Antonio Ayala

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 μg of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-α; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.

Protective effect of folic acid against oxidative stress produced in 21-day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period.

In this paper we show the protective effect of folic acid on oxidative stress in offspring caused by chronic maternal ethanol consumption during pregnancy and the lactation period. Glutathione reductase (GR) specific activity was assayed in liver and pancreas of offspring and mothers. In the offspring, these tissues were also assayed for markers of oxidative damage to lipids and proteins. The results show that ethanol exposure during pregnancy and lactation increased the specific activity of GR in tissues of the mothers (32–34% increase) as well as in the liver of their progeny (24%). Thiobarbituric acid reactive substances (TBARS) were also increased in the liver and pancreas of 21-day-old rats (37- and 54%, respectively). Alcohol also increased the amount of carbonyl groups in proteins in both tissues. These measures of ethanol-mediated oxidative stress were mitigated when pregnant rats were treated with folic acid concomitantly to ethanol administration. The antioxidant capacity of folic acid seems to be involved in its protective effect. The results obtained in the present work suggest that folic acid may be useful in the prevention of damage and promotion of health of the progeny of ethanol-treated rats.

Correlation between circulating biomarkers of oxidative stress of maternal and umbilical cord blood at birth

The objective of the work was to study the relationship between the oxidative state of the mother and the newborn at the moment of birth. We measured oxidative stress markers (carbonyl groups, lipid peroxides and total antioxidant capacity (TAC)) and found a good correlation between the oxidative state of the normal mother and the neonate, since a high mother oxidative stress corresponds to an even higher oxidative stress of the newborn in umbilical cord blood. We also found that smoking mothers and their newborns had a higher concentration of the carbonyl group, lipid peroxides and less TAC. Newborns from these mothers weighed significantly less than others at birth. These data suggest a need for interest in monitoring the oxidative state of mothers during the pregnancy period, especially taking into account that the oxidative level could be involved in later risks of metabolic diseases for both mother and newborn.

Protective effect of melatonin against the 1-methyl-4-phenylpyridinium-induced inhibition of Complex I of the mitochondrial respiratory chain

In the present study, a novel property of melatonin is shown: a protective effect of melatonin on the respiratory chain in isolated rat liver mitochondria and in striatal synaptosomes treated with 1‐methyl‐4‐phenylpyridinium ion (MPP+). The cellular damage caused by MPP+, a compound that produces a Parkinsonian‐like syndrome in humans, is the result of the mitochondrial respiration inhibition at the Complex I level and oxidative stress induction. Treatment of mitochondria with MPP+ inhibits the respiration rate. This effect was prevented by the inclusion of melatonin in the incubation mixture. This preventive effect, which is not related to the antioxidative properties of melatonin, seems to be due to the fact that melatonin prevents MPP+ interaction with Complex I. These results suggest that melatonin may protect against the effect of several Parkinsonogenic compounds that are associated with progressive impairment of mitochondrial function and increased oxidative damage.

Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study

IntroductionCritically ill patients suffer from oxidative stress caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Although ROS/RNS are constantly produced under normal circumstances, critical illness can drastically increase their production. These patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers or cofactors, and decreased activity of the enzymatic system involved in ROS detoxification. The pro-oxidant/antioxidant balance is of functional relevance during critical illness because it is involved in the pathogenesis of multiple organ failure. In this study the objective was to evaluate the relation between oxidative stress in critically ill patients and antioxidant vitamin intake and severity of illness.MethodsSpectrophotometry was used to measure in plasma the total antioxidant capacity and levels of lipid peroxide, carbonyl group, total protein, bilirubin and uric acid at two time points: at intensive care unit (ICU) admission and on day seven. Daily diet records were kept and compliance with recommended dietary allowance (RDA) of antioxidant vitamins (A, C and E) was assessed.ResultsBetween admission and day seven in the ICU, significant increases in lipid peroxide and carbonyl group were associated with decreased antioxidant capacity and greater deterioration in Sequential Organ Failure Assessment score. There was significantly greater worsening in oxidative stress parameters in patients who received antioxidant vitamins at below 66% of RDA than in those who received antioxidant vitamins at above 66% of RDA. An antioxidant vitamin intake from 66% to 100% of RDA reduced the risk for worsening oxidative stress by 94% (ods ratio 0.06, 95% confidence interval 0.010 to 0.39), regardless of change in severity of illness (Sequential Organ Failure Assessment score).ConclusionThe critical condition of patients admitted to the ICU is associated with worsening oxidative stress. Intake of antioxidant vitamins below 66% of RDA and alteration in endogenous levels of substances with antioxidant capacity are related to redox imbalance in critical ill patients. Therefore, intake of antioxidant vitamins should be carefully monitored so that it is as close as possible to RDA.

