Antioxidants (particularly superoxide dismutase) have been shown (347, 350) to attenuate endothelial dysfunction and preserve endothelial nitric oxide release.

From: Heart Physiology and Pathophysiology (Fourth Edition), 2001

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Metabolism in Surgical Patients

Courtney M. Townsend JR., MD, in Sabiston Textbook of Surgery, 2022

Biology of Acute Catabolism: Mineral and Antioxidant Alterations

Along with changes in macronutrients, inflammatory responses cause alterations in micronutrients (vitamins and minerals) from baseline physiology (Table 5.8).9,19 The most prominent of these responses is anemia, as IL-1 and TNF cause reduction in blood iron and zinc content.9,15,30 Since many microorganisms use iron and zinc as growth factors, it is speculated that these acute decreases in serum concentrations are part of protective immune responses against invading microorganisms.9,15,30 Moreover, these elements are decreased in serum, but they are not excreted from the body; they are stored in the liver and can be used again in cellular metabolism for the host after infection has resolved.9,15,30 While serum concentrations of both zinc and iron decrease, plasma copper concentrations rise because of the significant increase in ceruloplasmin, an additional acute phase protein.9,15,30 Deficiencies of water-soluble vitamins may also be identified, as diuresis begins during the resolution of the acute phase of stress.9,15,30


S. Stanner, E. Weichselbaum, in Encyclopedia of Human Nutrition (Third Edition), 2013


Antioxidants have the ability to scavenge free radicals in the human body and have been suggested to contribute to the protective effect of plant-based foods on diseases such as cardiovascular disease (CVD), cancer, and type 2 diabetes. However, evidence from supplementation studies using various antioxidants, including vitamin C, vitamin E, carotenoids, zinc, or selenium, does not support the hypothesis that antioxidants decrease risk of these diseases. Intervention studies highlight a lack of information on the safety of sustained intakes of moderate to high doses of micronutrient supplements and suggest that long-term harm cannot be ruled out, particularly in smokers.

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Complications of Diabetes Mellitus

Shlomo Melmed MB ChB, MACP, in Williams Textbook of Endocrinology, 2020

Diabetes Reduces Activity of Nuclear Erythroid-Related Factor 2, the Master Regulator of Antioxidant Gene Expression

The number of recognized ROS-regulating enzymes has increased substantially over the past 15 years.40 Examples include superoxide dismutases, catalases, glutathione peroxidases, glutathione reductase, thioredoxins, thioredoxin reductases, methionine sulfoxide reductases, and peroxiredoxins. The activity of these enzymes is largely determined by ROS-induced changes in their transcription. Increased transcription of many of these antioxidant enzymes is mediated by the transcription factor nuclear erythroid–related factor 2 (Nrf2), a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors.188 By regulating oxidant levels and oxidant signaling, Nrf2 participates in the control of the unfolded protein response, apoptosis, mitochondrial biogenesis, and stem cell regulation. Nrf2 also increases transcription of GLO1, the rate-limiting enzyme of the glyoxalase system, which prevents post-translational modification of proteins and histones by methylglyoxal, the major AGE precursor.189,190 It also increases transcription of the rate-controlling enzyme in the nonoxidative branch of the pentose phosphate pathway, transketolase. Activation of transketolase inhibits three of the major hyperglycemia-driven pathways implicated in the pathogenesis of diabetic vascular damage (the diacylglycerol-PKC pathway, the methylglyoxal-AGE formation pathway, and the hexosamine pathway) and inhibits hyperglycemia-induced NFκB activation.58 Preclinical studies using Nrf2 activators or Nrf2-deficient diabetic mice established that Nrf2 is a crucial endogenous modulator of ROS and protects from experimental diabetic nephropathy.191–193 In the kidneys ofdb/db mice, treatment with the tetracycline antibiotic minocycline increased Nrf2 protein levels, reduced glomerular oxidative stress markers, and ameliorated diabetic nephropathy.194

