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Aging; Cardiomyocytes; Mitochondria Envejecimiento; Cardiomiocitos; Mitocondrias Envelliment; Cardiomiòcits; Mitocondris

The present study evaluated the effects of feeding frequency (FF) and dietary protein/carbohydrate (P/CH) ratios on intestinal histomorphology, microbiota profile, and digestive and oxidative stress-related enzyme activities of gilthead seabream (Sparus aurata). To this purpose, two practical diets were formulated: one with 50% P and 10% CH (P50/CH10) and other with 40% P and 20% CH (P40/CH20). Triplicate groups of fish with9.1±0.01 gwere fed these diets for 60 days until visual satiation at a FF of 1, 2, or 3 meals per day. Distal intestine histomorphology was not affected by diet composition or FF. However, the pyloric caeca (PC) of fish fed 1 meal per day presented more gut fold height alterations than the other groups, except in fish fed diet P50/CH10 3 meals per day, where no changes was observed. Fish fed diet P40/CH20 3 meals per day also presented higher PC submucosa cellularity than the other groups. Fish fed diet P40/CH20 presented a higher number of operational taxonomic units, microbial richness, and diversity indices than fish fed diet P50/CH10. Amylase was the only measured digestive enzyme affected by the experimental conditions, presenting higher activity in fish fed diet P50/CH10 once per day. Glucose-6-phosphate dehydrogenase activity was lower in fish fed 2 meals per day than only 1. While catalase activity was lower in fish fed 2 than 3 meals per day. Glutathione reductase activity was the only measured parameter affected both by dietary P/CH ratio and FF, being inferior in fish fed once per day the P50/CH10 diet than the P40/CH20 diet and, also in the P50/CH10 diet, to fish fed 1 than those fed 3 meals per day. Overall, no major interactions was observed between dietary P/CH ratio and FF; however, a P40/CH20 diet fed 2 meals per day might be recommended for gilthead seabream juveniles.

Abstract Oxidative stress, which occurs when an organism is exposed to an adverse stimulus that results in a misbalance of antioxidant and pro-oxidants species, is the common denominator of diseases considered as a risk factor for SARS-CoV-2 lethality. Indeed, reactive oxygen species caused by oxidative stress have been related to many virus pathogenicity. In this work, simulations have been performed on the receptor binding domain of SARS-CoV-2 spike glycoprotein to study what residues are more susceptible to be attacked by ·OH, which is one of the most reactive radicals associated to oxidative stress. The results indicate that isoleucine (ILE) probably plays a crucial role in modification processes driven by radicals. Accordingly, QM/MM-MD simulations have been conducted to study both the ·OH-mediated hydrogen abstraction of ILE residues and the induced modification of the resulting ILE radical through hydroxylation or nitrosylation reactions. All in all, in silico studies show the importance of the chemical environment triggered by oxidative stress on the modifications of the virus, which is expected to help for foreseeing the identification or development of antioxidants as therapeutic drugs. Graphic abstract

[spa] La lesión por isquemia-reperfusión (IR) es la mayor causa de pérdida y disfunción de tejidos y órganos en trasplantes clínicos, como es el trasplante hepático. Durante la isquemia, la carencia de oxígeno provoca acumulación de especies reactivas de oxígeno (ROS), que causan daños a los hepatocitos a través de la peroxidación lipídica, la oxidación de proteínas, la disfunción mitocondrial y el daño al ADN. Posteriormente, las células de Kupffer y los neutrófilos acumulados se activan en respuesta a la muerte de los hepatocitos y causan inflamación hepática. Además, la acumulación de succinato y la depleción de trifosfato de adenosina (ATP) se han considerado eventos claves para prever los daños moleculares producidos en la reperfusión. El incremento de la demanda de hígados para el trasplante así como los hábitos actuales de la población hacen que se considere la utilización de hígados esteaóticos, menos óptimos y con mayores riesgos post-trasplantes, de cara a aumentar el pool y reducir las listas de espera. La preservación de los injertos hepáticos ha resultado ser una de las terapias más efectivas para conservar el tejido y minimizar el daño por IR, como es la preservación estática en frío y la utilización de los medios de preservación. Las soluciones de preservación clásicas, como son la solución University of Wisconsin (UW) y la solución HTK (histidina-triptófano-cetoglutarato), han sido las más utilizadas hasta la actualidad. Sin embargo, en los últimos años se han desarrollado nuevas estrategias de preservación, como es la solución Institute George Lopez (IGL-1), que contiene Polietilenglicol 35 (PEG35) como agente oncótico y glutatión (GSH) como antioxidante. El objetivo de esta tesis será evaluar la eficacia de los medios de preservación disponibles actualmente así como el papel del PEG35 y el GSH en la preservación estática en frío de hígados grasos. Para ello, se preservaron los injertos hepáticos grasos (24 h, 4 ºC) en las soluciones de preservación IGL-1 y sus modificaciones (IGL-0, sin PEG35; IGL- 2, PEG35 y GSH aumentado) y las soluciones clásicas UW y HTK. Los resultados obtenidos demuestran que el PEG35 mejora el estado hepático y confiere protección mitocondrial durante la isquemia, a través de la activación de la enzima mitocondrial Aldehído Deshidrogenasa 2 (ALDH2), reduciendo la acumulación de succinato y manteniendo los niveles de ATP respecto a la preservación sin PEG35. Además, activa el factor de transcripción Nrf2, promoviendo la respuesta redox y reduciendo el estrés oxidativo (TBARS, 4-HNE y AOPP). Por otro lado, en los hígados la preservados en las soluciones con presencia de GSH y PEG35 se presentan niveles menores de estrés oxidativo, inflamación, apoptosis y piroptosis; así como IGL-2 previene la secreción de citoquinas inflamatorias respecto las soluciones UW y HTK. Finalmente, dado que la solución IGL-2 muestra una mejora de la calidad del injerto, se propone su utilización en la preservación dinámica hipotérmica oxigenada (HOPE). En conclusión, la adición de PEG35 y GSH a los medios de preservación ha demostrado ser protectora en la preservación estática en frío de los hígados esteatósicos., [eng] Ischemia-reperfusion (I/R) injury is the main cause of loss and dysfunction of tissues and organs in clinical transplants, such as liver transplants. During ischemia, oxygen deprivation causes accumulation of reactive oxygen species (ROS), which cause damage to hepatocytes through lipid peroxidation, protein oxidation, mitochondrial dysfunction, and DNA damage. Subsequently, the accumulated Kupffer cells and neutrophils become activated in response to hepatocyte death and cause hepatic inflammation. In addition, the accumulation of succinate and the depletion of adenosine triphosphate (ATP) have been considered key events to prevent the molecular damage produced in reperfusion. The increased demand for livers for transplantation, as well as the current habits of the population, make the use of steaotic livers, less optimal and with higher post-transplant risks, be considered in order to increase the pool and reduce waiting lists. . Ischemic preconditioning has proven to be one of the most effective therapies for preserving tissue and minimizing I/R damage, such as cold static dehydration and the use of dehydration media. Classical solutions, such as the University of Wisconsin (UW) solution and the HTK (histidine-tryptophan-ketoglutarate) solution, have been the most widely used to date. However, in recent years new development strategies have been developed, such as the Institute George Lopez (IGL-1) solution, which contains Polyethylene Glycol 35 (PEG35) as an oncotic agent and glutathione as an antioxidant. The objective of this thesis will be to evaluate the efficacy of currently available methods of stabilization as well as the role of PEG35 and glutathione in cold static stabilization of fatty livers. For this, the fatty liver grafts were preserved (24 h, 4 ºC) in the solutions of IGL-1 and its modifications (IGL-0, without PEG35; IGL-2, PEG35 and warm glutathione) and the classic UW and HTK solutions. The results obtained show that PEG35 improves liver status and protects mitochondrial protection during ischemia, through the activation of the mitochondrial enzyme Aldehyde Dehydrogenase 2 (ALDH2), reduces the accumulation of succinate and maintains ATP levels with respect to achieved sin PEG35. Furthermore, it activates the transcription factor Nrf2, promotes the redox response and reduces oxidative stress (TBARS, 4-HNE and AOPP). On the other hand, livers preserved in UW and HTK solutions show higher levels of oxidative stress, inflammation, apoptosis and pyroptosis; while IGL-2 prevents oxidation and inflammation. Finally, given that the IGL-2 solution shows an improvement in graft quality, its use in hypothermic oxygenated dynamics (HOPE) is proposed. In conclusion, enhancement of PEG35 and glutathione to media proved to be protective in cold static due to steatotic livers.

