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Supplementation with vitamin C and N-Acetyl-Cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise

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Abstract

There has been no investigation to determine if the widely used over-the-counter, water-soluble antioxidants vitamin C and N-acetyl-cysteine (NAC) could act as pro-oxidants in humans during inflammatory conditions. We induced an acute-phase inflammatory response by an eccentric arm muscle injury. The inflammation was characterized by edema, swelling, pain, and increases in plasma inflammatory indicators, myeloperoxidase and interleukin-6. Immediately following the injury, subjects consumed a placebo or vitamin C (12.5 mg/kg body weight) and NAC (10 mg/kg body weight) for 7 d. The resulting muscle injury caused increased levels of serum bleomycin-detectable iron and the amount of iron was higher in the vitamin C and NAC group. The concentrations of lactate dehydrogenase (LDH), creatine kinase (CK), and myoglobin were significantly elevated 2, 3, and 4 d postinjury and returned to baseline levels by day 7. In addition, LDH and CK activities were elevated to a greater extent in the vitamin C and NAC group. Levels of markers for oxidative stress (lipid hydroperoxides and 8-iso prostaglandin F2alpha; 8-Iso-PGF2alpha) and antioxidant enzyme activities were also elevated post-injury. The subjects receiving vitamin C and NAC had higher levels of lipid hydroperoxides and 8-Iso-PGF2alpha 2 d after the exercise. This acute human inflammatory model strongly suggests that vitamin C and NAC supplementation immediately post-injury, transiently increases tissue damage and oxidative stress.

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... It is possible, therefore, that NAC could directly and indirectly relieve ECC-induced muscle damage. However, there is no consensus with regard to the efficacy of NAC ingestion (Childs et al. 2001;Whitehead et al. 2008;Kerksick et al. 2010). ...
... These findings suggest that ECC-related muscle damage may not be primarily influenced by the ROS produced during ECC, thus indicating that antioxidant ingestion may not be an effective strategy against muscle damage. In fact, ingestion of both vitamin C and NAC immediately after ECC was shown to exacerbate muscle damage in humans (Childs et al. 2001). Although the underlying reasons for the contradictory results remain unclear, differences in the exercise protocol, tissues examined, and analytical procedures all remain potentially important. ...
... Antioxidants that are ingested to inhibit muscle damage include vitamins C and E, N-acetylcysteine (NAC), taurine, and honokiol (Childs et al. 2001;Chiang et al. 2009;Silva et al. 2011;He et al. 2018). Supplementation of both vitamins C and E before downhill runs has been shown to ameliorate decreases in isometric force, CK efflux, DOMS, and leukocyte apoptosis in humans (see below) (Shafat et al. 2004;He et al. 2015He et al. , 2018. ...
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Eccentric contraction (ECC) often results in large and long-lasting force deficits accompanied by muscle soreness, primarily due to muscle damage. In this sense, exercises that involve ECC are less desirable. Paradoxically, exercise training that includes a substantial eccentric phase leads to a more powerful activation of the genes responsible for skeletal muscle remodeling (e.g., hypertrophy) than other types of training that emphasize a concentric or isometric phase. Therefore, effective strategies that lessen ECC-induced muscle damage will be of interest and importance to many individuals. The purpose of this brief review is to highlight the published literature on the effects of ECC and/or nutritional supplementations on proteins, lipids, metabolic and ionic changes, and enzyme activities in skeletal muscles subjected to an acute bout of ECC. First, we discuss the potential mechanisms by which ECC causes muscle damage. Previous findings implicate a Ca2+ overload-oxidative modification pathway as one possible mechanism contributing to muscle damage. Thereafter, the efficacy of two nutritional supplementations, i.e., L-arginine and antioxidant, is discussed because L-arginine and antioxidant would be expected to ameliorate the adverse effects of Ca2+ overload and oxidative modification, respectively. Of these, L-arginine ingestion before ECC seems likely to be the effective strategy for mitigating ECC-related proteolysis. More studies are needed to establish the effectiveness of antioxidant ingestion. The application of effective strategies against muscle damage may contribute to improvements in health and fitness, muscle function, and sports performance.
... NAC supplementation was administered to several specific groups of athletes, including cyclists [100,101], triathletes [73], rowers [99], and volleyball players [98] to determine their role in redox related changes. Researchers also evaluated the possible effects of NAC on exercise-induced oxidative stress and adaptive mechanisms in healthy untrained men [68][69][70]72,74,[80][81][82][83][84], recreationally trained men [13,74,[85][86][87][88][89][90][91][92], and endurance-trained men [17,[94][95][96]. Most studies primarily focused on the effects of NAC supplementation on GSH and GSH-related biomarkers in muscle [13,80,91,94] and plasma [68][69][70]74,82,83,85,90,91,98,99,101], and total or reduced NAC in muscle [17,101] and plasma [17,74,88]. ...
... Researchers also evaluated the possible effects of NAC on exercise-induced oxidative stress and adaptive mechanisms in healthy untrained men [68][69][70]72,74,[80][81][82][83][84], recreationally trained men [13,74,[85][86][87][88][89][90][91][92], and endurance-trained men [17,[94][95][96]. Most studies primarily focused on the effects of NAC supplementation on GSH and GSH-related biomarkers in muscle [13,80,91,94] and plasma [68][69][70]74,82,83,85,90,91,98,99,101], and total or reduced NAC in muscle [17,101] and plasma [17,74,88]. However, it is challenging to comment on the relationship between NAC and glutathione availability, as studies differ in dose [17,83,93,98,99], exercise type [68,69,83,91], and training status [83,91,98,101]. ...
... Combining NAC-supplements with other antioxidants is another interesting issue in regulating body antioxidant defences. Childs et al. [82] evaluated the supplementation with NAC (12.5 mg/kg) plus vitamin C (Vit C; 10 mg/kg) on an acute muscle injury induced by eccentric exercise in healthy untrained men. Results showed that concentrations of bleomycin detectable iron in serum and lactate dehydrogenase (LDH) and creatine kinase (CK) in plasma increased more in the NAC plus vitamin C supplementation group than in the placebo group. ...
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Exercise frequently alters the metabolic processes of oxidative metabolism in athletes, including exposure to extreme reactive oxygen species impairing exercise performance. Therefore, both researchers and athletes have been consistently investigating the possible strategies to improve metabolic adaptations to exercise-induced oxidative stress. N-acetylcysteine (NAC) has been applied as a therapeutic agent in treating many diseases in humans due to its precursory role in the production of hepatic glutathione, a natural antioxidant. Several studies have investigated NAC’s possible therapeutic role in oxidative metabolism and adaptive response to exercise in the athletic population. However, still conflicting questions regarding NAC supplementation need to be clarified. This narrative review aims to re-evaluate the metabolic effects of NAC on exercise-induced oxidative stress and adaptive response developed by athletes against the exercise, especially mitohormetic and sarcohormetic response.
... Childs et al. assessed CK, LDH and they indicated that both CK and LDH were significantly elevated from baseline levels on post-exercise measurements and returned to pre-exercise values by day 7. 20 We did not evaluate them on the 7 th day. Other studies demonstrated that CK levels increase significantly immediately after the exercise, then returning to preexercise CK levels on the72 nd hour. ...
... In our study, as well as other studies, found increased oxidative stress markers reported in blood as a result of the increased levels of lipid peroxidation products and enzymatic markers of muscle damage after eccentric exercise. 20,22 In our study, NO and glutathione levels, especially MDA levels immediately increased after the exercise, similarly to the studies of Atalay and Stagos. 8,23 However, other studies indicated glutathione levels decreased after the exercise. ...
... 29 In many studies, muscle soreness decreased on day 7 after eccentric exercise. 20,30 In our study, on the first day after exercise, it showed a significant increase and then it tended to decrease. ...
... Nine studies presented in this research, found nonsignifi cant/moderate results, in the use of antioxidants (beetroot juice, Vitamin C, N-acetyl-cysteine, Vitamin E, Grape consumption) for reducing biochemical markers of infl ammation and muscle damage [11][12][13][14][15][16][17][18][19][20]. Clifford T, et al. 2016, show that in muscle damage by eccentric exercise, the beetroot juice is effective to reduce muscle soreness [21]. ...
... Toscano L. T, et al. 2015, article evidences that supplementation with purple grape juice promotes increased time-to-exhaustion and increased antioxidant activity [22]. Childs A, et al. 2001, fi ndings suggest that supplementation with the antioxidants vitamin C and N-acetyl-cysteine immediately post-injury, may increase tissue damage and oxidative stress [13]. In contrast with the fi ndings, Chou, et al. 2018, demonstrate the effi cacy of a high dose of Vitamin C and E supplementation in short period (4 days) can attenuate tissue damage, and infl ammatory response [23]. ...
... Toscano L. T, et al. 2015, article evidences that supplementation with purple grape juice promotes increased time-to-exhaustion and increased antioxidant activity [22]. Childs A, et al. 2001, fi ndings suggest that supplementation with the antioxidants vitamin C and N-acetyl-cysteine immediately post-injury, may increase tissue damage and oxidative stress [13]. In contrast with the fi ndings, Chou, et al. 2018, demonstrate the effi cacy of a high dose of Vitamin C and E supplementation in short period (4 days) can attenuate tissue damage, and infl ammatory response [23]. ...
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p>Introduction: The Homo sapiens has one of the most amazing characteristic, adaptability. And when adaptability comes to mind, exercising is just by side. Exercising brings many benefits for our body and it is the greater stimulus to trigger musculoskeletal adaptation, starting at mitochondrial level (i.e. biogenesis) to muscular level (i.e. hypertrophy). Mainly when the exercise is of high performance or strenuous, the athlete need a time to recover from fatigue, muscular damage, over-increase of muscular inflammation series of muscle and to prevent overtraining syndrome. Following the concept of “Evidence Based Practice” that is use the best available evidence in clinical decisions, what should be the methods that really have efficacy to prevent or reduce muscle damage, muscle biochemical markers of inflammation and recover? The aim of this article is to search in the PubMed database about what can help our patients/athletes to recover faster, to avoid or to reduce muscle damage and inflammation. Methods: A search in the PubMed database with the keywords Muscle Skeletal, Inflammation, and Exercise; the keywords had none language translation but results in any language were accepted. Only clinical trials were searched. Results: 272 articles, 174 excluded (by exclusion criteria). The 98 selected articles were divided into subtopics to discuss their efficacy. Conclusion: This article evidences the most effective treatments or prevention techniques for improvement of muscle damage, inflammation biochemical markers and muscle recovery. In our knowledge it is the first in PubMed database that assemble diverse health care subjects, and it may serve as an easy guideline for clinical decision making. </p
... Mb, which has a lower molecular weight than the CK enzyme, is known to reach its highest value more quickly [29,30], and in this respect, our study increased Mb in all groups compared to CK values. According to Childs et al [31], studies performed with eccentric contractions showed an increase in Mb levels, and similarly, in our study, it was observed that Mb levels increased more than concentric and isometric groups at the end of the strength training performed by eccentric contraction. In another study, it was stated that myoglobin values increased as a result of the exercise protocol, which was arranged in a bicycle ergometer, containing high-density eccentric contractions [32]. ...
