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Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress

Corresponding Author

Baukje de Roos

Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK

Correspondence: Dr. Baukje de Roos, Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK

E-mail: [email protected]

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Garry G. Duthie,

Garry G. Duthie

Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK

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Baukje de Roos,

Corresponding Author

Baukje de Roos

Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK

Correspondence: Dr. Baukje de Roos, Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK

E-mail: [email protected]

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Garry G. Duthie,

Garry G. Duthie

Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK

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First published: 25 December 2014

https://doi.org/10.1002/mnfr.201400568

Citations: 34

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Abstract

The average length of human life is increasing, but so does the incidence of age- and lifestyle-related diseases. Improving diet and lifestyle is a key strategy for lifelong health and underlying mechanisms may well include increasing resilience pathways. The purpose of this review is to highlight and evaluate novel mechanisms by which dietary pro-oxidants, including bioactive phytochemicals and fatty acids, increase reactive oxygen species (ROS) concentrations just enough to activate transcription factor activation of nuclear factor erythroid 2 related factor 2 (Nrf-2) and heat shock factor (HSF), leading to an increase in levels of antioxidant enzymes and heat shock proteins that protect against the damaging effects of ROS. An increasing number of in vivo studies have now shown that dietary pro-oxidant compounds can increase the production of such resilience products. In most studies, dietary pro-oxidants normalized levels of antioxidant enzymes that were decreased by a range of different challenges, rather than raising levels of resilience products per se. Also, it is important to consider that the antioxidant response can be different for different organs. For future studies, however, the measurement of resilience markers may significantly improve our ability to prove the efficacy by which dietary bioactives with pro-oxidant capacities improve lifelong health.

Abbreviations

ARE: antioxidant response element
HSF: heat shock factor
HSP: heat shock protein
Keap1: Kelch-like ECH-associated protein 1
Nrf-2: nuclear factor erythroid 2 related factor 2
ROS: reactive oxygen species

1 Health and resilience

The ageing process occurs across the entire life course. It begins at conception and continues throughout infancy, childhood, adolescence, and maturity. Hence, early intervention to promote good health can take place at any stage in the life course. The key focus of early intervention is to slow down or prevent the development of debilitating health problems. Each stage in ageing has implications for the individual and for society, and we need to understand how problems can be prevented or mitigated. There are many potentially remedial factors and the components of an early intervention strategy could include, e.g., changing the behavior of individuals to make healthier choices and/or nutritional treatments and strategies. However, for this we would need improved information on the efficacy by which certain diets and their active components can improve health. There are three important questions that need to be addressed in considering health and the key motivators influencing healthy behavior. First of all, what is good health and how should it be measured? Second, what determines our resilience to disease? And finally, how can we intervene to improve resilience and maximize health?

2 Measuring health

Currently, most of us may argue that good health is merely being “free from disease or illness,” which we can only assess by measuring biomarkers of disease. The World Health Organization (WHO) defined health in 1948 as “a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity” 1. At the time, this definition was groundbreaking because of its breadth and ambition. However, in 1948 acute diseases presented the main burden of illness and chronic diseases led to early death. But disease patterns have changed. Chronic noncommunicable diseases, which include cardiovascular conditions, some cancers, chronic respiratory conditions, and type-2 diabetes, affect people of all ages, nationalities, and classes, and are now reaching epidemic proportions worldwide 2, 3. Indeed, ageing with chronic illnesses has become the norm. Such an increased prevalence of age-related diseases suggests that the WHO definition is outdated as it would leave most of us unhealthy most of the time 4.

Just as environmental scientists describe the health of the earth as the capacity of a complex system to maintain a stable environment within a relatively narrow range 5, it has been proposed that the formulation of health should be the “ability to adapt and to self-manage” 4, 6. In the physical domain, this would mean that when confronted with physiological stress, a healthy organism is able to mount a protective response, to reduce the potential for harm, and restore an (adapted) equilibrium 7. The instruments to measure health should then not only be, as is currently the case, assessment of the main prognostic and diagnostic biomarkers for chronic diseases, such as blood pressure, plasma lipids, and blood glucose 8. Such biomarkers are indicators for a disorder that has already developed. Instead, markers to measure health should relate to resilience, i.e. the ability to cope with stress, the ability to produce a protective response, and the ability to return to homeostasis after a stress challenge. In this case, resilience relates to prevent disease from happening in the first place, rather than being “free of disease.” Yet, there are currently few instruments for measuring aspects of health relating to an individual's capacity to cope and adapt, or to measure the strength of a person's physiological resilience 4.

3 Resilience pathways

Declining resilience to endogenous and exogenous stresses is considered a key aspect of aging-related disease development, causing a diminished ability to bounce back to homeostasis after being exposed to an acute challenge, such as illness, injury, or exertion. A growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of resilience and human pathologies. High levels of ROS are known to function as harmful products of aerobic metabolism, being an important cause of mitochondrial dysfunction 9. On the other hand, low levels of pro-oxidant molecules have been discovered to be beneficial to health by modulating transcription factor activation 10 (Fig. 1). This process is referred to as hormesis, an adaptive response of cells and organisms to a moderate (usually intermittent) stress. In the human body, ROS are metabolized by a series of antioxidant defense mechanisms using dietary derived or endogenously synthesized compounds. The purpose of these mechanisms is not to remove all ROS, but to control their levels to allow useful functions (i.e. defense and redox signaling) while minimizing oxidative damage 11. Two main cellular signaling pathways and molecular mechanisms that mediate hormetic responses involve the transcription factors nuclear factor erythroid 2 related factor 2 (Nrf-2) and heat shock factor (HSF).

