RESUMEN
For diabetic patients it is crucial to constantly monitor blood glucose levels to mitigate complications due to hyperglycaemia, including neurological issues and cognitive impairments. This activity leads to psychological stress, called "diabetes distress," a problem for most patients living with diabetes. Diabetes distress can exacerbate the hyperglycaemia effects on brain and negatively impact the quality of life, but the underlying mechanisms remain poorly explored. We simulated diabetes distress in adult zebrafish by modelling hyperglycaemia, through exposure to dextrose solution, along with chronic unpredictable mild stress (CUMS), and evaluated brain redox homeostasis by assessing reactive oxygen species (ROS) content, the antioxidant system, and effects on mitochondrial biogenesis and fission/fusion processes. We also evaluated the total, cytosolic and nuclear content of nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of redox balance, in the whole brain and total NRF2 in specific brain emotional areas. The combined CUMS + Dextrose challenge, but not the individual treatments, reduced total NRF2 levels in the entire brain, but strongly increased its levels in the nuclear fraction. Compensatory upregulation of antioxidant genes appeared inadequate to combat elevated levels of ROS, leading to lowering of the reduced glutathione content and total antioxidant capacity. CUMS + Dextrose treatment also upregulated transcription factors implicated in mitochondrial biogenesis and dynamics with a predominance of fission, which is consistent with increased oxidative stress. In conclusion, this study highlights the close interplay between hyperglycaemia and psychological distress causing overriding oxidative stress in the brain, rendering the organism vulnerable to the development of disease complications.
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Encéfalo , Homeostasis , Hiperglucemia , Factor 2 Relacionado con NF-E2 , Oxidación-Reducción , Especies Reactivas de Oxígeno , Proteínas de Pez Cebra , Pez Cebra , Animales , Encéfalo/metabolismo , Hiperglucemia/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Estrés Oxidativo , Estrés Psicológico/metabolismo , Antioxidantes/metabolismo , Glucosa/metabolismoRESUMEN
Microplastics have become a great worldwide problem and it's therefore important to study their possible effects on human and environmental health. In this study, zebrafish embryos were used to compare two different sizes of polystyrene microplastics (PS-MPs), 1 µm and 3 µm respectively, at 0.01, 0.1, 1.0 and 10.0 mgL-1, and were monitored up to 72 h. Toxicity tests demonstrated that neither of the PS-MPs altered the embryos' survival and the normal hatching process. Instead, higher concentrations of both sizes caused an increase of the heart rate and phenotypic changes. The PS-MPs of both sizes entered and accumulated in the larvae at the concentration of 10.0 mgL-1 and the same concentration caused an increase of apoptotic processes correlated to redox homeostasis changes. The reported results give a realistic view of the negative effects of exposure to PS-MPs and provide new information on their toxicity, also considering their sizes.
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Microplásticos , Poliestirenos , Animales , Humanos , Poliestirenos/toxicidad , Microplásticos/toxicidad , Plásticos/toxicidad , Pez Cebra/metabolismo , Estrés OxidativoRESUMEN
Phthalates are a family of aromatic chemical compounds mainly used as plasticizers. Among phthalates, di-n-butyl phthalate (DBP) is a low-molecular-weight phthalate used as a component of many cosmetic products, such as nail polish, and other perfumed personal care products. DBP has toxic effects on reproductive health, inducing testicular damage and developmental malformations. Inside the male reproductive system, the prostate gland reacts to both male and female sex steroids. For this reason, it represents an important target of endocrine-disrupting chemicals (EDCs), compounds that are able to affect the estrogen and androgen signaling pathways, thus interfering with prostate homeostasis and inducing several prostate pathologies. The aim of this project was to investigate the effects of DBP, alone and in combination with testosterone (T), 17ß-estradiol (E2), and both, on the normal PNT1A human prostate cell-derived cell line, to mimic environmental contamination. We showed that DBP and all of the tested mixtures increase cell viability through activation of both estrogen receptor α (ERα) and androgen receptor (AR). DBP modulated steroid receptor levels in a nonmonotonic way, and differently to endogenous hormones. In addition, DBP translocated ERα to the nucleus over different durations and for a more prolonged time than E2, altering the normal responsiveness of prostate cells. However, DBP alone seemed not to influence AR localization, but AR was continuously and persistently activated when DBP was used in combination. Our results show that DBP alone, and in mixture, alters redox homeostasis in prostate cells, leading to a greater increase in cell oxidative susceptibility. In addition, we also demonstrate that DBP increases the migratory potential of PNT1A cells. In conclusion, our findings demonstrate that DBP, alone and in mixtures with endogenous steroid hormones, acts as an EDC, resulting in an altered prostate cell physiology and making these cells more prone to cancer transformation.
