Influences of maternal corticosterone and selection for contrasting adrenocortical responsiveness in Japanese quail on developmental instability of female progeny.

Differences in developmental instability were assessed in female offspring of Japanese quail hens selected for reduced (low stress, LS) or exaggerated (high stress, HS) plasma corticosterone (B) response to stress and treated with a placebo or B during egg formation. Hens of each line were implanted (s.c.) with either a silastic tube containing no B (controls) or one filled with B. Female chicks hatched from each of the 4 line x implant treatment combinations were retained for examination of 3 bilateral traits at 130 d of age: length of the tibiotarsus, middle toe length, and distance between the auditory canal and the nares (face length, FL). Greater bilateral trait size variances were associated with measurement of tibiotarsus length (P < 0.04) and middle toe length (P < 0.06) in the HS line, supporting our previous findings in the opposite sex that developmental instability (i.e., fluctuating asymmetry, FA) of certain morphological traits is more pronounced in HS than LS adult quail. The HS quail are also known to exhibit greater adrenocortical responsiveness to a wide range of stressors, and they are more easily frightened than LS birds. Therefore, the line differences in FA (HS > LS) found previously in males and herein in females may simply reflect the differential responsiveness of the birds to chronic social and physical environmental stressors. In addition, the present study detected more (albeit marginally so, P < 0.06) bilateral variability (i.e., heightened FA) in FL of quail hatched from mothers treated with B, a finding entirely due to the very high FL variance observed in the female offspring of B-treated HS hens. Because others have found in ovo B treatment to be associated with heightened FA in chick tarsus bone length and because we have also demonstrated that greater yolk B deposition occurs in eggs from both unstressed and stressed HS quail hens than their LS counterparts, the present maternal B treatment may be acting independently, or in combination with HS genomic effects, to adversely affect developmental stability.

Proliferation and transmission patterns of Pasteurella multocida B:2 in goats.

This report describes the proliferation and transmission patterns of Pasteurella multocida B:2 among stressful goats, created through dexamethasone injections. Thirty seven clinically healthy adult goats were divided into three groups consisted of 15 goats in group A, 11 goats in group B and the remaining 11 in group C. At the start of the study, all goats of group A were exposed intranasally to 1.97 x 10(10) CFU/ml of live P multocida B:2. Dexamethasone was immediately administered intramuscularly for 3 consecutive days at a dosage rate of 1 mg/kg. The exposed goats were observed for signs of HS for a period of 1 month. At the end of the 1-month period, 11 goats from group B were introduced into and commingled with the surviving goats of group A before all goats from both groups were immediately injected intramuscularly with dexamethasone for 3 consecutive days. The treatment with dexamethasone was then carried out at monthly interval throughout the 3-month study period. Goats of group C were kept separately as negative control. Three surviving goats from each group were killed at 2-week interval for a complete post-mortem examination. Two (13%) goats of group A were killed within 24 hours after intranasal exposure to P multocida B:2 while another two (13%) goats from the same group were killed on day 40, approximately 10 days after the second dexamethasone injection. All four goats showed signs and lesions typical of haemorrhagic septicaemia. Bacteraemia was detected in 3 goats of group A that were having rectal temperature higher than 41degrees C. The P. multocida B:2 isolation pattern was closely associated with dexamethasone injections when significantly (p < 0.05) higher rate of isolations from both groups were observed after each dexamethasone injection. Transmission of P multocida B:2 from goats of group A to group B was successful when P multocida B:2 was isolated from goats of group B for a period of 28 days. There was a strong correlation between dexamethasone injections, rate of bacterial isolation and serum cortisol level. The IgG level showed an increasing trend 2 weeks after exposure to P multocida B:2 and remained high throughout the study period.

Investigation of emission-transmission misalignment artifacts on rubidium-82 cardiac PET with adenosine pharmacologic stress.

