The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression

The amyloid cascade hypothesis suggests that the insoluble and fibrillar form of beta-amyloid (A beta) may play a primary pathogenic role in Alzheimer disease at the molecular level. However, neither the rate of dementia nor the extent of neuronal change seems to correlate with the levels of amyloidotic plaques (i.e., aggregated/fibrillar A beta). Recent evidence suggests, however, that neurotoxicity may be exerted also by rather small soluble aggregates of A beta, including oligomers. To characterize the mechanisms underlying toxicity mediated by the various aggregation states of A beta peptides is then a major goal of research. In this work we investigated the effects of fibrillar, prefibrillar, and oligomeric A beta(1-42) on the induction of oxidative stress, cell death, and BACE-1 expression in NT2 neuronal cells. We found that prefibrillar and oligomeric A beta(1-42) resulted in a more dramatic increase in the oxidative stress markers 4-hydroxynonenal and hydrogen peroxide compared to fibrillar A beta(1-42). Moreover, increased oxidative stress levels also resulted in a more rapid and significant induction of both apoptotic and necrotic neuronal cell death. Accordingly, fibrillar A beta(1-42), but not the soluble nonfibrillar forms, was the only condition able to up-regulate BACE-1 expression and activity.     

"Effect of resveratrol on oxidative and inflammatory stress in liver and spleen of streptozotocin-induced type 1 diabetic rats"

"It has been well known that both oxidative stress and inflammatory activity play crucial roles in the pathogenesis of type 1 diabetes mellitus (T1DM). Resveratrol (RSV), a naturally occurring polyphenol found in grapes and red wine, has recently been shown to exert potent anti-diabetic, anti-oxidative and anti-inflammatory actions. In the present study, we investigated the effect of RSV on oxidative stress and inflammatory response in the liver and spleen of streptozotocin (STZ)-induced type 1 diabetic animal models. Male Long-Evans rats were injected with 65 mg/kg STZ to induce diabetes for 2 weeks, and subsequently administrated with the dosage of 0.1 or 1 mg/kg/day RSV for 7 consecutive days. Hepatic and splenic tissues were dissected for evaluation of oxidative and inflammatory stress. Oxidative stress was assessed by quantification of oxidative indicators including superoxide anion content, lipid and protein oxidative products, as well as manganese superoxide dismutase (Mn-SOD) and nitro-tyrosine protein expression levels. Inflammatory stress was evaluated by the levels of nuclear factor κB (NF-κB) and the proinflammatory cytokine tumor necrosis factorα (TNF-α), interleukin 1 β (IL-1 β ) and IL-6. The experimental results indicated that RSV significantly decreased oxidative stress (superoxide anion content, protein carbonyl level and Mn-SOD expression) in both tissues and hepatic inflammation (NF- κB and IL-1 β ), but implicated proinflammatory potential of RSV in diabetic spleen (TNF-α and IL-6). The results of this study suggest that RSV may serve as a potent antioxidant, but RSV possesses a proinflammatory potential in certain circumstances in diabetes."     

Comparative analysis of different dietary antioxidants on oxidative stress pathway genes in L6 myotubes under oxidative stress

Enhanced oxidative stress plays an important role in the progression and onset of diabetes and its complications. Strategies or efforts meant to reduce the oxidative stress are needed which may mitigate these pathogenic processes. The present study aims to investigate the in vitro ameliorative potential of nine antioxidant molecules in L6 myotubes under oxidative stress condition induced by 4-hydroxy-2-nonenal and also to comprehend the gene expression patterns of oxidative stress genes upon the supplementation of different antioxidants in induced stress condition. The study results demonstrated a marked increase in the level of malondialdehyde and protein carbonyl content with a subsequent increase in the free radicals that was reversed by the pretreatment of different dietary antioxidant. From the expression analysis of the oxidative stress genes, it is evident that the expression of these genes is modulated by the presence of antioxidants. The highest expression was found in the cells treated with Insulin in conjugation with an antioxidant. Resveratrol is the most potent modulator followed by Mangiferin, Estragole, and Capsaicin. This comparative analysis ascertains the potency of Resveratrol along with Insulin in scavenging the reactive oxygen species (ROS) generated under induced stress conditions through antioxidant defense mechanism against excessive ROS production, contributing to the prevention of oxidative damage in L6 myotubes.     

Methylglyoxal, oxidative stress, and hypertension

Pathogenic mechanisms for essential hypertension are unclear despite striking efforts from numerous research teams over several decades. Increased production of reactive oxygen species (ROS) has been associated with the development of hypertension and the role of ROS in hypertension has been well documented in recent years. In this context, it is important to better understand pathways and triggering factors for increased ROS production in hypertension. This review draws a causative linkage between elevated methylglyoxal level, methylglyoxal-induced production of ROS, and advanced glycation end products in the development of hypertension. It is proposed that elevated methylglyoxal level and resulting protein glycation and ROS production may be the upstream links in the chain reaction leading to the development of hypertension.     