Details are in the caption following the image — **Figure 1**
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The dose–response effect of pro-oxidant compounds on either resilience or oxidative stress.

3.1 The Nrf-2 pathway

One of the main signaling pathways involved in the oxidative stress response is the Keap1-Nrf2-ARE (where Keap1 is Kelch-like ECH-associated protein 1 and ARE is antioxidant response element). Indeed, Nrf2 signaling is the major cellular defense to relieve oxidative and electrophilic stresses 12. In the absence of oxidative stress, Nrf2 protein is continually degraded in the cytoplasm by an E3 ubiquitin ligase complex containing the regulatory protein Keap1. Keap1 contains multiple cysteine residues that, when modified by oxidation or electrophiles, accelerate its dissociation from Nrf2. This change allows Nrf2 protein to accumulate in the cytoplasm and translocate into the nucleus where it binds to the ARE present in target gene promoters and enhancers, driving their expression (Fig. 2) 12. Upon binding, Nrf2-ARE regulates the expression of key protective enzymes, including xenobiotic metabolizing enzymes (glutathione-S-transferases and NAD(P)H:quinone oxidoreductase-1), antioxidant enzymes (heme oxygenase-1, superoxide dismutase, glutathione peroxidase, and catalase), and enzymes involved in glutathione metabolism (such as glutamate cysteine ligase). Furthermore, Nrf2 activates proteasomal and chaperone proteins, indicating that Nrf2 has an important role also in the regulation of reparation and removal of damaged proteins 13. The Nrf2 pathway may be the most sensitive pathway for the presence of thiol-modifying molecules such as ROS or electrophilic small molecules, as a result of the presence of multiple, highly reactive, functionally important cysteine residues in Keap1. Recent findings indicate that different electrophiles modify distinct cysteine residues within Keap1, referred to as the “cysteine code.” Many of the oxidized products that are able to bind and activate Keap1, contain an α,β-unsaturated carbonyl group that can form Michael adducts with the SH-groups of the Keap1 signaling protein 13. In addition, isothiocyanates and sulfhydryl reactive metals were found to be the strongest activators of Nrf2 in a reporter assay system 12.

An increasing number of in vivo studies have provided evidence that various dietary bioactive phytochemicals and fatty acids can increase the production of protective enzymes products, or resilience products, likely through the Nrf2 pathway (Table 1) 14. These dietary compounds are believed to increase ROS concentrations just enough to activate relevant transcription factor activation, such as the ARE-regulated response and/or the heat shock response (HSR), but not cell death pathways 15. In that respect it is important to note that the treatment doses in a number of the animal studies were high and not necessarily dietary relevant. For such pharmacological doses, it could be argued that the induced response is toxicological, rather than an induced resilience response (Fig. 1). An example of this was presented by Bak et al., where the higher dose of 100 mg 6-shogaol-rich extract per kilogram failed to restore reduced antioxidant enzyme expression induced by diethylnitrosamine (Table 1) 16. It is also important to consider that regulation of, e.g., the antioxidant response can be different—and sometimes in an opposite direction—for different organs, and may well depend on mode of administration (Table 1) 17, 18.

Table 1. Overview of bioactive foods or food components that activate the antioxidant enzyme or heat shock response in in vivo studies