PURPOSE: This study was undertaken to determine if artifacts from misalignment of cardiac emission to transmission data is present in adenosine stress studies and if the artifact could be reproduced by intentional misalignment in normal exams. PROCEDURES: Seventy consecutive 82Rb myocardial perfusion studies were reviewed. Utilizing a quality control program, misalignment was assessed. The study was reprocessed after manual realignment to determine if the defect extent changed. Emission and transmission acquisitions in six normal studies also were intentionally misaligned. RESULTS: Twenty of 69 rest studies (29.0%) and 17 of 69 (24.6%) stress studies demonstrated misalignment. In four patients with stress misalignment, there was a significant change in clinical interpretation. Upon intentionally misaligning six normal studies, a lateral wall defect was reproduced. CONCLUSIONS: Emission-transmission misalignment occurs in 29.0% and 24.6% of 82Rb rest and adenosine stress studies, respectively. While there is a positive correlation of artifactual defects with misalignment, the presence and size of artifacts is variable and unpredictable at seemingly lesser degrees of misalignment.

Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior.

Aldosterone is the last component of the renin-angiotensin-aldosterone system inducing its peripheral effects via mineralocorticoid receptors (MR). Brain MR bind preferentially glucocorticoids. So far, the role of MR in behavioral functions has been investigated almost exclusively in relation to glucocorticoids. Recently, aldosterone itself has been linked to affective disorders. The aim of this study was to test the hypothesis that chronic elevation of circulating levels of aldosterone leads to increased anxiety. We have investigated the effects of chronic aldosterone treatment on (1) anxiety-like behavior, and (2) basal and stress-induced levels of selected hormones. Forty male Wistar rats were subcutaneously implanted with osmotic minipumps and treated with aldosterone (2 microg/100 g/day) or vehicle for two weeks. Aldosterone concentrations in plasma showed a mild (approximately four-fold) increase at the end of two-week aldosterone treatment. This mild hyperaldosteronism resulted in a significant enhancement of anxiety as demonstrated by alterations in all indicators of anxiety-like behavior measured in the open field and elevated plus-maze tests, without significant changes in measures of general locomotor activity. Aldosterone treatment affected not only the spatiotemporal measures of anxiety, but also the ethological parameters related to exploration and risk assessment. Chronic treatment with aldosterone was associated with increased water intake and decreased plasma renin activity, but failed to modify basal or stress-induced activity of the hypothalamic-pituitary-adrenocortical axis. The results provide evidence on anxiogenic action of prolonged increase in circulating aldosterone concentrations. Thus, aldosterone may represent an important target for future antidepressant and anxiolytic drug development.

Angiotensin and NMDA receptors in the median preoptic nucleus mediate hemodynamic response patterns to stress.

The brain renin-angiotensin system plays an important role in the regulation of arterial pressure in response to stress, in part due to activation of AT1 receptors in the hypothalamic median preoptic nucleus (MnPO) by endogenous angiotensin II (ANG II). N-methyl-d-aspartate (NMDA) receptors are also involved in the angiotensinergic signaling pathway through the MnPO. We investigated whether AT1 and NMDA receptors in the MnPO are responsible for variable hemodynamic response patterns to stress. Cocaine or startle with cold water evoked a pressor response in Sprague-Dawley rats due, in some rats [vascular responders (VR)], to a large increase in systemic vascular resistance (SVR) and, in other rats [mixed responders (MR)], to small increases in SVR and cardiac output (CO). Microinjection of the GABAA agonist muscimol into the MnPO to block synaptic transmission attenuated the cocaine- or stress-induced increase in SVR and the decrease in CO seen in VR without altering either response in MR. Likewise, administration of either an AT1 receptor antagonist, losartan, or an NMDA receptor antagonist, MK-801, attenuated the increase in SVR and the decrease in CO in VR in response to either cocaine (losartan and MK-801) or startle with cold water (losartan) without altering either response in MR. We propose that the MnPO is responsible for greater SVR responses in VR and that AT1 and NMDA receptors play an important role in greater SVR responses in VR. These data provide additional support for the critical role of the MnPO in cardiovascular responses to stress.

Stress-response hormesis and aging: "that which does not kill us makes us stronger".

Hormesis refers to the beneficial effects of a treatment that at a higher intensity is harmful. In one form of hormesis, sublethal exposure to stressors induces a response that results in stress resistance. The principle of stress-response hormesis is increasingly finding application in studies of aging, where hormetic increases in life span have been seen in several animal models.

Impairment of the stress response in matrinxã juveniles (Brycon amazonicus) exposed to low concentrations of phenol.