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Background and Study Aim. The aim of this study is to investigate the effects of different types of contractions on muscle damage and muscle fatigue in sedentary individuals. Material and Methods. Thirty healthy male sedentary individuals participated in the study. Strength training in different types of contractions applied in the study was applied 3 times a week for 8 weeks. Before the study, the training loads were determined by making maximal force measurements of all subjects. The 30 subjects participating in the study were divided into 3 groups: isometric (n = 10), concentric (n = 10) and eccentric (n = 10) contraction group. Appropriate amount of blood samples was taken from the elbow vein 2 times from all subjects, before the studies and at the end of the 8-week strength training. Results. It was observed that eight-week strength training did not cause muscle fatigue in all groups and did not create a statistically significant difference (P> 0.05). Strength training with isometric and concentric contractions for eight weeks significantly increased serum lactate dehydrogenase (LDH), C-reactive protein (CRP), myoglobin (Mb), interleukin 6 (IL-6) levels, while concentric strength training significantly reduced serum aspartate amino transferase (AST) levels. Strength training with eccentric contractions significantly increased serum LDH, CRP, AST, Mb and IL-6 levels, while significantly reducing serum tumor necrosis factor alpha (TNF-α) levels. Strength training with eccentric contractions significantly increased serum creatine kinase (CK), CRP, AST, IL-6 and Mb levels compared to strength training with isometric and concentric contractions at the end of the eight-week study period, but did not show the same significant effect in other parameters. Conclusions. As a result, it can be said that eccentric strength training performed in sedentary individuals leads to more muscle damage than isometric and concentric strength training.
... Paradoxically, long-term administration of NAC in humans increases oxidative stress after an acute muscle injury induced by eccentric exercise, with higher blood levels of markers of inflammation [177]. ...
Article
At the moment, little treatment options are available for Duchenne muscular dystrophy (DMD). The absence of the dystrophin protein leads to a complex cascade of pathogenic events in myofibres, including chronic inflammation and oxidative stress as well as altered metabolism. The attention towards dietary supplements in DMD is rapidly increasing, with the aim to counteract pathology-related alteration in nutrient intake, the consequences of catabolic distress or to enhance the immunological response of patients as nowadays for the COVID-19 pandemic emergency. By definition, supplements do not exert therapeutic actions, although a great confusion may arise in daily life by the improper distinction between supplements and therapeutic compounds. For most supplements, little research has been done and little evidence is available concerning their effects in DMD as well as their preventing actions against infections. Often these are not prescribed by clinicians and patients/caregivers do not discuss the use with their clinical team. Then, little is known about the real extent of supplement use in DMD patients. It is mistakenly assumed that, since compounds are of natural origin, if a supplement is not effective, it will also do no harm. However, supplements can have serious side effects and also have harmful interactions, in terms of reducing efficacy or leading to toxicity, with other therapies. It is therefore pivotal to shed light on this unclear scenario for the sake of patients. This review discusses the supplements mostly used by DMD patients, focusing on their potential toxicity, due to a variety of mechanisms including pharmacodynamic or pharmacokinetic interactions and contaminations, as well as on reports of adverse events. This overview underlines the need for caution in uncontrolled use of dietary supplements in fragile populations such as DMD patients. A culture of appropriate use has to be implemented between clinicians and patients’ groups.
... Selman et al. 82 proposed some possible explanations for the inability of antioxidants to ensure longevity in animals and to reduce the incidence of disease in humans. In vivo, some antioxidants may act more as prooxidants than antioxidants as they possibly constrain higher activation of the defense system to keep the status quo 83 . The knowledge of the mechanisms of bioavailability, biotransformation, and interaction of antioxidant supplements is yet insufficient. ...
Article
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This review article is focused on the impact of antioxidants and prooxidants on health with emphasis on the type of antioxidants that should be taken. Medical researchers suggest that diet may be the solution for the control of chronic diseases such as cardiovascular complications, hypertension, diabetes mellitus, and different cancers. In this survey, we found scientific evidence that the use of antioxidants should be limited only to the cases where oxidative stress has been identified. This is often the case of specific population groups such as postmenopausal women, the elderly, infants, workers exposed to environmental pollutants, and the obese. Before starting any supplementation, it is necessary to measure oxidative stress and to identify and eliminate the possible sources of free radicals and thus increased oxidative stress.
... The present findings confirm this suggestion showing significant increases pre-post exercise for the enzymatic defense (i.e., GPX, SOD, and GR), regardless of the type of exercise. Additionally, these findings are in line with previous studies reporting increased enzymatic antioxidant activities immediately following (1) anaerobic exercise, such as strength eccentric exercise [47] and 100 m swim [25], (2) aerobic exercise, such as low intensity running [27,28] or swimming [25] activities, and combined (anaerobic and aerobic) exercise, such as intermittent (6 × 150 m) sprints [26]. Authors of these studies also attributed increases in these enzymatic antioxidant levels to the increase of the oxygen consumption, acidosis, catecholamines, and xanthine oxidase activity. ...
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Currently, it is well accepted that physical exercise-induced oxidative stress may damage biological structures and impair cellular functions. However, it is still unclear which type of exercise results in the greatest oxidative stress responses among a healthy untrained population. The aim of the present study was to compare the acute oxidative stress response (i.e., 0 to 20 min) following different types of exercise (anaerobic, aerobic, and combined). Ten healthy, untrained males (19.5 ± 1.7 years) performed three randomized exercise bouts: anaerobic (30 s Wingate test), aerobic (30 min at 60% maximal aerobic power (MAP)) or combined (anaerobic and aerobic). Venous blood samples were collected before, as well as at 0 (P0), 5 (P5), 10 (P10), and 20 (P20) min after each session. Rates of malondialdehyde (MDA) and antioxidant activities (i.e., glutathione peroxidase (GPX), superoxide dismutase (SOD), glutathione reductase (GR), α-tocopherol, and total antioxidant status (TAS)) were assessed. Independent of exercise type, plasma MDA, GPX, SOD, and GR contents increased above baseline, whereas plasma α-tocopherol decreased under baseline after the test sessions (p < 0.05). Aerobic and anaerobic exercises generated faster responses (at P0) when compared to the combined exercise (P5 to P10) for the majority of the tested parameters. Plasma TAS content only increased following the aerobic exercise at P10 (p = 0.03). Five to twenty-minutes post exercise, the highest MDA response was registered in the aerobic condition, and the highest GPX and SOD responses were recorded in the anaerobic (at P5) and aerobic (at P20) conditions (p < 0.05). In conclusion, aerobic, anaerobic, or combined exercises have the potential to acutely increase oxidative stress and antioxidant activities, but with different responses magnitude. These findings confirm that oxidative stress response seems to be dependent on the intensity and the duration of the physical exercise and may help in understanding how varying exercise bouts influence the degree of oxidative stress among healthy untrained young adults.
... For instance, elevation in the circulation and oxidation of free fatty acids (FFA) in the post exercise period [98] could modulate the production of ROS [99] by increasing H 2 O 2 emission at complex-II and the electron-transferring flavoprotein (ETF) in skeletal muscle mitochondria [100]. Inflammation resulting from microtrauma to sarcomeres due to unaccustomed and/or eccentric exercise [101] leads to infiltration of neutrophils that generate bursts of superoxide via NOX activation [102]. Further, a number of proinflammatory cytokines released from skeletal muscle (i.e.: 'myokines') during contraction [103] such as interleukin-6 (IL-6) can persist in the circulation after exercise and continue to stimulate ROS generating enzymes including xanthine oxidase, lipoxygenase and NOXs [104]. ...
Article
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Antioxidant supplements are commonly consumed by endurance athletes to minimize exercise-induced oxidative stress, with the intention of enhancing recovery and improving performance. There are numerous commercially available nutritional supplements that are targeted to athletes and health enthusiasts that allegedly possess antioxidant properties. However, most of these compounds are poorly investigated with respect to their in vivo redox activity and efficacy in humans. Therefore, this review will firstly provide a background to endurance exercise-related redox signalling and the subsequent adaptations in skeletal muscle and vascular function. The review will then discuss commonly available compounds with purported antioxidant effects for use by athletes. N-acetyl cysteine may be of benefit over the days prior to an endurance event; while chronic intake of combined 1000 mg vitamin C + vitamin E is not recommended during periods of heavy training associated with adaptations in skeletal muscle. Melatonin, vitamin E and α-lipoic acid appear effective at decreasing markers of exercise-induced oxidative stress. However, evidence on their effects on endurance performance are either lacking or not supportive. Catechins, anthocyanins, coenzyme Q10 and vitamin C may improve vascular function, however, evidence is either limited to specific sub-populations and/or does not translate to improved performance. Finally, additional research should clarify the potential benefits of curcumin in improving muscle recovery post intensive exercise; and the potential hampering effects of astaxanthin, selenium and vitamin A on skeletal muscle adaptations to endurance training. Overall, we highlight the lack of supportive evidence for most antioxidant compounds to recommend to athletes.
... The principal producer of ROS is the mitochondrial respiratory chain, primarily in the forms of O 2 _ and H 2 O 2. Vitamin C is not, however, an effective scavenger or neutralizer of hydrogen peroxide (H 2 O 2 ) [65]. Under certain conditions vitamin C can act pro-oxidatively, for example in connection with metals such as iron or mixed with N-acetyl-cysteine [18]. Vitamin C reacts not only with ROS but also with reactive nitrogen species (RNS) (nitric oxide NO, nitrogen dioxide NO 2 ) [25]. ...
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Vitamin C, first described over 90 years ago, is still being discovered by scientists today. Current epigenetic, nutrigenetic, and nutrigenomic research has given us a new understanding on why vitamin C is essential for optimal health at every stage of life. Ascorbic acid is involved in epigenetic reprogramming as an indispensable enzymatic cofactor in DNA demethylation in early preimplantation of embryos in utero, a process regulating fetal growth and development. Another role of vitamin C in pregnancy is associated with genetic variants in sodium-dependent vitamin C transporters (SVCT) that may be connected with spontaneous preterm birth as a result of premature membrane rupture. Vitamin C, as an exogenous antioxidant supports an endogenous, internal antioxidant system and protects against damage to DNA and cell membranes, especially against lipid peroxidation in tissues like brain or reproductive cells. Currently, ascorbic acid is believed to be a neuromodulator of glutamatergic, dopaminergic, and GABAergic transmission pointing to its role as a modulator of human behavior. Genetic variants of vitamin C transporters are considered to be one of many possible predisposing factors associated with Chronic Non-Communicable Diseases (NCDs) such as cancer, cardiovascular disease, osteoporosis, or neurodegenerative diseases (all are characterized by a significant overproduction of free radicals). The most efficient in protection against free-radical damage to DNA are fresh vegetables and fruits containing ascorbic acid, as advised by WHO and FAO (FAO/WHO 2004). Consuming 5 servings of fresh and cold vegetables and fruits daily allows for a constant supply of vitamin C and prevents its deficiency.
... A study carried out in 2003, demonstrated that co-supplementation with vitamin C and E in the morning may protect against elevations in inflammatory mediators, whereas ingestion of antioxidants immediately before a high-fat meal had no beneficial effects (Carroll and Schade, 2003). Furthermore, it has been reported that vitamin C supplementation increases oxidative stress after eccentric exercise (Childs et al., 2001). Therefore, the reasons for the discrepancy in our results of vitamin C and E co-supplementation between participants of different ages might be due to the differences in the level of oxidative stress at different ages, the timing of antioxidant ingestion, and other possible mechanisms between antioxidants and CRP that are not fully understood. ...