Bioactive food or food component	Model	Design, dose, and exposure	Effects on resilience outcomes compared with control group	References
Polyphenols and phenolics
Quercetin	Prostate cancer induced (MNU and testosterone treated) rats	Vehicle control, cancer-induced control, cancer-induced + quercetin (200 mg/kg BW/orally) and quercetin (200 mg/kg BW) three times a week for 16 wk	↑ SOD, CAT, GPx, GR, and GST activities in prostate lobes of cancer-induced rats with quercetin supplement ↑ SOD, CAT, GPX, GR, and GST activities in prostate lobes of quercetin-supplemented rats	43
Quercetin and catechin	Wistar Unilever rats	Control flavonoid free diet or this diet enriched with quercetin or catechin (2 g/kg diet)	No effect on liver enzyme activity of CAT, GPx, and SOD by quercetin or catechin ↑ NQO1 activity in liver of mice fed catechin No changes in hepatic TBARS	45
Catechin	Swiss albino mice	Tamoxifen treatment with or without pretreatment with catechin (40 mg/kg)	↓ SOD production and TBARS in hepatic mitochondria	80
Curcumin	Inbred male Swiss albino mice	Control diet or this diet supplemented with 0.01 or 0.05% curcumin, for 16 days. Mice were given 1 mg B[a]P in corn oil or corn oil as vehicle by gavage on 15th day of dietary pretreatment	↑ GST and NQO1 activity, protein levels, and mRNA expression in liver and lungs of mice fed 0.05% curcumin ↑ Activity and protein levels of GST isoforms in liver of mice fed 0.05% curcumin ↑ Total Nrf2 protein in liver and lungs of mice fed 0.05% curcumin No change in hepatic PGE2 levels between groups	81
Curcumin	Kunming mice—arsenic toxicity model	Control mice or mice with arsenic (10, 50, and 100 mg/L drinking water) with or without curcumin (200 mg/kg) administrated by gavage, twice 1 wk for 6 wk	↑ Nrf2 hepatic protein levels in livers of curcumin-treated mice ↑ Hepatic NQO1 and HO-1 protein levels in livers of curcumin-treated mice	23
Curcumin	C57BL/6J/Nrf2^−/− mice and WT C57BL/6J mice	Curcumin (1000 mg/kg, dissolved in 50% PEG 400 solution) or vehicle only by gavage. Mice were sacrificed 3 and 12 h after curcumin treatment or 3 h after vehicle treatment	Regulation of Nrf2 genes (involved in ubiquitination and proteolysis, electron transport, detoxification, transport, apoptosis and cell cycle control, cell adhesion, kinase and phosphatase, and many phase II detoxification/antioxidant enzyme genes) by curcumin in liver and small intestine of WT mice but not in knockout mice	54
EGCG	C57BL/6J/Nrf2^−/− mice and WT C57BL/6J mice	EGCG (200 mg/kg, dissolved in 50% PEG 400 solution) or vehicle only by gavage. Mice were sacrificed 3 and 12 h after curcumin treatment or 3 h after vehicle treatment	Regulation of Nrf2 genes (involved in ubiquitination and proteolysis, electron transport, detoxification, transport, apoptosis and cell cycle control, cell adhesion, kinase and phosphatase) by EGCG in liver and small intestine of WT mice but not in knockout mice	53
Genistein	Wistar Unilever rats	Control flavonoid free diet or this diet enriched with genistein (2 g/kg), for 3 wk	↑ Hepatic mRNA and activity levels of NQO1 No change in total GST, CAT, GPx, and SOD activity, and no change in Nrf2 protein levels No changes in hepatic TBARS	33
Naringin	High fat diet—streptozotocin-induced type 2 diabetic rats	Control diet, high-fat control diet with naringin (0, 25, 50, or 100 mg/kg/day, by mouth)	↑ SOD and Gpx activities in liver, kidney, pancreas, and serum in naringin-fed rats ↓ TBARS in liver, kidney, pancreas, and serum in naringin-fed rats ↑ HSP72 expression in liver, kidney, and pancreas of naringin-fed rats	32
Resveratrol	C57 BL6 mice—hyperlipidemia model	Chow or high-fat diet with or without resveratrol (0.1% w/w), minipump administration of vehicle or resveratrol at a flow rate of 0.25 μL/h to give a dosage of 100 mg/kg/day	No effect on CuZnSOD protein levels in different tissues of mice fed resveratrol ↑ MnSOD protein level in brain in mice fed resveratrol against high-fat diet but not by minipump ↓ MnSOD protein level in heart tissue of mice fed resveratrol ↓ GPx activity in brain tissue of mice fed resveratrol against high-fat diet or osmotic minipump ↑ GPx activity in heart tissue of mice fed resveratrol against high-fat diet ↑ CAT activity in heart tissue of mice fed resveratrol against a high-fat diet or osmotic minipump, but not in liver or brain tissue	33
Plants, plant extracts, or freeze-dried plant powder
Anthocyanins from strawberry	Wistar rat—acute toxicity model	Control diet or this diet with a doxorubicin injection, a doxorubicin injection and freeze-dried cultivar Adria supplementation or a doxorubicin injection, and cultivar Sveva supplementation (both 10 g/100 g of strawberry lyophilized extract) for 16 wk	↑ Hepatic SOD, CAT, GPx, GR, and GST activities in rats supplemented with freeze-dried strawberry ↑ NQO1 protein levels in rats supplemented with freeze-dried strawberry ↓ Hepatic protein carbonyls, TBARS, and hydroperoxides in rats fed the strawberry extracts	24
Green tea extract	C57BL/6 mice—PCB-induced toxicity model	PCB challenge (control) or this challenge with 1% w/w green tea extract	↑ Hepatic mRNA expression of CAT, GPx, GR, GST, NQO1, and SOD1 in livers of mice fed green tea extract ↑ NQO1 and GSR protein in livers of mice fed green tea extract ↑ Nrf2 activation in livers of mice fed green tea extract	25
Welsh onion (Allium fistulosum L., Alliaceae) green leaves	ICR mice—inflammation model	Carrageenan-induced hind paw edema (control), intraperitoneally injected indomethacin (10 mg/kg), or Welch onion extract administered orally (0.25, 0.5, and 1 g/kg) for 2 h before the injection of carrageenan	↑ Activities of CAT, SOD, and GPX upon consumption of Welsch onion extract ↓ Hepatic TBARS in mice fed Welsh onion extract	28
Humulus lupulus L. (Cannabaceae, hops)	Sprague-Dawley rats	Control diet plus vehicle injection with sesame oil, control diet plus injection of pure xanthohumol (100 mg/kg BW/day); experimental diet containing 4′-bromoflavone (150 mg/kg BW/day) plus vehicle control, experimental diet containing powdered hop extract (7.5 g/kg BW/day) plus vehicle control injection	↑ NQO1 activity in the liver and mammary gland of the positive control 4′-bromoflavone treated rats ↑ NQO1 activity in the liver of xanthohumol and hop extract treated rats ↑ GST activity in the liver and mammary gland, of rats treated with the hop extract	82