Peroxisomes, oxidative stress, and inflammation

Peroxisomes are intracellular organelles mediating a wide variety of biosynthetic and biodegradative reactions.Included among these are the metabolism of hydrogen peroxide and other reactive species,molecules whose levels help define the oxidative state of cells.Loss of oxidative equilibrium in cells of tissues and organs potentiates inflammatory responses which can ultimately trigger human disease.The goal of this article is to review evidence for connections between peroxisome function,oxidative stress,and inflammation in the context of human health and degenerative disease.Dysregulated points in this nexus are identified and potential remedial approaches are presented.     

Hepatitis C virus, ER stress, and oxidative stress

Hepatitis C virus (HCV) replication is associated with the endoplasmic reticulum (ER), where the virus causes stress. Cells cope with ER stress by activating an adaptive program called the unfolded protein response (UPR), which alleviates this stress by stimulating protein folding and degradation in the ER and down-regulating overall protein synthesis. Recent work suggests that HCV also alters ER calcium homeostasis, inducing oxidative stress. Future progress in understanding the control that HCV exerts over the ER will provide insight into viral strategies for pathogenesis and persistence in chronically infected patients.     

Mitochondria, oxidative stress and aging

In the eighties, Miquel and Fleming suggested that mitochondria play a key role in cellular aging. Mitochondria, and specially mitochondrial DNA (mtDNA), are major targets of free radical attack. At present, it is well established that mitochondrial deficits accumulate upon aging due to oxidative damage. Thus, oxidative lesions to mtDNA accumulate with age in human and rodent tissues. Furthermore, levels of oxidative damage to mtDNA are several times higher than those of nuclear DNA. Mitochondrial size increases whereas mitochondrial membrane potential decreases with age in brain and liver.

Recently, we have shown that treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E or the Ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and oxidation of mitochondrial glutathione. Moreover, the extract EGb 761 also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver. Thus, mitochondrial aging may be prevented by antioxidants. Furthermore, late onset administration of certain antioxidants is also able to prevent the impairment in physiological performance, particularly motor co-ordination, that occurs upon aging.     

Mitochondria,oxidative stress and aging

In the eighties, Miquel and Fleming suggested that mitochondria play a key role in cellular aging. Mitochondria, and specially mitochondrial DNA (mtDNA), are major targets of free radical attack. At present, it is well established that mitochondrial deficits accumulate upon aging due to oxidative damage. Thus, oxidative lesions to mtDNA accumulate with age in human and rodent tissues. Furthermore, levels of oxidative damage to mtDNA are several times higher than those of nuclear DNA. Mitochondrial size increases whereas mitochondrial membrane potential decreases with age in brain and liver.

Recently, we have shown that treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E or the Ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and oxidation of mitochondrial glutathione. Moreover, the extract EGb 761 also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver. Thus, mitochondrial aging may be prevented by antioxidants. Furthermore, late onset administration of certain antioxidants is also able to prevent the impairment in physiological performance, particularly motor co-ordination, that occurs upon aging.     

Monitoring of transglutaminase2 under different oxidative stress conditions

Transglutaminase 2 (TG2) is a multifunctional calcium-dependent enzyme which catalyzes the post-translational protein crosslinking with formation of intra- or inter-molecular epsilon(gamma-glutamyl)lysine bonds or polyamine incorporation. The up-regulation and activation of TG2 have been reported in a variety of physiological events, including cell differentiation, signal transduction, apoptosis, and wound healing, as well as in cell response to stress evoked by different internal and external stimuli. Here we review TG2 role in cell response to redox state imbalance both under physiological and pathological conditions, such as neurodegenerative disorders, inflammation, autoimmune diseases and cataractogenesis, in which oxidative stress plays a pathogenetic role and also accelerates disease progression. The increase in TG activity together with mitochondrial impairment and collapse of antioxidant enzymatic cell defences have been reported to be the prominent biochemical alterations becoming evident prior to neurodegeneration. Moreover, oxidative stress-induced TG2 pathway is involved in autophagy inhibition and aggresome formation, and TG2 has been suggested to function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or proteasomal degradation. Literature data suggest a strong association between oxidative stress and TG2 up-regulation, which in turn may result in cell survival or apoptosis, depending on cell type, kind of stressor, duration of insult, as well as TG2 intracellular localization and activity state. In particular, it may be suggested that TG2 plays a pro-survival role when the alteration of cell redox state homeostasis is not associated with intracellular calcium increase triggering TG2 transamidation activity.     