Nrf2 is expressed constitutively, and its intranuclear levels are controlled post-translationally. In the absence of inducers, Nrf2 associates with the redox-sensitive protein Kelch-like erythroid cell–derived protein with cap ‘n’ collar homology–associated protein 1 (Keap1), where it is rapidly polyubiquinated by Keap1-associated cullin-3–RING E2 ubiquitin ligase proteins and degraded by proteasomes. Nrf2 bound to Keap1 is released by ROS oxidation of critical cysteine thiols of Keap1, or by the reaction of these thiols with ROS-generated electrophiles such as glycolysis-derived methylgloxal and unsaturated fatty acid peroxidation-derived 4-hydroxynonenal. Phosphorylation of Nrf2 by protein kinases such as casein kinase 2 (CK2) may help target Nrf2 to the nucleus. After forming heterodimers with small Maf proteins, Nrf2 binds to the antioxidant response element (ARE) to induce transcription of its target genes. Export of Nrf2 from the nucleus is controlled by phosphorylation. Src family members such as Fyn phosphorylate Nrf2 at Tyr568, causing export from the nucleus and degradation.195 Reduction of Nrf2 protein in the cytosolic compartment is mediated by β-transducin repeat–containing protein, a substrate adaptor for the S-phase kinase-associated protein 1−Cul1−F-box protein E3 ubiquitin ligase, which targets GSK3β-phosphorylated Nrf2 to the proteosome196 (Fig. 37.16).


M. GABRIEL KHAN MD, FRCP[C], FRCP[LONDON], FACP, FACC, in Encyclopedia of Heart Diseases, 2006

4. The SPACE Study

The Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease (SPACE) study is a study of a small, high-risk group of patients: 196 patients on hemodialysis with cardiovascular disease followed for a median of 519 days. The vitamin E group decreased the relative risk for a composite primary end point of myocardial infarction, ischemic stroke, peripheral vascular disease, and unstable angina by 54%.

A similar study involving a group of 40 cardiac transplant patients treated for one year with 400 IU of vitamin E given twice daily for one year caused less coronary progression compared with those not given vitamins (p = 0.008). In cardiac transplant patients accelerated atherogenesis commonly occur.

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COPD : Pathogenesis and Natural History

V. Courtney Broaddus MD, in Murray & Nadel's Textbook of Respiratory Medicine, 2022

Mechanisms of Oxidant Injury and Antioxidants

Oxidant stress and injury resulting fromreactive oxygen species (ROS) is the ultimate trigger for the four major pathologic changes (SAD, mucus abnormalities, emphysema, and pulmonary microvascular changes) culminating in distinct COPD clinical phenotypes. The principal ROS are superoxide anion, hydrogen peroxide, and the hydroxyl radical, the most damaging ROS.198,199 ROS arise either exogenously, from CS and air pollution, or endogenously. Mainstream CS contains high concentrations of oxidants (1014 molecules/puff) and 3000 ppm nitric oxide/puff, and over 4700 chemical compounds.200 ROS in CS range from short-lived oxidants, such as the superoxide radical and nitric oxide, to long-lived organic radicals, such as semiquinones.199

Aerosols from vaping and heat-not-burn tobacco products have much lower free radical levels than CS201 but do emit volatile carbonyls, furans, and toxic metals, including chromium, lead, and nickel. Inhalational exposure to e-cigarette vapor causes adverse respiratory outcomes in animal models.202–206 One study of e-cigarette users showed elevated lung concentrations ofneutrophil elastase (NE) and thematrix metalloproteinases (MMPs)-2 and -9 with no change in antiprotease concentrations.207 Insights have come from the public use data files for the Population Assessment of Tobacco and Health, which collected nationally representative, population-based, longitudinal data three times from 2013 to 2016. Results imply that use of e-cigarettes is a risk factor for respiratory disease, independent of combustible tobacco smoking, and that dual use, the most common pattern, is riskier than using either alone.208 These devices were also recently associated with a syndrome of acute lung injury in humans209 (see alsoChapter 65).

Smoking and other oxidative inhalational stressors induce endogenous ROS production by lung epithelial cells,alveolar macrophages (AMø), and other phagocytes. Reduced nicotinamide adenine dinucleotide phosphate oxidase is the principal intracellular ROS source, but mitochondrial respiration and the xanthine/xanthine oxidase system also participate.199 The impact of oxidant stress is amplified in smokers due to the increased levels of iron in their lungs,210 which, by redox cycling of Fe++ and Fe+++ (via the Fenton and Haber-Weiss reactions), can produce the highly toxic hydroxyl radical. Phagocytes also produce two very damaging oxidants, hypochlorous acid and hypobromous acid, via cell-type specific enzymes that include myeloperoxidase and eosinophil peroxidase. During severe AE-COPD, oxidant stress in the lungs increases markedly in parallel with neutrophil recruitment.211 Oxidative stress can be measured by a host of biomarkers.212