In this study we measured plasma cortisol, plasma glucose, plasma sodium and potassium, and liver and gill hsp70 levels in juvenile matrinxã (Brycon amazonicus) subjected to a 96 h exposure to phenol (0, 0.2, and 2.0 ppm), and the effect of this exposure on their ability to respond to a subsequent handling stress. Fish were sampled prior to initiation of exposure and 96 h, and at 1, 6, 12, and 24 h post-handling stress. During the 96 h exposure, plasma cortisol and glucose levels remained unchanged in all treatments. While plasma sodium levels were significantly reduced in all groups, plasma potassium levels only decreased in fish exposed to 0 and 0.2 ppm of phenol. Liver hsp70 levels decreased significantly at 96 h in fish exposed to 2.0 ppm of phenol. All groups, except fish exposed to 0.2 ppm of phenol, were able to increase plasma cortisol and glucose levels after handling stress. Fish exposed to 2.0 ppm of phenol showed decreased gill and liver hsp70 levels after the handling stress. Our data suggest that exposure to phenol may compromise the ability of matrinxã to elicit physiological responses to a subsequent stressor.

Preventive effect of a traditional herbal medicine, Hochu-ekki-to, on immunosuppression induced by surgical stress.

PURPOSE: To examine the effect of preoperative administering of a Japanese traditional herbal medicine, Hochu-ekki-to (TJ-41), on immunosuppression induced by surgical stress in patients with gastrointestinal malignancies. METHODS: To monitor the immune functions, the mitochondrial membrane potential (MMP) and natural killer (NK) cell activity prior to and following operation were measured in peripheral blood lymphocytes (PBL) in patients with (n = 20) or without (n = 27) the preoperative administering of TJ-41 for 7 days. The plasma catecholamine and interleukin (IL)-6 levels were also analyzed prior to and following the operation. RESULTS: The numbers of MMP-high CD56-positive cells (NK cells) and NK cell activities in the TJ-41-treated group were significantly higher than those in the control group (P = 0.026 and P = 0.037, respectively). An elevation of plasma noradrenaline and IL-6 following surgery was also inhibited by the preoperative administering of TJ-41 (P = 0.023 and P = 0.039, respectively). A positive correlation between MMP-high CD56-positive cell numbers and NK cell activity in PBL treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) in vitro suggested that MMP measurement in CD56-positive cells can serve as a convenient alternative to evaluate the NK cell activity. CONCLUSION: Our findings suggest that the preoperative administering of TJ-41 prevents surgical stress-induced immunosuppression by maintaining the NK cell activity and inhibiting the elevation of stress mediators.

Expression of heat shock transcription factors and heat shock protein 72 in rat retina after intravitreal injection of low dose N-methyl-D-aspartate.

The heat shock response is a genetically well-ordered process for cell to generate heat shock protein (HSP). Various stressors can trigger the response through heat shock transcriptional factor (HSF) regulation. Recent studies demonstrated that preconditioning of N-methyl-d-aspartate (NMDA) at non-lethal levels has neuroprotective effects, but the exact mechanisms are unclear. We hypothesize that the protective mechanisms of NMDA preconditioning could involve HSP expression. To understand the regulatory mechanisms of HSP under stress, we examined the expression of Hsp72, HSF1 and HSF2 in the adult rat retina after intravitreal injection of NMDA. Retinal ganglion cell (RGC) counting with retrograde labeling showed that 8 nmol, but not 0.8 nmol, of intravitreal NMDA reduced RGC survival. Western blotting and immunohistochemistry showed that non-lethal (0.8 nmol) doses of NMDA induced a time-dependent expression of HSF1 and HSF2, and that the expression of HSF1 and HSF2 in the RGC layer peaked between 9 and 18 h after injection. Parallel to the increased HSF expression, immunohistochemistry and in situ hybridization demonstrated that Hsp72 mRNA and protein expression increased 9 and 12 h after non-lethal NMDA injection, respectively. Our findings suggest that the expression of HSF1 and HSF2 is associated with the Hsp72-related stress response.

Mitochondria are involved in stress response of A549 alveolar cells to halothane toxicity.