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Results of the studies assessed the effect of vitamins C and E co-supplementation on circulating levels of C-reactive protein (CRP) were contradictory. We carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of vitamins C and E co‑supplementation on CRP. A systematic search was carried out in PubMed, Scopus, Ovid, Cochrane, Embase, and the web of science without any language and time restriction up to 31 March 2019, to retrieve the RCTs which examined the effect of vitamins C and E co-supplementation on CRP. Meta-analyses were carried out using a random effects model, and I2 index was used to evaluate the heterogeneity. Search yielded 5134 publications. Eight RCTs were eligible. Results indicate that vitamins C and E co-supplementation had no significant effect on serum levels of CRP (weighted mean difference (WMD) and 95% confidence interval (CI) with random effects model analysis: -0.22 mg/l (-0.85, 0.41), p = 0.5). Results of the subgroup analysis demonstrated that following vitamins C and E co-supplementation, serum levels of CRP significantly reduced in participants with ages ≥30 years old, whereas, serum CRP levels significantly increased in participants with ages <30 years old. Results of the present meta-analysis indicated the beneficial effect of vitamins C and E co-supplementation on CRP in participants with ages ≥30 years old, and not in younger participants. However, further well-designed RCTs are needed.
... We should be reminded at this point that vitamin C deficiency may adversely affect health (e.g. scurvy, cataract, atherosclerosis) [4,37]. ...
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Study aim : The purpose of this study was to compare intake of antioxidant vitamins (A, C, E) in young women with various levels of physical activity. Material and methods : The study included 3 groups of females: 40 women with no extra physical activity (Sedentary), 40 women involved in regular, moderate sports activities (Recreationally Active) and 40 female athletes competing at an international level (Athletes). Participants’ diet was assessed on the basis of 3-day diet records which were analysed using the computer program ‘Dieta 5.0’. Body composition was evaluated by the bioelectrical impedance analysis (BIA) method. Results : Athletes were characterized by the lowest body fat and highest lean body mass in comparison with the other groups. They also showed the highest intake of energy, proteins and carbohydrates compared to Active and Sedentary women. The consumption of vitamin A amounted to 180.0% of RDA in Athletes, 98.8% in Recreationally Active and 97.8% in Sedentary women. Vitamin C intake in Athletes equalled 275.0% of RDA, whereas the deficiency of this vitamin was observed in Recreationally Active and Sedentary women (62.3% and 46.1% of RDA, respectively). The study groups showed consumption of vitamin E at the level of 146.7% of AI in Athletes, 115.0% in Recreationally Active and 111.3% in Sedentary women. Conclusion : Athletes consumed excessive amounts of antioxidant vitamins. Recreationally Active and Sedentary women met the demand for vitamin A and E, but the intake of vitamin C was not sufficient, which could lead to health problems. The current findings also indicate that energy intake was at a low level regardless of the study group.
... The main nonenzymatic antioxidants include VC and E. The antioxidant defenses of the body are usually adequate to prevent substantial tissue damage, whereas the stress situation in which there is imbalance could lead to deleterious effects [11].Vitamin C is able to protect endogenous lipids from detectable oxidative damage induced by aqueous peroxyl radicals and other reactive oxygen species [12]. Previous studies investigating the protective effects of supplementation with VC have been inconclusive: inhibition of lipid peroxidation [13],[14], no effect [15], [16], and even increased lipid peroxidation [17]. Since, VC is water-soluble it´s availability may be adequate after a single dose usage, and hypothetically there may be no need for prolonged supplementation. ...
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The depression of the immune system function that is typically observed after strenuous exercise is believed to be possibly mediated by stress hormones, cytokines and oxidative stress. The aim of this study was to measure immunoendocrine and oxidative stress responses after the ingestion of two different doses of Vitamin C (VC) supplementation. Twenty-four healthy untrained males participated in a 30-min exercise at 75%Vo2max. Immediately pre-exercise, the participants received either of the following regimens: placebo, 500 mg and 1000 mg of VC. Blood samples were obtained prior to ingestion, immediately after ingestion, 2hrs after ingestion and also 2hrs and 24hrs after exercise. Vitamin C used in doses of 500 mg and 1000 mg could significantly increase the plasma VC concentration and antioxidant capacity in both vitamin receiving groups. The increase in total antioxidant capacity (TAC) followed a significant decrease in post-exercise oxidative stress markers like malondialdehyde (MDA) (P<0.05). Markers of inflammation (total leukocytes, neutrophils and IL-6), muscle damage, creatine kinase (CK) and stress hormone (cortisol) were found to significantly increase in response to the exercise (P<0.05), but VC supplementation failed to decrease these factors significantly. The results suggest that acute supplementation with moderate and high doses of VC might prevent exercise-induced lipid peroxidation but not inflammatory markers.
... Although many studies have shown potential therapeutic effects by antioxidant supplementation [28][29][30], results from several others remain inconsistent. For example, supplementation with vitamin C and N-acetylcysteine was found to increase oxidative stress and cell damage following eccentric exercise [31]. Similarly, in a recent study by Bailey et.al, a combination of vitamins C and E was shown to increase markers of oxidative stress and inflammation [32]. ...
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In recent years, the consumption of chocolate and, in particular, dark chocolate has been “rehabilitated” due to its high content of cocoa antioxidant polyphenols. Although it is recognized that regular exercise improves energy metabolism and muscle performance, excessive or unaccustomed exercise may induce cell damage and impair muscle function by triggering oxidative stress and tissue inflammation. The aim of this review was to revise the available data from literature on the effects of cocoa polyphenols on exercise-associated tissue damage and impairment of exercise performance. To this aim, PubMed and Web of Science databases were searched with the following keywords: “intervention studies”, “cocoa polyphenols”, “exercise training”, “inflammation”, “oxidative stress”, and “exercise performance”. We selected thirteen randomized clinical trials on cocoa ingestion that involved a total of 200 well-trained athletes. The retrieved data indicate that acute, sub-chronic, and chronic cocoa polyphenol intake may reduce exercise-induced oxidative stress but not inflammation, while mixed results are observed in terms of exercise performance and recovery. The interpretation of available results on the anti-oxidative and anti-inflammatory activities of cocoa polyphenols remains questionable, likely due to the variety of physiological networks involved. Further experimental studies are mandatory to clarify the role of cocoa polyphenol supplementation in exercise-mediated inflammation.
... The cellular mechanism underlying muscle damage is still unclear, but recent studies have suggested that exercise-induced oxidative stress damage may be a cellular mechanism involved in the development of muscle damage, and supplementation with antioxidants (such as vitamin C, vitamin E, N-acetyl-cysteine, and fish oil) has been investigated as a potential strategy to reduce muscle damage. Although some studies reported no effect of antioxidants on muscle damage responses and increased oxidative stress (Close et al., 2006;Gray et al., 2014), other studies found augmented muscle damage responses and no change in oxidative stress (Bryer & Goldfarb, 2006;Childs, Jacobs, Kaminski, Halliwell, & Leeuwenburgh, 2001;Nie & Lin, 2004). Nevertheless, in addition to metabolic responses, we examined the loss of performance, which is more commonly used as an indicator of muscle damage. ...
Article
Purpose: The purpose of this study was to investigate (a) time-dependent changes in muscle damage (MD) biomarkers, oxidative stress (OS) indices, and maximum strength performance; (b) the relationship between changes in maximum strength performance and changes in MD and OS indices; and (c) whether eccentric exercise-induced MD is related to OS. Method: Twenty-nine male volunteers (age: 22.13 ± 3.1 years) participated in the study. Participants performed 60 maximal eccentric actions of the elbow flexors at a constant velocity of 60°·s⁻¹. Maximum isokinetic strength (MIS), visual analog scale soreness scores, serum creatine kinase (CK) activity, total antioxidant status, total oxidant status (TOS), protein carbonyl (PCO), and 8-hydroxydeoxyguanosine level were analyzed. Blood samples were obtained before, immediately after, and 24 h, 48 h, and 96 h after the eccentric exercise. Change in total work (%ΔTWk), peak torque (%ΔPT), and OS index were calculated. Results: CK, PCO, and TOS significantly increased over time (p < .05). However, no significant main effect was observed for MIS or any other investigated biomarkers (p > .05). MIS was not related to MD or OS indices. However, %ΔTWk demonstrated a moderate inverse correlation with OS indices. No significant relationship was observed between %ΔPT and any of the selected biomarkers. Conclusions: Our findings confirm the hypothesis that acute eccentric exercise increases MD biomarkers and OS indices. However, indices of OS damage were significantly related, particularly, to the strength loss of flexors. This finding suggests that the decline in strength performance is not the primary determinant of the magnitude of MD following voluntary eccentric contraction.
... It has been proposed that in some conditions, vitamin C alone or mixed with N-acetyl-cysteine could act as a pro-oxidant (Fenton reaction). Vitamin C (12.5 mg/kg) and N-Acetyl Cysteine (10 mg/ kg) for 7 days transiently increased tissue damage and oxidative stress after an acute muscle injury induced by eccentric exercise [42]. ...
Article
Purpose of review: Although vitamin C is essentially a nontoxic vitamin; however, it is important to be aware regarding the safety of high doses before the wide clinical use. Recent findings: Minor side effects of vitamin C have been reported, many being reported in earlier studies. High doses of vitamin C (up to 1.5 g/kg three times a week as intravenously) were safe in cancer patients with normal renal function and perfect glucose-6-phosphate dehydrogenase activity. As the dose and duration of administration of vitamin C in sepsis are lower and shorter than those used in cancer patients, it seems that it is relatively safe for this population. In ongoing trials, safety of high doses of vitamin C is considered. Summary: Data regarding the safety of high doses of vitamin C are scant. Until more data become available, caution should be applied in the use of high doses of vitamin C in patients with hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, renal dysfunction, kidney stone, oxaluria, and pediatrics.
... More specifically, neutrophils are early inflammatory responders and known to be a source of oxidative stress (Vollaard et al., 2005;Smith et al., 2008). In addition, myeloperoxidase (MPO), which is also highly expressed in neutrophils and released during the respiratory burst (Childs et al., 2001), is not an oxygen radical per se, but at elevated concentrations is also known to cause tissue damage. Schneider and Tiidus (2007) suggested inclusion of intramuscular MPO assessment in investigations aimed at elucidating the extent of neutrophil activity in muscle (Schneider and Tiidus, 2007). ...
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The purpose of this study was to investigate if exertional rhabdomyolysis induced by an acute bout of plyometric exercise in untrained individuals was associated with histological characteristics of skeletal muscle, creatine kinase (CK) polymorphism or secondary damage. Twenty-six healthy male untrained individuals completed a bout of plyometric exercise (10 sets of 10 maximal squat jumps, with each standardized to achieve at least 95% of individual maximal jump height). Blood samples were taken, and perceived pain was scored immediately before the exercise intervention and 6 h, 1, 2, and 3 days post-intervention. Muscle biopsies were collected 9 or 4 days before (baseline) and 3 days after plyometric jumps. Subjects were divided into two groups, high (n = 10) and low responders (n = 16), based on a cut-off limit for exertional rhabdomyolysis of peak CK activity ≥ 1000 U/L in any post-exercise blood sample. Perceived pain was more severe assessed in squat than standing position. Low responders perceived more pain at 6 h and 1 day, while high responders perceived more pain than low responders on days three and four after exercise; structural (dystrophin staining) and ultra-structural (transmission electron microscopy) analysis of muscle fibers revealed no baseline pathology; damage was evident in all individuals in both groups, with no difference between high and low responders in either damage or fiber type proportion. High responders had significantly higher total white blood cell and neutrophil counts 6 h and significantly higher C-reactive protein (CRP) 6 h and days one and two after exercise compared to low responders. High responders had significantly greater muscle myeloperoxidase (MPO) levels in baseline and 3 day post-exercise biopsies compared to baseline of low responders. MLCK C49T single polymorphism was present in 26% of volunteers, whose CK responses were not higher than those with MLCK CC or CT genotype. In conclusion, perceived pain is more effectively assessed with potentially affected muscle under eccentric strain, even if static. High CK responders also have pronounced CRP responses to unaccustomed plyometric exercise intervention. Exertional rhabdomyolysis after unaccustomed eccentric exercise may be related to underlying inability to resolve intramuscular MPO.