Seaweed extracts and unsaturated fatty acids from Ulva lactuca	Transgenic (B6C3-ARE-Tg) mice	Single dose of 200 μL (50 mg seaweed fraction/kg) administered by gavage	↑ NQO1 mRNA expression in lung, brain, stomach, and heart tissue ↑ Expression of multiple Nrf2 protective genes in heart tissue	83
Bilberry (Vaccinium myrtillius L.) pomace extract	Healthy subjects and ileostomy patients	Single dose of 10 g bilberry extract corresponding to a total of 2.5 g anthocyanins	↑ PBMC transcripts of NQO1 after bilberry extract ↓ PBMC transcripts of HO-1 and Nrf2 after bilberry extract	84
Green tea (Camellia sinensis, Theaceae)	ICR mice—oxidative damage model	Control group receiving orally distilled water daily with intraperitoneally administered olive oil (1 mL/kg BW) twice per week, five treatment groups receiving i.p. administered CCl₄ (20% in olive oil) (1 mL/kg BW) twice per week of which one group received distilled water daily, one group received silymarin daily (200 mg/kg), and three groups were orally administered green tea powder dissolved in distilled water at doses of 125, 625, and 1250 mg/kg daily, for 8 wk	↑ Activities of CAT, GSH-Px, and GR in livers of mice receiving green tea extract, but no dose-dependent effect No difference in GSH levels in the liver between treatment groups ↓ Liver TBARS in mice fed green tea extract	20
Phenolic compounds from Rosemary (Rosmarinus officinalis L.)	Wistar rats—hypercholesterolemia model	Control diet group, five hypercholesterolemic diet groups receiving water, aqueous rosemary extract (7 or 140 mg/kg BW), or nonesterified phenolic rosemary fraction (7 and 14 mg/kg BW) by gavage for 4 wk	↑ Activity of tissue SOD, CAT, and GPx in mice fed nonesterified phenolic rosemary fraction ↓ TBARS in serum and various tissues of rats fed rosemary extract	34
Broccoli extract and the essential oils of turmeric, thyme, and rosemary	Wistar rats—model of inflammatory bowel disease	Control diet, or this diet supplemented with broccoli extract (8750 mg/kg broccoli sprouts extract), Curcuma longa oil (1494 mg/kg diet), Thymus vulgaris oil (618 mg/kg) or Rosmarinus officinalis oil (680 mg/kg) at pretreatment phase for 7 days, followed by DSS treatment of 6 days, and recovery of 6 days	↑ Colonic Keap1 expression and expression of HO1, GPx2, GSTK1, P1, and T2 in mice fed rosemary oil only	29
6-Shogaol-rich extract from ginger	Balb/c mice	Treatment with 6-shogaol-rich extract (10 and 100 mg/kg BW) or positive control silymarin (100 mg/kg BW), and challenged with diethylnitrosoamine (30 mg/kg BW) 3 days per week for 3 wk	↑ Expression of Nrf2 and HO-1 in the liver of mice fed 6-shogaol-rich extract No effect on enzyme expression in mice treated with higher dose (100 mg/kg) of 6-shogaol extract ↓ Hepatic TBARS in mice fed ginger extract	16
Alperujo extract, hydroxytyrosol, and 3,4-dihydroxyphenylglycol	Vitamin E deficient Rowett Hooded Lister rats	Five groups on a vitamin E deficient diet for 10 wk and then this diet supplemented with either alperujo extract, hydroxytyrosol and dα-tocopherol (vitamin E) at a concentration of 100 mg/kg diet, or DHPG at a concentration of 10 mg/kg diet, or no additional supplement, for a further 2 wk. One intervention group was maintained on a vitamin E adequate diet (100 mg dα-tocopherol/kg)	Regulation of hepatic mitochondrial aldehyde dehydrogenase ↓ Plasma TBARS by alperujo extract	21
Commercial preparation of phenols from olives, olive oil, and olive mill wastewater	Healthy subjects	Ninety-eight healthy subjects ingested 2 mL of a commercially available OMWW preparation and blood was drawn just before and 1 h after ingestion of the preparation	No change in plasma antioxidant capacity ↑ Increase in total plasma glutathione concentration (both the reduced and oxidized forms) No change in the glutathione reduced:oxidized ratio	50
Turmeric and carrot seed extracts	Wistar rats	Control group and control group receiving 0.2 mL DMSO by gavages as vehicle. Four treatment groups receiving different doses of turmeric extract (100, 200 mg/kg BW) and carrot seed extract (200, 400 mg/kg BW) by gavage	↑ SOD, CAT, and GPx activity in liver of mice fed carrot seed extract ↑ SOD and CAT activity in liver of mice fed turmeric extract ↓ Hepatic TBARS in mice fed extracts	85
Blackberry extract	Sprague-Dawley rats—oxidative damage model	Control group, control receiving CCl4 (1 g/kg), groups receiving CCl4 plus blackberry extract (100, 200, or 400 mg/kg, or blackberry extract (400 mg/kg) only. Oral administration every other day for 15 days	↑ Activity of SOD, CAT, GPx, and GR in livers of rats fed blackberry extract	22
Strawberry extracts were obtained from Adria, Sveva, and Alba cultivars	Wistar rats	Control group, ethanol group receiving PEG 400 and then 1 mL of ethanol, positive control group received 100 mg/kg of BW of quercetin dissolved in 10% PEG 400, intervention groups received 40 mg/kg BW of strawberry crude extract dissolved in 10% PEG 400 per day, by gavage, for 10 days	↑ Enzyme activities of SOD and CAT in gastric mucosa after strawberry extract intake	86
Syzygium gratum (S. gratum)	C57BL/6J mice	Distilled water control, S. gratum aqueous extract (0.25 or 1 g/kg/day) once a day for 30 days	↑ Hepatic HO-1 activity and HO-1 mRNA expression in the liver in mice fed Syzygium gratum extract No effect on γ-GCL activity between groups	35
Grape pomace	New Zealand white rabbits—model of hyperlipidemia	Control diet, high cholesterol diet, or this diet supplemented with 0.2% grape seed extract, 0.2% grape peel extract, 10% grape seed powder, 10% grape peel powder, 0.1% grape seed extract, 0.1% grape peel extract, 5% grape seed powder, or 5% grape peel powder	↑ GST in liver tissue of animals fed grape peel powder ↑ GPx and CAT activity in liver tissue of animals fed grape seed extract ↓ Serum TBARS in rabbits fed extracts, but no change in hepatic TBARS between groups	46
Garlic and aged black garlic	db/db (^+/+) C57BL/KsL mice—model of hyperlipidemia	Control diet or this diet containing 5% freeze-dried garlic or aged black garlic for 7 wk	↑ SOD and GPx activities in liver of mice fed garlic and aged black garlic ↑ CAT activity in liver of mice fed aged black garlic ↓ Hepatic TBARS in mice fed garlic and aged black garlic	36
