The clonal selection/defence paradigm appears unable to reconcile immune function with homeostatic activity whereas organismic homeostasis is central to immune function in the network/autopoiesis paradigm. The aim of this investigation, therefore, was to test the proposition that immune function, that is not clonally driven (central immune system activity), contributes to organismic homeostasis in collaboration with psychoneural responses. In one experiment sheep were confined, either in groups or individually, and the time course of changes in cortisol levels, behaviour and T lymphocyte numbers were monitored. In another study, soldiers were monitored during the stressful experience of recruit training. The combined results suggest that, at least when the immune response is not clonally driven, the psychoneural system and the central immune system may not be operating independently of each other but rather as sub-networks of the organismic network. Consequently, homeostasis is properly characterised as a property of the whole organism. In autopoietic terms, then, homeostasis could be defined as the maintenance of network stability. / Doctor of Philosophy (PhD)

This thesis is concerned with cellular responses to stress including the adaptive response to H2O2, and the cellular roles of sumoylation in stress responses. 286 H2O2-sensitive Saccharomyces cerevisiae deletion mutants were screened and YAP1, SKN7, GAL11, RPE1, TKL1, IDP1 were identified to be important for adaptation to H2O2. The mutants fell into two groups based on their responses to acute and chronic doses of H2O2. Transcription factors Yap1p, Skn7p and Gal11p were important for both acute and chronic responses to H2O2. Yap1p and Skn7p were needed for up-regulation of anti-oxidant functions rather than generation of NADPH or glutathione. Adaptation was reduced in strains deleted for GPX3 and YBP1, which are involved in sensing H2O2 and activating Yap1p, but to a lesser extent than YAP1 deletion. RPE1, TKL1 and IDP1 deletants affected in NADPH production were chronically sensitive to H2O2, but resistant to an acute dose and other mutants affected in NADPH generation were also affected in adaptation. These mutants overproduced reduced glutathione (GSH) but maintained normal cellular redox homeostasis. Over-production of GSH was not regulated by transcription of the gene encoding -glutamylcysteine-synthetase. The Skn7p transcription factor is therefore important for the adaptive response to oxidative stress-induced by H2O2, and NADPH generation is also required for adaptation. The roles of sumoylation in stress responses and transcriptional regulation were examined by deleting the SUMO ligases Siz1p and Siz2p. Siz1p is required for tolerance to copper ions and DNA damage repair. Siz2p is involved in repression of stress responses, particularly oxidative stress and is required for activation of nucleotide and RNA metabolism, DNA processing and cell division. Both Siz1p and Siz2p act in parallel in the repressing heat-shock responses and in reducing chronological life span. Genome-wide transcriptional analysis showed that Siz1p and Siz2p repress the mitochondrial retrograde pathway and arginine biosynthesis, while activating some carbon and nitrogen metabolism genes. Sumoylation of proteins in the wild type was induced by nitrogen starvation or mitochondrial inhibition during the initial treatment. However, nitrogen starvation led to some protein degradation, while the SUMO-conjugated proteins were recycled in cells with disrupted mitochondrial functions.

In the wild, when an animal is exposed to predators or harsh conditions, the stress response is often associated with fleeing behaviors, which are seen as increased locomotor behavior. Handling-stress procedures and intracerebroventricular (icy) injection of corticotropin-releasing factor (CRF) have both been shown to cause an increase in locomotor activity in roughskin newts (Taricha granulosa). The present experiments were designed to determine if icv administration of corticosterone (CORT) prevents stress-induced locomotor increases in activity, if it prevents CRF-induced increases in locomotor activity, and if the time-course and pharmacological specificity of the CORT effects on locomotor activity fit the model for intracellular or membrane receptors. In experiment 1, newts which had been injected with CORT or dexamethasone (DEX) received a standardized handling-stress procedure. Corticosterone administration was able to suppress the increase in locomotor activity in newts exposed to handling-stress at 20 minutes after administration. This effect was transient (no longer present at 2 hours after the injection) and not mimicked by DEX, a synthetic glucocorticoid that binds to intracellular and not membrane receptors. In experiments 2 and 3, either CORT or DEX was administered in the same icy injection with CRF. CORT suppressed CRF-induced locomotor activity in some cases, but this action of CORT seems to be context dependent. Results for DEX-injected newts were confounded the failure of CRF to induced significant increases in locomotor activity. There was variability in the effect of CRF on locomotor activity across seasons. Based on time-course and specificity, it appears that CORT can modulate locomotor activity in newts through mechanisms involving the membrane receptor. Variability in the effects of CRF on locomotor activity in newts suggests there may be seasonal differences in responses to stress. / Graduation date: 1998

Thesis (M.S.)--Oregon State University, 2007. / Printout. Includes bibliographical references (leaves 39-43). Also available on the World Wide Web.

Thesis (Ph. D.)--University of Hong Kong, 1987.

Thesis (Ph. D.)--University of Oregon, 2002. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 125-137). Also available for download via the World Wide Web; free to University of Oregon users.

Genes involved in xenobiotic metabolism and antioxidant signaling are enhanced in the liver of long-lived models, suggesting that a link exists between increased stress resistance and longevity assurance. The ability of certain dietary components such as electrophiles and molecules with high redox potential to induce low-dose stimulation of the endogenous cellular adaptive response is proposed to confer increased resistance to environmental stressors, and thereby present a strategy for lifespan assurance. Recently the term ‘hormetics' was applied to dietary antioxidants possessing this activity, in particular those functioning as indirect antioxidants through the induction of stress responsive pathways. Despite recognition of vitamin E as an essential micronutrient in the diet, very little is still known about its biological role, therefore further investigation into its signaling properties and those of its metabolites are required. This thesis details an investigation into the potential role of vitamin E and its long-chain metabolites in the cellular adaptive stress response in a representative hepatic cell line (HepG2), with the purpose of identifying preliminary targets to aid further comprehension of the role of vitamin E in human health and disease. A global transcriptomic approach was used to identify genes differentially regulated by alpha-tocopherol, these included candidates involved in phase I and II xenobiotic metabolism, the cellular antioxidant response and DNA damage repair. Determination of intracellular alpha-tocopherol levels indicated that up-regulation of gene targets occurred in a concentration-dependent manner. Furthermore, this induction occurred in the presence of significantly elevated levels of short-chain metabolites, alpha-carboxymethylbutyl-hydroxychroman (CMBHC) and alpha-carboxyethyl-hydroxychroman (CEHC), suggesting that metabolism of alpha-tocopherol may be important for its signaling function in HepG2 cells. The role of long-chain metabolites of alpha-tocopherol in cellular stress responsive signaling was also investigated in HepG2 cells. The long-chain metabolites were found to alter mitochondrial metabolism in a concentration-dependent manner, and subsequently to induce components of the Nrf-2 signaling pathway suggesting that these metabolites may be potential hormetic agents, and require further investigation into their role in human health.

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