... These findings renew the long-standing perspective that ROS may harm muscle tissues and must be restrained. In fact, several authors have recently proposed that elevated antioxidant supplementation may likely be harmful [3] and may promote muscle damage and possibly hinder recovery in sports [48]. ...
Article
Objectives: The aim of this study was to verify the effects of supplementation with antioxidants (vitamins C and E) on oxidative stress, delayed-onset muscle soreness (DOMS), and performance in football players during a recovery period after an exercise-induced oxidative stress protocol. Methods: Twenty-one football athletes were randomly assigned to two groups: placebo and antioxidant-supplemented. Supplementation was performed in a double-blind, controlled manner using vitamin C (500 mg/d) and E (400 UI/d) for 15 d. After 7 d of supplementation, athletes were submitted to an exercise-induced oxidative stress protocol consisting of plyometric jumping and strength resistance sets to exhaustion. Blood samples, performance tests, and DOMS were determined before and 24, 48, and 72 h after exercise. Results: Antioxidant supplementation was continued during the recuperation week and for a total of 15 d. Antioxidant supplementation caused a significant increase in plasma vitamins C and E. The antioxidant supplementation could inhibit oxidative stress characterized by elevated lipid peroxidation markers malondialdehyde and total lipid peroxidation as well as reduced ratio of glutathione to oxidized glutathione promoted by exercise. Antioxidant supplementation, however, did not significantly reduce the plasma creatine kinesis concentration or DOMS during the recovery days. Likewise, supplementation with vitamin C and E did not improve lower body power, agility, or anaerobic power, nor did it provide any indication of faster muscle recovery. Conclusion: Antioxidant supplementation does not attenuate elevated markers of muscle damage or muscle soreness promoted by acute exercise and do not exert any ergogenic effect on football performance of young athletes, although it reduced oxidative stress.
... Os estudos epidemiológicos confirmam que sob condições fisiológicas normais, a vitamina C atua principalmente como um antioxidante; no entanto, pode ocorrer uma transição de um estado saudável para um estado patológico desencadeando a atividade pró-oxidante em determinadas circunstâncias (POLJSAK; IONESCU, 2009;CHAKRABORTHY et al., 2014). Sugeriu-se que a vitamina C sozinha ou misturada com N-acetilcisteína, que é um agente mucolítico utilizado no controle da overdose de paracetamol/acetaminofeno, poderia ser tóxica, atuando como um pró-oxidante (PODMORE et al., 1998;CHILDS et al., 2001). O estado pró-oxidante vem sendo relacionado a várias patologias, como: doenças cardiovasculares, doenças neurodegenerativas, doenças autoimunes e cânceres, ora como sua causa, em alguns casos como consequência (VELLOSA et al., 2013). ...
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A vitamina C ou ácido ascórbico (AA) é um elemento essencial para o ser humano e, por não ser metabolizado pelo corpo, necessitamos da sua ingestão pela dieta e/ou suplementação. As funções do AA no corpo são inúmeras, tais como: cofator para enzimas, biossíntese de hormônios e ação antioxidante, entretanto, estudos relatam que o consumo de AA em doses elevadas pode oferecer riscos à saúde. Deste modo buscou-se analisar os efeitos descritos da suplementação de AA. Realizamos uma revisão bibliográfica, dividida em duas perspectivas: uma histórica, com publicações de 1753-2012; e outra contemporânea, com estudos realizados entre 1990-2017. A pesquisa foi realizada no Science Direct, Scielo, PubMed, Scopus, Portal de Periódicos da Capes e em livros, utilizando as palavras-chave: vitamina C, ácido ascórbico, estresse oxidativo, antioxidante e pró-oxidante. A suplementação com AA é controversa, sendo descrito tanto o seu efeito antioxidante, como o pró-oxidante. A sua efetividade na prevenção e no tratamento do resfriado, diabete e câncer é questionável. Determinados grupos de pessoas mostram-se mais suscetíveis à toxicidade e aos danos do AA, podendo apresentar incidência de cálculos renais e interferência na função plaquetária. Concluímos que a suplementação em doses excessivas de AA pode ocasionar uma transição de um estado saudável para o patológico, desencadeando uma atividade pró-oxidante. Além disso, a dose ótima a ser ingerida e o limiar entre a dose benéfica e a prejudicial, é discutível. Desse modo, a suplementação de vitamina C deve ser realizada com cautela, com prescrição e acompanhamento de profissionais da saúde.
... It is interesting that both antioxidants can not suppress this stress, and even increase it. In this stuation, the conversion of ascorbic acid into the ascorbyl radical by reactive species generated during exercise may be major factor (Childs et al., 2001 ). An other important antioxidant β-carotene has also similar effects. ...
Article
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The safe use of antioxidants and reliable antioxidant applications are a new and important area of debate that has been continuing for decades. Today, antioxidant plants, phytochemicals and products are the most popular supplements. Most of them are sold without a prescription, even though they are used like a medicine. We know many scientific reports on the benefits of antioxidants but there are also studies that question whether antioxidant products have harmful effects. Nowadays antioxidant safety is the one of the most important medical topics at oxidant-antioxidant balance and oxidative stress. A physiological balance exists between oxidants and antioxidants in the organism only when both of the forces are present. Studies which document that antioxidant supplementation, inhibits the reactions and effects of free radicals are common. But, it is still unclear which exogen antioxidants and doses should be used to have an efective defense and also what safe limit is for use. It is possible that many of antioxidant phytochemicals and supplements can cause harmful changes in tissues by initiating different mechanisms. The most important question related to the use of antioxidants and antioxidant safety is the names, amounts, kinds and forms of them. The term antioxidative stress is a new strategic word on oxidant-antioxidant balance as like as oxidative stress. Antioxidants may cause stress in tisssues which refers to antioxidative stress. An extraordinary attention on antioxidative stress is a necessity for today's medical disciplines. The further studies are needed to clarify the harmful effects of antioxidants and antioxidative stress for the antioxidant safety. We aimed to focuse on the antioxidant-induced stress. For this reason, some reports on the harmful effects of antioxidants have been discussed in this paper. Keywords: antioxidative stress, harmful effects of antioxidants, antioxidant safety
... Egzersizle birlikte GSH düzeyi (Childs, Jacobs, Kaminski, Halliwell & Leeuwenburgh, 2001;Hellsten, Sjödin, Richter & Bangsbo, 1998;Hellsten ve ark., 2001;İnal Akyüz, Turgut, & Getsfrid, 2001;Marzatico, Pansarasa, Bertorelli, Somenzini & Della Valle, 1997;Svensson ve ark., 2002ve Thompson ve ark., 2003 (Clarkson, 1995) değişmediğini ifade etmiştir (Husain, 2003). Egzersiz çalışmalarının sonuçlarındaki bu farklılık büyük ölçüde egzersizin tipine, şiddetine, sıklığına ve süresine (egzersiz protokollerinin farklılığına) bağlıdır. ...
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z Bu çalışmanın amacı; farklı sürelerde yapılan koşu bandı egzersizlerinin sıçan kas dokusu üzerinde meydana gelen oksidatif stres parametrelerine etkisini belirlemektir. Sunulan çalışmada ağırlıkları 280-350 gram olan Albino Wistar cinsi 32 adet erkek sıçan kullanılmıştır. Sıçanlara, 13 hafta boyunca koşu bandı egzersiz protokolü, kısa (15 dakika, n:8), orta (30 dakika, n:8) ve yüksek (60 dakika, n:8) düzeyde, beş gün arasında uygulanmıştır. Biyokimyasal çalışmalar için her süpernatanttan süperoksit dismutaz aktivitesi (SOD), malondialdehit (MDA) seviyeleri ve glutatyon (GSH) seviyeleri sırasıyla ELISA kitleriyle her bir rat kas dokusu ikişer tekrarlamalı olarak ölçülmüştür. Deneylerden elde edilen sonuçlar ortalama ± standart sapma olarak verildi ve 0.05'in altındaki P değerleri, istatistiksel açıdan anlamlı olarak kabul edilmiştir. Gruplar arası farkın önemlilik derecesi tek yönlü varyans analizi (ANOVA) testi ile ve post-hoc testlerinden "LSD" tekniği kullanılarak belirlenmiştir. Kontrol grubu 23,07±3,38 (U/mg protein), Koşu 15 dk. grubu 19,82±4,77 (U/mg protein), Koşu 30 dk. 20,88±4,18 (U/mg protein) Koşu 60 dk. 22,15±3,85 (U/mg protein) SOD değeri olarak tespit edilmiştir. Kontrol grubu 0,43±0,6 (nmol/mg protein), Koşu 15 dk. grubu 0,35±0,3 (nmol/mg protein), Koşu 30 dk. 0,23±0,6 ab (nmol/mg protein), Koşu 60 dk. 0,24±0,1(nmol/mg protein), GSH değeri olarak tespit edilmiştir. Kontrol grubu 0,19±0,02 (nmol/mg protein), Koşu 15 dk. grubu 0,12±0,03 (nmol/mg protein), Koşu 30 dk. 0,14±0,01 (nmol/mg protein), Koşu 60 dk. 0,14±0,01 (nmol/mg protein), GSH değeri olarak tespit edilmiştir. Sonuç olarak farklı sürelerde yapılan koşu bandı egzersizi sıçan kas dokusunda meydana gelen oksidatif stres parametreleri üzerinde pozitif etkisinin olduğu tespit edilmiştir. Farklı sürelerde yapılan egzersizler ile birlikte alınan antioksidan desteğinin kas dokusu üzerinde daha etkili olabileceği önerilebilir. Abstract Aim of this study was planned to determine the effect of treadmill exercises made on different occasions on the oxidative stress parameters on the rat muscle tissue. In the present study, 32 Male Albino Wistar rats weighing 280-350 grams were used. Rats were administered a treadmill exercise protocol for 13 weeks, short (15 minutes, n:8), modarate (30 minutes, n:8) and long time (60 minutes, n:8) for five days. For each biochemical study, superoxide dismutase activity (SOD), malondialdehyde (MDA) levels and glutathione (GSH) levels from each supernatant were measured in duplicate in each rat muscle tissue by ELISA kits, respectively. Results from the experiments were given as mean±standard deviation, and P values below 0.05 were considered statistically significant. The significance level difference between groups was determined using the one-way analysis of variance (ANOVA) test and post-hoctests using the "LSD" technique. The control group consisted of 23,07 ± 3,38 (U/mg protein), 15 min group (19,82 ± 4,77 U/mg protein) and 30,88 ± 4,18 (U/Running was determined as SOD value of 60 min 22.15 ± 3.85 (U/mg protein). The control group consisted of 0,43 ± 0,6 (nmol/mg protein), 15 minutes group with 0,35 ± 0,3 (nmol/mg protein), 30 minutes 0,23 ± 0,6 ab (nmol/mg protein), Running 60 min 0,24 ± 0,1 (nmol / mg protein), GSH value. The control group consisted of 0.19 ± 0.02 (nmol/mg protein), 15 min group of running 0.12 ± 0.03 (nmol/mg protein), running 30 min 0.14 ± 0.01 (nmol/mg protein), Running was 0,14 ± 0,01 (nmol/mg protein), GSH valuefor 60 min. As a result, it was determined that treadmill exercise performed at different times had a positive effect on the oxidative stress parameters occurring in rat muscle. It may be suggested that the antioxidant supplementation taken with the exercises made at different times may be more effective on muscle tissue.