Kai Singbartl, Alexander Zarbock, in Critical Care Nephrology (Second Edition), 2009



Originally developed as a mucolytic agent for treatment of a variety of pulmonary diseases, and later used as an antidote for acetaminophen poisoning, N-acetylcysteine (NAC) also is the best-studied antioxidant in the context of ARF, especially for the prevention of radiocontrast agent–induced nephropathy. NAC is a synthetic derivative of cysteine, which is one of three amino acids that make up glutathione. Glutathione is a cellular thiol that is essential for antioxidant defense. NAC itself also is capable of scavenging ROS by providing sulfhydryl groups.4 Animal as well as human clinical studies have identified potential mechanisms by which NAC may potentially confer renal protection. These mechanisms include attenuation of tubular necrosis and medullary hypoperfusion during renal ischemia-reperfusion,5 as well as reduction of leukocyte apoptosis and blunted oxidative stress response in patients undergoing hemodialysis.6,7 Clinical studies examining the efficacy of NAC have focused on the prevention of radiocontrast-induced nephropathy or ARF after vascular or cardiac surgery.

Although numerous clinical trial studies as well as several meta-analyses have evaluated the potential for NAC to prevent radiocontrast-induced nephropathy, substantial controversy remains regarding its beneficial effect on preservation of renal function (recently reviewed by Stacul and colleagues8). Moreover, the effects of NAC on “hard” outcome parameters, such as morbidity, mortality, and need for chronic hemodialysis, are still unknown. Several aspects of study design have contributed to this confusion. Although a majority of studies have included patients undergoing (interventional) coronary angiography, patient populations have been very heterogeneous, especially with respect to risk stratification. Great variability also has been noted in dose (ranging from 300 to 1200 mg), duration (for up to 48 hours after the procedure), and mode (enteral versus intravenous) of NAC administration; concomitant hydration has been inconsistent as well. Furthermore, a recent study in healthy volunteers has provided evidence that NAC itself has a direct effect on serum creatinine concentrations9: NAC induced a decrease in serum creatinine concentrations without any changes in cystatin C, an independent measure of glomerular filtration rate. It is possible, then, that after administration of NAC for the prevention of radiocontrast-induced nephropathy, serum creatinine concentrations may have falsely indicated preserved or even improved glomerular filtration rate.

Because of its low cost and excellent safety and tolerance, prophylaxis of radiocontrast-induced nephropathy with NAC is still very popular. Nonetheless, recent consensus statements8 and a meta-analysis10 do not support the routine use of NAC for this purpose. Instead, they recommend new randomized trials of large sample size and with the inclusion of “hard” outcome data, as well as a more cautious interpretation of existing data (see Chapter 51).

Randomized clinical studies examining the effectiveness of NAC in preventing ARF after cardiac or major vascular surgery have yielded negative results. Even with high-dose NAC administration or selection of high-risk patients, such as those with preexisting renal dysfunction, no benefit of NAC over placebo has been demonstrated.11,12 Although some studies revealed a trend toward lower serum creatinine concentrations after NAC administration, it remains unclear whether this change actually reflected better renal function or NAC-specific effects on serum creatinine concentrations. At present, the prophylactic use of NAC before major vascular or cardiac surgery cannot be recommended.

Ascorbic Acid

Administration of ascorbic acid has conferred protection from oxidative stress in animal models of postischemic ARF and drug-induced nephrotoxicity. Current belief holds that ascorbic acid acts through an increase in antioxidant activity and elimination of oxidation reactions. Ascorbic acid also can regenerate other antioxidants and act thereby as a co-antioxidant. It significantly affects the antioxidant status 2 hours after oral ingestion.13 Because of its excellent safety record in humans and attractive pharmacoeconomic profile, ascorbic acid also has become of interest for the prevention of drug-induced nephropathy.

Data from only one double-blind, placebo-controlled trial are currently available.13 Compared with placebo treatment, oral administration of 3 g of ascorbic acid before injection of radiocontrast agents, followed by two additional 2-g doses after the procedure, provided a significant reduction in radiocontrast-induced nephropathy, defined by a transient increase in serum creatinine. Despite these promising results, further randomized, controlled trials, including large-scale, multi-institutional studies, are necessary to confirm these findings.

