Modulation of peroxynitrite-induced fibroblast injury by hesperetin: a role for intracellular scavenging and modulation of ERK signalling

Peroxynitrite is thought to contribute to the progression of many diseases including cardiovascular disease, cancer, and neurodegenerative disorders. We report that pre-treatment of fibroblasts with the citrus flavanone, hesperetin, prior to peroxynitrite exposure protects against peroxynitrite-mediated cytotoxicity. This protection was partially mediated by the intracellular scavenging of peroxynitrite by hesperctin as exposure of fibroblasts to peroxynitrite following hesperetin loading led to the formation of two intracellular nitrohesperetin derivatives. In addition, protection appeared to be mediated by hesperetin-induced changes in MAP kinase signalling. Exposure of fibroblasts to hesperetin led to concentration-dependent increases in the phosphorylation of ERK1/2 and was observed to restore peroxynitrite-mediated decreases in ERK1/2 phosphorylation. We propose that the protective potential of hesperetin in fibroblasts may be mediated both by intracellular scavenging of peroxynitrite and by modulation of fibroblast signalling. (c) 2006 Elsevier Inc. All rights reserved.

Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury

Cellular actions of isoflavones may mediate the beneficial health effects associated with high soy consumption. We have investigated protection by genistein and daidzein against oxidative stress-induced endothelial injury. Genistein but not daidzein protected endothelial cells from damage induced by oxidative stress. This protection was accompanied by decreases in intracellular glutathione levels that could be explained by the generation of glutathionyl conjugates of the oxidised genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone. Both isoflavones evoked increased protein expression of gamma-glutamylcysteine synthetase-heavy subunit (gamma-GCS-HS) and increased cytosolic accumulation and nuclear translocation of Nrf2. However, only genistein led to increases in the cytosolic accumulation and nuclear translocation of Nrf1 and the increased expression of and activity of glutathione peroxidase. These results suggest that genistein-induced protective effects depend primarily on the activation of glutathione peroxidase mediated by Nrf1 activation, and not on Nrf2 activation or increases in glutathione synthesis. (c) 2006 Elsevier Inc. All rights reserved.

Theory of mind in children with traumatic brain injury

Objective: This study was designed to examine the existence of deficits in mentalizing or theory of mind (ToM) in children with traumatic brain injury (TBI). Research design: ToM functioning was assessed in 12 children aged 6-12 years with TBI and documented frontal lobe damage and compared to 12 controls matched for age, sex and verbal ability. Brief measures of attention and memory were also included. Main outcome and results: The TBI group was significantly impaired relative to controls on the advanced ToM measure and a measure of basic emotion recognition. No difference was found in a basic measure of ToM. Conclusion: Traumatic brain damage in childhood may disrupt the developmental acquisition of emotion recognition and advanced ToM skills. The clinical and theoretical importance of these findings is discussed and the implications for the assessment and treatment of children who have experienced TBI are outlined.

The effect of a perceptual cognitive task on exercise performance: the dual-task condition after brain injury

Objective: To examine the effect of additional cognitive demand on cycling performance in individuals with acquired brain injury (ABI). Design: Prospective observational study. Setting: Rivermead Rehabilitation Centre. Participants: Ten individuals with ABI ( 7 men, 3 women) ( traumatic brain injury 7, tumour 1, stroke 2) and 10 healthy controls ( 6 men, 4 women). Intervention: Individuals were asked to maintain a set cadence during a three-stage incremental cycling test in both single-task ( no additional task) and dual-task ( whilst performing an additional cognitive task) conditions. Results: The ABI group showed a slight slowing in cadence in stages 1 and 3 of the graded exercise test from the single-to the dual-task condition, although this was not significant ( p less than or equal to 0.05). The control group showed no slowing of cadence at any incremental stage. When directly comparing the ABI with the control group, the change in cadence observed in dual-task conditions was only significantly different in stage 3 ( p less than or equal to 0.05). Conclusions: Clinicians should be aware of the possibility that giving additional cognitive tasks ( such as monitoring exercise intensity) while individuals with acquired brain injury are performing exercises may detrimentally affect performance. The effect may be more marked when the individuals are performing exercise at higher intensities.

Diacylglycerol-induced protection against injury during ischemia and reperfusion can be achieved without activation of protein kinase C in the rat heart: Comparative studies with ischemic preconditioning