... Of primary concern is a temporary decrease in muscle function (strength, power, speed, economy of movement) that is accompanied by reduced range of motion (Jamurtas et al. 2005;Howatson et al. 2008;Damas et al. 2016;Qamar et al. 2019). Furthermore, there is often evidence of muscle swelling, muscle soreness, decreased pain threshold, increase of oxidative stress markers (Childs et al. 2001;Lee et al. 2002;Sacheck et al. 2003) and rise of various inflammatory interleukins, C-reactive protein (CRP), tenascin C, which can be accompanied by elevated intramuscular proteins (creatine kinase; CK, myoglobin; MYO, lactate dehydrogenase; LDH, for example); these can be present for several days following the damaging bout of exercise (Byrne et al. 2004;Hyldahl et al. 2014;Warren et al. 1999;Harty et al. 2019;Qamar et al. 2019;Baumert et al. 2016). Delayed-onset of muscle soreness (DOMS), a common symptom of EIMD, typically appears between 8 and 24 h after the muscle-damaging exercise, peaks between 24 and 48 h and usually subsides within 96 h (Damas et al. 2016;Jones et al. 1987). ...
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PurposeThis review provides an overview of the current knowledge of the nutritional strategies to treat the signs and symptoms related to EIMD. These strategies have been organized into the following sections based upon the quality and quantity of the scientific support available: (1) interventions with a good level of evidence; (2) interventions with some evidence and require more research; and (3) potential nutritional interventions with little to-no-evidence to support efficacy.Method Pubmed, EMBASE, Scopus and Web of Science were used. The search terms ‘EIMD’ and ‘exercise-induced muscle damage’ were individually concatenated with ‘supplementation’, ‘athletes’, ‘recovery’, ‘adaptation’, ‘nutritional strategies’, hormesis’.ResultSupplementation with tart cherries, beetroot, pomegranate, creatine monohydrate and vitamin D appear to provide a prophylactic effect in reducing EIMD. β-hydroxy β-methylbutyrate, and the ingestion of protein, BCAA and milk could represent promising strategies to manage EIMD. Other nutritional interventions were identified but offered limited effect in the treatment of EIMD; however, inconsistencies in the dose and frequency of interventions might account for the lack of consensus regarding their efficacy.Conclusion There are clearly varying levels of evidence and practitioners should be mindful to refer to this evidence-base when prescribing to clients and athletes. One concern is the potential for these interventions to interfere with the exercise-recovery-adaptation continuum. Whilst there is no evidence that these interventions will blunt adaptation, it seems pragmatic to use a periodised approach to administering these strategies until data are in place to provide and evidence base on any interference effect on adaptation.
... It is important to note, however, that many studies have concluded that intake of these antioxidants does not affect exercise performance or muscle injury [119][120][121][122][123]. The inconsistencies between these results could be attributed to differences in the conditions of antioxidant intake (i.e., type, dose, duration, timing, etc.) and the exercise protocol. ...
Article
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It is well established that the increase in reactive oxygen species (ROS) and free radicals production during exercise has both positive and negative physiological effects. Among them, the present review focuses on oxidative stress caused by acute exercise, mainly on evidence in healthy individuals. This review also summarizes findings on the determinants of exercise-induced oxidative stress and sources of free radical production. Moreover, we outline the effects of antioxidant supplementation on exercise-induced oxidative stress, which have been studied extensively. Finally, the following review briefly summarizes future tasks in the field of redox biology of exercise. In principle, this review covers findings for the whole body, and describes human trials and animal experiments separately.
... Ascorbic acid (vitamin C, cofactor for catecholamines synthesis that is involved in the biosynthesis of carnitine-stimulating carbohydrates oxidation and energy generation) is crucial for healthy cellular life. Its deficiency causes impairment of ATP production and b-oxidation [72]. The lack of tocopherol (vitamin E, cofactor in desaturation of saturated fatty acids, and lipid soluble antioxidant), causes excessive oxidative degradation of tocopherol and leads to downregulation of respiratory activity [73,74]. ...
Chapter
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Micro nutrients (minerals and vitamins), as well as macro nutrients (proteins, fats, and carbohydrates) which are crucial substrates/co-factors in the metabolic pathways regulating DNA synthesis/repair and gene expression, are totally necessary for the optimal health, vital for growth, normal development of organs, body at whole, proper immune function, restoring resistance to infections, and can significantly affect cell growth, tissue differentiation, cancer incidence, aging and homeostasis. Dis balance in nutrients supplementation leads to genomic instability, compromises normal function of cellular pathways and triggers development of chronic diseases. Micro nutrients play vital roles in functional integrity of the body physical barriers which are associated with natural defence antimicrobial s, including interferons (IFNs), phagocytes, and NK cells, which are crucial in regulation of the inflammatory process. During the viral infestation, most viruses manipulate the host cell’s metabolism to optimize the bio-synthetic needs, affecting cross talk between the immune system and central metabolism. Also, nutritional deficiency affects not only the hosts vital functions, but also the invading viral pathogen. The main deficits discovered during the viral infection usually include micro nutrient and macro nutrient abnormalities, such as reduced level of several vitamins, minerals, trace elements, amino acids including cysteine, tripeptide and others. These deficiencies can promote and strengthen viral parthenogenesis by weakening the immune system of the host, making it prone to development secondary infections. Specific micro nutrients can inhibit viral infection at various stages of the viral life cycle, that include blocking virus entry and virus multiplication, blocking virus activation in latently infected cells and prevents virus spread. Viral pathogens, such as COIVD-19, SARS, MERS and influenza can cause a massive “cytokine storm”, which triggers acute respiratory and multiple organ dysfunction, with following physiological deterioration and can lead to sudden death in several individuals. Proper supplementation with specific micro- and macro nutrients was found to suppress pro-inflammatory cytokines, increase anti-inflammatory cytokines and can contribute to balancing function of cellular inflammatory pathways during the onset and development of the viral infections. The main aim of this Chapter is to demonstrate an importance and mechanism of micro- and macro nutrients contribution to development of a potential inhibition of viral parthenogenesis, as well as suggest the specific types of functional food which can accompany micro- and macro nutrients supplementation during viral diseases prevention and maintenance.
... Importantly, regular or moderate exercises were demonstrated to benefit cellular antioxidant management. Thus, administration of antioxidant supplements is disputed, which are supported by several studies, indicating that antioxidant supplements have a detrimental effect on the health and performance benefits of exercise training (Childs et al., 2001;McAnulty et al., 2005). The balance between ROS production and elimination determines whether they benefit or harm human bodies. ...
Article
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Exercise plays an important role in the physiology, often depending on its intensity, duration, and frequency. It increases the production of reactive oxygen species (ROS). Meanwhile, it also increases antioxidant enzymes involved in the oxidative damage defense. Prolonged, acute, or strenuous exercise often leads to an increased radical production and a subsequent oxidative stress in the skeletal muscles, while chronic regular or moderate exercise results in a decrease in oxidative stress. Notably, under pathological state, such as obesity, aging, etc., ROS levels could be elevated in humans, which could be attenuated by proper exercise. Significantly, exercise stimulates the development of beige adipose tissue and potentially influence the function of brown adipose tissue (BAT), which is known to be conducive to a metabolic balance through non-shivering thermogenesis (NST) and may protect from oxidative stress. Exercise-related balance of the ROS levels is associated with a healthy metabolism in humans. In this review, we summarize the integrated effects of exercise on oxidative metabolism, and especially focus on the role of brown and beige adipose tissues in this process, providing more evidence and knowledge for a better management of exercise-induced oxidative stress.
... Several studies indicated that oral administration of antioxidants before exercise is effective in inhibiting exercise-induced oxidative stress and muscle damage because it suppresses ROS generation during exercise and the subsequent activation of the redox-sensitive inflammatory cascade [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. In contrast, other studies showed that the intake of the antioxidants does not affect oxidative damage or muscle injury caused by strenuous exercise [27][28][29][30][31][32][33][34][35]. The inconsistencies between these results could be attributed to differences in the conditions of antioxidant intake (i.e. ...
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Background: Excessive production of free radicals caused by many types of exercise results in oxidative stress, which leads to muscle damage, fatigue, and impaired performance. Supplementation with royal jelly (RJ) or coenzyme Q10 (CoQ10) has been shown to attenuate exercise-induced oxidant stress in damaged muscle and improve various aspects of exercise performance in many but not all studies. Nevertheless, the effects of treatments based on RJ plus CoQ10 supplementation, which may be potentially beneficial for reducing oxidative stress and enhancing athletic performance, remain unexplored. This study aimed to examine whether oral RJ and CoQ10 co-supplementation could improve high-intensity interval exercise (HIIE) performance in swimmers, inhibiting exercise-induced oxidative stress and muscle damage. Methods: Twenty high-level swimmers were randomly allocated to receive either 400 mg of RJ and 60 mg of CoQ10 (RJQ) or matching placebo (PLA) once daily for 10 days. Exercise performance was evaluated at baseline, and then reassessed at day 10 of intervention, using a HIIE protocol. Diene conjugates (DC), Schiff bases (SB), and creatine kinase (CK) were also measured in blood plasma and saliva before and immediately after HIIE in both groups. Results: HIIE performance expressed as number of points according to a single assessment system developed and approved by the International Swimming Federation (FINA points) significantly improved in RJQ group (p = 0.013) compared to PLA group. Exercise-induced increase in DC, SB, and CK levels in plasma and saliva significantly diminished only in RJQ group (p < 0.05). Regression analysis showed that oral RJQ administration for 10 days was significantly associated with reductions in HIIE-induced increases in plasmatic and salivary DC, SB, and CK levels compared to PLA. Principal component analysis revealed that swimmers treated with RJQ are grouped by both plasmatic and salivary principal components (PC) into a separate cluster compared to PLA. Strong negative correlation between the number of FINA points and plasmatic and salivary PC1 values was observed in both intervention groups. Conclusion: The improvements in swimmers' HIIE performance were due in significant part to RJQ-induced reducing in lipid peroxidation and muscle damage in response to exercise. These findings suggest that RJQ supplementation for 10 days is potentially effective for enhancing HIIE performance and alleviating oxidant stress. Abbreviations: RJ, royal jelly; CoQ10, coenzyme Q10; HIIE, high-intensity interval exercise; DC, diene conjugates; SB, Schiff bases; CK, creatine kinase; RJQ, royal jelly plus coenzyme Q10; PLA, placebo; FINA points, points according to a single assessment system developed and approved by the International Swimming Federation; ROS, reactive oxygen species; 10H2DA, 10-hydroxy-2-decenoic acid; AMPK, 5'-AMP-activated protein kinase; FoxO3, forkhead box O3; MnSOD, manganese-superoxide dismutase; CAT, catalase; E, optical densities; PCA, principal component analysis; PC, principal component; MCFAs, medium-chain fatty acids; CaMKKβ, Ca2+/calmodulin-dependent protein kinase β; TBARS, thiobarbituric acid reactive substances; MDA, malondialdehyde.
... On the other hand, the usage of N-acetylcysteine and α-lipoic acid can determine a temporary improvement of lipid peroxidation, inhibition of glycogen production and mitochondrial damage [150,151]. ...