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Aerobic organisms use molecular oxygen in several reactions, including those in which the oxidation of substrate molecules is coupled to oxygen reduction to produce large amounts of metabolic energy. The utilization of oxygen is associated with the production of ROS, which can damage biological macromolecules but also act as signaling molecules, regulating numerous cellular processes. Mitochondria are the cellular sites where most of the metabolic energy is produced and perform numerous physiological functions by acting as regulatory hubs of cellular metabolism. They retain the remnants of their bacterial ancestors, including an independent genome that encodes part of their protein equipment; they have an accurate quality control system; and control of cellular functions also depends on communication with the nucleus. During aging, mitochondria can undergo dysfunctions, some of which are mediated by ROS. In this review, after a description of how aging affects the mitochondrial quality and quality control system and the involvement of mitochondria in inflammation, we report information on how vitamin E, the main fat-soluble antioxidant, can protect mitochondria from age-related changes. The information in this regard is scarce and limited to some tissues and some aspects of mitochondrial alterations in aging. Improving knowledge of the effects of vitamin E on aging is essential to defining an optimal strategy for healthy aging.
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Estrés Oxidativo , alfa-Tocoferol , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , alfa-Tocoferol/farmacología , alfa-Tocoferol/metabolismo , Mitocondrias/metabolismo , Oxígeno/metabolismo , Vitamina E/farmacologíaRESUMEN
Ketone bodies (KBs) are an alternative energy source under starvation and play multiple roles as signaling molecules regulating energy and metabolic homeostasis. The mechanism by which KBs influence visceral white adipose tissue physiology is only partially known, and our study aimed to shed light on the effects they exert on such tissue. To this aim, we administered 1,3-butanediol (BD) to rats since it rapidly enhances ß-hydroxybutyrate serum levels, and we evaluated the effect it induces within 3 h or after 14 days of treatment. After 14 days of treatment, rats showed a decrease in body weight gain, energy intake, gonadal-WAT (gWAT) weight, and adipocyte size compared to the control. BD exerted a pronounced antioxidant effect and directed redox homeostasis toward reductive stress, already evident within 3 h after its administration. BD lowered tissue ROS levels and oxidative damage to lipids and proteins and enhanced tissue soluble and enzymatic antioxidant capacity as well as nuclear erythroid factor-2 protein levels. BD also reduced specific mitochondrial maximal oxidative capacity and induced endoplasmic reticulum stress as well as interrelated processes, leading to changes in the level of adipokines/cytokines involved in inflammation, macrophage infiltration into gWAT, adipocyte differentiation, and lipolysis.