A prospective, randomized, single-center preliminary study was performed in patients with keratoconus stages I–III (Amsler–Krumeich), who received a high rich docosahexaenoic acid (DHA) (1000 mg/day) supplement for 3 months versus untreated patients. One eye per patient was evaluated. Thirty-four patients were recruited (75% men, mean age 31 years), with 15 randomized to the control group and 19 to the DHA-treated group. Corneal topography variables and plasma biomarkers of oxidative stress and inflammatory status were evaluated. A panel of fatty acids in blood samples was also assessed. There were significant between-group differences in the astigmatism axis, asphericity coefficient, and intraocular pressure in favor of the DHA group. Additionally, between-group significant differences in total antioxidant capacity (TAC), malondialdehyde (MDA), free glutathione (GSH) and GSH/GSSG ratio, as well as reduced values of inflammatory markers, including interleukin (IL)-4, IL-6, and vascular endothelial growth factor (VEGF-A) were found. These preliminary findings support the usefulness of the antioxidant and anti-inflammatory effects of DHA supplementation for targeting underlying pathophysiological mechanisms of keratoconus. Prolonged duration of DHA supplementation may be needed to detect more noticeable clinical changes in corneal topography.

Williams-Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder. This research was funded by Ministerio de Ciencia e Innovación (AEI/MINEICO/FEDER, UE), grant number: SAF2016-78508-R to V.C. and PID2020-113634RB-C2 to G.E.; from Association “Autour des Williams” to V.C.; and Generalitat de Catalunya (2017-SGR1794) to L.A.P.J.

Peer reviewed: True, Funder: International Agency for Research on Cancer (IARC), Funder: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Funder: NIHR Imperial Biomedical Research Centre (BRC), Funder: Danish Cancer Society (Denmark), Funder: Ligue Contre le Cancer, Funder: Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Funder: Institut National de la Santé et de la Recherche Médicale (INSERM), Funder: German Cancer Aid, Funder: German Cancer Research Center (DKFZ), Funder: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Funder: Federal Ministry of Education and Research (BMBF), Funder: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Funder: Compagnia di San Paolo, Funder: National Research Council, Funder: Dutch Ministry of Public Health, Welfare and Sports (VWS), Funder: Netherlands Cancer Registry (NKR), Funder: LK Research Funds, Funder: Dutch Prevention Funds, Funder: Dutch ZON (Zorg Onderzoek Nederland), Funder: World Cancer Research Fund (WCRF), Funder: Statistics Netherlands, Funder: Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Funder: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Funder: Catalan Institute of Oncology—ICO, Funder: Swedish Cancer Society, Funder: Swedish Research Council, Funder: County Councils of Skåne and Västerbotten, Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: -0.071 (95% CI: -0.085; -0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

Background: Although there is scientific evidence of the presence of immunometabolic alterations in major depression, not all patients present them. Recent studies point to the association between an inflammatory phenotype and certain clinical symptoms in patients with depression. The objective of our study was to classify major depression disorder patients using supervised learning algorithms or machine learning, based on immunometabolic and oxidative stress biomarkers and lifestyle habits. Methods: Taking into account a series of inflammatory and oxidative stress biomarkers (C-reactive protein (CRP), tumor necrosis factor (TNF), 4-hydroxynonenal (HNE) and glutathione), metabolic risk markers (blood pressure, waist circumference and glucose, triglyceride and cholesterol levels) and lifestyle habits of the participants (physical activity, smoking and alcohol consumption), a study was carried out using machine learning in a sample of 171 participants, 91 patients with depression (71.42% women, mean age = 50.64) and 80 healthy subjects (67.50% women, mean age = 49.12). The algorithm used was the support vector machine, performing cross validation, by which the subdivision of the sample in training (70%) and test (30%) was carried out in order to estimate the precision of the model. The prediction of belonging to the patient group (MDD patients versus control subjects), melancholic type (melancholic versus non-melancholic patients) or resistant depression group (treatment-resistant versus non-treatment-resistant) was based on the importance of each of the immunometabolic and lifestyle variables. Results: With the application of the algorithm, controls versus patients, such as patients with melancholic symptoms versus non-melancholic symptoms, and resistant versus non-resistant symptoms in the test phase were optimally classified. The variables that showed greater importance, according to the results of the area under the ROC curve, for the discrimination between healthy subjects and patients with depression were current alcohol consumption (AUC = 0.62), TNF-α levels (AUC = 0.61), glutathione redox status (AUC = 0.60) and the performance of both moderate (AUC = 0.59) and vigorous physical exercise (AUC = 0.58). On the other hand, the most important variables for classifying melancholic patients in relation to lifestyle habits were past (AUC = 0.65) and current (AUC = 0.60) tobacco habit, as well as walking routinely (AUC = 0.59) and in relation to immunometabolic markers were the levels of CRP (AUC = 0.62) and glucose (AUC = 0.58). In the analysis of the importance of the variables for the classification of treatment-resistant patients versus non-resistant patients, the systolic blood pressure (SBP) variable was shown to be the most relevant (AUC = 0.67). Other immunometabolic variables were also among the most important such as TNF-α (AUC = 0.65) and waist circumference (AUC = 0.64). In this case, sex (AUC = 0.59) was also relevant along with alcohol (AUC = 0.58) and tobacco (AUC = 0.56) consumption. Conclusions: The results obtained in our study show that it is possible to predict the diagnosis of depression and its clinical typology from immunometabolic markers and lifestyle habits, using machine learning techniques. The use of this type of methodology could facilitate the identification of patients at risk of presenting depression and could be very useful for managing clinical heterogeneity., This study was supported in part by grants from the Carlos III Health Institute through the Ministry of Science, Innovation and Universities (PI15/00662, PI15/0039, PI15/00204, PI19/01040), co-funded by the European Regional Development Fund (ERDF) “A way to build Europe”, CIBERSAM, and the Catalan Agency for the Management of University and Research Grants (AGAUR 2017 SGR 1247). We also thank CERCA Programme/Generalitat de Catalunya for institutional support. Work partially supported by Biobank HUB-ICO-IDIBELL, integrated in the Spanish Biobank Network and funded by Instituto de Salud Carlos III (PT17/0015/0024) and by Xarxa Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncologia de Catalunya (XBTC). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. YSC work is supported by the FPI predoctoral grant (FPI 2016/17) from Universidad Autonoma de Madrid. VS received an Intensification of the Research Activity Grant from the Instituto de Salud Carlos III (INT21/00055) during 2022

International audience; The cause of structural valve deterioration (SVD) is unclear. Therefore, we investigated oxidative stress markers in sera from patients with bioprosthetic heart valves (BHVs) and their association with SVD. Blood samples were taken from SVD (Phase A) and BHV patients during the first 24 (Phase B1) and >48 months (Phase B2) after BHV implantation to assess total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrotyrosine (NT). The results show that MDA levels increased significantly 1 month after surgery in all groups but were higher at 6 months only in incipient SVD patients. NT levels increased gradually for the first 24 months after implantation in the BHV group. Patients with transcatheter aortic valve implantation (TAVI) showed even higher levels of stress markers. After >48 months, MDA and NT continued to increase in BHV patients with a further elevation after 60–72 months; however, these levels were significantly lower in the incipient and established SVD groups. In conclusion, oxidative stress may play a significant role in SVD, increasing early after BHV implantation, especially in TAVI cases, and also after 48 months’ follow-up, but decreasing when SVD develops. Oxidative stress potentially represents a target of therapeutic intervention and a biomarker of BHV dysfunction.

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression.

Although antioxidants can act locally to react with an oxidant, oral administration of “antioxidants” is quite useless in treating oxidative stress in tissues. Furthermore, it does not make sense to consider a vitamin as an antioxidant, but vitamin B3 leads to the in vivo formation of compounds that are essential for reducing this stress. A rigorous treatment of the subject indicates that to deal with oxidative stress, the most direct approach is to enhance the innate antioxidant mechanisms. The question is whether this is possible through daily activities. Diets can contain the necessary components for these mechanisms or may induce the expression of the genes involved in them. Another possibility is that pro-oxidant molecules in food increase the sensitivity and power of the detoxification pathways. This option is based on well-known DNA repair mechanisms after exposure to radiation (even from the Sun), or strong evidence of induction of antioxidant capacity after exposure to powerful pro-oxidants such as H2O2. More experimental work is required to test whether some molecules in food can increase the expression of antioxidant enzymes and/or improve antioxidant mechanisms. Identifying effective molecules to achieve such antioxidant power is critical to the food and nutraceutical industries. The potential of diet-based interventions to combat oxidative stress must be viewed from a new perspective.

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from C9orf72 patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from C9orf72 patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from C9orf72 patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress and impaired mitochondrial function obtained by measuring the enzymatic activities of mitochondrial respiratory chain complexes, specifically of complex III activity. Furthermore, the results also reveal that C9orf72 patients showed an accumulation of p62 protein levels, suggesting the alteration of the autophagy process, and significantly higher protein levels of SUMO2/3 (p = 0.03). Our results provide new data reinforcing that C9orf72 cells suffer from elevated oxidative damage to biomolecules and organelles and from increased protein loads, leading to insufficient autophagy and an increase in SUMOylation processes.