Moderate exercise combined with proper nutrition are considered protective factors against cardiovascular disease and musculoskeletal disorders. However, physical activity is known not only to have positive effects. In fact, the achievement of a good performance requires a very high oxygen consumption, which leads to the formation of oxygen free radicals, responsible for premature cell aging and diseases such as heart failure and muscle injury. In this scenario, a primary role is played by antioxidants, in particular by natural antioxidants that can be taken through the diet. Natural antioxidants are molecules capable of counteracting oxygen free radicals without causing cellular cytotoxicity. In recent years, therefore, research has conducted numerous studies on the identification of natural micronutrients, in order to prevent or mitigate oxidative stress induced by physical activity by helping to support conventional drug therapies against heart failure and muscle damage. The aim of this review is to have an overview of how controlled physical activity and a diet rich in antioxidants can represent a "natural cure" to prevent imbalances caused by free oxygen radicals in diseases such as heart failure and muscle damage. In particular, we will focus on sulfur-containing compounds that have the ability to protect the body from oxidative stress. We will mainly focus on six natural antioxidants: glutathione, taurine, lipoic acid, sulforaphane, garlic and methylsulfonylmethane.
... Supplementation with vitamin C and N-acetylcysteine after an acute muscle injury induced by eccentric exercise caused an increase in markers of oxidative stress and lipid peroxidation [51]. Also, administration of vitamins C and E together to half and full Ironmen triathletes resulted in increased oxidative stress [52]. ...
Article
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This paper is a literature overview of the complex relationship between vitamin C and two opposing physiological states, physical activity and sleep. The evidence suggests a clinically important bidirectional association between these two phenomena mediated by different physiological mechanisms. With this in mind, and knowing that both states share a connection with oxidative stress, we discuss the existing body of evidence to answer the question of whether vitamin C supplementation can be beneficial in the context of sleep health and key aspects of physical activity, such as performance, metabolic changes, and antioxidant function. We analyze the effect of ascorbic acid on the main sleep components, sleep duration and quality, focusing on the most common disorders: insomnia, obstructive sleep apnea, and restless legs syndrome. Deeper understanding of those interactions has implications for both public health and clinical practice.
... For example, it has been suggested that iron is released from ferrite during inflammation and sepsis (Biemond et al., 1984) while vitamin C reacts easily with Fe +3 and forms ascorbyl radical and Fe +2 which in turn reacts with H2O2 and generates the HO . radical which is extremely harmful to biomolecules (Childs et al., 2001). ...
... Despite its efficacy, eccentric overload exercises (EOEs) may alter muscle structure and function to a greater extent than concentric contractions, leading to some discomfort and muscle soreness in athletes performing this type of exercise. Muscle soreness perceived by these athletes could be associated with damage in the muscle fibres after eccentric exercise, normally accompanied by local inflammation and increased lipid peroxidation (LPO), which could cause membrane rupture (Baker et al., 2004;Childs et al., 2001). Damage results in an increase in the concentration of inflammatory markers and different interleukins in the muscle (Buford et al., 2009) as well as the release of intracellular content (e. g. muscle enzymes) to the bloodstream (Conceicao et al., 2012). ...
Article
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The aim of this study was to analyse the acute effects of a concentric exercise and two different eccentric overload exercises (EOEs) on blood markers of muscle damage (i.e. creatine kinase [CK], lactate dehydrogenase [LDH], myoglobin [Myo], and malondialdehyde [MDA]) and muscle contractile properties. Ten healthy, young (27 ± 1.5 years, 179 ± 6 cm, 78.7 ± 10.8 kg), physically active men (3.5 ± 1.9 h·w-1) randomly performed three training sessions using the following protocols: a half-squat (HS) as a concentric exercise, and exercises using Versapulley (VP) or YoYo isoinertial technology (YIT) as EOEs (4 x 7 repetitions with a 2 min rest interval between sets). Blood samples and tensiomyography measurements were obtained after each training session. Repeated measures analysis of variance (ANOVA) followed by the Tukey test was used to detect differences between the four time points of each variable. The standardized difference or effect size (ES, 90% confidence limit) in the selected variables was calculated using the basal SD. After all exercises, a greater activity of CK, LDH, and concentration of Myo, and MDA were found compared to baseline values (p < 0.05). A substantially greater activity of CK, LDH, and Myo concentration, but not MDA, were found after EOEs when compared to the HS protocol. Substantially lower tensiomyography results in the rectus femoris (RF) were reported, irrespective of the exercise mode performed. Also, no substantial differences were obtained in the biceps femoris (BF) between EOEs and the HS protocol. Time of contraction (Tc) in the RF was possibly to very likely lower in the HS in comparison to EOEs. Additionally, muscular displacement (Dm) in the RF was substantially lower in the HS compared to EOEs. VP produced higher concentrations of damage markers than YIT and concentric exercise did. Furthermore, tensiomyography variables showed similar activation in both exercises, although higher specific fatigue (in the RF) was registered in the traditional HS.
... Hence, the ineffectiveness of vitamin C in Sahraee's survey can be justified by the low dose and oral route of vitamin C administration. Besides, the combined use of NAC and vitamin C can act as pro-oxidants in humans during some inflammatory states as reported by Child' et al. after an acute muscle injury induced by eccentric exercise [25]. Pre-transplant, high-dose intravenous vitamin C in another RCT could decrease DGF duration, however failed to reduce DGF incidence. ...
Article
Background and aim There are several observational and interventional studies regarding the advantages of sufficient serum levels of vitamin C and the evaluation of the effects of vitamin C supplementation post kidney transplantation. These studies have been put together to investigate the role of vitamin C post-kidney transplantation and make suggestions for designing future studies based on the use of vitamin C supplements or nutritional interventions among these patients. Methods This narrative review was done by searching in the Embase, PubMed, and SCOPUS databases. Results The results are presented in several sections as follows; nutritional status, potential protective effects, safety concerns, and medications/laboratory tests interactions of vitamin C. Conclusions: Kidney transplant recipients are prone to vitamin C deficiency, which is related to higher mortality based on several long-term observational studies. Vitamin C supplementation improves endothelial function and creatinine clearance. Vitamin C is considered as a safe supplement, however, side effects such as kidney stones, pro-oxidant effect, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, impact on lymphocytic activity, acid-base disturbance, and increased sodium load following its administration have been reported. Interaction of vitamin C and cyclosporine is the most important interaction with post-renal transplant medications. Vitamin C also interferes with creatinine assay using Jaffe and enzymatic methods.
... They concluded that the rate of oxidative stress increase after supplementation was much greater than the harm caused by eccentric exercise alone. One of the reasons why these supplements show a pro-oxidant property both in vitro and in vivo is their high reactivity with some intermediate metals such as iron [120]. In another study, male mice were fed 200 mg/kg b.w of the antioxidant supplement named acacia polyphenol and ran on a treadmill for 10 min at a speed of 15 m/min. ...
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Purpose: Eccentric exercise induces a decrease in vascular endothelial function. Curcumin, a major component of turmeric, has potent antioxidant and anti-inflammatory properties that are associated with vascular protective effects. The present study examined the effect of acute supplementation of curcumin on eccentric exercise-induced endothelial dysfunction in healthy young men. Methods: Fourteen healthy sedentary young men (range, 21-29 years) were assigned to either the curcumin (n = 6) or placebo (n = 8) group. All subjects consumed either curcumin or placebo before exercise, and eccentric exercise of the elbow flexors was performed with their nondominant arm. Before and 60 min after exercise, brachial artery flow-mediated dilation (FMD), as an indicator of endothelial function, was measured in the non-exercised arm. Results: Brachial artery FMD significantly decreased following eccentric exercise (p < 0.05) in the placebo group, but acute supplementation with curcumin before exercise nullified this change. The change in FMD before and after eccentric exercise between the placebo and curcumin groups was significantly different (p < 0.05). Conclusion: The present study found that acute curcumin supplementation could attenuate the decrease in endothelial function, as measured by FMD, following eccentric exercise in healthy young men.
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Copper has been suggested to facilitate oxidative tissue injury through a free radical-mediated pathway analogous to the Fenton reaction. By applying the ESR spin-trapping technique, evidence for hydroxyl radical formation in vivo was obtained in rats treated simultaneously with copper and ascorbic acid. A secondary radical spin-trapping technique was used in which the hydroxyl radical formed the methyl radical upon reaction with dimethylsulfoxide. The methyl radical was then detected by ESR spectroscopy as its adduct with the spin trap phenyl-N-t-butylnitrone (PBN). Because copper excreted into the bile from treated animals is expected to be maintained in the Cu(I) state (by ascorbic acid or glutathione), a chelating agent that would redox-stabilize it in the Cu(I) state was used to prevent ex vivo redox chemistry. Bile samples were collected directly into solutions of bathocuproinedisulfonic acid, a Cu(I)-stabilizing agent, and 2,2'-dipyridyl, a Fe(II)-stabilizing agent. If these precautions were not taken, radical adducts were generated ex vivo and could be mistaken for radical adducts generated in vivo and excreted into the bile. Besides the PBN/.CH3 adduct, three other radical adducts were produced in vivo and excreted in bile.
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Electron spin resonance (ESR) spectroscopy has been used to investigate hydroxyl radical generation in rats with chronic dietary iron loading. A secondary radical spin-trapping technique was used where hydroxyl radical forms methyl radical upon reaction with DMSO. The methyl radical was then detected by ESR spectroscopy as its adduct with the spin trap alpha-phenyl-N-t-butylnitrone (PBN). This adduct was detected in the bile of rats 10 wk after being fed an iron-loading diet and 40 min after the i.p. injection of the spin trap PBN dissolved in DMSO. Bile samples were collected into a solution of the ferrous stabilizing chelator 2,2'-dipyridyl in order to prevent the generation of radical adducts ex vivo during bile collection. Identification of the ESR spectrum of the major radical adduct as that of PBN/.CH3 provides evidence for the generation of the hydroxyl radical during iron supplementation. Desferal completely inhibited in vivo hydroxyl radical generation stimulated by high dietary iron intake. No radical adducts were detected in rats which were fed the control diet for the same period of time. This is the first evidence of hydroxyl radical generation in chronic iron-loaded rats.
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A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
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Superoxide dismutase (SOD) activity was measured by seven assay methods. The nitrite method was found to be the best for our SOD assay kit. This method was then modified to give better sensitivity and minimize interference by coexisting protein, a factor which has been previously ignored. Hydroxylamine or its O-sulfonic acid, xanthine oxidase, hypoxanthine, EDTA, and the sample were incubated with or without KCN at pH 8.2, 37°C, for 30 min. Diazo dye-forming reagent was added and the absorption was measured at 550 nm. Human plasma and erythrocyte lysate from healthy adults and Down's syndrome patients were assayed by this SOD kit and by the cytochrome c method. Our kit gave 8.5 times higher sensitivity than the cytochrome c method. This high sensitivity allowed the use of a simple spectrophotometer and, moreover, only one dilution was needed to determine the SOD unit with the help of our formulas. Good recovery, reproducibility, and stability of reagents were demonstrated.
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Adult, untrained NMRI mice were exhausted on a motor-driven treadmill by an intermittent-type running programme. Serial cryostate sections for the staining of NADH-tetrazolium reductase, ß-glucuronidase, ß-N-acetylglucosaminidase, and ß-glycerophosphatase activities and for making hematoxylin-eosin staining were cut from m. quadriceps femoris 1, 2, 3, 5, 7, and 15 days after physical exhaustion. A strong increase in the activities of ß-glucuronidase and ß-N-acetylglucosaminidase, was observed 7 days after exhaustion and the activity changes, which were similar for the both glycosidases, were more prominent in the highly oxidative red compared to less oxidative white fibres. Activity granules were more numerous in the perinuclear than the interfibrillar area of red fibres. Spots were arranged like longitudinal chains between myofibrils. Activity in connective tissue was usually observed only in animals exhausted 3–7 days earlier. Simultaneous activity in fibres exceeded that in connective tissue ß-Glycerophosphatase activity was not, by the method used, seen in histologically “healthy” or normal-looking fibres. in samples taken 2–5 days after exhaustion some degenerating and necrotic fibres were observed. Inflammatory reaction was also observed being at its strongest five days after loading when mononuclear cells were seen inside necrotic fibres. The number of regenerating muscle cells was most abundant 7 days after exhaustion. It is suggested that temporary hypoxia, which accompanies exhaustive physical exercise in skeletal muscle, upsets the energy metabolism and homeostasis of fibres and causes the observed histological and histochemical alterations, which posses features typical of both lethal and sublethal acute cell injury.