The role of protein kinase C (PKC) activation in ischemic preconditioning remains controversial. Since diacylglycerol is the endogenous activator of PKC and as such might be expected cardioprotective, we have investigated whether: (i) the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol (DOG) can protect against injury during ischemia and reperfusion; (ii) any effect is mediated via PKC activation; and (iii) the outcome is influenced by the time of administration. Isolated rat hearts were perfused with buffer at 37°C and paced at 400 bpm. In Study 1, hearts (n=6/group) were subjected to one of the following: (1) 36 min aerobic perfusion (controls); (2) 20 min aerobic perfusion plus ischemic preconditioning (3 min ischemia/3 min reperfusion+5 min ischemia/5 min reperfusion); (3) aerobic perfusion with buffer containing DOG (10 μM) given as a substitute for ischemic preconditioning; (4) aerobic perfusion with DOG (10 μM) during the last 2 min of aerobic perfusion. All hearts then were subjected to 35 min of global ischemia and 40 min reperfusion. A further group (5) were perfused with DOG (10 μM) for the first 2 min of reperfusion. Ischemic preconditioning improved postischemic recovery of LVDP from 24±3% in controls to 71±2% (P<0.05). Recovery of LVDP also was enhanced by DOG when given just before ischemia (54±4%), however, DOG had no effect on the recovery of LVDP when used as a substitute for ischemic preconditioning (22±5%) or when given during reperfusion (29±6%). In Study 2, the first four groups of study were repeated (n=4–5/group) without imposing the periods of ischemia and reperfusion, instead hearts were taken for the measurement of PKC activity (pmol/min/mg protein±SEM). PKC activity after 36 min in groups (1), (2), (3) and (4) was: 332±102, 299±63, 521±144, and 340±113 and the membrane:cytosolic PKC activity ratio was: 5.6±1.5, 5.3±1.8, 6.6±2.7, and 3.9±2.1 (P=NS in each instance). In conclusion, DOG is cardioprotective but under the conditions of the present study is less cardioprotective than ischemic preconditioning, furthermore the protection does not appear to necessitate PKC activation prior to ischemia.

Involvement of ERK, Akt and JNK signalling in H2O2-induced cell injury and protection by hydroxytyrosol and its metabolite homovanillic alcohol

The olive oil polyphenol, hydroxytyrosol (HT), is believed to be capable of exerting protection against oxidative kidney injury. In this study we have investigated the ability of HT and its O-methylated metabolite, homovanillic alcohol (HVA) to protect renal cells against oxidative damage induced by hydrogen peroxide. We show that both compounds were capable of inhibiting hydrogen peroxide-induced kidney cell injury via an ability to interact with both MAP kinase and PI3 kinase signalling pathways, albeit at different concentrations. HT strongly inhibited death and prevented peroxide-induced increases in ERK1/2 and JNK1/2/3 phosphorylation at 0.3 microM, whilst HVA was effective at 10 microM. At similar concentrations, both compounds also prevented peroxide-induced reductions in Akt phosphorylation. We suggest that one potential protective effect exerted by olive oil polyphenols against oxidative kidney cell injury may be attributed to the interactions of HT and HVA with these important intracellular signalling pathways.

Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease

RATIONALE: Children with congenital heart disease are at risk of gut barrier dysfunction and translocation of gut bacterial antigens into the bloodstream. This may contribute to inflammatory activation and organ dysfunction postoperatively. OBJECTIVES: To investigate the role of intestinal injury and endotoxemia in the pathogenesis of organ dysfunction after surgery for congenital heart disease. METHODS: We analyzed blood levels of intestinal fatty acid binding protein and endotoxin (endotoxin activity assay) alongside global transcriptomic profiling and assays of monocyte endotoxin receptor expression in children undergoing surgery for congenital heart disease. MEASUREMENTS AND MAIN RESULTS: Levels of intestinal fatty acid binding protein and endotoxin were greater in children with duct-dependent cardiac lesions. Endotoxemia was associated with severity of vital organ dysfunction and intensive care stay. We identified activation of pathogen-sensing, antigen-processing, and immune-suppressing pathways at the genomic level postoperatively and down-regulation of pathogen-sensing receptors on circulating immune cells. CONCLUSIONS: Children undergoing surgery for congenital heart disease are at increased risk of intestinal mucosal injury and endotoxemia. Endotoxin activity correlates with a number of outcome variables in this population, and may be used to guide the use of gut-protective strategies.

Start where you are: Graphic ordering influences improvisational dance

This article is an analysis and reflection on the role of lists and diagrams in Start where you are, a multimedia improvisational piece performed as part of square zero independent dance festival: the second edition/la deuxième édition. This interdisciplinary festival was organised by collective (gulp) dance projects and took place in Ottawa, Canada, in August 2005. Start where you are was the result of a collaboration between the authors: two dance artists (Andrew and MacKinnon, the principals of (gulp)) and a visual communication designer (Gillieson). A sound artist and a lighting technician also participated in the work. This is a post-performance retrospective meant to analyze more closely the experience that meshed the evidentiary weight of words and graphics with the ephemerality and subjectivity of movement-based live performance. It contextualizes some of the work of collective (gulp) within a larger tradition of improvisation in modern dance. It also looks at how choice-making processes are central to improvisation, how they relate to Start, and how linguistic material can intersect with and support improvisational performance. Lastly, it examines some characteristics of lists and diagrams, unique forms of visual language that are potentially rich sources of material for improvisation.