Migraine, Helicobacter pylori, and oxidative stress

BACKGROUND: The aim of this study was to ascertain whether oxidative stress is a causative factor of migraine attacks for Helicobacter pylori-infected migraineurs. MATERIALS AND METHODS: A total of 35 consecutive migraine patients without aura who came to gastroenterology polyclinic with various complaints and diagnosed H. pylori infection were included in the study group and compared with a group of 29 patients (control group) without migraine and H. infection. H. pylori infection was diagnosed by histopathological biopsies, which were taken by endoscopy (Olympus-GIFXQ240 endoscope). Both the diagnosis and the classification of migraine were made according to the International Headache Society criteria. Blood samples for nitric oxide were taken from patients with migraine during headache-free period as well as the control group. The interaction of nitric oxide was measured by the determination of both nitrite and nitrate concentrations in the sample. RESULTS: The study group included 31 women and 4 men (mean age 49 +/- 8 years) and the control group included 25 women and 4 men (mean age 52.6 +/- 11 years). The mean frequency of migraine attacks was 2.94 +/- 1.58 days/month and the mean duration of attacks was 21.2 +/- 3 hours. It was found that the study group has lower nitrate levels than the control group. CONCLUSIONS: Our results do not support the role of oxidative stress in patients suffering from H. pylori infection and migraine.     

Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition

Mutations in DJ-1 gene have been linked to autosomal recessive early onset parkinsonism (AR-EOP). Although the mechanism of neuronal cell death due to DJ-1 mutation has not been fully elucidated, loss of DJ-1 function was considered to cause the phenotype. Here, we demonstrated that the down regulation of endogenous DJ-1 of the neuronal cell line by siRNA enhanced the cell death which was induced by oxidative stress, ER stress, and proteasome inhibition, but not by pro-apoptotic stimulus. The cell death with hydrogen peroxide was dramatically rescued by over-expression of wild-type DJ-1, but not by that of L166P mutant DJ-1. Furthermore, DJ-1 rescued the cell death caused by over-expression of Pael receptor, which was a substrate of Parkin, another gene product for autosomal recessive juvenile parkinsonism. These results suggest that loss of protective activity of DJ-1 from neuro-toxicity induced by these stresses contributes to neuronal cell death in AR-EOP with mutant DJ-1.     

Renal oxidative stress, oxygenation, and hypertension

Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria, and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by ANG II that limits oxygen delivery and increases oxidative stress, resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport, and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of ANG II activity, by either blocking ANG II type 1 receptors or angiotensin-converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. Therefore, it seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage, and perhaps also persistence the high blood pressure.     

Selenium, oxidative stress, and health aspects

Metabolic processes which generate oxidants and antioxidants are governed by genetic disposition as well as environmental factors. Changes in lifestyle, including increased environmental pollution, sun exposure, and dietary habits modify the challenge of the organism by reactive oxygen species. Defense mechanisms are reinforced by increasing dietary intake of antioxidants and micronutrients such as vitamins and selenium (Se). Se deficiency has been recognized to promote some disease states. Epidemiological findings link a lowered Se status to neurodegenerative and cardiovascular diseases as well as to increased cancer risk. While evidence exists to suggest that additional selenocompounds would be beneficial in some health conditions, results from future intervention trials are needed to substantiate the argument for increasing Se intake. Several pieces of the puzzle concerning the molecular mechanisms underlying the reactive oxygen species-triggered disease state and intervention by enzymatic antioxidants have been elucidated. A novel concept of protection of stromal cells against the dominating influence of tumor cells in tumor-stroma interaction by selenocompounds and other antioxidants is presented herein, which may translate into therapeutic strategies in chemoprevention of tumor invasion.     

Copper, oxidative stress, and human health

Copper (Cu), a redox active metal, is an essential nutrient for all species studied to date. During the past decade, there has been increasing interest in the concept that marginal deficits of this element can contribute to the development and progression of a number of disease states including cardiovascular disease and diabetes. Deficits of this nutrient during pregnancy can result in gross structural malformations in the conceptus, and persistent neurological and immunological abnormalities in the offspring. Excessive amounts of Cu in the body can also pose a risk. Acute Cu toxicity can result in a number of pathologies, and in severe cases, death. Chronic Cu toxicity can result in liver disease and severe neurological defects. The concept that elevated ceruloplasmin is a risk factor for certain diseases is discussed. In this paper, we will review recent literature on the potential causes of Cu deficiency and Cu toxicity, and the pathological consequences associated with the above. Finally, we will review some of the potential biochemical lesions that might underlie these pathologies. Given that oxidative stress is a characteristic of Cu deficiency, the role of Cu in the oxidative defense system will receive special attention. The concept that excess Cu may be a precipitating factor in Alzheimer's disease is discussed.     

Epigenetics,oxidative stress,and Alzheimer disease

Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the β-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-β (Aβ). Increased Aβ levels promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Aβ-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain.