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Background: Ethanol (EtOH), one of the most widely consumed substances of abuse, can induce brain damage and neurodegeneration. EtOH is centrally metabolized into acetaldehyde, which has been shown to be responsible for some of the neurophysiological and cellular effects of EtOH. Although some of the consequences of chronic EtOH administration on cell oxidative status have been described, the mechanisms by which acute EtOH administration affects the brain's cellular oxidative status and the role of acetaldehyde remain to be elucidated in detail. Methods: Swiss CD‐I mice were pretreated with the acetaldehyde‐sequestering agent d‐penicillamine (DP; 75 mg/kg, i.p.) or the antioxidant lipoic acid (LA; 50 mg/kg, i.p.) 30 minutes before EtOH (2.5 g/kg, i.p.) administration. Animals were sacrificed 30 minutes after EtOH injection. Glutathione peroxidase (GPx) mRNA levels; GPx and glutathione reductase (GR) enzymatic activities; reduced glutathione (GSH), glutathione disulfide (GSSG), glutamate, g‐L‐glutamyl‐L‐cysteine (Glut‐Cys), and malondialdehyde (MDA) concentrations; and protein carbonyl group (CG) content were determined in whole‐brain samples. Results: Acute EtOH administration enhanced GPx activity and the GSH/GSSG ratio, while it decreased GR activity and GSSG concentration. Pretreatment with DP or LA only prevented GPx activity changes induced by EtOH. Conclusions: Altogether, these results show the capacity of a single dose of EtOH to unbalance cellular oxidative homeostasis.

Este artículo se encuentra disponible en la siguiente URL: https://www.nature.com/articles/s41598-021-99448-w.pdf Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment.

Ischemic retinopathies (IRs) are the main cause of severe visual impairment and sight loss, and are characterized by loss of blood vessels, accompanied by hypoxia, and neovascularization. Actual therapies, based on anti-vascular endothelial growth factor (VEGF) strategies, antioxidants or anti-inflammatory therapies are only partially effective or show some adverse side effects. Abscisic acid (ABA) is a phytohormone present in vegetables and fruits that can be naturally supplied by the dietary intake and has been previously studied for its benefits to human health. It has been demonstrated that ABA plays a key role in glucose metabolism, inflammation, memory and tumor growth. This review focuses on a novel and promising role of ABA as a potential modulator of angiogenesis, oxidative status and inflammatory processes in the retina, which are the most predominant characteristics of the IRs. Thus, this nutraceutical compound might shed some light in new therapeutic strategies focused in the prevention or amelioration of IRs-derived pathologies. Generalitat Valenciana (Prometeo 94/2016) and Universitat Jaume I (UJI-A2016-03) 5.014 JCR (2019) Q1, 56/297 Biochemistry & Molecular Biology, 7/61 Chemistry, Medicinal, 10/139 Food Science & Technology 1.100 SJR (2019) Q1, 23/130 Clinical Biochemistry; Q2, 133/456 Biochemistry, 140/300 Cell Biology, 176/414 Molecular Biology, 61/186 Physiology No data IDR 2019 UEV

Oxidative stress has been widely studied in association to ultra-endurance sports. Although it is clearly demonstrated the increase in reactive oxygen species and free radicals after these extreme endurance exercises, the effects on the antioxidant defenses and the oxidative damage to macromolecules, remain to be fully clarified. Therefore, the aim of this study was to elucidate the impact of an ultramarathon race on the plasma markers of oxidative stress of 32 runners and their post-race recovery, with especial focused on sex and age effect. For this purpose, the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR) activity, as well as the lipid peroxidation product malondialdehyde (MDA) and the carbonyl groups (CG) content were measured before the race, in the finish line and 24 and 48 h after the race. We have reported an increase of the oxidative damage to lipids and proteins (MDA and CG) after the race and 48 h later. Moreover, there was an increase of the GR activity after the race. No changes were observed in runners’ plasma GPx activity throughout the study. Finally, we have observed sex and age differences regarding damage to macromolecules, but no differences were found regarding the antioxidant enzymes measured. Our results suggest that several basal plasma markers of oxidative stress might be related to the extent of muscle damage after an ultraendurance race and also might affect the muscle strength evolution.

Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.