3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase Inhibitors

3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) re-ductase inhibitors, or statins, have demonstrated a variety of pleiotropic effects in addition to their cholesterol-lowering potency.14 The main feature of these pleiotropic or cholesterol-independent effects of statins appears to be restoration or improvement of endothelial function. Statins improve endothelial function by increasing the bioavailability of nitric oxide, promoting reendothelialization, inhibiting inflammatory responses, and reducing oxidative stress.15 Statins have been shown to lower ROS production by inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity.15 In addition to endothelial cells, these effects also have been demonstrated in smooth muscle cells and leukocytes.

Clinical data supporting the broad application of statins for their antioxidative properties are rather limited. A retrospective study,16 which included more than 1000 patients undergoing coronary angiography, indicated that the risk for radiocontrast-induced nephropathy was lower in patients who had received statins before the procedure. Initiation of treatment with statins, however, had no effect on survival or need for dialysis. Review of data from a prospective, multicenter regional registry of patients undergoing percutaneous coronary interventions showed that patients who had been on statin therapy before the procedure had a lower incidence of radiocontrast-induced nephropathy.17 Although these data emphasize the need for initiation of statin therapy before coronary angiography, if indicated, they do not provide enough evidence to support the broad use of statins in patients who otherwise lack indications for therapy with such agents.

Although treatment with statins improved the lipid profile in patients after renal transplantation, as expected, such agents had no short-term effect on renal function.18

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The Role of Oxidative Stress in Endometriosis

Aditi Mulgund MD, ... Ashok Agarwal PhD, in Handbook of Fertility, 2015


Antioxidants are a defense mechanism produced by the body to neutralize the effects of ROS. They can be enzymatic and nonenzymatic. Nonenzymatic sources of antioxidants include vitamin C, vitamin E, selenium, zinc, beta carotene, carotene, taurine, hypotaurine, and glutathione. Enzymatic antioxidants include SOD, catalase, glutaredoxin, and glutathione reductase [64]. However, as the body ages, antioxidant levels decline, resulting in a disruption in the balance between antioxidants and prooxidant molecules. This results in the generation of oxidative stress and in turn, overrides the scavenging capacity by antioxidants either due to the diminished availability of antioxidants or excessive generation of ROS. Therefore, supplementation with oral oxidants may help to alleviate oxidative stress and its contribution to the pathogenesis of obstetrical disease such as endometriosis [65]. Only the most relevant antioxidants beneficial to endometriosis will be discussed.

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Quercetin and antioxidant potential in diabetes

Francis I. Achike, Dharmani D. Murugan, in Diabetes (Second Edition), 2020

Classification and sources of antioxidants

Antioxidants can be classified into two major types based on their source: natural and synthetic antioxidants (antioxidants can also be classified on the basis of their water/lipid solubility). Natural antioxidants either are synthesized in human body through metabolic processes or are supplemented from other natural sources, and their activity very much depends upon their physical and chemical properties and mechanism of action. This can be further divided into two categories: enzymatic antioxidants and nonenzymatic antioxidants.

Enzymatic antioxidants are uniquely produced in the human body. They include SOD, glutathione peroxidase (GPx), and CAT, with SOD and CAT being the most ubiquitous antioxidants in vivo.36 SOD catalyzes the reduction of superoxide anions to hydrogen peroxide and oxygen. SOD competes with nitric oxide (NO) for superoxide anion, which inactivates NO to form peroxynitrite. It, therefore, promotes the activity of NO by scavenging superoxide anions.37 CAT neutralizes hydrogen peroxide through decomposing it into molecular oxygen and water while GPx converts hydrogen peroxide and lipid peroxides to water and lipid alcohol, respectively.36

Nonenzymatic antioxidants can be found endogenously or exogenously from diet. Major intrinsic nonenzymatic antioxidants, include metal binding proteins, glutathione, UA, melatonin, bilirubin, and polyamines. Dietary antioxidants such as vitamin E, vitamin C, carotenoids, some minerals (e.g., zinc, manganese, copper, selenium) and polyphenols (flavonoids, phenolic acids, stilbenes, lignans) can affect the activity of endogenous antioxidants.38 Exogenous antioxidants are required for the proper functioning of enzymes. Their absence is known to affect the metabolism of many macromolecules. They act as cofactors for the enzymatic antioxidants. Exogenous antioxidants are present in significant amounts in commonly consumed fruits, vegetables, beverages (juices, tea, coffee), nuts, and cereal products. The natural sources of exogenous nonenzymatic antioxidants are summarized in Table 29.1.