During inhalation anaesthesia lung epithelial cells are directly exposed to halogenated hydrocarbons such as halothane. Information about the effects of volatile anaesthetics on lung cells is rather limited although their noxious effect on the A549 alveolar cells has been shown recently. The present study indicated that halothane decreases cell viability, impairs DNA integrity and provokes stress-induced apoptosis in A549 cells when applied at clinically relevant concentrations. Data obtained clearly demonstrated intensive expression of anti-apoptotic Bcl-2 protein during treatment with all tested concentrations. In post-treatment periods the increased DNA injury was accompanied by reduction of Bcl-2 expression. We concluded that the in vitro effect of halothane on lung cells involved alteration in the expression of proteins of the mitochondrial apoptotic pathway.

Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress.

A disintegrin and metalloprotease (ADAM) 10 is the main candidate enzyme for the alpha-secretase processing of the amyloid precursor protein (APP). Neuron-specific ADAM10 overexpression proved beneficial in the APP[V717I] mutant Alzheimer mouse model [Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456-1464]. Since Alzheimer patients have a high prevalence for epileptic seizures, we investigated the effects of ADAM10 modulation under conditions of experimentally induced epileptic seizures. In this context we also examined whether ADAM10 effects were influenced by APP levels. Therefore we compared severity of kainate-induced seizures, neurodegeneration and inflammation in double transgenic mice overexpressing functional ADAM10 or a dominant negative ADAM10 mutant in the APP[V717I] background with single transgenic ADAM10 modulated mice. Double transgenic dominant negative ADAM10dn/APP[V717I] mice suffered from stronger epileptic seizures, had a longer recovery period and showed more neurodegeneration and glial activation in the hippocampal region than double transgenic mice moderately overexpressing functional ADAM10 (ADAM10mo/APP[V717I]) and APP[V717I] mice with endogenous ADAM10 levels. This suggests that ADAM10 activity is necessary to provide neuroprotection against excitotoxicity in the APP[V717I] mouse model. Interestingly, increased expression of functional ADAM10 above the endogenous level did not correlate with a better protection against seizures and neurodegeneration. Furthermore, ADAM10 dominant negative mice without transgenic APP overexpression (ADAM10dn) were seizing for a shorter time and showed less neuronal cell death and neuroinflammation after kainate injection than wild-type mice, which shows beneficial effects of ADAM10 inhibition in context with neurodegeneration. In contrast, mice with a high ADAM10 overexpression showed more seizures and stronger neuronal damage and inflammation than wild-type mice and mice with moderate ADAM10 overexpression. Hence, additional cleavage products of ADAM10 may counterbalance the neuroprotective effect of alpha-secretase-cleaved APP in the defense against excitotoxicity. Our findings highlight the need of a careful modulation of ADAM10 activity for neuroprotection depending on substrate availability and on neurotoxic stress conditions.

Decreased epithelial barrier function evoked by exposure to metabolic stress and nonpathogenic E. coli is enhanced by TNF-alpha.

A defect in mitochondrial activity contributes to many diseases. We have shown that monolayers of the human colonic T84 epithelial cell line exposed to dinitrophenol (DNP, uncouples oxidative phosphorylation) and nonpathogenic Escherichia coli (E. coli) (strain HB101) display decreased barrier function. Here the impact of DNP on macrophage activity and the effect of TNF-alpha, DNP, and E. coli on epithelial permeability were assessed. DNP treatment of the human THP-1 macrophage cell line resulted in reduced ATP synthesis, and, although hyporesponsive to LPS, the metabolically stressed macrophages produced IL-1beta, IL-6, and TNF-alpha. Given the role of TNF-alpha in inflammatory bowel disease (IBD) and the association between increased permeability and IBD, recombinant TNF-alpha (10 ng/ml) was added to the DNP (0.1 mM) + E. coli (10(6) colony-forming units), and this resulted in a significantly greater loss of T84 epithelial barrier function than that elicited by DNP + E. coli. This increased epithelial permeability was not due to epithelial death, and the enhanced E. coli translocation was reduced by pharmacological inhibitors of NF-kappabeta signaling (pyrrolidine dithiocarbamate, NF-kappabeta essential modifier-binding peptide, BAY 11-7082, and the proteosome inhibitor, MG132). In contrast, the drop in transepithelial electrical resistance was unaffected by the inhibitors of NF-kappabeta. Thus, as an integrative model system, our findings support the induction of a positive feedback loop that can severely impair epithelial barrier function and, as such, could contribute to existing inflammation or trigger relapses in IBD. Thus metabolically stressed epithelia display increased permeability in the presence of viable nonpathogenic E. coli that is exaggerated by TNF-alpha released by activated immune cells, such as macrophages, that retain this ability even if they themselves are experiencing a degree of metabolic stress.

Alcohol-induced stress in painful alcoholic neuropathy.

Chronic alcohol consumption induces a painful small-fiber peripheral neuropathy, the severity of which increases during alcohol withdrawal. Chronic alcohol consumption also produces a sustained increase in stress hormones, epinephrine and corticosterone, that is exacerbated during alcohol withdrawal. We report that adrenal medullectomy and administration of a glucocorticoid receptor antagonist, mifepristone (RU 38486), both prevented and reversed a model of painful peripheral neuropathy in alcohol binge-drinking rats. Chronic administration of stress levels of epinephrine to rats that had undergone adrenal medullectomy and were being fed the alcohol diet reconstituted this phenotype. Intrathecal administration of oligodeoxynucleotides antisense to the beta(2)-adrenergic- or glucocorticoid-receptor also prevented and reversed the pro-nociceptive effects of ethanol. Our results suggest a convergence of the effects of mediators of the hypothalamic-pituitary- and sympathoadrenal-stress axes on sensory neurons in the induction and maintenance of alcohol-induced painful peripheral neuropathy.

Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents.

ER stress can cause hepatic insulin resistance and steatosis. Increased VLDL secretion could protect the liver from ER stress-induced steatosis, but the effect of lipid-induced ER stress on the secretion of VLDL is unknown. To determine the effect of lipids on hepatic ER stress and VLDL secretion, we treated McA-RH7777 liver cells with free fatty acids. Prolonged exposure increased cell triglycerides, induced steatosis, and increased ER stress. Effects on apoB100 secretion, which is required for VLDL assembly, were parabolic, with moderate free fatty acid exposure increasing apoB100 secretion, while greater lipid loading inhibited apoB100 secretion. This decreased secretion at higher lipid levels was due to increased protein degradation through both proteasomal and nonproteasomal pathways and was dependent on the induction of ER stress. These findings were supported in vivo, where intravenous infusion of oleic acid (OA) in mice increased ER stress in a duration-dependent manner. apoB secretion was again parabolic, stimulated by moderate, but not prolonged, OA infusion. Inhibition of ER stress was able to restore OA-stimulated apoB secretion after prolonged OA infusion. These results suggest that excessive ER stress in response to increased hepatic lipids may decrease the ability of the liver to secrete triglycerides by limiting apoB secretion, potentially worsening steatosis.

Biological response of chickens (Gallus gallus domesticus) induced by corticosterone and a bacterial endotoxin.

Experiments were conducted with chickens exposed to corticosterone and lipopolysaccharide (LPS) from Escherichia coli, with the aim of evaluating and differentiating their effects on endocrine, metabolic and immune response. Both, corticosterone and LPS significantly elevated plasma corticosterone concentrations and increased heterophil to lymphocyte (H/L) ratios 1 h, 3 h and 24 h post-treatments. Repeated exposure to corticosterone caused a prolonged elevation of plasma corticosterone concentration and H/L ratio. Data on blood metabolites demonstrated that corticosterone stimulated hyperglycaemia, hypercholesterolemia and hypertriglyceridemia. In contrast, LPS induced hypocholesterolemia and hypotriglyceridemia at 24 h post-injection. Weight gain and relative weight of the spleen and bursa were reduced in chickens treated with corticosterone. The LPS did not show any significant effect on weekly weight gain, but stimulated an increase in the relative weight of the spleen. Corticosterone initially stimulated antibody responsiveness to infectious bronchitis virus (IBV) vaccination, but thereafter the titres decreased. This was in contrast to LPS which depressed the antibody titre to IBV vaccination. It was concluded that the biological response of chickens induced by corticosterone could be differed from the response to LPS. The major difference occurred in metabolic, growth and immune activities. It appears that, both corticosterone and LPS differently alter physiological, metabolic and immunological responses of chickens through an activation of different molecular components (cytokines and chemokines) and neuroendocrine-immune network systems.