[cat] El Se és un micronutrient essencial que participa en diferents funcions en humans i en animals a través de la seva incorporació en forma de selenocisteïna (Sec) a les selenoproteïnes. Una ingesta inadequada de Se es considera un factor de risc per diverses malalties cròniques associades a l’estrès oxidatiu i a la inflamació. La seva incorporació com a suplement en les dietes d’aviram és una manera efectiva de disminuir els efectes negatius de l’estrès que pateixen els animals degut a l’increment en els paràmetres de producció de la industria avícola. En el present estudi s’investiga el paper de l’anàleg de la hidroxi-selenometionina (àcid 2-hidroxi-4-metilselenobutanoic, HMSeBA), una font orgànica de Se, per donar suport a la síntesi de selenoproteïnes i a la protecció davant l’estrès oxidatiu, en dues línies cel·lulars: cèl·lules intestinals Caco-2 i macròfags (derivats de monòcits humans THP-1). El paper de l’HMSeBA en la resposta inflamatòria dels macròfags també s’ha estudiat. Per estudiar els efectes de la deficiència de Se, es va desenvolupar un model de privació de Se en ambdues línies cel·lulars. L’estudi va prosseguir amb l’avaluació dels efectes de la suplementació amb aquesta font orgànica de Se. En aquests dos models, es va estudiar la capacitat de l’HMSeBA sobre l’expressió de selenoproteïnes com la glutatió peroxidasa (GPX), la tioredoxina reductasa (TXNR) o la selenoproteïna P1 (SELENOP). A més, també es va estudiar la capacitat antioxidant de l’HMSeBA en cèl·lules estimulades amb H2O2, amb Salmonella Enteritidis o amb lipopolisacàrid (LPS), a través de la determinació de les espècies reactives d’oxigen (ROS), la formació de productes secundaris d’oxidació i l’autofluorescència de les cèl·lules. Per tal d’estudiar el paper de l’HMSeBA en la resposta inflamatòria, es va determinar la producció de citocines i la capacitat fagocítica i bactericida. En cèl·lules Caco-2, l’activitat GPX i l’expressió gènica de GPX1 juntament amb l’expressió tant proteica com gènica de SELENOP van disminuir significativament en el model de privació de Se; mentre que l’expressió gènica de GPX2 i la producció de ROS van incrementar. No es van observar canvis en l’activitat TXNRD. Quan les cèl·lules es van suplementar amb HMSeBA, l’activitat GPX i TXNRD, l’expressió gènica de GPX1 i GPX2 i l’expressió tant proteica com gènica de SELENOP van incrementar significativament. De manera similar, després de l’estimulació amb H2O2 o Salmonella Enteritidis, es va observar una disminució en la producció de ROS, en la peroxidació lipídica i en la carbonilació proteica. En macròfags, la privació de Se va induir una reducció de l’activitat GPX, de l’expressió gènica de GPX1 i de l’expressió tant proteica com gènica de SELENOP. La suplementació amb HMSeBA va incrementar l’expressió gènica de GPX1 i de SELENOP i va ser capaç de reduir la producció de ROS després de l’estimulació amb H2O2. En cèl·lules estimulades amb LPS, l’HMSeBA va incrementar l’expressió gènica de GPX1 i va reduir l’estrès oxidatiu així com la producció de citocines. La capacitat fagocítica i bactericida van incrementar també amb aquesta font de Se. Les cèl·lules Caco-2 i els macròfags poden utilitzar HMSeBA com a font de Se per la síntesi de selenoproteïnes, protegint la cèl·lula de l’estrès oxidatiu. A més, l’HMSeBA modula positivament la resposta inflamatòria per tal d’evitar el possible dany produït per macròfags altament activats., [eng] Se is an essential micronutrient which plays a role in different functions in humans and animals through its incorporation into selenoproteins as selenocysteine (Sec). Inadequate dietary Se is considered a risk factor for several chronic diseases associated with oxidative stress and inflammation. Its incorporation as a supplement in poultry diets has become an effective way to diminish the negative effects of the stress caused to animals due to the increase in production parameters in poultry industry. The present study investigates the role of the hydroxy-selenomethionine analogue (2-hydroxy-4-methylselenobutanoic acid, HMSeBA), an organic form of Se, in supporting selenoprotein synthesis and protecting against oxidative stress in two cell lines: intestinal Caco-2 cells and macrophages (derived THP-1 human monocytes). HMSeBA role in inflammatory response has also been studied in macrophages. To study the effects of Se deficiency in cells, a model of Se deprivation was developed in both cell lines. The study was then moved forward to evaluate the effects of this organic Se source in a model of Se supplementation. In these two models, HMSeBA capacity to support selenoprotein synthesis, such as glutathione peroxidase (GPX), thioredoxin reductase (TXNRD) or selenoprotein P1 (SELENOP), was studied. Moreover, HMSeBA antioxidant capacity was also studied in cells stimulated with H2O2, Salmonella Enteritidis or lipopolysaccharide (LPS), by determining reactive oxygen species (ROS) production, secondary oxidation products and cell autofluorescence. To study the role of HMSeBA in inflammatory response, cytokine production as well as phagocytic and killing capacity were also studied. In Caco-2 cells, GPX activity and GPX1 gene expression together with both protein and gene expression of SELENOP in the Se-deprived model were significantly decreased; while GPX2 gene expression and ROS production were significantly increased. There were no effects in TXNRD activity. When cells were supplemented with HMSeBA, GPX and TXNRD activity, GPX1 and GPX2 gene expression and both SELENOP gene and protein expression were significantly increased. Similarly, a decrease in ROS, lipid peroxidation and protein carbonylation after H2O2 or Salmonella Enteritidis treatment were observed. In macrophages, Se deprivation induced a reduction in GPX activity, GPX1 gene expression and both SELENOP protein and gene expression. HMSeBA supplementation upregulated gene expression of GPX1 and SELENOP and was capable of decreasing ROS production after H2O2 treatment. In LPS-stimulated macrophages, HMSeBA upregulated GPX1 gene expression and reduced oxidative stress and cytokine production. Phagocytic and killing capacity were enhanced by this Se source. Caco-2 cells and macrophages can use HMSeBA as a Se source for selenoprotein synthesis, resulting in protection against oxidative stress. Moreover, HMSeBA positively modulates the inflammatory response to avoid the potential toxic insult produced by highly activated macrophages.

One of the etiopathogenic factors frequently associated with generalized organ damage after spinal cord injury corresponds to the imbalance of the redox state and inflammation, particularly of the respiratory, autonomic and musculoskeletal systems. Our goal in this review was to gain a better understanding of this phenomenon by reviewing both animal and human studies. At the respiratory level, the presence of tissue damage is notable in situations that require increased ventilation due to lower thoracic distensibility and alveolar inflammation caused by higher levels of leptin as a result of increased fatty tissue. Increased airway reactivity, due to loss of sympathetic innervation, and levels of nitric oxide in exhaled air that are similar to those seen in asthmatic patients have also been reported. In addition, the loss of autonomic control efficiency leads to an uncontrolled release of catecholamines and glucocorticoids that induce immunosuppression, as well as a predisposition to autoimmune reactions. Simultaneously, blood pressure regulation is altered with vascular damage and atherogenesis associated with oxidative damage. At the muscular level, chronically elevated levels of prooxidants and lipoperoxidation associated with myofibrillar atrophy are described, with no reduction or reversibility of this process through antioxidant supplementation.

Transient potential receptor vanilloid 2 (TRPV2) is widely expressed through the nervous system and specifically found in neuronal subpopulations and some glial cells. TRPV2 is known to be sensitized by methionine oxidation, which results from inflammation. Here we aim to characterize the expression and regulation of TRPV2 in myelination pathologies, such as hypomyelination and demyelination. We validated the interaction between TRPV2 and its putative interactor Opalin, an oligodendrocyte marker, in mixed glial cultures under pro-and anti-inflammatory conditions. Then, we characterized TRPV2 time-course expression in experimental animal models of hypomyelination (jimpy mice) and de-/remyelination (cuprizone intoxication and experimental autoimmune encephalomyelitis (EAE)). TRPV2 showed upregulation associated with remyelination, inflammation in cuprizone and EAE models, and downregulation in hypomyelinated jimpy mice. TRPV2 expression was altered in human samples of multiple sclerosis (MS) patients. Additionally, we analyzed the expression of methionine sulfoxide reductase A (MSRA), an enzyme that reduces oxidated methionines in TRPV2, which we found increased in inflammatory conditions. These results suggest that TRPV2 may be a key player in myelination in accordance with the recapitulation hypothesis, and that it may become an interesting clinical target in the treatment of demyelination disorders., The authors acknowledge financial support from the Spanish Government MCIN/AEI/ 10.13039/501100011033 (Project BFU2017-87843-R- to B.C. and A.P.-M.; Project PID2020-120222GB-I00 to A.P.-M.).