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Lead (Pb) is known to disrupt the pro-oxidant/anti-oxidant balance of tissues which leads to biochemical and physiological dysfunction. The present study investigated the effects of exposure on the redox status of the lenses of Fisher 344 rats and examined whether antioxidant or chelator administration reversed these changes. Animals were given 5 weeks of 2000 ppm Pb exposure followed by 1 week of either antioxidant, chelator or distilled water administration. Glutathione (GSH) and cysteine (CYS) levels decreased in the Pb-exposed group. N-acetylcysteine or 2,3-dimercaptopsuccinic acid (Succimer) supplementation following Pb intoxication resulted in increases in the GSH and CYS levels. Protein bound glutathione (PSSG) and cysteine (PSSC) increased following Pb exposure. In the Succimer-treated animals, the PSSG decreased significantly. The glutathione disulfide (GSSG) levels remained unchanged. Malondialdehyde (MDA) levels, a major lipid peroxidation byproduct, increased following Pb exposure and decreased following Succimer treatment. Our results suggest that antioxidant supplementation, as well as chelation, following Pb exposure may enhance the reductive status of lenses.
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The dopamine analogue 6-hydroxydopamine (6-OHDA) is selectively toxic to catecholaminergic neurons. Because of its selectivity for neuroblastic cells in the sympathetic nervous system lineage, 6-OHDA has been suggested as a chemotherapeutic agent for targeted treatment of patients with neuroblastoma. We tested the hypothesis that the toxicity of 6-OHDA is caused by its interaction with serum ferric transferrin (Fe-TF) resulting in release of iron. We further hypothesized that this iron, through its redox-cycling by 6-OHDA, triggers generation of reactive oxygen species. 6-OHDA-induced release of iron from Fe-TF was demonstrated by:  (1) low-temperature EPR spectroscopic evidence for decay of the characteristic Fe-TF signal (g = 4.3) and appearance of the high-spin signal from iron chelated by 6-OHDA oxidation products; (2) spectrophotometric detection of complexing of iron with the Fe2+ chelator ferrozine; (3) redox-cycling of ascorbate yielding EPR-detectable ascorbate radicals; and (4) generation of hydroxyl radicals as evidenced by EPR spectroscopy of their adduct with a spin trap, 5,5‘-dimethylpyrroline oxide (DMPO) (DMPO-OH). Our low-temperature EPR studies showed that in human plasma, 6-OHDA caused iron release only under nitrogen gas but not under air or oxygen. The absence of a 6-OHDA effect in plasma under aerobic conditions was most likely due to its ferroxidase activity [with consequent reuptake of Fe(III) by apoTF] and catalytic oxidation of 6-OHDA by ceruloplasmin. Modeling of these plasma activities by a stable nitroxide radical, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPOL), resulted in protection of plasma Fe-TF against iron release under nitrogen. Parenteral administration of 6-OHDA to mice resulted in iron release from Fe-TF as evidenced by transformation of the Fe-TF low-temperature EPR signal that was indistinguishable from that seen in in vitro models. In addition, administration of the iron chelator deferoxamine (DFO) to mice prior to administration of toxic doses of 6-OHDA resulted in a decrease in activity impairment of mice as compared to that seen with 6-OHDA alone. These findings underscore the physiological and pharmacological relevance of 6-OHDA-mediated iron release from Fe-TF and suggest that iron chelators (DFO) may be used for prevention of 6-OHDA toxicity.
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Patients with sepsis have low concentrations of antioxidants, including ascorbic acid, and also have increased concentrations of markers of free radical damage. Although ascorbic acid is a potent antioxidant, it can act as a prooxidant by promoting iron-catalysed reactions. We measured baseline total vitamin C and bleomycin-detectable "free" iron levels and ascorbyl radical concentrations before and after intravenous infusion of 1 g ascorbic acid in patients with sepsis and healthy control subjects. Vitamin C concentrations were decreased in patients compared to healthy subjects (p < 0.0001), and "free" iron was increased (p < 0.002). Preinfusion ascorbyl radical concentrations were not different in patients and controls. Postinfusion ascorbyl radical levels increased in both controls and patients, with larger increases in healthy subjects (p < 0.0001), suggesting suboptimal basal vitamin C levels and increased scavenging of a constant oxidant pool by ascorbate in the controls. In the patients, who were all vitamin C deficient, infused ascorbate was rapidly consumed, either via the promotion of redox cycling of iron or as a result of radical scavenging. This study demonstrates markedly different handling of infused ascorbate in patients with sepsis and healthy subjects, and further studies are needed to elucidate the relative anti- and pro-antioxidant mechanisms of ascorbate in patients with raised "free" iron levels.
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The effects of co-supplementing healthy volunteers with iron (14 mg/day ferrous sulphate) and vitamin C (either 60 mg/day or 260 mg/day as ascorbic acid) on levels of oxidative DNA damage in white blood cells were studied. The subjects were divided into two groups: one group of 20 volunteers with a higher mean initial level of plasma vitamin C (71.9 ± 14.0 μmol/l) and a second group of 18 volunteers with a lower mean level (50.4 ± 25.8 μmol/l). In the first group there was a significant rise in several oxidative DNA base damage products and in total oxidative DNA damage in DNA extracted from white blood cells, but not in 8-hydroxyguanine, after 6 weeks of supplementation. However, after 12 weeks levels returned approximately to normal. In the group with the lower initial level of plasma ascorbate, presupplemental levels of oxidative DNA damage were higher and decreased on supplementation with iron and ascorbate. Since oxidative DNA damage has been suggested as a risk factor for the development of cancer, the implications of increased levels in well-nourished subjects after iron/ascobate supplementation are disturbing in view of the frequent use of dietary supplements containing both iron salts and ascorbate.
Article
The activity of certain enzymes of energy metabolism (cytochrome c oxidase, citrate synthase, malate dehydrogenase, and lactate dehydrogenase) and of lysosomes (beta-glucuronidase, beta-N-acetylglucosamindase, arylsuphatase, ribonuclease, deoxyribonuclease, acid phosphatase, and cathepsin D) was assayed from m. rectus femoris of mice trained 5 days per week, 1 hr per day for 4 weeks according to 4 different programmes: I. running speed 20 m/min, horizontal track, II. 25 m/min, horizontal track, III. 20 m/min 8 degrees uphill inclination, and IV. 25 m/min 8 degrees uphill inclination. Oxidative capacity increased and anaerobic capacity decreased without distinction between the different traning programmes. Of acid hydrolases assayed the activities of beta-glucuronidase and cathepsin D were increased independently of training intensity. Simultaneous histochemical observations on beta-glucuronidase and arylsulphatase activities in the contralateral m. rectus femoris showed more intense staining in red as compared to white muscle fibres. It is suggested that training affected the red fibres and that the applied level of loading was probably too low to cause major involvement of white fibres.
Article
Adult, untrained NMRI mice were exhausted on a motor-driven treadmill by an intermittent-type running programme. Serial cryostate sections for the staining of NADH-tetrazolium reductase, beta-glucuronidase, beta-N-acetylglucosaminidase, and beta-glycerophosphatase activities and for making hematoxylin-eosin staining were cut from m. quadriceps femoris 1, 2, 3, 5, 7, and 15 days after physical exhaustion. A strong increase in the activities of beta-glucuronidase and beta-N-acetylglucosaminidase was observed 7 days after exhaustion and the activity changes, which were similar for the both glycosidases, were more prominent in the highly oxidative red compared to less oxidative white fibres. Activity granules were more numerous in the perinuclear than the interfibrillar area of red fibres. Spots were arranged like longitudinal chains between myofibrils. Activity in connective tissue was usually observed only in animals exhausted 3--7 days earlier. Simultaneous activity in fibres exceeded that in connective tissue. beta-Glycerophosphatase activity was not, by the method used, seen in histologically "healthy" or normal-looking fibres. In samples taken 2--5 days after exhaustion some degenerating and necrotic fibres were observed. Inflammatory reaction was also observed being at its strongest five days after loading when mononuclear cells were seen inside necrotic fibres. The number of regenerating muscle cells was most abundant 7 days after exhaustion. It is suggested that temporary hypoxia, which accompanies exhaustive physical exercise in skeletal muscle, upsets the energy metabolism and homeostasis of fibres and causes the observed histological and histochemical alterations, which possess features typical of both lethal and sublethal acute cell injury.
Article
Although N-acetyl-L-cysteine (Mucomyst) is an effective mycolytic, numerous investigations have failed to demonstrate a consistent improvement in pulmonary mechanics following its use. In order to determine whether its beneficial mucolytic activity might be counterbalanced by a deleterious direct effect on cilia, we studied its effect on the activity of ciliated epithelium in the ferret tracheal organ culture system. N-acetyl-L-cysteine consistently caused progressive time-dependent ciliostasis at concentrations clinically employed, with complete ciliary paralysis within 8 hr. The effect was only partially reversed by the removal of the drug. Control preparations retained full ciliary activity for 3 to 12 weeks. In order to determine the active site on the N-acetyl-L-cysteine molecule, we investigated the ciliostatic effects of five of its chemical analogs. Isomolar N-acetyl-L-alanine was not ciliostatic, indicating the necessity of a sulfhydryl group for activity. Ciliostasis was independent of isomeric structure, acetylation, and chain length, as evidenced by the similar ciliostatic effects of L-cysteine, D-cysteine, 2-mercaptoethylamine, and N-acetyl-L-homocysteine. We conclude that N-acetyl-L-cysteine induces partially reversible ciliostasis of tracheal epithelium via its sulfhydryl group; prolonged use of this drug may impair mucociliary clearance.
Article
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Article
A study was made of the interaction of plasma ascorbate and ascorbate free radical (AFR) with exogenously added iron. The quantitative determination of AFR has the advantage that transient increases in ascorbate oxidation can be directly monitored by e.p.r. spectroscopy. An AFR signal was found in the plasma of all donors and was unaffected by superoxide dismutase, catalase and the strong iron chelator deferoxamine. These findings and the rapid decrease in AFR under a nitrogen atmosphere suggest that plasma AFR is probably a result of air auto-oxidation. Iron loading of plasma did not affect the intensity of the AFR signal until the iron concentration approached or exceeded the plasma latent iron-binding capacity. In iron-overloaded plasma, the intensity of the AFR signal increased to about 10 times the normal level before decreasing rapidly to undetectable levels after 15-20 min. Determination of plasma ascorbate showed that the disappearance of AFR was due to a complete loss of the vitamin. When 50 microM-ascorbate was loaded with iron in iso-osmotic phosphate buffer there was an increase in the AFR signal, independent of the iron concentration, which was stable at least for 15 min. Thus the rate of ascorbate loss in the iso-osmotic phosphate buffer was considerably lower than in iron-overloaded plasma. The addition of different iron chelators produced comparable effects on the intensity of the AFR signal in both iron-overloaded plasma and ascorbate solution. These results suggest that the characteristic behaviour of plasma AFR after iron loading is due to its specific iron-binding capacity and to plasma ferroxidase activity. The ferroxidase activity of plasma is important to promote the transfer of Fe2+ into transferrin without a transient ascorbate oxidation. Spin-trapping studies with 5,5-dimethyl-1-pyrroline N-oxide and N-t-butyl-alpha-phenylnitrone revealed that iron-overloaded plasma was unable to produce spin-trap adducts even in the presence of 50-300 microM-hydrogen peroxide or 100 microM-azide. Evidence of OH. radical formation was obtained only after the addition of EDTA. Therefore, iron-overloaded plasma itself does not produce a Fenton reaction and, if ascorbate does indeed have a free-radical-mediated pro-oxidant role, it is not detectable in plasma by spin-trapping experiments.
