Toxicity of Amyloid β Peptide: Tales of Calcium,Mitochondria, and Oxidative Stress

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Abeta) peptides. Although the disease undoubtedly reflects the interaction of complex multifactorial processes, Abeta itself is toxic to neurons in vitro and the load of Abeta in vivo correlates well with the degree of cognitive impairment. There has therefore been considerable interest in the mechanism(s) of Abeta neurotoxicity. We here review the basic biology of Abeta processing and consider some of the major areas of focus of this research. It is clear that both AD and Abeta toxicity are characterized by oxidative stress, alterations in the activity of enzymes of intermediary metabolism, and mitochondrial dysfunction, especially impaired activity of cytochrome c oxidase. Studies in vitro also show alterations in cellular calcium signaling. We consider the mechanisms proposed to mediate cell injury and explore evidence to indicate which of these many changes in function are primary and which secondary.     

Stress and the epigenetic landscape: a link to the pathobiology of human diseases?

Accumulating evidence points to a major role for chronic stress of cell renewal systems in the pathogenesis of important human diseases, including cancer, atherosclerosis and diabetes. Here we discuss emerging evidence that epigenetic abnormalities may make substantial contributions to these stress-induced pathologies. Although the mechanisms remain to be fully elucidated, we suggest that chronic stress can elicit heritable changes in the chromatin landscape that 'lock' cells in abnormal states, which then lead to disease. We emphasize the need to investigate epigenetic states in disease and links to stress and to consider how the knowledge gained through these studies may foster new means of disease prevention and management.     

Sociologists,Archbishops, and ‘making a verb of a noun’

ABSTRACT

Contemporary discussion about race has a tendency to set off out without first checking the rear view mirror. In Theories of Race and Ethnicity: Contemporary Debates and Perspectives, in contrast, Murji and Solomos identify what has and has not been covered, and so appeal at the outset for a ‘more sustained’ account of changing research agendas of race and ethnic relations. Taken as a whole, the collection allows the editors to contemplate ‘what factors explain the mobilizing power of ideas about race and ethnicity in the contemporary environment?' and whether indeed ‘it is the “real” rather than race that should be placed in quotation marks’.     

Stress and the developing hippocampus: a double-edged sword?

The mechanisms that regulate neuronal function are a sum of genetically determined programs and experience. The effect of experience on neuronal function is particularly important during development, because early-life positive and adverse experience (stress) may influence the still “plastic” nervous system long-term. Specifically, for hippocampal-mediated learning and memory processes, acute stress may enhance synaptic efficacy and overall learning ability, and conversely, chronic or severe stress has been shown to be detrimental. The mechanisms that enable stress to act as this “double-edged sword” are unclear. Here, we discuss the molecular mediators of the stress response in the hippocampus with an emphasis on novel findings regarding the role of the neuropeptide known as corticotropin-releasing hormone (CRH). We highlight the physiological and pathological roles of this peptide in the developing hippocampus, and their relevance to the long-term effects of early-life experience on cognitive function during adulthood.     

When Does Stress End? Evidence of a Prolonged Stress Reaction in Shiftworking Truck Drivers

This study aimed to analyze individual cortisol levels in relation to work conditions, sleep, and health parameters among truck drivers working day shifts (n?=?21) compared to those working irregular shifts (n?=?21). A total of 42 male truck drivers (39.8?±?6.2 yrs) completed questionnaires about sociodemographics, job content, work environment, health, and lifestyle. Rest-activity profiles were measured using actigraphy, and cardiovascular blood parameters were collected. Salivary cortisol samples were obtained: (i) at waking time, (ii) 30?min after waking, and (iii) at bedtime, during both one workday and one day off from work. Irregular-shift workers, compared to day-shift workers, showed significantly higher waist-hip ratio, very-low-density lipoprotein (VLDL) cholesterol, tiredness after work, years working as a driver, truck vibration, and less job demand (p?<?.05). High cortisol levels in irregular-shift workers were correlated with certain stressors, such as short sleep duration and low job satisfaction, and to metabolic parameters, such as total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), VLDL, and triglycerides. Day-shift workers had higher cortisol levels collected 30?min after waking (p?=?.03) and a higher cortisol awakening response (CAR; p?=?.02) during workdays compared to off days. Irregular-shift workers had higher cortisol levels on their off days compared to day-shift workers (p?=?.03). In conclusion, for the day-shift workers, a higher cortisol response was observed on workdays compared to off days. Although no direct comparisons could be made between groups for work days, on off days the irregular-shift workers had higher cortisol levels compared to day-shift workers, suggesting a prolonged stress response in the irregular-shift group. In addition, cortisol levels were correlated with stressors and metabolic parameters. Future studies are warranted to investigate further stress responses in the context of irregular work hours. (Author correspondence: crmoreno@usp.br)     

Synthesis and moisture absorption and retention activities of a carboxymethyl and a quaternary ammonium derivative of α,α-trehalose

Carboxymethyl α,α-trehalose (CMT) and a quaternary ammonium derivative of α,α-trehalose (QT) were successfully prepared, and their moisture absorption and retention activities were assessed. Results showed that both CMT and QT had better moisture absorption abilities at 43% and 81% relative humidity (RH) than α,α-trehalose. In addition, the two α,α-trehalose derivatives had better moisture retention abilities than α,α-trehalose under three humidity conditions: 81% RH, 43% RH, and under dry conditions. Therefore, carboxymethylation and quaternarization could improve the moisture absorption and retention abilities of α,α-trehalose. CMT and QT showed better moisture absorption ability and moisture retention ability than that of hyaluronan (HA), and could potentially find a use as moisture retention ingredient, for example, in cosmetics.     