The combination of physical exercise and a balanced diet presents substantial health benefits and could improve fish production. However, the redox balance can be affected by training regimen, dietary macronutrient ratio and their interaction. In this study, we conjointly evaluated the effects of physical activity (by voluntary swimming (VS) or sustained swimming as exercise (Ex)) and diet composition (by high-protein (HP) or high-lipid (HE) commercial diets) after 6 weeks on oxidative stress status in liver, white muscle and red muscle of gilthead sea bream juveniles. The HE diet increased the biochemical redox markers’ thiobarbituric acid reactive substances (TBARS), advanced oxidation protein products (AOPP) and reduced thiols (-SH) in the different tissues. Exercise increased AOPP and -SH levels in liver but reduced TBARS levels in white muscle. Regarding the expression of oxidative stress, chaperones and apoptosis-related genes, the VSHE group showed the highest values and the VSHP the lowest, whereas the application of sustained swimming partially equalized those differences. Diet composition modulated the enzyme activity, prioritizing the superoxide dismutase and catalase in the HE-fed groups and the glutathione-related enzymes in the HP groups. Exercise also altered enzyme activity, but in a tissue-dependent manner. Overall, the redox balance in gilthead sea bream juveniles can be affected by diet composition and sustained swimming. However, the response will partly depend on the interaction between these factors and the tissue studied. Therefore, the combination of an adequate diet and sustained exercise could be used in fish production to improve the physiological redox status.

Rice is the most important crop for the majority of population across the world with sensitive behavior toward heavy metals such as chromium (Cr) in polluted regions. Although, there is no information on the Cr resistance phenotyping in rice. Herein, two different groups of rice cultivars (normal, and hybrid) were used, each group with 14 different rice cultivars. Firstly, seed germination analysis was conducted by evaluating various seed germination indices to identify the rice cultivars with greatest seed germination vigor. Furthermore, exposure of chromium (Cr) toxicity to 28 different rice varieties (NV1-NV14, HV1-HV14) caused noticeable plant biomass reduction. Subsequently, NV2, NV6, NV10, NV12, NV13 (normal type), HV1, HV4, HV8, and HV9 (hybrid types) were pragmatic as moderately sensitive varieties, while NV3, NV4, NV9, and NV14 (normal type), HV3, HV6, HV7, and HV13 were observed as moderately tolerant. Although, NV7, and HV10 were ranked most sensitive cultivars, and NV11, and HV14 were considered as most tolerant varieties as compared to the other rice (both groups) genotypes. Afterward, Cr induced reduction in chlorophyll pigments were significantly lesser in HV14 relative to NV11, NV7, and especially HV10, and as a result HV14 modulated the total soluble sugar level as well as reduced ROS accumulation, and MDA contents production by stimulating the antioxidant defense mechanism conspicuously which further reduced the electrolyte leakage as well. Our outcomes provide support to explore the Cr tolerance mechanism in cereal crops as well as knowledge about rice breeding with increased tolerance against Cr stress. This research was supported by National Natural Science Foundation of China (No. 32072127), Zhejiang Provincial Natural Science Foundation (No. LY21C130006), Dabeinong Funds for Discipline Development and Talent Training in Zhejiang University, Collaborative Innovation Center for Modern Crop Production co-sponsored by Province and Ministry (CIC-MCP) and Zhenjiang International-joint fund (No. GJ2020010). The authors would like to extend their sincere appreciation to the Researchers Supporting Project Number (RSP-2021/168), King Saud University, Riyadh, Saudi Arabia.

This study aimed to assess the effects of dietary increasing concentrations of Aloe vera (AV) powder of 0.5%, 2.5% and 5% on the growth performance, hepatic oxidative status, histology, and lipid metabolism and cellular signaling pathways-related genes' expression in gilthead sea bream (Sparus aurata). The preliminary phytochemical analysis revealed the richness of the dried AV extract on total phenol content, total flavonoid content, and condensed tannins when compared to the lyophilized sample. The dried extract showed a good DPPH-radical scavenging activity and its profiling by HPLC-DAD-ESI-MS revealed the presence of anthraquinones namely aloin A, aloin B and their hydroxyl (7-hydroxyaloin A and 7-hydroxyaloin B) and methyl-hydroxy (8-O-methyl-7-hydroxyaloin A and 8-O-methyl-7-hydroxyaloin B) derivatives as well as aloeresin A and B. The AV supplementation in fish diet did not affect growth performance (WG, WGR, and SGR) and feed utilization (FI, FCR, FER), and HSI indexes. However, the hepatic insulin-like growth factors (IGF-I and II) levels were significantly enhanced. Genes' expression levels of enzymes or transcription factors involved in lipolysis (lpl, hsl, and atgl), beta-oxidation (pparα, hadh), fatty acid transporters (cd36, fabp11) and lxrα were significantly down-regulated by the two high concentrations of AV powder. In contrast, fatty acid synthase (fas), a key gene of lipogenesis was significantly up regulated by dietary AV 5% powder supplementation. The induction of fas together with the down-regulation of peroxisome proliferator-activated receptor (pparα) and hydroxyacyl-coenzyme A dehydrogenase (hadh) could explain the lipid accumulation resulting in hepatic steatosis, which was confirmed by histological analysis, since the diets at the two higher concentrations (AV 2.5% and AV 5%) induced a significant increase in the number and diameter of hepatic lipid vacuoles in a dose dependent manner. Moreover, the mRNA levels of protein kinase B named (akt), mammalian target of rapamycin (mtor) and extracellular regulated kinase (erk1/2) involved in cell survival and proliferation were decreased by all AV powder supplemented diets. AV 5% increased catalase and glutathione S transferase activities suggesting a cellular strategy to fight against reactive oxygen species (ROS) accumulation. In conclusion, dietary supplementation with AV 0.5% is recommended for gilthead sea bream feed formulation, as it stimulates the igf-i expression. However, higher levels of AV should be avoided as they might cause lipid metabolism disruption, oxidative stress and liver steatosis.

El cos humà està colonitzat per bacteris comensals que habiten superfícies i fluids de l'organisme, una comunitat coneguda com a microbiota, amb implicacions en la salut humana. La presència o absència de determinades espècies bacterianes altera el funcionament fisiològic, fet que ha impulsat estudis dirigits a conèixer el seu paper en algunes malalties, com per exemple la infertilitat. Sota la hipòtesi que la microbiota pot alterar paràmetres seminals i espermàtics associats a la infertilitat masculina, s'han proposat un seguit d'objectius per a estudiar-ho. S'han valorat paràmetres relacionats amb la integritat de l'ADN espermàtic com l'estat de compactació de la cromatina, la fragmentació de l'ADN o l'estrès oxidatiu, juntament amb els paràmetres clínics d'un seminograma. En primer lloc, s'ha valorat la relació entre aquests paràmetres per, a continuació, caracteritzar la microbiota seminal a través de la seqüenciació del gen ribosomal 16S complet mitjançant les plataformes MiSeq d'Illumina i MinION d'Oxford Nanopore Technologies, i buscar-hi associacions amb els paràmetres valorats. S'han pogut establir relacions entre un biomarcador recentment descrit, el potencial oxidant-reductor, i altres paràmetres més coneguts com el pH, l'estat de compactació de la cromatina o la fragmentació d'ADN. S'ha descrit la composició bacteriana seminal, integrada principalment per Firmicutes, Bacteroidetes, Proteobacteria i Actinobacteria, i s'han establert relacions entre alguns gèneres i famílies amb els paràmetres de qualitat seminal. El cuerpo humano está colonizado por bacterias comensales que habitan superficies y fluidos del organismo, una comunidad conocida como microbiota, con implicaciones en la salud humana. La presencia o ausencia de determinadas especies bacterianas altera el funcionamiento fisiológico, lo que ha impulsado estudios dirigidos a conocer su papel en algunas enfermedades, como por ejemplo la infertilidad. Bajo la hipótesis de que la microbiota puede alterar parámetros seminales y espermáticos asociados a la infertilidad masculina, se han propuesto una serie de objetivos para estudiarlo. Se han valorado parámetros relacionados con la integridad de l'ADN espermático como el estado de compactación de la cromatina, la fragmentación de l'ADN o el estrés oxidativo, junto con los parámetros clínicos de un seminograma. En primer lugar, se ha valorado la relación entre estos parámetros para, a continuación, caracterizar la microbiota seminal a través de la secuenciación del gen ribosomal 16S completo mediante las plataformas MiSeq de Illumina y MinION de Oxford Nanopore Technologies, buscando asociaciones con los parámetros valorados. Se han podido establecer relaciones entre un biomarcador recientemente descrito, el potencial oxidante-reductor, y otros parámetros más conocidos como el pH, el estado de compactación de la cromatina o la fragmentación d'ADN. Se ha descrito la composición bacteriana seminal, integrada principalmente por Firmicutes, Bacteroidetes, Proteobacteria y Actinobacteria, y se han establecido relaciones entre algunos géneros y familias con los parámetros de calidad seminal. The human body is colonized by commensal bacteria that inhabit the body's surfaces and fluids, a community known as microbiota, with implications for human health. The presence or absence of certain bacterial species alters physiological functioning, which has led to studies aimed at understanding their role in some diseases, such as infertility. Under the hypothesis that the microbiota may alter seminal and sperm parameters associated with male infertility, some objectives have been proposed. Parameters related to sperm DNA integrity such as chromatin compaction, DNA fragmentation, or oxidative stress have been assessed, along with the clinical parameters of a seminogram. The relationship between these parameters was first assessed, and then seminal microbiota was characterized through full-length 16S ribosomal gene sequencing using Illumina MiSeq and Oxford Nanopore Technologies MinION platforms, and relationship was assessed with the rated parameters. Relationships have been established between a recently described biomarker, oxidation-reduction potential, and other better-known parameters such as pH, chromatin compaction, or DNA fragmentation. The seminal bacterial composition, composed mainly of Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, has been described, and relationships have been established between some genus and families with the seminal quality parameters.