Low selenium diet increases the dopamine turnover in prefrontal cortex of the rat

It has been proposed that interaction of catecholamines and indoleamines with free radicals may result in the formation of endogenous neurotoxins. In order to better understand the mechanisms involved in neurodegenerative disorders showing evidence of oxidative stress, we have studied the basal concentrations and the turnover rates of dopamine, noradrenaline, serotonin and their metabolites in the prefrontal cortex of rats that were fed on control or low selenium diets. Nutritional deficit of selenium decreases the brain antioxidant protection in experimental conditions by the decrease in glutathione peroxidase activity. The dopamine and serotonin turnover increased and noradrenaline and 5-hydroxy-3-indoleacetic acid turnover decreased compared to experimental control animals. The increase of dopamine turnover in experimental rats was accompanied by an increase in tyrosine hydroxylase activity. These results suggest that the decrease of brain protection against oxidative damage could induce brain damage by disturbing the turnover rate of some monoamines.

Oxidative inactivation of tyrosine hydroxylase in substantia nigra of aged rat

Study of the tyrosine hydroxylase enzyme from substantia nigra and striatum during the aging period of the rat has discovered a significant decrease (55%) of TH activity in substantia nigra between 12 and 24 mo of age. The amount of TH in substantia nigra also decreased (30%) during aging. This loss in TH activity of substantia nigra appears to be produced by the decrease in TH content along with an inactivation process. Our finding showed a significant increase of carbonyl groups in the proteins of rat substantia nigra with aging. A statistically significant increase of carbonyl groups in TH enzyme was found in aged rat brain substantia nigra, indicating that oxidative damage could be the inactivation process that explains the decrease in TH activity found during aging. This hypothesis was corroborated by the fact that when rat striatal homogenate was incubated with hydrogen peroxide, there was a time-dependent decrease in TH activity, which highly correlated with measurements of carbonyl groups content of TH enzyme. The importance of these results may be in their relationship, considering that substantia nigra is preferentially affected in many neurodegenerative disorders.

Effects of aging on the various steps of protein synthesis: fragmentation of elongation factor 2

The possible mechanism responsible for the in vivo protein synthesis decline during aging was studied. In order to determine the effect of aging on the various steps of protein synthesis, we determined the ribosomal state of aggregation and the time of assembly and release of polypeptide chains in the process of protein synthesis in rat liver. The results suggest that elongation is the most sensitive step to aging. A molecular study of the Elongation Factor 2 (EF-2), the main protein involved in the elongation step, shows that this protein has a higher content of carbonyl groups and is less active in old rats. In addition, the molecular mass analysis of EF-2 shows that this protein becomes fragmented in old rats. A similar pattern of fragmentation is found in 3-month-old rats suffering oxidative stress, in that the decline in protein synthesis is similar to that found in old rats. These data suggest that: i) oxidative stress seems to be involved in the modifications of EF-2 observed during aging, and ii) the observed modifications (oxidation and fragmentation) of EF-2 could account for the decline in protein synthesis in old animals.

Chronic stress as a risk factor for Alzheimer’s disease

Abstract This review aims to point out that chronic stress is able to accelerate the appearance of Alzheimer’s disease (AD), proposing the former as a risk factor for the latter. Firstly, in the introduction we describe some human epidemiological studies pointing out the possibility that chronic stress could increase the incidence, or the rate of appearance of AD. Afterwards, we try to justify these epidemiological results with some experimental data. We have reviewed the experiments studying the effect of various stressors on different features in AD animal models. Moreover, we also point out the data obtained on the effect of chronic stress on some processes that are known to be involved in AD, such as inflammation and glucose metabolism. Later, we relate some of the processes known to be involved in aging and AD, such as accumulation of β-amyloid, TAU hyperphosphorylation, oxidative stress and impairement of mitochondrial function, emphasizing how they are affected by chronic stress/glucocorticoids and comparing with the description made for these processes in AD. All these data support the idea that chronic stress could be considered a risk factor for AD.