A study on pathogenesis of sudden death syndrome in broiler chickens.

Sudden death syndrome (SDS) in fast growing broiler chickens has been recognized as a patho-physiological entity for four decades, but its pathogenesis still remains unknown. More recent investigations provided evidence that link SDS to cardiac arrhythmia, but the mechanism triggering arrhythmogenesis and factors responsible for fatal outcome are poorly understood. In order to understand the chain of events leading to SDS in broilers, the present study focused on putative mechanisms that trigger arrhythmia and mechanisms that predispose the myocardium to fatal arrhythmia. Susceptibility of broilers to cardiac arrhythmia under stress conditions was evaluated using a simulated stress test with epinephrine. Detailed histopathological evaluation of the broiler heart was undertaken to identify structural features that may predispose the myocardium to fatal arrhythmia. The simulated stress challenge revealed that many broilers are highly susceptible to stress induced cardiac arrhythmia. In some broilers the stress challenge induced severe ventricular arrhythmia, and the life threatening nature of this arrhythmia was evidenced by the fact that several birds showing the most severe arrhythmic responses, died suddenly within several days after the stress challenge. Examination of hearts of broilers that died of SDS revealed microscopic lesions in the cardiomyocytes, and widespread changes in the sub-endocardial and mural His-Purkinje system (HPS). Immune staining for Caspase-3 confirmed that numerous Purkinje cells in the left ventricular myocardium from broiler chickens that died of SDS were undergoing apoptosis. The observed lesions suggest that the electrical stability of the myocardium was compromised. Taken together, our findings indicate that stress is a most likely trigger of cardiac arrhythmia in broilers, whereas the pathological changes seen in the myocardium and in the HPS in fast growing broilers provide a very conducive milieu for sustained ventricular arrhythmia. In cases where the electrical stability of the myocardium is compromised, even an episodic arrhythmic event may readily degenerate to catastrophic ventricular fibrillation and sudden death. We conclude that the combination of stress and changes in the cardiomyocytes and HPS are the key requisite features in the pathogenesis of SDS.

Involvement of mitochondria in endoplasmic reticulum stress-induced apoptotic cell death pathway triggered by the prion peptide PrP(106-126).

Prion disorders are progressive neurodegenerative diseases characterized by extensive neuronal loss and by the accumulation of the pathogenic form of prion protein, designated PrP(Sc). Recently, we have shown that PrP(106-126) induces endoplasmic reticulum (ER) stress, leading to mitochondrial cytochrome c release, caspase 3 activation and apoptotic death. In order to further clarify the role of mitochondria in ER stress-mediated apoptotic pathway triggered by the PrP peptide, we investigated the effects of PrP(106-126) on the Ntera2 human teratocarcinoma cell line that had been depleted of their mitochondrial DNA, termed NT2 rho0 cells, characterized by the absence of functional mitochondria, as well as on the parental NT2 rho+ cells. In this study, we show that PrP(106-126) induces ER stress in both cell lines, given that ER Ca2+ content is low, glucose-regulated protein 78 levels are increased and caspase 4 is activated. Furthermore, in parental NT2 rho+ cells, PrP(106-126)-activated caspase 9 and 3, induced poly (ADP-ribose) polymerase cleavage and increased the number of apoptotic cells. Dantrolene was shown to protect NT2 rho+ from PrP(106-126)-induced cell death, demonstrating the involvement of Ca2+ release through ER ryanodine receptors. However, in PrP(106-126)-treated NT2 rho0 cells, apoptosis was not able to proceed. These results demonstrate that functional mitochondria are required for cell death as a result of ER stress triggered by the PrP peptide, and further elucidate the molecular mechanisms involved in the neuronal loss that occurs in prion disorders.

Stress-mediated hormetic modulation of aging, wound healing, and angiogenesis in human cells.