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Environmental air pollution and resulting acid rain have the effect of increasing aluminum levels in water bodies. We studied the effects of aluminum on fish gills, the tissue most exposed to aluminum, using zebrafish as an experimental model. Adult zebrafish were exposed to an aluminum concentration found in polluted environments (11 mg/L) for 10, 15 and 20 days and the effects on gill morphology, redox homeostasis (ROS content, NADPH oxidase, NOX, activity, oxidative damage, antioxidant enzymes, total antioxidant capacity, in vitro susceptibility to oxidants) and on behavioural and metabolic parameters (routine respiratory oxygen consumption rMO2, tail-beating frequency, cytochrome oxidase activity and muscle lactate content) were evaluated. Exposure to aluminum affects branchial histology, inducing alterations in primary and secondary lamellae and redox homeostasis, modifying ROS levels, NOX activity, lipid and protein oxidative damage, antioxidant enzymes, and total antioxidant capacities, and increases rMO2. The effects exhibited a time-dependent behaviour, suggesting the activation of an adaptive response. These changes are associated with a transition of muscle metabolism from aerobic to anaerobic, as suggested by the increase in muscle lactate content, which is probably functional to preserve locomotor performance. Overall, the results here reported provide new insights into the toxicity mechanisms of Al exposure on gill tissue and the subsequent adaptive response of aquatic species.
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Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/metabolismo , Antioxidantes/metabolismo , Branquias/metabolismo , Aluminio/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Oxidación-Reducción , Homeostasis , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/metabolismoRESUMEN
While a low level of ROS plays a role in cellular regulatory processes, a high level can lead to oxidative stress and cellular dysfunction. Insulin resistance (IR) is one of the dysfunctions in which oxidative stress occurs and, until now, the factors underlying the correlation between oxidative stress and IR were unclear and incomplete. This study aims to explore this correlation in skeletal muscle, a tissue relevant to insulin-mediated glucose disposal, using the hyperthyroid rat as a model of oxidative stress. The development of IR in the liver from hyperthyroid animals has been widely reported, whereas data concerning the muscle are quite controversial. Thus, we investigated whether hyperthyroidism induces IR in skeletal muscle and the role of oxidative stress in this process. Particularly, we compared the effects of hyperthyroidism on IR both in the absence and presence of vitamin E (Vit E), acting as an antioxidant. Putative correlations between ROS production, oxidative stress markers, antioxidant capacity and changes in intracellular signalling pathways related to insulin action (AKT) and cellular stress response (EIF2α; JNK; PGC1α; BIP; and NRF1) were investigated. Moreover, we assessed the effects of hyperthyroidism and Vit E on the expression levels of genes encoding for glucose transporters (Slc2a1; Slc2a4), factors involved in lipid homeostasis and insulin signalling (Pparg; Ppara, Cd36), as well as for one of the IR-related inflammatory factors, i.e., interleukin 1b (Il1b). Our results suggest that hyperthyroidism-linked oxidative stress plays a role in IR development in muscle and that an adequate antioxidant status, obtained by vitamin E supplementation, that mitigates oxidative stress, may prevent IR development.
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Following the discovery of superoxide dismutase enzymes [...].
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Antioxidantes , Superóxido Dismutasa , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Catalasa , Especies Reactivas de OxígenoRESUMEN
Benzodiazepines, psychotropics drugs used for treating sleep disorders, anxiety and epilepsy, represent a major class of emerging water pollutants. As occurs for other pharmaceutical residues, they are not efficiently degraded during sewage treatment and persist in effluent waters. Bioaccumulation is already reported in fish and small crustaceans, but the impact and consequences on other "non-target" aquatic species are still unclear and nowadays of great interest. In this study, we investigated the effects of a pharmaceutical preparation containing the benzodiazepine delorazepam on the embryogenesis of Xenopus laevis, amphibian model species, taxa at high risk of exposure to water contaminants. Environmental (1 µg/L) and two higher (5 and 10 µg/L) concentrations were tested on tadpoles up to stage 45/46. Results demonstrate that delorazepam interferes with embryo development and that the effects are prevalently dose-dependent. Delorazepam reduces vitality by decreasing heart rate and motility, induces marked cephalic and abdominal edema, as well as intestinal and retinal defects. At the molecular level, delorazepam increases ROS production, modifies the expression of some master developmental genes and pro-inflammatory cytokines. The resulting stress condition significantly affects embryos' development and threatens their survival. Similar effects should be expected as well in embryos belonging to other aquatic species that have not been yet considered targets for these pharmaceutical residues.
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Embrión no Mamífero , Contaminantes Químicos del Agua , Animales , Benzodiazepinas , Desarrollo Embrionario , Nordazepam/análogos & derivados , Preparaciones Farmacéuticas , Contaminantes Químicos del Agua/toxicidad , Xenopus laevisRESUMEN
Thyroid hormones are normally involved in glycaemic control, but their excess can lead to altered glucose metabolism and insulin resistance (IR). Since hyperthyroidism-linked increase in ROS results in tissue oxidative stress that is considered a hallmark of conditions leading to IR, it is conceivable a role of ROS in the onset of IR in hyperthyroidism. To verify this hypothesis, we evaluated the effects of vitamin E on thyroid hormone-induced oxidative damage, insulin resistance, and on gene expression of key molecules involved in IR in the rat liver. The factors involved in oxidative damage, namely the total content of ROS, the mitochondrial production of ROS, the activity of antioxidant enzymes, the in vitro susceptibility to oxidative stress, have been correlated to insulin resistance indices, such as insulin activation of hepatic Akt and plasma level of glucose, insulin and HOMA index. Our results indicate that increased levels of oxidative damage ROS content and production and susceptibility to oxidative damage, parallel increased fasting plasma level of glucose and insulin, reduced activation of Akt and increased activation of JNK. This last result suggests a role for JNK in the insulin resistance induced by hyperthyroidism. Furthermore, the variation of the genes Pparg, Ppara, Cd36 and Slc2a2 could explain, at least in part, the observed metabolic phenotypes.
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The antioxidant role of mitochondrial uncoupling protein 3 (UCP3) is controversial. This work aimed to investigate the effects of UCP3 on the heart of mice housed at thermoneutral temperature, an experimental condition that avoids the effects of thermoregulation on mitochondrial activity and redox homeostasis, preventing the alterations related to these processes from confusing the results caused by the lack of UCP3. WT and KO UCP3 mice were acclimatized at 30 °C for 4 weeks and hearts were used to evaluate metabolic capacity and redox state. Tissue and mitochondrial respiration, the activities of the mitochondrial complexes, and the protein expression of mitochondrial complexes markers furnished information on mitochondrial functionality. The levels of lipid and protein oxidative damage markers, the activity of antioxidant enzymes, the reactive oxygen species levels, and the susceptibility to in vitro Fe-ascorbate-induced oxidative stress furnished information on redox state. UCP3 ablation reduced tissue and mitochondrial respiratory capacities, not affecting the mitochondrial content. In KO UCP3 mice, the mitochondrial complexes activities were lower than in WT without changes in their content. These effects were accompanied by an increase in the level of oxidative stress markers, ROS content, and in vitro susceptibility to oxidative stress, notwithstanding that the activities of antioxidant enzymes were not affected by UCP3 ablation. Such modifications are also associated with enhanced activation/phosphorylation of EIF2α, a marker of integrated stress response and endoplasmic reticulum stress (GRP778 BIP). The lack of UCP3 makes the heart more prone to oxidative insult by reducing oxygen consumption and increasing ROS. Our results demonstrate that UCP3 helps the cell to preserve mitochondrial function by mitigating oxidative stress. (AU)
Asunto(s)
Humanos , Antioxidantes/metabolismo , Mitocondrias Cardíacas , Proteína Desacopladora 3 , Proteínas Mitocondriales , Ratones Noqueados , Especies Reactivas de OxígenoRESUMEN