Garlic extract	Sprague-Dawley albino rats—acute toxicity model	Arsenic-free distilled water, NaAsO₂ in de-ionized water (5 mg/kg BW/day), and intervention group receiving NaAsO₂ (5 mg/kg BW/day) immediately followed by garlic extract (20 mg/kg BW/day) for 5 days	↑ Activity of CAT and SOD in liver, kidney, and ovary tissue of rats receiving garlic extract ↓ TBARS in ovary, liver, and kidney of rats fed garlic extract	26
Selenium and green tea extract	Kunming mice	Daily intragastric administration (0.6 mL) of saline (control); regular tea extract, selenium green tea extract (0.167, 0.333, and 0.669 μg Se/mL), regular tea plus selenite (0.333 μg Se/mL), selenite solution (0.333 μg of Se/mL), or 8, 5-fluorouracil, for 8 days	↓ Blood GPx and SOD activity in mice receiving regular tea, selenium-green tea extract, and selenite	87
Edible artichoke (Cynara scolymus L.)	Wistar rats	Control diet or this diet supplemented with artichoke (138 g/kg of diet)	↑ RBC Gpx activity in rats fed the artichoke diet No change in SOD, GR, and CAT activity in mice fed artichoke	88
Broccoli seeds and isothiocyanates	Nrf2^+/+ and Nrf2^−/− mice	Control diet with broccoli seeds at 15% (by weight) for 7 days	↑ NQO1 and GST enzyme activities in stomach, small intestine and liver of Nrf2^+/+ mice, but no change in the large intestine ↑ Levels of GSTA1/2, GSTA3, and GSTM1/2 subunits in stomach, liver, and small intestine of Nrf2^+/+ mice	89
Soy isoflavone	Wistar rats	Soy-deficient or soy protein diet for 12–16 months, or a soy-deficient diet for 10 months, switched to soy protein diet for 2 or 6 months	↑ MnSOD, γ-glutamylcysteine synthetase, and cytochrome c oxidase mRNA levels in liver tissue from rats fed the soy protein diet	90
Isoflavone-rich soy isolate	C57BL6	Control diet or this diet supplemented with 1.08 g isoflavone-rich soy isolate/kg diet for 60 days. The soy isolate contained 400 mg/g isoflavone aglycones (226 mg/g genistein and 174 mg/g daidzein)	↑ Activities of CAT and SOD in livers of mice fed soy isolate No change in activities of Se-GPx and non-Se-GPx in mice fed soy isolate	91
Flaxseed	Wistar albino rats—acute toxicity model	Control diet with and without CCL4 challenge, and control diet supplemented with flaxseed (5 and 10%) for 14 days followed by single oral dose of CCl4 (2.0 g / kg BW)	↑ Catalase, peroxidase, and SOD activities in livers of rats pretreated with 5% flaxseed	27
White, brown, and germinated brown rice	New Zealand white rabbits—hyperlipidemia model	Control diet, high cholesterol diet (0.5 g/100 g) or this diet with 19.8% white rice powder, 19.0% brown rice powder, or 19.5% germinated brown rice powder	↑ RBC SOD and GPx activity by all rice grains ↓ Plasma TBARS levels in rabbits fed germinated brown rice, whereas no differences for brown and white rice fed rabbits	37
Fermented cowpea flour (Vigna unguiculata)	Albino Wistar rats	Casein–methionine control diet, raw or fermented V. unguiculata diets prepared with cowpea seed flour (75 g/kg BW)	↑ Hepatic activity of Cu/Zn-SOD, Mn-SOD, GPx, and CAT by fermented V. unguiculata diets ↑ Cu/Zn-SOD activity by raw V. unguiculata ↓ Mn-SOD and CAT activity by raw V. unguiculata	92
Fructan from roots of Arctium lappa L.	d-Galactose (d-Gal) induced aging ICR mice model	Intraperitoneal injection of d-galactose (500 mg/kg/day) combined with oral administered of ascorbic acid (100 mg/kg/day) or Arctium lappa L. polysaccharide (100, 200, and 400 mg/kg/day) for 8 wk	↑ SOD, GSH-Px, and CAT activity in serum and liver of mice supplemented with Arctium lappa L. polysaccharide ↓ Serum and liver TBARS in mice fed the highest doses of fructan	19
Organosulfur compounds
Diallyl trisulfide	C57BL/6 mice	0.1 mL of sodium carboxymethyl cellulose vehicle by gavage or diallyl trisulfide (0.5 or 2 mg in sodium carboxymethyl cellulose per mouse) by gavage every other day for 2 wk	↑ mRNA expression of HO-1 and NQO1 in the stomach in mice treated with diallyl trisulfide ↑ Accumulation of Nrf2 in stomach tissue of mice treated with diallyl trisulfide	93
Brassica-derived isothiocyanate sulforaphane	C57BL/6 mice—DSS-induced acute colitis model	PBS (control) or 25 mg/kg BW of sulforaphane per os for 7 days. Subsequently, acute colitis was induced by administering 4% DSS via drinking water for 5 days	↑ Expression of glutamate cysteine ligase catalytic subunit in sulforaphane pretreated animals ↑ (trend) mRNA levels of NQO1 and HSP70 in sulforaphane-treated mice No effect on mRNA levels of HO-1 in sulforaphane-treated mice	30
Sulforaphane	CD-1 mice—alcohol intolerance model	Control diet or this diet with sulforaphane (20 μmol per 3 g diet) for 7 days. After fasting overnight, they were gavaged with 35% v/v ethanol (2.0 g ethanol/kg BW)	↑ ALDH activity and mRNA expression in liver, fore stomach, glandular stomach, and proximal small intestine in sulforaphane-treated mice ↑ Rate of elimination of acetaldehyde after administration of ethanol in sulforaphane-treated mice	31
Sulforaphane	Nrf2^+/+ and Nrf2^−/− mice	Exposure to 4.8 mg/m³ of the synthetic arsenic dust for 30 min/day. Sulforaphane was intraperitoneally injected (10 mg/kg) every other day for 14 days	↑ Nrf2 in lung tissue by arsenic ↑ Nrf2 by intraperitoneal injection of sulforaphane ↑ expression of NQO1, γGCS, and HO-1 with the highest level seen in the combined treatment group	55
Allyl-isothiocyanate and sulforaphane	C57BL/6 mice—hyperlipidemia model	High-fat diet and administration of allyl-isothiocyanate or PBS by gavage for 7 days	↑ Nuclear Nrf2 protein level and mRNA expression in the liver of mice fed allyl-isothiocyanate ↑ HO-1 mRNA expression in the liver of mice fed allyl-isothiocyanate	39
Diallyl sulfide	SD rats	Diallyl sulfide was given daily by gavage (100 or 500 mg/kg BW/day) for 7 consecutive days The positive control group was treated with NAC (500 mg/kg BW). The vehicle group was treated with soybean oil, and the group treated with ddH2O was the blank	↑ Pulmonic catalase, GST, GPx, and GRd activities in mice fed diallyl sulfide ↑ Pulmonic SOD, glutathione peroxidase, NAD(P)H:quinone oxidoreductase 1, and catalase mRNA levels in mice fed diallyl sulfide	94
Sulforaphane and sulforaphane–glutathione conjugate	TRAMP mice—model of prostate cancer	Control diet or experimental diet containing 2% or 8% broccoli sprouts for 16 wk	↑ Protein levels of HO-1, Nrf2, and Keap1 in prostate lysates	44