Diabetic patients present an increased susceptibility to frequent and protracted infections. The recognition of an impaired immune system has implications for the diagnosis, treatment and outcome of infections. Nuclear Factor kappa B (NF-kappaB) is a redox sensitive transcription factor involved in immune response, cell proliferation and apoptosis that has been associated to the development of diabetic complications. Herein we study the effects of high glucose on oxidative stress markers (malondialdeyde and glutathione contents) and NF-kappaB activity in U937 cells (a human promonocytic cell line). Furtheremore effects of lutein treatment in lymphocytes from diabetic rats was studied. The results show that high glucose induces oxidative stress in immune system cells, both in vitro and in vivo, as well as an increase in their NF-kappaB activity. It is also showed that lutein, a natural antioxidant without hypoglycemiant properties, is able to prevent all the alterations observed. Thus, this study confirms the role of oxidative stress in the immune system impairment described in diabetes, and allows the proposal of antioxidants for the clinical management of the diabetes-associated susceptibility to infections.

5 pages, 3 figures.-- PMID: 17964420 [PubMed].-- Printed version published on Dec 2007., Antioxidants can be useful as a supportive therapy in diabetes, and we try to elucidate some of the mechanisms by which these compounds are able to protect from diabetic complications. For this purpose we have assayed, in vitro and in vivo, the ability of CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran), an antioxidant able to scavenge nitrogen reactive species, to protect glutathione peroxidase (GPx) activity. Glucose, in vitro, inhibited GPx activity in a concentration-dependent manner; CR-6 was able to protect GPx activity from glucose-induced inactivation. Alloxan-induced experimental diabetes in mice promoted oxidative stress in the retina and hippocampus, after 3 weeks of hyperglycemia. CR-6 administration prevented not only the alterations of oxidative stress markers (tissue GSH and malondialdehyde (MDA) concentration and GPx activity) but also the impairment of retinal function (as assessed by the modifications in electroretinogram b-wave amplitude). The findings herein confirm the role of nitrogen reactive species in diabetes; therefore, antioxidants effectively quenching these species, such as CR-6, should be considered for the adjuvant treatment of diabetes., Partially supported by Project PI03/1710 from FIS to F.B.-M. and PRUCHA06/29 from FUSP to F.J.R.

Wolfberry (Lycium barbarum) extracts have been used in the treatment of some retinal degenerative diseases, mostly associated with other antioxidants. The ones this chapter focuses on are retinitis pigmentosa and age-related macular degeneration. Hereditary retinal dystrophies are a broad (and growing) group of hereditary disorders affecting the retina. Retinitis pigmentosa is perhaps the best known of them and is sometimes (inaccurately) used as a synonym for some of the other conditions in this category. Although these two entities show completely different etiologies: The first one is a group of hereditary diseases in which photoreceptor death occurs due to different mutations, and in the second the loss of photoreceptors is associated to the aging process, in both oxidative damage has been claimed as a pathophysiological mechanism. The present chapter reviews the antioxidant chemical features of wolfberry and wolfberry extracts, the oxidative mechanisms involved in the pathophysiology of photoreceptor cell death, and the existing data on the use of wolfberry for retinal degenerations.

Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction.

Oxidative stress markers and functional tests were studied to confirm early biochemical and functional changes in retina and hippocampus of diabetic mice. The effects of lutein treatment were also tested. Mice were induced diabetic by alloxan injection and divided into subgroups: control, control+lutein, diabetic, diabetic+lutein, diabetic+insulin, and diabetic+insulin+lutein. Treatments started on Day 4 after alloxan injection and animals were sacrificed on Day 14. Malondialdehyde and glutathione concentrations and glutathione peroxidase activity were measured as oxidative stress markers. The following functional tests for retina and hippocampus were performed: electroretinogram and Morris water maze test. NFkappaB activity was also measured. Oxidative stress and NFkappaB activity increase in the retina and hippocampus after 15 days of diabetes. Impairment of the electroretinogram and a correlation between latencies of the water maze test and glycated hemoglobin (HbA1c) levels were observed. Lutein prevented all these changes even under hyperglycemic conditions. Retina appears to be affected earlier than hippocampus by diabetes-induced oxidative stress. Although a proper glycemic control is desirable in preventing the development of diabetic complications, it is not sufficient to prevent them completely. Lutein could be an appropriate coadjuvant treatment for the changes observed in this study.

