of induction. I also created two degrees of perceptual distractor – high and low – and explored whether the degree of perceptual similarity between target and test items altered children’s strategy preference. A further 52 children were tested in Study 2, to examine whether children showing a perceptual-bias were in fact basing their choice on maturation categories. A gradual transition was observed from perceptual to category induction. However, this transition could not be due to the inability to inhibit high perceptual distractors as children of all ages were equally distracted. Children were also not basing their strategy choices on maturation categories. In Study 3, I investigated category structure (featural vs. relational category rules) and domain (natural vs. artefact) on inductive preference. I tested 403 children. Each child was assigned to either the featural or relational condition, and completed both a natural kind and an artefact task. A further 98 children were tested in Study 4, on the effect of using stimuli labels during the tasks. I observed the same gradual transition from perceptual to category induction preference in Studies 3 and 4. This pattern was stable across domains, but children developed a category-bias one year later for relational categories, arguably due to the greater demands on executive function (EF) posed by these stimuli. Children who received labels during the task made significantly more category choices than those who did not receive labels, possibly due to priming effects. Having investigated influences affecting the developmental trajectory, I continued by exploring the driving mechanism behind the development of category induction. In Study 5, I tested 60 children on a battery of EF tasks as well as my induction task. None of the EF tasks were able to predict inductive variance, therefore EF development is unlikely to be the driving factor behind the transition. Finally in Study 6, I divided 252 children into either a comparison group or an intervention group. The intervention group took part in an interactive educational session at Twycross Zoo about animal adaptations. Both groups took part in four induction tasks, two before and two a week after the zoo visits. There was a significant increase in the number of category choices made in the intervention condition after the zoo visit, a result not observed in the comparison condition. This highlights the role of knowledge in supporting the transition from perceptual to category induction. I suggest that EF development may support induction development, but the driving mechanism behind the transition is an accumulation of knowledge, and an appreciation for the importance of category membership.