Fatty acids
Dietary fatty acids	Metabolic syndrome patients	High-saturated fatty acid diet, high-monounsaturated fatty acid diet, and two low-fat, high-complex carbohydrate diets supplemented with n-3 polyunsaturated fatty acids or placebo for 12 wk, or given as fat challenge	↑ mRNA expression of SOD1, SOD2, GR, GPx1, GPx4, TXNRD1, and Nrf2 in PBMC after the high-saturated fat meal ↑ Nuclear Nrf2 protein levels after the high-saturated fat meal ↓ Cytoplasmic Nrf2 protein levels after the high-saturated fat and low fat with n-3 fatty acids	95
Dietary fatty acids	Metabolic syndrome patients	High-saturated fatty acid diet, high-monounsaturated fatty acid diet, and two low-fat, high-complex carbohydrate diets supplemented with n-3 polyunsaturated fatty acids or placebo for 12 wk, or given as fat challenge	↓ Postprandial in CAT, GPx, and TXNRD1 mRNA in adipose tissue of mice fed the high-saturated fat meal ↑Keap1 mRNA in adipose tissue of mice fed the high saturated fat meal	96
Fish oil	C57BL/6 mice	Control diet, safflower oil control diet, and fish oil diet for 3 wk.	↑ HO-1 mRNA expression after fish oil in all tissues apart from spleen and brain ↑ Plasma 4-HHE levels in mice consuming fish oil ↓ Plasma 4-HNE levels in mice consuming fish oil	97
Fish oil	ApoE^–/– mice—hyperlipidemia model	Control diet and high-fat diet rich in fish oil or corn oil (200 g/kg) for 10 wk	↑ Hepatic SOD and CAT activities in mice fed with fish oil No significant difference in GPx activity in mice fed fish oil compared to corn oil No difference of TBARS levels in LDL between groups	38
Fish oil	Sprague-Dawley rats	Diets supplemented with saturated fat, fish oil, or control oil (17% by weight) for 4 wk	↑ Mn-SOD and GPx mRNA in rats fed fish oil No changes in expression of CAT	98
Oxidized fish oil	Healthy subjects		No changes in RBC antioxidant enzyme activity ↓ Plasma 4-HNE levels in fish oil group No change in urinary 8-iso-PGF2α between groups	99
Lycopene or fish oil	Healthy subjects	Three-month intervention with two 15 mg lycopene soft gel capsules daily, 1 g fish oil (1098 mg EPA + 549 mg DHA) capsule daily, or placebo capsules	Modulation of the Nrf2-mediated oxidative response in both supplement groups	100
cis9, trans11-conjugated linoleic acid	ApoE^–/– mice—hyperlipidemia model	High-fat, high-cholesterol diet with 7% of fat w/w as linoleic acid (control, 7% of fat w/w as cis9, trans11-CLA, or 7% of fat w/w as trans10, cis12-CLA)	↑ Different posttranslational forms of HSP70 in mice fed cis9, trans11-conjugated linoleic acid	40
Extra virgin olive oil	Healthy subjects	Control group or consumption of extra virgin olive oil as only added fat plus an extra daily dose of 50 mL for 6 wk	↑ RBC CAT activity after intake of extra virgin olive oil ↓ RBC SOD and GPx activity after intake of extra virgin olive oil	101
10-Nitro-oleic acid	WT angiotensin II-induced hypertension model and Cys521/ser sEH redox-dead knock in mice	Daily gavage with conjugated linoleic acid and sodium nitrate in 200 μL PEG400 for 5 days	↓ Hydrolase activity and blood pressure in the angiotensin II induced hypertension model in WT but not KI mice by 10-nitro-oleic acid ↑ EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios in WT but not KI mice following NO2-OA treatment ↓ sEH activity in WT mice fed linoleic acid and nitrite, whereas KI mice were unaffected	60
Juices and alcohol
Tropical fruit juices	Albino Wistar rats	Control diet with water or 100, 200, or 400 mg of tropical fruit juices (FA or FB) per kg BW for 4 wk	↓ Hepatic SOD and CAT activities by 200 mg/kg BW FA ↓ RBC GPx activity in mice fed 400 mg/kg BW FB ↓ TBARS in livers in mice fed both fruit juices	102
Fruit juices	Wistar rats	Control diet with tap water or fruit juices (grapefruit, apple, blackcurrant, apple/blackcurrant, orange) for 7 days, or quercetin control (0.1 g/kg BW) during last for days of study	No change in SOD, GR, GPx, and CAT activities in RBC by any of the fruit juices or by quercetin ↓ MDA levels in plasma in mice fed apple, black currant, and apple/blackcurrant juices	103
Açaí juice	ApoE^−/− mice—hyperlipidemia model	Control diet with or without 5% freeze-dried açaí juice powder	↑ mRNA expression of GR and GPx3 in açaí juice powder fed mice ↑ GR activities in serum and liver and GPx activity in serum in açaí juice powder fed animals No difference in GPx activity in liver between groups	41
Red wine	Wistar rats—hyperlipidemia model	Low-fat diet control group, four high-fat diet groups receiving 770–1360 μL water, 800–1380 μL red wine with low antioxidant activity, 790–1170 μL red wine with intermediate antioxidant activity, or 820–1340 μL red wine with high antioxidant activity daily, by gavage, for 4 wk	No effects on antioxidant enzyme activity in liver	42
Combination interventions
Coffee, thyme, broccoli, rosemary, turmeric and red onion	EpRE-luc reporter mice	Vehicle with or without extract by gavage	↑ EpRE-luc activity in extract-fed animals	56
EGCG plus sulforaphane	Nrf2^−/− or C57BL/6J mice	Vehicle with or without sulforaphane (45 mg/kg) and EGCG (100 mg/kg) by gavage	↓ Nrf2-dependent genes in prostate tissue of Nrf2^−/− mice	104
Antioxidant supplements	Healthy subjects	Intake of two capsules per day, for 4 wk, with a 4-wk washout period in between active dose or placebo	↑ GPx activity in red blood cells upon supplementation No change in SOD activity in red blood cells upon supplementation ↑ HSP70 synthesis in isolated lymphocytes following heat shock from 37 to 42.5°C	57
Diet rich in various antioxidant foods, or kiwifruit diet	Healthy subjects	Diet rich in various antioxidant foods, or three kiwifruits per day, or a control diet, for 8 wk	↑ Regulation of genes with regulatory motif for aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator in both intervention groups ↑ Plasma antioxidant markers in both intervention groups	58
Mixture of vitamins and minerals	C57BL/6 mice	Control diet with or without an antioxidant mixture containing β-carotene, vitamins C and E, selenium, and zinc	↑ HSP70 gene expression in liver and brain of mice fed dietary vitamins and minerals, but no effect in spleen ↑ SOD gene expression in spleen and liver of mice fed dietary vitamins and minerals ↓ TBARS in liver homogenate from mice receiving antioxidant mixture	18