Breastfeeding and human milk are widely accepted as optimal for human infants' nutrition. Nowadays lifestyle often makes it difficult to maintain or even initiate human lactation. This situation is mostly related to the workload of women away from home. New approaches are needed to enable maternal lactation under these circumstances. Human breastmilk storage for differed use is one possibility. The aim of this study was to assess changes in glutathione peroxidase (GPx) activity and in the concentration of the lipid peroxidation marker, malondialdehyde (MDA), when human milk was kept refrigerated or frozen. Thirty-two human milk samples were assayed for GPx activity and MDA concentration. Samples were divided in three aliquot portions, the first to be immediately analysed, the second to be refrigerated at 4 degrees C and analysed 24 h thereafter, and the third to be frozen at -20 degrees C and assayed after 10 days. GPx activity was significantly decreased in refrigerated and in frozen milk, when compared to their control samples. MDA was increased only in refrigerated milk but not in frozen samples. Thus, freezing seems better than refrigeration in order to prevent lipid peroxidation in stored human milk samples.

A major pathogenic mechanism of chronic alcoholism involves oxidative burden to liver and other cell types. We show that adult neurogenesis within the dentate gyrus of the hippocampus is selectively impaired in a rat model of alcoholism, and that it can be completely prevented by the antioxidant ebselen. Rats fed for 6 weeks with a liquid diet containing moderate doses of ethanol had a 66.3% decrease in the number of new neurons and a 227–279% increase in cell death in the dentate gyrus as compared with paired controls. Neurogenesis within the olfactory bulb was not affected by alcohol. Our studies indicate that alcohol abuse, even for a short duration, results in the death of newly formed neurons within the adult brain and that the underlying mechanism is related to oxidative or nitrosative stress. Moreover, these findings suggest that the impaired neurogenesis may be a mechanism mediating cognitive deficits observed in alcoholism.

Serum malondialdehyde (MDA) levels are increased in human immunodeficiency virus (HIV)-infected children, as it happens also in infected adult individuals. Introduction of high activity antiretroviral therapy (HAART) has promoted an intense decline in morbidity and mortality of these patients. Here we present data on the effect of HAART on serum MDA of HIV+ children and compare them with levels prior to HAART. MDA levels reflect, as other markers do, the HAART-induced clinical improvement and probably also the pro-oxidant/antioxidant side effects of the different drugs used. The results herein allow the proposal of including serum MDA levels as an additional parameter for the clinical management of HIV+ children.

Purpose: Cocaine abuse is a major public health problem with multiple-related complications. Indeed, cocaine can affect almost every organ of the human body, but little is known about its effects on the visual system. The main purpose of this work was to study if topiramate was able to reverse changes in retinal metabolism and retinal function induced by chronic cocaine exposure in adult rats. Materials and methods: Sixteen Wistar rats were treated with a daily oral dose of cocaine during 36 days. Sixteen rats receiving NaCl 0.9% served as controls. Eight control and eight cocaine animals were administered topiramate from day 18 to day 36 of the experiment. Malondialdehyde (MDA), glutathione (GSH) and glutamate content, as well as glutathione peroxidase (GPx) activity in retina tissue homogenates were determined. Retinal function was assessed by electroretinogram (ERG). Results: Glutamate concentration was increased in the retinas of cocaine-treated rats. No changes in oxidative stress parameters were observed in the retinas of cocaine-treated rats when compared with the control ones. Cocaine induced a decrease in the a-wave and b-wave ERG amplitude. The administration of topiramate reversed cocaine-induced increase in glutamate concentration and had little effect on a-wave and b-wave ERG amplitude. Topiramate, a drug used during the last decade for the treatment of epileptic seizures, is able to reverse the cocaine-induced alterations observed in retinal glutamate concentration. Conclusions: We can conclude that retinal glutamate metabolism and function may be affected by exposure to cocaine. We confirm that topiramate, a treatment recently proposed for cocaine dependence, is also able to recover partially cocaine-induced changes in the retina.