Society increase in live expectancy will cause a rise in Alzheimer’s Disease (AD) diagnosis, thus, there is a need to further understand how it works. One of the main culprits of this disease amyloid-β peptide (Aβ), this protein has a physiological function as monomers. But, once starts to aggregate, Aβ becomes neurotoxic. In this thesis, I have demonstrated a novel physiological function of monomeric Aβ as inductor of insulin receptor signalling, while its oligomers block the same signalling. I have described a neurotoxic feedback loop between oligomeric Aβ and an increase in BACE1 presence. I have studied novel calcium regulators in the development of the disease. I showed a novel pathway that links Aβ as a blocker of LTP. Finally, I have characterised the region of interaction of albumin c-terminus with Aβ and its neuroprotective effect. L’increment en l’esperança de vida a la nostre societat generarà un augment en el nombre de persones diagnosticades amb la malaltia d’ Alzheimer. Per això, és necessari poder comprendre millor el seu funcionament. Un dels principals actors d’aquesta malaltia es la proteïna β- amiloide, aquesta proteïna en estat monomèric te funcions fisiològiques, però quan agrega es torna neurotòxica. En aquesta tesis he demostrat una nova funció fisiològica de l’Aβ com a inductor de la senyalització regulada pel receptor d’insulina, mentre que els oligòmers la bloquegen. He descrit un cercle viciós entre Aβ oligomerica i un increment en la presencia de BACE1. He estudiat el paper de nous reguladors de calci en el desenvolupament d’AD. He mostrat una nova relació entre Aβ i el bloqueig del LTP. Finalment he caracteritzat la regió d’interacció del c-terminus de l’albúmina i l’Aβ i el seu paper neuroprotector.

Rationale: Accumulating evidence suggests that chronic alcohol consumption is associated with excessive oxidative damage and neuroinflammatory processes and these events have been associated to early alcohol withdrawal. In the present research we wonder if brain oxidative stress and neuroinflammation remains altered during prolonged withdrawal situations and whether these alterations can be correlated with relapse behavior in alcohol consumption. The effects of alcohol reintroduction were also evaluated Methods: We have used a model based on the alcohol deprivation effect (ADE) within a cohort of wild-type male Wistar rats. Two subpopulations were identified according to the alcohol relapse-like drinking behavior displayed (ADE and NO-ADE subpopulations). Oxidized and reduced glutathione content was determined within the hippocampus and the amygdala using a mass spectrometry method. The levels of mRNA of seven different inflammatory mediators in the prefrontal cortex of rats were quantified. All the analyses were performed in two different conditions: after 21-day alcohol deprivation (prolonged abstinence) and after 24 h of ethanol reintroduction in both subpopulations. Results: ADE and NO-ADE rats showed different endophenotypes. ADE rats always displayed a significant lower alcohol intake rate and ethanol preference than NO-ADE rats. The results also demonstrated the existence of altered brain redox and neuroinflammation status after prolonged abstinence exclusively in ADE rats. Moreover, when ethanol was reintroduced in the ADE subpopulation, altered oxidative stress and neuroinflammatory markers were restored. Conclusions: Present findings provide new mechanisms underlying the neurobiology of relapse behavior and suggest the development of new pharmacological approaches to treat alcohol-induced relapse.

The health benefits of fruit juices have been associated with their high content of antioxidant compounds. Commercial juice has been traditionally heat-processed to destroy microorganisms and enzymes. However, high temperatures induce undesirable changes in the nutritional value of the juice. High-intensity pulsed electric fields (HIPEF) are being studied as an alternative to heat treatments. In addition, in vitro and in vivo methods have been recommended to determine the antioxidant potential of juices in a complementary manner. Thus, the antioxidant activity of untreated, high-intensity pulsed electric fields (HIPEF) or heat-treated fruit juices (tomato, apple, pineapple and orange) was studied using in vitro (TEAC, DPPH, FRAP and Folin-Ciocalteu) and in vivo assays (Saccharomyces cerevisiae). Vitamin C and total phenolic compounds in these juices were determined. The highest antioxidant activities (12.01 mmol of Trolox/L) were obtained through the Folin-Ciocalteu assay in orange juices. The lowest values (0.119 mmol of Trolox/L) were found in apple juice analysed by the FRAP assay. Vitamin C content varied from 10 mg/L (orange juice) to 344 mg/L (orange juice). The highest concentration of total phenolic compounds was determined in orange juice (1238 mg/L), whereas the lowest value was found in tomato juices (149 mg/L). The effect of HIPEF and thermal processing on the antioxidant potential of juices depended on the fruits used to prepare the juices and the antioxidant activity assay conducted. Vitamin C concentration was directly related to the antioxidant activity analysed by Folin-Ciocalteu and FRAP methods and the S. cerevisiae growth rate. S. cerevisiae yeast can be used as a feasible in vivo assay to further determine the antioxidant activity of fruit juices. This study has been carried out with financial support from Universitat de Lleida through a joint Agrotecnio/IRBLleida grant. This work was also supported by the Ministerio de Economia y Competividad (Spain) through the Project BFU2010-17656 and by the Generalitat de Catalunya (2014SGR/1000). Judit Puigpinos thanks University of Lleida for the predoctoral grant.

Hyperactivation of the KEAP1-NRF2 axis is a common molecular trait in carcinomas from different origin. The transcriptional program induced by NRF2 involves antioxidant and metabolic genes that render cancer cells more capable of dealing with oxidative stress. The TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) is an important regulator of glycolysis and the pentose phosphate pathway that was described as a p53 response gene, yet TIGAR expression is detected in p53-null tumors. In this study we investigated the role of NRF2 in the regulation of TIGAR in human carcinoma cell lines. Exposure of carcinoma cells to electrophilic molecules or overexpression of NRF2 significantly increased expression of TIGAR, in parallel to the known NRF2 target genes NQO1 and G6PD. The same was observed in TP53KO cells, indicating that NRF2-mediated regulation of TIGAR is p53-independent. Accordingly, downregulation of NRF2 decreased the expression of TIGAR in carcinoma cell lines from different origin. As NRF2 is essential in the bone, we used mouse primary osteoblasts to corroborate our findings. The antioxidant response elements for NRF2 binding to the promoter of human and mouse TIGAR were described. This study provides the first evidence that NRF2 controls the expression of TIGAR at the transcriptional level.

The precise function of CERKL, a Retinitis Pigmentosa (RP) causative gene, is not yet fully understood. There is evidence that CERKL is involved in the regulation of autophagy, stress granules, and mitochondrial metabolism, and it is considered a gene that is resilient against oxidative stress in the retina. Mutations in most RP genes affect photoreceptors, but retinal pigment epithelium (RPE) cells may be also altered. Here, we aimed to analyze the effect of CERKL overexpression and depletion in vivo and in vitro, focusing on the state of the mitochondrial network under oxidative stress conditions. Our work indicates that the depletion of CERKL increases the vulnerability of RPE mitochondria, which show a shorter size and altered shape, particularly upon sodium arsenite treatment. CERKL-depleted cells have dysfunctional mitochondrial respiration particularly upon oxidative stress conditions. The overexpression of two human CERKL isoforms (558 aa and 419 aa), which display different protein domains, shows that a pool of CERKL localizes at mitochondria in RPE cells and that CERKL protects the mitochondrial network—both in size and shape—against oxidative stress. Our results support CERKL being a resilient gene that regulates the mitochondrial network in RPE as in retinal neurons and suggest that RPE cell alteration contributes to particular phenotypic traits in patients carrying CERKL mutations.

There is evidence that both omega-3 polyunsaturated fatty acids (n-3 PUFAs) and choline can influence sports performance, but information establishing their combined effects when given in the form of krill oil during power training protocols is missing. The purpose of this study was therefore to characterize n-3 PUFA and choline profiles after a one-hour period of high-intensity physical workout after 12 weeks of supplementation. Thirty-five healthy power training athletes received either 2.5 g/day of Neptune krill oilTM (550 mg EPA/DHA and 150 mg choline) or olive oil (placebo) in a randomized double-blind design. After 12 weeks, only the krill oil group showed a significant HS-Omega-3 Index increase from 4.82 to 6.77% and a reduction in the ARA/EPA ratio (from 50.72 to 13.61%) (p < 0.001). The krill oil group showed significantly higher recovery of choline concentrations relative to the placebo group from the end of the first to the beginning of the second exercise test (p = 0.04) and an 8% decrease in total antioxidant capacity post-exercise versus 21% in the placebo group (p = 0.35). In conclusion, krill oil can be used as a nutritional strategy for increasing the HS-Omega-3 Index, recover choline concentrations and address oxidative stress after intense power trainings.

BackgroundIncreasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy.Methods and ResultsIn aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, fibrotic collagen remodeling, nuclear translocation of pNRF2 and increased 3’-nitrotyrosine levels all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression.ConclusionsAllopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.HIGHLIGHTSXanthine oxidoreductase (XOR) is upregulated in the aortic aneurysm of Marfan syndrome (MFS) both in patients and young mice.Allopurinol halts the formation and progression of aortic aneurysm in MFS miceAllopurinol reduces a variety of oxidative stress-associated molecular reactions.Allopurinol prevents MFS endothelial-dependent vasodilator dysfunction.The antioxidant action of allopurinol suggests its repositioning for pharmacological use in MFS aortopathy.GRAPHICAL ABSTRACT

Administration of the recombinant analog of the pancreatic amyloid amylin, Pramlintide, has shown therapeutic benefits in aging and Alzheimer's disease (AD) models, both on cognition and amyloid-β (Aβ) pathology. However, the neuroprotective mechanisms underlying the benefits of Pramlintide remain unclear. Given the early and critical role of oxidative stress in AD pathogenesis and the known reactive oxygen species (ROS) modulating function of amyloids, we sought to determine whether Pramlintide's neuroprotective effects involve regulation of oxidative stress mechanisms. To address this, we treated APP/PS1 transgenic mice with Pramlintide for 3 months, starting at 5.5 months prior to widespread AD pathology onset, and measured cognition (Morris Water Maze), AD pathology, and oxidative stress-related markers and enzymes in vivo. In vitro, we determined the ability of Pramlintide to modulate H2O2-induced oxidative stress levels. Our data show that Pramlintide improved cognitive function, altered amyloid-processing enzymes, reduced plaque burden in the hippocampus, and regulated endogenous antioxidant enzymes (MnSOD and GPx1) and the stress marker HO-1 in a location specific manner. In vitro, Pramlintide treatment in neuronal models reduced H2O2-induced endogenous ROS production and lipid peroxidation in a dose-dependent manner. Together, these results indicate that Pramlintide's benefits on cognitive function and pathology may involve antioxidant-like properties of this compound.

Oxidative stress and hormonal regulation are hallmarks of a/biotic stress responses in plants. However, little is known about their linkage with whole-organismal mortality in long-lived species. Here, we examined the validity of photo-oxidative stress markers and stress-related phytohormones as predictive proxies of mortality risk in the perennial herb Plantago lanceolata. Capitalizing on its broad ecological niche, we examined photo-oxidative stress markers (Fv/Fm ratio, contents of chlorophylls, carotenoids, and tocochromanols, and the extent of lipid peroxidation) and stress-related phytohormones (ABA, salicylic acid and jasmonates contents) as proxies of mortality in three populations of sub-tropical and Mediterranean habitats: Virginia (VA, U.S.A.), Catalonia (CAT, Spain), and Queensland (QLD, Australia). Stress markers were measured together with the vital rates of survival, growth, and reproduction on a total of 279 individuals. Stress marker data were collected during the summer and death/survival was monitored after two and four months. Whole-organism mortality was similarly high in both sub-tropical non-native populations (ca. 30 % after a drought in VA and QLD), but lower in the native population (ca. 10 % in CAT). The contents of antioxidants (lutein, zeaxanthin, β-carotene) and the de-epoxidation state of the xanthophyll cycle (DPS) were good proxies of mortality risk in VA and QLD. DPS and all carotenoid contents per unit of chlorophyll were lower four months in advance in dead than in alive plants in VA and QLD, thus suggesting reduced photoprotective capacity increased the mortality risk in non-native populations. We show that whole-organismal mortality in P. lanceolata is associated with a reduced capacity to enhance photoprotection under abiotic stress conditions. The validity of various stress markers as predictive proxies of mortality risk is discussed.

During the last years, epigenetic processes have emerged as important factors for many neurodegenerative diseases, such as Alzheimer’s diseases (AD). These complex diseases seem to have a heritable component; however, genome-wide association studies failed to identify the genetic loci involved in the eatiology. So, how can these changes be transmitted from one gen-eration to the next? Answering this question would allow us to understand how the environ-ment can affect human populations for multiple generations and explain the high prevalence of neurodegenerative diseases, such as AD. This review pays particular attention to the relationship among epigenetics, cognition, and neurodegeneration across generations, deepening the under-standing of the relevance of heritability in neurodegenerative diseases. In fact, we highlight some recent examples of EI induced by experiences, focusing on their contribution of processes in learning and memory, to point out new targets for therapeutic interventions. Here, we first describe the prominent role of epigenetic factors in memory processing. Then, we briefly discuss aspects of EI. And ends, we summarize evidence of how epigenetic marks inherited by experi-ence and/or environmental stimuli contribute to cognitive status offspring, since better knowledge of EI can provide clues in the appearance and development of age-related cognitive decline and AD.

In this work beclomethasone dipropionate was loaded into liposomes and hyalurosomes modified with mucin to improve the ability of the payload to counteract the oxidative stress and involved damages caused by cigarette smoke in the airway. The vesicles were prepared by dispersing all components in the appropriate vehicle and sonicating them, thus avoiding the use of organic solvents. Unilamellar and bilamellar vesicles small in size (~117 nm), homogeneously dispersed (polydispersity index lower than 0.22) and negatively charged (~−11 mV), were obtained. Moreover, these vesicle dispersions were stable for five months at room temperature (~25 °C). In vitro studies performed using the Next Generation Impactor confirmed the suitability of the formulations to be nebulized as they were capable of reaching the last stages of the impactor that mimic the deeper airways, thus improving the deposition of beclomethasone in the target site. Further, biocompatibility studies performed by using 16HBE bronchial epithelial cells confirmed the high biocompatibility and safety of all the vesicles. Among the tested formulations, only mucin-hyalurosomes were capable of effectively counteracting the production of reactive oxygen species (ROS) induced by cigarette smoke extract, suggesting that this formulation may represent a promising tool to reduce the damaging effects of cigarette smoke in the lung tissues, thus reducing the pathogenesis of cigarette smoke-associated diseases such as chronic obstructive pulmonary disease, emphysema, and cancer.

The role of 2-hydroxy-(4-methylseleno)butanoic acid (OH-SeMet), a form of organic selenium (Se), in selenoprotein synthesis and inflammatory response of THP1-derived macrophages stimulated with lipopolysaccharide (LPS) has been investigated. Glutathione peroxidase (GPX) activity, GPX1 gene expression, selenoprotein P (SELENOP) protein and gene expression, and reactive oxygen species (ROS) production were studied in Se-deprived conditions (6 and 24 h). Then, macrophages were supplemented with OH-SeMet for 72 h and GPX1 and SELENOP gene expression were determined. The protective effect of OH-SeMet against oxidative stress was studied in H2O2-stimulated macrophages, as well as the effect on GPX1 gene expression, oxidative stress, cytokine production (TNFα, IL-1β and IL-10), and phagocytic and killing capacities after LPS stimulation. Se deprivation induced a reduction in GPX activity, GPX1 gene expression, and SELENOP protein and gene expression at 24 h. OH-SeMet upregulated GPX1 and SELENOP gene expression and decreased ROS production after H2O2 treatment. In LPS-stimulated macrophages, OH-SeMet upregulated GPX1 gene expression, enhanced phagocytic and killing capacities, and reduced ROS and cytokine production. Therefore, OH-SeMet supplementation supports selenoprotein expression and controls oxidative burst and cytokine production while enhancing phagocytic and killing capacities, modulating the inflammatory response, and avoiding the potentially toxic insult produced by highly activated macrophages. Keywords: cytokine production; glutathione peroxidase; immune response; macrophage polarization; oxidative stress; phagocytosis; selenium deprivation; selenoprotein P; 2-hydroxy-(4-methylseleno)butanoic acid

[eng] INTRODUCTION: Pulmonary manifestations are the main cause of morbidity and mortality in more than 90 % of cystic fibrosis (CF) patients who exceed the neonatal period. The chronic immune-inflammatory process, exacerbated by recurrent bacterial infections that induce an increase in oxidative stress, is a key component of the progressive destruction that occurs in their respiratory tract. Thus, the increase in reactive oxygen species due to the persistent activation of neutrophils, together with reduced anti-oxidant protection are the main contributors to oxidative stress and poor control of the immune-inflammatory response in CF patients. OBJECTIVE: The main aim of this study is the identification and characterization of new genes involved in oxidative stress in CF human respiratory epithelial cells (oxidative stress- related CF modifying genes) using a randomized siRNA library. MATERIAL AND METHODS: A high-throughput screening was performed using a randomized siRNA library introduced into the 6CFSMEo- CF bronchial epithelial cell line. Cells were then submitted to oxidative stress (H2O2). The genes whose silencing (inhibition of expression) induced resistance to H2O2-mediated apoptosis were identified. RESULTS: After three successive screening rounds using a siRNA convergent expression module, 181 unique siRNAs sequences conferring oxidative stress resistance were obtained. From these, 167 were confirmed using a high-throughput reverse transfection technique and cell viability assay. By launching the 167 statistically significant oxidative stress-resistant siRNA sequences unveiled in the genetic screening against the Genebank database and contrasting them using the BLAST tool, we obtained a set of 444 siRNA target genes. The high-throughput silencing approach was validated confirming the relevance of two selected genes: TNFRSF1B and KCNQ1OT1. Data mining in public drug databases using the siRNA target genes obtained in the RNAi screen and its first interactors identified novel repurposable drugs that were able to induce resistance to oxidative stress in CF airway epithelial cells. CONCLUSIONS: The introduction of a randomized library of siRNA in pulmonary epithelial cells and the subsequent large-scale screening of clones resistant to a lethal concentration of H2O2 allows the identification of new genes related to oxidative stress susceptibility in these cells through bioinformatic analysis. These analyses have indicated that the target genes are involved in pathways related to neuron term, RNA-splicing, oxidative stress and inflammation, cell cycle and metabolism, among others. Such functional genomics methodology, in addition to increasing the knowledge of the pathophysiology of CF respiratory epithelial cells, can contribute to the development of new therapeutic targets and both repurposable drug- and siRNA-based treatment strategies that would directly benefit CF patients.