Article
We have studied the effects of N-acetylcysteine which is thought to have antioxidant properties, on the susceptibility of low-density lipoprotein to oxidation and on whole-blood glutathione concentrations in six healthy volunteers. N-acetylcysteine was given orally in a dosage of at 1.2 g per day for 4 weeks, followed by 2.4 g per day for a further two weeks. The susceptibility of low-density lipoprotein toin vitro Cu2+-oxidation was determined by continuously measuring the formation of conjugated dienes. Whole-blood concentrations of reduced and oxidized glutathione were also determined. N-acetylcysteine had no effect on the susceptibility of LDL to oxidation. Concentrations of vitamin E in the serum and in low-density lipoprotein were not changed. Compared with controls the concentration of glutathione in N-acetylcysteine treated subjects was reduced (−48 %) and the concentration of oxidized glutathione was higher (+80%). The GSH/GSSG-ratio, a marker of oxidative stress was 83 % lower. The results do not support the supposed antioxidative action of N-acetylcysteine. It seems more likely that N-acetylcysteine acts as a pro-oxidant in the dosage used.
Article
Oxidative DNA damage, as expressed by 8-hydroxydeoxyguanosine (8-OHdG), was investigated in calf thymus DNA exposed to either ultraviolet radiation or to FeCl2/H2O2 in a Fenton-like reaction. The influence of iron (absent in the UV system and present in the FeCl2/H2O2 system) and pH (7.4 and 4.0) on the effect of glutathione (GSH), ascorbate, and 5-aminosalicylic acid (5-ASA, a drug used in the treatment of chronic inflammatory bowel diseases) was examined in these systems. Without iron, all three compounds considerably reduced 8-OHdG formation (i.e., acted as scavengers), while in the presence of iron salts, 8-OHdG formation was accelerated (except for GSH at pH 7.4), i.e., the compounds acted as prooxidants. This effect was augmented at low pH. The prooxidant property of 5-ASA may have implications for its clinical use. Maximum scavenging effect for all the compounds investigated was obtained at much lower doses than the maximum enhancing effect. This demonstrates that to the end of oxy-radical scavenging, the concentration of the GSH, ascorbate, and 5-ASA, respectively, should be chosen to obtain maximum antioxidant effect and minimum prooxidant effects. The significance of this finding for the selection of antioxidant dose is important but remains to be investigated further.
Article
Several studies indicate the presence of hydroxyl radical (OH.) as well as its involvement in the myocardial reperfusion injury. A transition metal-like iron is necessary for the conversion of superoxide anion (O2-) to a highly reactive and cytotoxic hydroxyl radical (OH.). In the present study, we have examined the generation of OH. and free iron in reperfused hearts following either normothermic (37 degrees C) or hypothermic ischemia (5 degrees C). Employing the Langendorff technique, isolated rat hearts were subjected to global ischemia for 30 min at 37 degrees C or 5 degrees C and were then reperfused for 15 min at 37 degrees C. The results of the study suggest that both the OH. generation in myocardium and free iron release into perfusate were significantly lower in hearts made ischemic at 5 degrees C as compared to 37 degrees C. Release of myoglobin and lactic acid dehydrogenase into perfusate also followed a similar pattern. Furthermore, in in vitro studies, chemically generated O2- at 5 degrees C caused a significantly lower rate of oxidation of oxymyoglobin as well as generation of OH. and free iron as compared to 37 degrees C. These results suggest that (1) reperfusion of hypothermic ischemic heart is associated with a reduction in the generation of OH. and cellular damage compared to that of normothermic ischemic heart, and (2) myoglobin, an intracellular protein, is a source of free iron and plays a role in the reperfusion injury mediated by free radicals.
Article
N-acetyl-cysteine (NAC), when given orally, has been shown to prevent gastric damage induced by ethanol, but when administered intraperitoneally, it appears to potentiate such damage. In an effort to resolve these seemingly discordant findings, fasted rats (six per group) received 1 ml of saline or 20% NAC orally or intraperitoneally (ip). Two hours or 15 min later, they received 1 ml of 100% ethanol orally. At sacrifice 5 min later, rats receiving oral pretreatment with 20% NAC at both 15 and 120 min prior to ethanol exposure demonstrated a significant reduction in the magnitude of gastric injury when compared with saline controls. In contrast, actual promotion of ethanol damage was noted when NAC was given intraperitoneally, but was more pronounced when NAC was administered 15 min prior to exposing the mucosa to 100% ethanol. In all animals receiving intraperitoneal NAC, large amounts of peritoneal fluid (4-6 ml/rat) were recovered at the time of sacrifice, most of which occurred within 15 min of NAC administration; these more pronounced peritoneal effects at 15 min after NAC correlated with the more severe injury from ethanol at this time period compared to 120 min after intraperitoneal NAC. Saline controls had no peritoneal fluid. Mucosal glutathione (GSH) levels generally paralleled these results in that a significant decrease in tissue GSH occurred at 15 min following intraperitoneal NAC when compared with controls; at 120 min after intraperitoneal NAC, GSH levels were similar to control values. Additional experiments demonstrated that within 15 min following NAC administration, systemic blood pressure dropped by approximately 20% and basically remained unchanged over the next 2 hr; intraperitoneal saline had no sustained adverse effects on blood pressure. It was concluded that the inability of NAC to prevent ethanol injury when given intraperitoneally in contrast to orally is related to the drop in blood pressure secondary to NAC's peritoneal irritant effects, which presumably altered gastric mucosal blood flow, thus obivating its ability to prevent ethanol damage under these conditions. Furthermore, the decreased levels in mucosal GSH following the hypotension induced by intraperitoneal NAC suggest that perturbations in GSH metabolism may also have contributed to the decreased resistance to ethanol injury.
Article
Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.
Article
Reductive release of iron from ferritin may catalyze cytotoxic radical reactions like the Haber-Weiss reaction. The ability of ·O−2 to mobilize Fe(II) from ferritin was studied by using the xanthine/xanthine oxidase reaction, with and without superoxide dismutase, and with bathophenanthroline sulphonate as the chelator. Not more than one or two Fe(II)/ferritin molecules could be released by an ·O−2-dependent mechanism, even after repeated exposures of ferritin to bursts of ·O−2. The amount of releaseable iron depended on the size and the age of the iron core, but not on the iron content of the protein shell of ferritin which was manipulated by chelators and addition of FeCl3. The kinetic characteristics of the ·O−2 mediated iron release indicated the presence of a small pool of readily available iron at the surface of the core. The very limited ·O−2 dependent release of iron from ferritin is compatible with a protective role of ferritin against toxic iron-catalyzed reactions.
Article
Mercaptopropionylglycine (MPG) has a marked cardioprotective action in several model systems of ischaemia-reoxygenation injury. Suggested mechanisms of action include scavenging of hydroxyl radical and of hypochlorous acid and reacting with an oxidant formed by reaction of myoglobin with H2O2, thereby slowing lipid peroxidation stimulated by myoglobin-H2O2 mixtures. This oxidant seems not to be singlet O2 or hydroxyl radical. Studies in vitro show that scavenging of hypochlorous acid is a feasible mechanism of cardioprotective action for MPG in vivo in ischaemia/reperfusion systems to which neutrophil-mediated injury contributes. However, the poor ability of MPG to inhibit lipid peroxidation stimulated by myoglobin/H2O2 mixtures and its ability to increase iron ion release from myoglobin in the presence of a large excess of H2O2 suggests that MPG is unlikely to protect the myocardium by interfering with oxidants produced by the myoglobin-H2O2 system.
Article
Analysis of fresh plasma from normal volunteers by negative ion chemical ionization GC/MS reveals what appear to be multiple PGF2 compounds with levels ranging from approximately 5 to 40 pg/ml. Interestingly, storage of plasma at -20 degrees C for several months was found to markedly increase the levels of these compounds to about 1000-4000 pg/ml, approximately 50-fold higher than levels detected in fresh plasma. Further studies aimed at understanding this observation revealed that alkaline hydrolysis of plasma lipids also yielded quantities of these compounds in the range that were detected in stored plasma. Employing a number of approaches such as deuteriated derivatives, hydrogenation, immunoreactivity with an anti-9 alpha, 11 beta-PGF2 antibody, and electron ionization mass spectral analysis, convincing evidence was obtained that these compounds in both stored and base-treated plasma were in fact PGF2 compounds. Formation of these compounds was found to occur by a nonenzymatic oxidative process in that the antioxidant, butylated hydroxytoluene, and the reducing agent, triphenylphosphine, markedly suppressed their formation. Evidence is presented to support a proposed mechanism that oxidative formation of these compounds involves the formation of endoperoxide intermediates which are directly reduced by naturally occurring biological substances to PGF2 compounds. Formation of these compounds occurs very readily in biological fluids. This finding has important ramifications not only for analysis of enzymatically derived PGF2 compounds but also for other eicosanoids which can be formed by this same nonenzymatic process. These analytical concerns apply to both immunoassay methods and physical methods of analysis such as gas chromatography/mass spectrometry.
Article
Hydrogen peroxide and organic hydroperoxides react with haemoglobin to release iron which can be complexed to apotransferrin, bleomycin and desferrioxamine. This released iron promotes deoxyribose degradation by a Fenton reaction, DNA degradation in the presence of bleomycin and stimulates lipid peroxidation. It is likely that iron released from haemoglobin is the true generator of hydroxyl radicals in the Fenton reaction. Hydroxyl radical Lipid peroxidation Transferrin iron binding Heme-protein iron release Hemoglobin Fenton catalyst Desferrioxamine Bleomycin-detectable iron.
Article
We have examined the effects of O2-derived free radicals on oxymyoglobin, the myocardial intracellular protein involved in the storage and transport of O2. The oxyradicals generated by the xanthine/xanthine oxidase system decreased the concentration of oxymyoglobin. Based on the decreases in absorbance peaks at 581 nm and 415 nm it is estimated that out of a 10 nmol decrease in oxymyoglobin, 5 nmol appears to be oxidized to ferrimyoglobin (deoxygenation), while haem was removed from the other 5 nmol of haem protein. These processes were inhibited by both catalase alone and superoxide dismutase in combination with catalase, but not by either superoxide dismutase alone or deferoxamine. These results suggest that among H2O2, OH. and O2.-, only H2O2 causes the removal of haem and the oxidation of oxymyoglobin. Furthermore, the oxyradicals also released 3 microM free iron from oxymyoglobin, which is at least 5-fold less than the 15 nmol loss of oxymyoglobin. The loss of oxymyoglobin also preceded the release of free iron. These results indicate that oxymyoglobin oxidation and haem removal occur before the removal of free iron. Thus myoglobin appears to be highly susceptible to free radical attack, and this may represent yet another mechanism of free radical-mediated cellular injury.