Inflammation results in the production of free radicals. We evaluated the anti-inflammatory and antioxidant capacity of lipoic acid in an experimental uveitis model upon a subcutaneous injection of endotoxin into Lewis rats. The role of oxidative stress in the endotoxin-induced uveitis model is well-known. Besides, the Th1 response classically performs a central part in the immunopathological process of experimental autoimmune uveitis. Exogenous sources of lipoic acid have been shown to exhibit antioxidant and anti-inflammatory properties. Our results show that lipoic acid treatment plays a preventive role in endotoxin-induced oxidative stress at 24 h post-administration and reduced Th1 lymphocytes-related cytokines by approximately 50–60%. Simultaneously, lipoic acid treatment caused a significant reduction in uveal histopathological grading and in the protein concentration in aqueous humors, but not in cellular infiltration.

Naltrexone, an antagonist of 𝜇�-opioid receptors, is clinically used as adjuvant therapy of alcohol dishabituation. The aim of the present work was to test the effect of 1 mg/kg body weight of naltrexone to revert oxidative stress-related biochemical alterations, in the hippocampus and serum of chronic alcoholic adult rats. Malondialdehyde concentration was increased and glutathione peroxidase activity was decreased in hippocampus and serum of alcohol-treated rats. Naltrexone treatment restored these alterations. The in vitro antioxidant ability of Ntx could not justify these effects considering the doses used. Thus this apparent protective effect of Ntx can only be attributed to its pharmacological effects, as herein discussed. Ministerio de Educacion y Ciencia SAF2010-21317 Universidad Catolica de Valencia "San Vicente Martir" 2012-029-001 Plan Nacional sobre Drogas 2010/059 AI/ICB-Santander 07/12

Este artículo se encuentra disponible en la siguiente URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155353 Aims. The main goal of this study was to evaluate the presence of oxidative damage and to quantify its level in gestational diabetes. Methods. Thirty-six healthy women and thirty-six women with gestational diabetes were studied in the three trimesters of pregnancy regarding their levels of oxidative stress markers. These women were diagnosed with diabetes in the second trimester of pregnancy. Blood glucose levels after 100g glucose tolerance test were higher than 190, 165 or 145 mg/dl, 1, 2 or 3 hours after glucose intake. Results. The group of women with gestational diabetes had higher serum malondialdehyde levels, with significant differences between groups in the first and second trimester. The mean values of serum glutathione peroxidase activity in the diabetic women were significantly lower in the first trimester. In the group of women with gestational diabetes there was a negative linear correlation between serum malondialdehyde concentration and glutathione peroxidase activity in the second and third trimester. Conclusions. In this observational and longitudinal study in pregnant women, the alterations attributable to oxidative stress were present before the biochemical detection of the HbA1c increase. Usual recommendations once GD is detected (adequate metabolic control, as well as any other normally proposed to these patients) lowered the concentration of malondialdehyde at the end of pregnancy to the same levels of the healthy controls. Serum glutathione peroxidase activity in women with gestational diabetes increased during the gestational period.

AIMS Early ethanol consumption could be a risk factor for young brain integrity and its maturation, and also for the development of addictive behaviors in adulthood. Neuronal nitric oxide synthase (nNOS) expressing neurons are specifically located in the subgranular layer (SGL) of dentate gyrus and may be relevant for hippocampal neurogenesis. The focus of this work is aimed to determine local changes in the nNOS-like immunoreactive (nNOS-LIR) cell populations of the SGL after chronic ethanol exposure in young adult and mature adult rats. METHODS We used the nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (NADPH-d) reaction as a qualitative marker of nNOS enzyme activity. We also analyzed the nNOS-LIR cell density by the nNOS immunocytochemistry in order to compare these two methods of labeling. Dorsal striatum (CPu) was also analyzed in order to compare two neural areas with high nNOS-LIR cell density. RESULTS The young adult group showed less hippocampal NADPH-d(+) cell density than the mature adult group. Interestingly, the NADPH-d(+) cell density was increased in the SGL of the young adult ethanol-treated group, whereas it decreased in the mature adult ethanol-treated group, when compared with their respective controls. No change was observed in any of the groups for the hippocampal nNOS-LIR cell density and no differences could be established in CPu for nNOS-LIR and NADPH-d(+) cell densities in any of the groups studied. CONCLUSION The NADPH-d expression is affected by chronic ethanol exposure in opposite ways between both age groups studied. Further studies are needed to evaluate the relative importance of these findings, especially when considering human subjects