Nowadays, more and more young people want to experience illegal, psychoactive substances, without knowing the risks of exposure. Besides affecting social life, psychoactive substances also have an important effect on consumer health. We summarized and analyzed the published literature data with reference to the mechanism of free radical generation and the link between chemical structure and oxidative stress related to dopaminergic neurotransmission. This review presents data on the physicochemical properties, on the ability to cross the blood brain barrier, the chemical structure activity relationship (SAR), and possible mechanisms by which neuronal injuries occur due to oxidative stress as a result of drug abuse such as "bath salts", amphetamines, or cocaine. The mechanisms of action of ingested compounds or their metabolites involve intermediate steps in which free radicals are generated. The brain is strongly affected by the consumption of such substances, facilitating the induction of neurodegenerative diseases. It can be concluded that neurotoxicity is associated with drug abuse. Dependence and oxidative stress are linked to inhibition of neurogenesis and the onset of neuronal death. Understanding the pathological mechanisms following oxidative attack can be a starting point in the development of new therapeutic targets.

Cuando Rafael decidió pedir un plato de habas durante la cena de un congreso de trabajo, un compañero de profesión le comentó: ¡Hoy vas a hacer trabajar a tus eritrocitos (también llamados glóbulos rojos)! El comentario le sorprendió, dado que siempre había entendido que las habas tenían un carácter antioxidante que ayudaba a mejorar los procedimientos del estrés oxidativo. Este se desarrolla en el cuerpo con el paso de los años. Pero la realidad muestra que las habas también contienen oxidantes o pro oxidantes como la vicina o la convicina, por lo que su consumo produce un incremento del estrés oxidativo.

Polyphosphate (polyP) is a polymer of hundreds of phosphate residues present in all organisms. In mammals, polyP is involved in crucial physiological processes, including coagulation, inflammation, and stress response. However, after decades of research, the metabolic enzymes are still unknown. Here, we purify and identify Nudt3, a NUDIX family member, as the enzyme responsible for polyP phosphatase activity in mammalian cells. We show that Nudt3 shifts its substrate specificity depending on the cation; specifically, Nudt3 is active on polyP when Zn2+ is present. Nudt3 has in vivo polyP phosphatase activity in human cells, and importantly, we show that cells with altered polyP levels by modifying Nudt3 protein amount present reduced viability upon oxidative stress and increased DNA damage, suggesting that polyP and Nudt3 play a role in oxidative stress protection. Finally, we show that Nudt3 is involved in the early stages of embryo development in zebrafish. This work was supported by and is part of the I+D+i grant ref. PGC2018-096597-B-I00 (to J.J.) by the Spanish Ministerio de Ciencia e Innovación (MCIN). B.S.-M. was the recipient of a grant from the Agència de Gestió d’Ajuts Universitaris i de Recerca AGAUR ref. 2016FI_B 00025. H.J.J. was supported by the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy (CIBBS, EXC-2189, Project ID 390939984).

CERKL és un gen causant de Retinosi Pigmentària, una malaltia genètica de caràcter mendelià, malaltia caracteritzada per la mort dels fotoreceptors i que, amb el pas del temps, desemboca en ceguera. Malgrat els esforços de diferents grups d’investigació, incloent-hi el nostre grup (que va ser el descobridor del gen), la funció de CERKL encara roman desconeguda. Els intents a l’hora de generar un model animal que mimetitzi el fenotip humà han dificultat l’estudi funcional d’aquest gen i, conseqüentment, s’ha alentit poder trobar una teràpia efectiva que pugui aturar la progressió de la malaltia o curar als pacients amb mutacions a CERKL. Per aquest motiu, en aquesta Tesi ens plantejarem estudiar el paper de CERKL a la retina i així, apropar-nos al disseny efectiu d’una teràpia o tractament que millori el pronòstic de la malaltia. Els objectius concrets plantejats en aquesta Tesi són: 1. Generació i caracterització d’un nou model murí de Cerkl 1.1. Generació de ratolins Cerkl knockout mitjançant la tècnica d’edició gènica CRISPR/Cas9 1.2. Caracterització fenotípica de la retina dels ratolins Cerkl knockout en comparació amb ratolins control (wild-type) 2. Determinació del paper de CERKL davant un estímul d’estrès oxidatiu tan in vitro com in vivo 2.1. Estudi de la dinàmica cel·lular de CERKL in vitro 2.2. Identificar el rol de CERKL en resposta a un estímul d’estrès oxidatiu o lumínic in vivo i ex vivo 2.3. Generar i caracteritzar l’expressió de CERKL en organoides tridimensionals de retina a partir de fibroblasts d’un pacient i un control 2.4. Determinar la resposta front a l’estrès oxidatiu en els organoides 2.5. Comparar l’efecte de l’estrès oxidatiu en el model humà d’organoides i les retines del model murí 3. Comprovar l’efectivitat de l'alliberament d'àcids nucleics mitjançant nanopartícules d’or com a prova de principi de teràpia gènica 3.1. Determinar el sistema d’entrada de les nanopartícules en cèl·lules en cultiu 3.2. Comprovar l’eficiència d’entrada de les nanopartícules en cèl·lules en cultiu en comparació amb els lipoplexes convencionals 3.3. Explorar la possibilitat d’alliberar àcids nucleics terapèutics mitjançant nanopartícules en retines ex vivo.

Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose‐6‐phosphate dehydrogenase (G6PD), which catalyzes the rate‐limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD‐Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild‐type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3‐month‐old G6PD‐Tg mice than in wild‐type counterparts, whereas the levels of pro‐apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL+ apoptotic cells were all lower in 9‐month‐old G6PD‐Tg than in wild‐type counterparts. Unexpectedly, G6PD overexpression triggered low‐grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression., This work was funded by Multi Target and View FEDER/CM‐B2017/BMD‐3688 and MINECO/FEDER SAF2017‐86107‐R to IVN. JMBM was supported by a PhD CSIC contract.

The connection between DNA folding and chromatin conformation has been much studied but the relation between the modulation of chromatin conformation and biological processes such as DNA damage, cell differentiation and DNA replication, still remains unclear. To better understand these mechanisms, an interdisciplinary study combining several technologies is required to provide an integrative view of what happens from the level of nucleosome interactions up to whole genome organisation. In this thesis, we aimed to set up chromatin conformation methodologies such as Hi-C and Micro-C to analyse the effect of DNA damage and cell differentiation on 3D chromatin structure. Chromatin structure is affected by DNA damage caused by UV irradiation or oxidative stress. In our study, the effects of UV irradiation and oxidative stress on 3D genome structure were analysed from nucleosome positioning to chromatin conformation. Molecular Dynamics simulation and Coarse grained modelling provided a 3D model of the whole genome of Saccharomyces cerevisiae in normal and stressed conditions. The conditions of UV irradiation that was applied created a decrease of chromatin interactions increasing chromatin flexibility. In addition, oxidative stress induced chromatin changes with an increase of inter-chromosomal interactions and a reduction of intra-chromosomal interactions. These effects were associated with a decrease in the number of chromatin interaction domains (CID) as well as the insulation score. The reduction of CID is correlated with a reduction of cohesin loading factor complex (SCC2/SCC4) bound to the chromatin upon oxidative stress. In addition, nucleosome contacts were globally reduced, especially in upregulated genes and DNA damaged regions. Concerning nucleosome positioning, a general increase of the fuzziness score was observed both in upregulated and downregulated genes, and in regions of DNA damage in response to oxidative stress. Overall, our results showed a decrease in the number of nucleosomes and a tendency of the chromatin to be more open at short-range distances while, at long-range distances, the genome seems to be more compact in response to oxidative stress. One hypothesis could be that chromatin decondensation can contribute to facilitate DNA repair. MD simulations were used to build two models: one at the scale of the chromatin fibre and the other one for the whole genome. Finally, high resolution microscopy combined with Capture-MNase-Seq, Capture-Hi-C and coarse grain models were used to study the conformational changes occurring during cell reprograming from fibroblast to hiPSC. A specific region containing NANOG and STELLA loci as well as GADPH and IFFO1 as control genes was selected. Capture- MNase-Seq and Capture-Hi-C revealed that nucleosomes tend to be fuzzier in the pluripotent hiPSC cells and that the TADs were reorganized during cell differentiation.