Aging is amenable to intervention and prevention by mild stress-induced hormesis. Previously, we have reported that repeated mild heat stress has antiaging and other beneficial effects on growth and a range of cellular and biochemical characteristics of normal human skin fibroblasts and keratinocytes undergoing aging in vitro. We have also established a model system of sugar-induced premature senescence in human cells, which can be useful for monitoring the protective and hormetic effects of other treatments. We have now initiated studies on testing the hormetic effects of glyoxal and heat shock on the wound-healing capacity of skin fibroblasts and on the angiogenic ability of endothelial cells. The effects of glyoxal on the extent of wound closure in vitro showed a typical biphasic hormetic curve with 20-40% stimulation at lower doses (up to 0.125 mmol) and more than 50% inhibition at concentrations above 0.5 mmol. In the case of angiogenesis by endothelial cells, measured by the standard tube formation assay on Matrigel, a prior exposure to mild heat shock at 41 degrees C for 1 h increased the total tube length and total number of junctions by 30-60% and 10-14%, respectively. In contrast, a severe heat shock at 42.5 degrees C had slightly inhibitory effects on total tube length and the number of junctions. These data add to the ever-growing body of evidence in support of the view that mild stress-induced hormesis can be a useful approach for the modulation, intervention, and prevention of aging and age-related impairments.

Abeta 1-42 induces mild endoplasmic reticulum stress in an aggregation state-dependent manner.

Alzheimer's disease (AD) is characterized by the aggregation of misfolded proteins. Previously we reported activation of the unfolded protein response (UPR) in AD neurons. A potential source for UPR activation in AD neurons may be the increased levels of beta-amyloid (Abeta). In this study, we used preparations enriched in oligomeric or fibrillar Abeta (1-42) to investigate the role of the conformational state of Abeta in UPR activation in differentiated neuroblastoma cells. Both oligomeric and fibrillar Abeta (1-42) do not induce BiP expression to the extent that it can be detected in a pool of cells. However, using a fluorescent UPR reporter cell line that allows analysis of individual cells, we demonstrated mild activation of the UPR by oligomeric but not fibrillar Abeta (1-42). We showed that oligomeric Abeta (1-42) is significantly more toxic to cells primed for UPR than is fibrillar Abeta (1-42), indicating that activation of the UPR contributes to oligomer-specific Abeta (1-42) toxicity. Because UPR activation is observed in AD brain at a stage that precedes the massive fibrillar Abeta deposition and tangle formation, this may indicate a role for nonfibrillar Abeta in the induction of the UPR in AD neurons.

Evaluation of models using corticosterone and adrenocorticotropin to induce conditions mimicking physiological stress in commercial broilers.

Three experiments (Exp) were conducted to delineate a suitable model for inducing conditions mimicking physiological stress with minimal bird handling. For Exp 1, Ross x Ross 308 male chicks were fed a control diet or a diet containing 5 mg of corticosterone (CS)/kg from d 1 to 7. For Exp 2, Ross x Ross 508 broilers received 1 of 4 dietary treatments: control; control + 4 IU/kg of BW of adrenocorticotropin (ACTH)/d i.m. from d 21 to 27; control + 8 IU/kg of BW of ACTH/d i.m. from d 21 to 27; or control + 15 mg of CS/kg of diet for 14 d from 21 to 35 d of age. In Exp 3, Ross x Ross 308 broilers were fed high or low nutrient density (ND) from 1 to 41 d of age, and 0 or 20 mg of CS/kg of diet from 18 to 21 d of age. Performance parameters (BW gain, feed intake, feed conversion, and mortality) were measured in all 3 experiments. In Exp 1, CS administration significantly decreased BW gain and decreased feed intake and mortality. In Exp 2, although ACTH injection resulted in significantly depressed performance responses relative to the control, CS administration yielded significantly stronger results. In Exp 3, ND and CS interacted (P = 0.04) to affect feed intake from d 0 to 34. Broilers fed diets containing high ND and CS had higher feed intake than broilers fed low ND and CS. From 0 to 21 and 0 to 42 d, CS decreased feed intake. Increased dietary ND improved BW gain and feed conversion in Exp 3. Also, CS decreased and increased BW gain and feed conversion, respectively, during all periods in Exp 3. Dietary addition of CS negatively impacted performance of broilers, and increasing dietary amino acid density did not ameliorate these effects.