et al., The aim of this study was to demonstrate the existence of alterations in glutathione and cholesterol homeostasis in brain mitochondria from alcoholic rats. Glutathione concentration decreased, whereas oxidized glutathione and cholesterol contents increased in these organelles, suggesting the ethanol-induced generation of reactive oxygen species, and the impairment of mitochondrial uptake of glutathione, possibly due to the increase in cholesterol deposition. The release of apoptogenic proteins was increased after stimulating mitochondria from the brain of alcoholic rats with atractyloside. As a conclusion, chronic alcohol consumption might sensitize brain mitochondria to apoptotic stimuli, and promote the subsequent release of apoptotic proteins., This work was supported in part by Funds from Ministerio de Ciencia e Innovación (SAF 2007- 66801), Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), Ingenio 2010 initiative, RTA (Red de Transtornos Adictivos) and Consolider programms from Instituto de Salud Carlos III, Coopernicus-Santander Programm of the Universidad CEU- Cardenal Herrera, Dirección General de Drogodependencias (Generalitat Valenciana) and FEPAD (Fundación para el Estudio, Prevención y Ayuda a la Drogadicción).

Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycemia. It is often associated with complications, such as cataracts. Cataract, characterized by cloudiness or opacity of the eye lens, is the leading cause of blindness worldwide. The present study investigated the effect of lutein, alone or combined with insulin on the progression of eye lens opacities in streptozotocin-diabetic rats for a period of 12 weeks. Tissue markers of oxidative stress were also determined at the end of the experiment. Herein we demonstrate that lutein treatment prevents the development and progression of cataracts (0 eyes with mature cataract, and ten out of 16 eyes with clear lenses in the lutein-treated diabetic animals group, vs. seven and three eyes in the non-treated diabetic group, respectively). Lipid peroxidation is significantly increased in diabetic lens (up to three-fold); lutein and insulin, alone or in combination, are able to prevent this alteration. Only insulin and lutein together could prevent the diabetes-induced decrease of glutathione content. The combined treatment with lutein and insulin is useful in preventing the development of cataracts in streptozotocin-induced diabetic rats, supporting its utility in diabetes management, especially when a tight metabolic control is difficult to achieve.

Aim: Pasteurization is the thermal treatment usually applied in milk banks to eliminate the risk of transmission of infectious agents. The aim of this study was to investigate the effect of heat processing upon the antioxidant properties of human milk. Methods: Milk samples collected from 31 healthy women were subjected to two different pasteurization techniques: Holder pasteurization (63°C for 30 min) and high pasteurization (75°C for 15 sec) and oxidative stress markers (glutathione, glutathione peroxidase activity, malondialdehyde and total antioxidant capacity) were determined in comparison to fresh milk. Results: Malondialdehyde concentration was the same in all samples, while there was a decrease in glutathione concentration and total antioxidant capacity in milk samples subjected to thermal processing versus fresh milk samples. However, the drop in these parameters was seen to be significantly greater when applying Holder pasteurization. Both thermal treatments induced considerable and similar loss of glutathione peroxidase activity. Conclusion: Thermal processing of human milk implies a decrease in its antioxidant properties but, when necessary, high pasteurization should be the election method in terms of milk oxidative status.

Aims: Ethanol consumption originates a wide spectrum of disorders, including alteration of visual function. Oxidative stress is included among the mechanisms by which alcohol predisposes nervous tissue to injury. Retina, which is the neurosensorial eye tissue, is particularly sensitive to oxidative stress. Methods: In this study we analyze the effect of long-term alcohol consumption on oxidative stress parameters of the rat retina, and its correlation to retinal function, as well as to the expression of the antiapoptotic protein Bcl-2. We also study the protective effect of ebselen, a synthetic selenoorganic antioxidant. Results: Herein we show that ethanol has a toxic effect on rat retina associated with oxidative stress. Decreases in retina glutathione concentration and increases in malondialdehyde content in whole eye homogenate significantly correlate with ERG b-wave decrease and Bcl-2 overexpression. We also show how ebselen is able to prevent all the alterations observed. Conclusion: Chronic ethanol consumption induces oxidative stress in rat retina associated with an impairment of ERG and Bcl-2 overexpression, suggesting a role for glial cells. All these alterations in the rat allow the proposal of an alcoholic retinopathy in this species.