Reflections of ecological differences? Stress responses of sympatric Alpine chamois and red deer to weather,forage quality,and human disturbance

Depending on the habitats they live in, temperate ungulates have adapted to different degrees to seasonally changing forage and weather conditions, and to specific escape strategies from predators. Alpine chamois, a mountain ungulate, and red deer, originally adapted to open plains, would therefore be expected to differ in their physiological responses to potential stressors. Based on 742 chamois and 1557 red deer fecal samples collected year‐round every 2 weeks for 4 years at the same locations within a strictly protected area in the Swiss Alps, we analyzed glucocorticoid metabolite (FGM) concentrations for both species. Results from linear mixed effects models revealed no physiological stress response to changing visitor numbers, but instead to drought conditions for both species during summer. In winter, FGM concentrations increased with increasing snow height in both species, but this response was modulated by temperature in red deer. Chamois showed a stronger stress response to increasing snow height during November and December than between January and March, while FGM concentrations increased with decreasing temperature throughout winter. An increase in FGM concentrations with decreasing forage digestibility during winter was found only for red deer. The results are thus partly in contradiction to expectations based on feeding type and adaptations to different habitats between the two species. The lack of a response to forage digestibility in chamois may reflect either better adaptation to difficult feeding conditions in subalpine forests, or, by contrast, strong constraints imposed by forage quality. The similar responses of both species to weather conditions in winter suggest that climatic factors at the elevations examined here are sufficiently harsh to be limiting to temperate ungulates regardless of their specific adaptations to this environment.     

Preparation and characterization of a novel polymorph of indiplon, Form α

A new polymorph α of indiplon was discovered, initially prepared by two methods, and further characterized by various means including single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), variable temperature powder X-ray diffraction (VT-PXRD), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), Fourier transform Raman (FT-Raman) spectroscopy and solubility determination. The crystal structure of Form α as analyzed by SCXRD differ from the three previously reported polymorphs, Form I, II, and III. In addition, PXRD and solubility measurements could clearly distinguish between Form α and Form I. Slight differences between the two forms were also detected by FT-Raman. No differences between Form α and I were observed by DSC, which was explained by VT-PXRD results showing a solid-solid phase change from Form α to Form I during the heating process. Solubility measurements at various temperatures showed that the two polymorphs were mutually monotropic and that Form I was the relatively thermodynamically stable crystal form.     

Effect of Zinc and Melatonin on Oxidative Stress and Serum Inhibin-B Levels in a Rat Testicular Torsion–Detorsion Model

The present study was aimed to examine the effects of 3-week zinc and melatonin administration on testicular tissue injury and serum Inhibin-B levels caused by unilateral testicular torsion–detorsion in rats. The study was performed on 60 Wistar Albino-type adult male rats. The animals were allocated to 6 groups in equal numbers. 1. Control; 2. Sham; 3. Ischemia–reperfusion; 4. Zinc + ischemia–reperfusion; 5. Melatonin + ischemia–reperfusion; 6. Zinc + melatonin + ischemia–reperfusion. Zinc and melatonin were administered before ischemia–reperfusion at doses of 5 and 3 mg/kg respectively, by intraperitoneal route for a period of 3 weeks. Testicular torsion–detorsion procedures consisted of ischemia for 1 h and then reperfusion for another hour of the left testis. Blood and testicular tissue samples were collected to analyze erythrocyte and tissue GSH and plasma and tissue MDA, Inhibin-B levels. The highest erythrocyte and testis GSH values were found in zinc, melatonin, and zinc + melatonin groups (p < 0.001). Torsion–detorsion group has significantly lower erythrocyte GSH levels and higher plasma MDA values (p < 0.001). Serum inhibin-B and spermatogenic activity levels in the torsion–detorsion group were also significantly lower than those in the other groups (p < 0.001). However, zinc-, melatonin-, and melatonin + zinc-supplemented groups have higher inhibin-B and spermatogenetic activity (p < 0.001). The results of the study show that zinc, melatonin, and melatonin + zinc administration partially restores the increased oxidative stress, as well as the reduced inhibin-B and spermatogenic activity levels in testes ischemia–reperfusion in rats. Suppressed inhibin-B levels in the testicular tissue may be a marker of oxidative stress.     