The antioxidant role of mitochondrial uncoupling protein 3 (UCP3) is controversial. This work aimed to investigate the effects of UCP3 on the heart of mice housed at thermoneutral temperature, an experimental condition that avoids the effects of thermoregulation on mitochondrial activity and redox homeostasis, preventing the alterations related to these processes from confusing the results caused by the lack of UCP3. WT and KO UCP3 mice were acclimatized at 30 °C for 4 weeks and hearts were used to evaluate metabolic capacity and redox state. Tissue and mitochondrial respiration, the activities of the mitochondrial complexes, and the protein expression of mitochondrial complexes markers furnished information on mitochondrial functionality. The levels of lipid and protein oxidative damage markers, the activity of antioxidant enzymes, the reactive oxygen species levels, and the susceptibility to in vitro Fe-ascorbate-induced oxidative stress furnished information on redox state. UCP3 ablation reduced tissue and mitochondrial respiratory capacities, not affecting the mitochondrial content. In KO UCP3 mice, the mitochondrial complexes activities were lower than in WT without changes in their content. These effects were accompanied by an increase in the level of oxidative stress markers, ROS content, and in vitro susceptibility to oxidative stress, notwithstanding that the activities of antioxidant enzymes were not affected by UCP3 ablation. Such modifications are also associated with enhanced activation/phosphorylation of EIF2α, a marker of integrated stress response and endoplasmic reticulum stress (GRP778 BIP). The lack of UCP3 makes the heart more prone to oxidative insult by reducing oxygen consumption and increasing ROS. Our results demonstrate that UCP3 helps the cell to preserve mitochondrial function by mitigating oxidative stress.
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Antioxidantes , Mitocondrias Cardíacas , Proteína Desacopladora 3 , Animales , Antioxidantes/metabolismo , Ratones , Ratones Noqueados , Mitocondrias Cardíacas/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Proteína Desacopladora 3/genéticaRESUMEN
Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures. More recently, the feature of the mitochondrial antioxidant system, which does not specifically deal with intramitochondrial ROS, was discovered. Indeed, the mitochondrial antioxidant system detoxifies exogenous ROS species at the expense of reducing the equivalents generated in mitochondria. Thus, mitochondria are also a sink of ROS. These observations highlight the importance of the mitochondrial antioxidant system, which should be considered in our understanding of ROS-regulated processes. These processes include cell signaling and the progression of metabolic and neurodegenerative disease.
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The ability of aerobic organisms to cope with the attack of radicals and other reactive oxygen species improves by feeding on foods containing antioxidants. Microalgae contain many molecules showing in vitro antioxidant capacity, and their food consumption can protect cells from oxidative insults. We evaluated the capacity of dietary supplementation with 1% dried Chlorella sorokiniana strain 211/8k, an alga rich in glutathione, α-tocopherol, and carotenoids, to counteract an oxidative attack in vivo. We used the hyperthyroid rat as a model of oxidative stress, in which the increase in metabolic capacities is associated with an increase in the release of mitochondrial reactive oxygen species (ROS) and the susceptibility to oxidative insult. Chlorella sorokiniana supplementation prevents the increases in oxidative stress markers and basal oxygen consumption in hyperthyroid rat livers. It also mitigates the thyroid hormone-induced increase in maximal aerobic capacities, the mitochondrial ROS release, and the susceptibility to oxidative stress. Finally, alga influences the thyroid hormone-induced changes in the factors involved in mitochondrial biogenesis peroxisomal proliferator-activated receptor-γ coactivator (PGC1-1) and nuclear respiratory factor 2 (NRF-2). Our results suggest that Chlorella sorokiniana dietary supplementation has beneficial effects in counteracting oxidative stress and that it works primarily by preserving mitochondrial function. Thus, it can be useful in preventing dysfunctions in which mitochondrial oxidative damage and ROS production play a putative role.