Oxidative stress (OS) results from an imbalance between the production of reactive oxygen species and the cellular antioxidant capacity. OS plays a central role in neurodegenerative diseases, where the progressive accumulation of reactive oxygen species induces mitochondrial dysfunction, protein aggregation and inflammation. Regulatory non-protein-coding RNAs (ncRNAs) are essential transcriptional and post-transcriptional gene expression controllers, showing a highly regulated expression in space (cell types), time (developmental and ageing processes) and response to specific stimuli. These dynamic changes shape signaling pathways that are critical for the developmental processes of the nervous system and brain cell homeostasis. Diverse classes of ncRNAs have been involved in the cell response to OS and have been targeted in therapeutic designs. The perturbed expression of ncRNAs has been shown in human neurodegenerative diseases, with these changes contributing to pathogenic mechanisms, including OS and associated toxicity. In the present review, we summarize existing literature linking OS, neurodegeneration and ncRNA function. We provide evidences for the central role of OS in age-related neurodegenerative conditions, recapitulating the main types of regulatory ncRNAs with roles in the normal function of the nervous system and summarizing up-to-date information on ncRNA deregulation with a direct impact on OS associated with major neurodegenerative conditions.

Acute high-intensity exercise can impair the immune system, and lead to oxidative stress. Cocoa intake might help in protecting against oxidative damage and impaired immune functioning. The aim of this study was to establish the effect of cocoa and cocoa fibre on the oxidative status and the immunoglobulin (Ig) production of rats following a bout of acute exercise on a treadmill. The production of reactive oxygen species (ROS) by macrophages and the concentration of serum and mucosal Ig was assessed 16 h after the running session. Exercise increased ROS production and decreased the serum IgG concentration and the salivary gland IgM content. A cocoa fibre-enriched diet prevented the increased ROS production and the reduction in salivary IgM induced by exercise, although it decreased the IgA content in serum and the salivary glands. Overall, cocoa, by means of its fibre content, can partially prevent the alterations in ROS and Ig production induced by a single session of intensive running exercise.

Hemopexin and α1-microglobulin act as scavengers to eliminate free heme-groups responsible for hemoglobin-induced oxidative stress. The present study evaluated maternal and fetal plasma concentrations of these scavengers in the different phenotypes of placenta-mediated disorders. Singleton pregnancies with normotensive fetal growth restriction [FGR] (n = 47), preeclampsia without FGR (n = 45) and preeclampsia with FGR (n = 51) were included prospectively as well as uncomplicated pregnancies (n = 49). Samples were collected at delivery and ELISA analysis was applied to measure the hemopexin and α1-microglobulin concentrations. In maternal blood in preeclampsia with and without FGR, hemopexin was significantly lower (p = 0.003 and p

The antioxidant effect of compounds is regularly evaluated by in vitro assays that do not have the capability to predict in vivo protective activity or to determine their underlying mechanisms of action. The aim of this study was to develop an experimental system to evaluate the in vivo protective effects of different antioxidant compounds, based on the zebrafish embryo test. Zebrafish embryos were exposed to tert-butyl hydroperoxide (tBOOH), tetrachlorohydroquinone (TCHQ) and lipopolysaccharides from Escherichia coli (LPS), chemicals that are known inducers of oxidative stress in zebrafish. The developmental toxic effects (lethality or dysmorphogenesis) induced by these chemicals were modulated with n-acetyl l-cysteine and N&omega, nitro l-arginine methyl ester hydrochloride, dimethyl maleate and dl-buthionine sulfoximine in order to validate the oxidant mechanism of oxidative stress inducers. The oxidant effects of tBOOH, TCHQ, and LPS were confirmed by the determination of significant differences in the comparison between the concentration&ndash, response curves of the oxidative stress inducers and of the modulators of antioxidant status. This concept was also applied to the study of the effects of well-known antioxidants, such as vitamin E, quercetin, and lipoic acid. Our results confirm the zebrafish model as an in vivo useful tool to test the protective effects of antioxidant compounds.

Friedreich's ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those 'antioxidant' drugs that went beyond the disease's models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.

Achieving high embryo quality following IVF and ICSI procedures is a key factor in increasing fertility outcomes in human infertile couples. While the male factor is known to underlie infertility in about 50% of cases, studies performed in human infertile couples have not been able to define the precise effect of sperm affectations upon embryo development. This lack of consistency is, in most cases, due to the heterogeneity of the results caused by the multiple male and female factors that mask the concrete effect of a given sperm parameter. These biases can be reduced with the use of animal gametes, being a good approach for basic researchers to design more homogeneous studies analyzing the specific consequences of a certain affectation. Herein, we conducted a systematic review (March 2020) that assessed the relationship between sperm oxidative stress alterations and IVF/ICSI outcomes in nonhumans mammals. The review was conducted according to PRISMA guidelines and using the MEDLINE-PubMed and EMBASE databases. Thirty articles were included: 11 performed IVF, 17 conducted ICSI, and two carried out both fertilization methods. Most articles were conducted in mouse (43%), cattle (30%) and pig models (10%). After IVF treatments, 80% of studies observed a negative effect of sperm oxidative stress on fertilization rates, and 100% of studies observed a negative effect on blastocyst rates. After ICSI treatments, a positive relationship of sperm oxidative stress with fertilization rates (75% of studies) and with blastocyst rates (83% of studies) was found. In conclusion, the present systematic review shows that sperm oxidative stress is associated with a significant reduction in fertilization rates and in vitro embryo development The authors acknowledge the support from the Ministry of Science and Innovation, Spain (Grants: RYC-2014-15581 and AGL2017-88329-R) and the Regional Government of Catalonia, Spain (Grant: 2019-SGR-1229)

Current therapies for diabetic retinopathy (DR) incorporate blood glucose and blood pressure control, vitrectomy, photocoagulation, and intravitreal injections of anti-vascular endothelial growth factors or corticosteroids. Nonetheless, these techniques have not been demonstrated to completely stop the evolution of this disorder. The pathophysiology of DR is not fully known, but there is more and more evidence indicating that oxidative stress is an important mechanism in the progression of DR. In this sense, antioxidants have been suggested as a possible therapy to reduce the complications of DR. In this review we aim to assemble updated information in relation to in vitro experiments, animal studies and clinical trials dealing with the effect of the antioxidants on DR.

The spermatozoon is a highly specialized cell, whose main function is the transport of the intact male genetic material into the oocyte. During its formation and transit throughout male and female reproductive tracts, sperm cells are internally and externally surrounded by reactive oxygen species (ROS), which are produced from both endogenous and exogenous sources. While low amounts of ROS are known to be necessary for crucial physiological sperm processes, such as acrosome reaction and sperm-oocyte interaction, high levels of those species underlie misbalanced antioxidant-oxidant molecules, generating oxidative stress (OS), which is one of the most damaging factors that affect sperm function and lower male fertility potential. The present work starts by reviewing the different sources of oxidative stress that affect sperm cells, continues by summarizing the detrimental effects of OS on the male germline, and discusses previous studies addressing the consequences of these detrimental effects on natural pregnancy and assisted reproductive techniques effectiveness. The last section is focused on how antioxidants can counteract the effects of ROS and how sperm fertilizing ability may benefit from these agents This research was funded by the Ministry of Science, Innovation and Universities, Spain (Grants: RYC2014-15581) and the Regional Government of Catalonia, Spain (2017-SGR-1229)

Several yeast species, belonging to Saccharomyces and non-Saccharomyces genera, play fundamental roles during spontaneous must grape fermentation, and recent studies have shown that mixed fermentations, co-inoculated with S. cerevisiae and non-Saccharomyces strains, can improve wine organoleptic properties. During active dry yeast (ADY) production, antioxidant systems play an essential role in yeast survival and vitality as both biomass propagation and dehydration cause cellular oxidative stress and negatively affect technological performance. Mechanisms for adaptation and resistance to desiccation have been described for S. cerevisiae, but no data are available on the physiology and oxidative stress response of non-Saccharomyces wine yeasts and their potential impact on ADY production. In this study we analyzed the oxidative stress response in several non-Saccharomyces yeast species by measuring the activity of reactive oxygen species (ROS) scavenging enzymes, e.g., catalase and glutathione reductase, accumulation of protective metabolites, e.g., trehalose and reduced glutathione (GSH), and lipid and protein oxidation levels. Our data suggest that non-canonical regulation of glutathione and trehalose biosynthesis could cause poor fermentative performance after ADY production, as it corroborates the corrective effect of antioxidant treatments, during biomass propagation, with both pure chemicals and food-grade argan oil., This work has been supported by grants AGL2011-24353 and AGL2014- AGL2014-52984-R from the Spanish Ministry of Economy and Competitiveness (MINECO) to E.M, and it was performed as part of the Programme VLC/Campus, Microcluster IViSoCa (Innovation for a Sustainable Viticulture and Quality), and Microcluster BBLM (Model Yeasts in Biomedicine & Biotechnology). E.G-S. was a predoctoral fellow of the JAE program and R.G-P. was a predoctoral fellow of the I3P program, both from the CSIC (Spanish National Research Council).