Oxidative Stress,Redox Homeostasis and Cellular Stress Response in Ménière’s Disease: Role of Vitagenes

Ménière’s disease (MD) is characterized by the triad of fluctuating hearing loss, episodic vertigo and tinnitus, and by endolymphatic hydrops found on post-mortem examination. Increasing evidence suggests that oxidative stress is involved in the development of endolymphatic hydrops and that cellular damage and apoptotic cell death might contribute to the sensorineural hearing loss found in later stages of MD. While excess reactive oxygen species (ROS) are toxic, regulated ROS, however, play an important role in cellular signaling. The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) as well as the thioredoxin/thioredoxin reductase system. In this study we tested the hypothesis that in MD patients measurable increases in markers of cellular stress response and oxidative stress in peripheral blood are present. This study also explores the hypothesis that changes in the redox status of glutathione, the major endogenous antioxidant, associated with abnormal expression and activity of carbonic anhydrase can contribute to increase oxidative stress and to disruption of systemic redox homeostasis which can be associated to possible alterations on vulnerable neurons such as spiral ganglion neurons and consequent cellular degeneration. We therefore evaluated systemic oxidative stress and cellular stress response in patients suffering from Meniere’s disease (MD) and in age-matched healthy subjects. Systemic oxidative stress was estimated by measuring protein oxidation, such as protein carbonyls (PC) and 4-hydroxynonenal (HNE) in lymphocytes of MD patients, as well as ultraweak luminescence (UCL) as end-stable products of lipid oxidation in MD plasma and lymphocytes, as compared to age-matched controls, whereas heat shock proteins Hsp70 and thioredoxin (Trx) expression were measured in lymphocytes to evaluate the systemic cellular stress response. Increased levels of PC (P < 0.01) and HNE (P < 0.05) have been found in lymphocytes from MD patients with respect to control group. This was paralleled by a significant induction of Hsp70, and a decreased expression of Trx (P < 0.01), whereas a significant decrease in both plasma and lymphocyte ratio reduced glutathione GSH) vs. oxidized glutathione (GSSG) (P < 0.05) were also observed. In conclusion, patients affected by MD are under condition of systemic oxidative stress and the induction of vitagenes Hsp70 is a maintained response in counteracting the intracellular pro-oxidant status generated by decreased content of GSH as well as expression of Trx. The search for novel and more potent inducers of vitagenes will facilitate the development of pharmacological strategies to increase the intrinsic capacity of vulnerable ganglion cells to maximize antidegenerative mechanisms, such as stress response and thus cytoprotection.     

Biomarkers of Oxidative Stress Study II: Are oxidation products of lipids,proteins, and DNA markers of CCl4 poisoning?

Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.     

Prophylactic Role of a Herbomineral Drug “Thamira Parpam” Against Cysteamine-Induced Oxidative Stress in Liver and Duodenum of Rats

Copper is known as Gunma Kaalan in Siddha literature, which means that the drug is effective for healing ulcers. The herbomineral drug “Thamira parpam” is prepared by calcining the purified copper foils with rock salt, lime juice, bracteated birth wort juice, and Alangium root decoction according to Siddha medicine. Our study investigated the possible role of Thamira parpam (TP) in the management of cysteamine-induced duodenal ulcers. Cysteamine (400 mg kg^?1?body weight^?1, two doses at 4 h interval) orally given to rats resulted in high ulcer index, increased TBARS with concomitant depletion of antioxidants such as superoxide dismutase, glutathione, glutathione peroxidase, and inflammatory markers cathepsin D, and myeloperoxidase (p?<?0.01). Herbomineral drug TP (0.5, 1, and 2 mg/kg, p.o.) challenged with cysteamine attenuated the elevation of TBARS and imbalance of antioxidants. In the increases in liver inflammatory markers, tissue histopathology changes were not severe in TP treatment. Positive control omeprazole (25 mg/kg, body weight, orally) showed considerable protection against anomaly in biochemical parameters and tissue histology. Hence, our results indicate that the attenuation of oxidative stress by the herbomineral drug in experimentally induced damage to liver and duodenum of rats could be mediated by free radical quenching property.     

Structure and stability of Gyuba, a β-lactoglobulin chimera

β-lactoglobulin (LG) contains nine β-strands (strands A-I) and one α-helix. Strands A-H form a β-barrel. At neutral pH, equine LG (ELG) is monomeric, whereas bovine LG (BLG) is dimeric, and the I-strands of its two subunits form an intermolecular β-sheet. We previously constructed a chimeric ELG in which the sequence of the I-strand was replaced with that of BLG. This chimera did not dimerize. For this study, we constructed the new chimera we call Gyuba (which means cow and horse in Japanese). The amino acid sequence of Gyuba includes the sequences of the BLG secondary structures and those of the ELG loops. The crystal structure of Gyuba is very similar to that of BLG and indicates that Gyuba dimerizes via the intermolecular β-sheet formed by the two I-strands. Thus, the entire arrangement of the secondary structural elements is important for LG dimer formation.