Summary excludes studies assessing the effects of herbal medicine, medicinal plants, or probiotics, or studies without an appropriate control group. These studies were extracted from a PubMed search on the August 5, 2014 using the search term (diet or food) and (antioxidant enzyme* or HSP70 or Nrf2 OR heme oxygenase or aldehyde dehydrogenase or soluble epoxide hydrolase) and “in vivo.” ALDH, aldehyde dehydrognase; B[a]P, benzo[a]pyrene; BW, body weight; CCL₄, carbon tetrachloride; CAT, catalase; DSS, dextran sodium sulfate; GR, glutathione reductase; GST, glutathione-S-transferase; EGCG, epigallocatechin-3-gallate; EpRE, electrophile response element; γ-GCL, gamma-glutamylcysteine ligase; Gpx, glutathione peroxidase; HO-1, heme oxygenase 1; HSP70, heat shock protein 70; Keap1, kelch-like ECH-associated protein 1; NQO1, NAD(P)H dehydrogenase, quinone 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PBMC, peripheral blood mononuclear cells; PBS, phosphate buffered saline; RBC, red blood cells; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substance; TRAMP, the transgenic adenocarcinoma of the mouse prostate; TXNRD1, thioredoxin reductase 1.

In most studies, dietary bioactives did not raise levels of these resilience products per se, but rather enhanced homeostasis and recovery by normalizing levels of antioxidant enzymes that were decreased by a range of different challenges, including the induction of aging 19, oxidative stress 20-22, acute toxicity 23-27, acute inflammation 28-30, alcohol intolerance 31, hyperlipidemia 32-42, or carcinogenesis 43, 44 (Table 1). Supplementation with bioactives often did not significantly modulate an antioxidant response in the absence of a challenge (Table 1). Inclusion of challenge tests in a study design has been a promising concept in the substantiation of efficacy 4 to test “the ability to adapt” to measurable oxidative damage.