Table 29.1. Some common natural exogenous nonenzymatic antioxidants and their typical sources.

Compound name Common natural sources References
Minerals Magnesium Whole gran, leafy green vegetables, legumes, nuts, fish [39]
Selenium Cereal, bread, meat, fish, egg, milk/dairy products [40]
Vitamins Vitamin A Green and yellow vegetables, dairy products, fruits, organ meat [41]
Vitamin C Citrus fruits, vegetables, cereal, beef, poultry, fish [42]
Vitamin E Almond, safflower oil, fish oil, broccoli, soybean oil [44]
Caretonoids β-carotene, lycopene, lutein, and zeaxanthin Green vegetables, carrot, parsley, blackcurrant, bell pepper, crustacean [45]
Polyphenols Flavonoids
Flavanones (hesperistin, naringin, naringenin) Spice (dried oregano), grapefruit, citrus fruits (lemon, orange) [46]
Flavones (quercetin, myricetin, apigenin) Spice (saffron), cranberries, apple, asparagus, broccoli, cabbage, ginger, onion, okra, beans [47]
Flavan-3-ols (catechin, epigallocatechin, epigallocathechin-3-gallate) Apples, pecan, broad beans, pistachio, wine, tea (black, green), soybean
Anthocyanadins (cyanidin) Berries, grape, plum, pistachio, wine, black beans [46]
Isoflavones (genistein) Soybeans and soy food, legumes
Lignans (lariciresinol, matairesinol, secoisolariciresinol) Oilseeds (i.e., flax, soy, rapeseed, and sesame), whole-grain [48]
cereals (i.e., wheat, oats, rye, and barley), legumes, various vegetables, and fruit (particularly berries)
Phenolic acids (hydroxybenzoic, hydroxycinnamic and hydroxyphenylacetic acids) Coffee, walnuts, plums, blueberries [49]
Stilbenes (resveratrol, combretastatin A-4 and pterostilbene) mulberries, peanuts, grapes, red wine [50]
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Role of Oxidative Stress in the Pathogenesis of Insulin Resistance and Type 2 Diabetes

Erik J. Henriksen, in Bioactive Food as Dietary Interventions for Diabetes (Second Edition), 2019

6.1 General Concepts of Antioxidant Properties

Antioxidants can be defined as compounds that act in cells as redox couples to scavenge ROS and to maintain cells in a more reduced redox state. While the cell expresses a plethora of endogenous factors that can function as antioxidants, such as superoxide dismutase and glutathione, strategies that can reduce oxidative stress systemically and in cells are predominantly interventions involving the provision of exogenous antioxidants, either in the diet or by ingestion or infusion of a purified form of the antioxidant compound. Food-based antioxidant interventions will be covered in other chapters of this book, and a comprehensive discussion of chemical antioxidants and their use in treating insulin resistance and other metabolic dysfunctions is beyond the scope of this chapter. The reader is referred to excellent reviews on antioxidant interventions in insulin resistance and diabetes.29–31 However, we will cover in this chapter the utility of one antioxidant compound, α-lipoic acid (ALA), which has been comprehensively studied for its effects on metabolic regulation in insulin-sensitive tissues.

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Antioxidants in Breast Milk of Lactating Mothers with HIV

Sheu K. Rahamon, ... Olatunbosun G. Arinola, in HIV/AIDS, 2018


Antioxidants play important roles in growth, development, detoxification, and effective immune responses. It is reported that the serum concentrations of antioxidants are altered in people living with human immunodeficiency virus (HIV). However, there is the dearth of information on the effects of HIV on the quality of breast milk, especially its antioxidants components. The breast milk of lactating mothers with HIV contains all the antioxidants that are normally found in human milk, although there are slight alterations. Breast milk concentrations of copper, iron, total antioxidant potential, riboflavin, vitamin B6, vitamin C, and folate are lower in lactating mothers with HIV compared with HIV-negative mothers. Other antioxidant trace elements and vitamins are in comparable concentrations. It appears that shedding of HIV is not only the problem with breastfeeding but also a reduction in breast milk concentrations of certain antioxidants that are vital for infant growth and survival.

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