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Free radicals are chemical species (atoms, molecules, or ions) containing one or more unpaired electrons in their external orbitals and generally display a remarkable reactivity. The evidence of their existence was obtained only at the beginning of the 20th century. Chemists gradually ascertained the involvement of free radicals in organic reactions and, in the middle of the 20th century, their production in biological systems. For several decades, free radicals were thought to cause exclusively damaging effects . This idea was mainly supported by the finding that oxygen free radicals readily react with all biological macromolecules inducing their oxidative modification and loss of function. Moreover, evidence was obtained that when, in the living organism, free radicals are not neutralized by systems of biochemical defences, many pathological conditions develop. However, after some time, it became clear that the living systems not only had adapted to the coexistence with free radicals but also developed methods to turn these toxic substances to their advantage by using them in critical physiological processes. Therefore, free radicals play a dual role in living systems: they are toxic by-products of aerobic metabolism, causing oxidative damage and tissue dysfunction, and serve as molecular signals activating beneficial stress responses. This discovery also changed the way we consider antioxidants. Their use is usually regarded as helpful to counteract the damaging effects of free radicals but sometimes is harmful as it can block adaptive responses induced by low levels of radicals.
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Radicales Libres/metabolismo , Oxidantes/metabolismo , Animales , Antioxidantes/metabolismo , Humanos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Currently, it is known that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. It is also known that mitochondria, because of their capacity to produce free radicals, play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including the stimulation of permeability transition pore opening. This process leads to mitoptosis and mitophagy, two sequential processes that are a universal route of elimination of dysfunctional mitochondria and is essential to protect cells from the harm due to mitochondrial disordered metabolism. To date, there is significant evidence not only that the above processes are induced by enhanced reactive oxygen species (ROS) production, but also that such production is involved in the other phases of the mitochondrial life cycle. Accumulating evidence also suggests that these effects are mediated through the regulation of the expression and the activity of proteins that are engaged in processes such as genesis, fission, fusion, and removal of mitochondria. This review provides an account of the developments of the knowledge on the dynamics of the mitochondrial population, examining the mechanisms governing their genesis, life, and death, and elucidating the role played by free radicals in such processes.
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Mitocondrias/metabolismo , Dinámicas Mitocondriales/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/genética , Factores de Transcripción/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Mitocondrias/genética , Dinámicas Mitocondriales/fisiología , Mitofagia/genética , Estrés Oxidativo/fisiología , Proteínas Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/genéticaRESUMEN
Mitochondria are both the main sites of production and the main target of reactive oxygen species (ROS). This can lead to mitochondrial dysfunction with harmful consequences for the cells and the whole organism, resulting in metabolic and neurodegenerative disorders such as type 2 diabetes, obesity, dementia, and aging. To protect themselves from ROS, mitochondria are equipped with an efficient antioxidant system, which includes low-molecular-mass molecules and enzymes able to scavenge ROS or repair the oxidative damage. In the mitochondrial membranes, a major role is played by the lipid-soluble antioxidant vitamin E, which reacts with the peroxyl radicals faster than the molecules of polyunsaturated fatty acids, and in doing so, protects membranes from excessive oxidative damage. In the present review, we summarize the available data concerning the capacity of vitamin E supplementation to protect mitochondria from oxidative damage in hyperthyroidism, a condition that leads to increased mitochondrial ROS production and oxidative damage. Vitamin E supplementation to hyperthyroid animals limits the thyroid hormone-induced increases in mitochondrial ROS and oxidative damage. Moreover, it prevents the reduction of the high functionality components of the mitochondrial population induced by hyperthyroidism, thus preserving cell function.
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Antioxidantes/farmacología , Hipertiroidismo/tratamiento farmacológico , Hipertiroidismo/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Vitamina E/farmacología , Animales , Suplementos Dietéticos , Modelos Animales de Enfermedad , Humanos , Hígado/metabolismo , Miocardio/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Ratas , Glándula Tiroides/metabolismoRESUMEN
From their discovery in biological systems, reactive oxygen species (ROS) have been considered key players in tissue injury for their capacity to oxidize biological macromolecules [...].