A number of studies have indicated upregulation of the antioxidant response as well as direct antioxidant action as evidenced by lower levels of thiobarbituric acid reactive substances. However, others report modulation of the antioxidant response only (Table 1) 21, 33, 38, 45, 46. It has been suggested that the impact of a direct antioxidant action of polyphenols in humans may be minimal, and that the role of polyphenols in targeted transcriptional gene regulation, such as the Nrf2/Keap1 pathway, could be more important 47. For example, we found that the in vivo free radical scavenging properties of olive phenolics in alperujo, an olive production by-product, appeared relatively modest in a vitamin E deficient rat model. But proteomics and subsequent network analysis revealed that the olive phenolics regulated protein and activity levels of hepatic mitochondrial aldehyde dehydrogenase (ALDH2), a key enzyme of cardioprotection (Table 1) 48. Expression of many aldehyde dehydrogenases is regulated by Nrf2, but it is currently uncertain whether this is also the case for ALDH2 49. Another study by Visioli et al. found that a commercial extract containing phenolics from olives, olive oil, and olive mill wastewater did not affect plasma antioxidant capacity, whereas it did significantly increase total plasma glutathione concentrations. The authors suggested that such an effect could be modulated through the antioxidant response element (ARE) mediated increase in phase II enzyme expression, including that of gamma-glutamylcysteine ligase and glutathione synthetase (Table 1) 50.

The use of transgenic mice models has provided new insights in the role of Nrf2 in the antioxidant response. Nrf2^–/– mice are seemingly normal, but show a decreased capacity to cope with oxidative insults 51. Genes that are lower in Nrf2-null mice compared with wild-type (WT) mice are those important in the detoxification of ROS, such as superoxide dismutase 1 and 2, catalase, and peroxiredoxin 1, as well as the genes for epoxide hydrolase-1, UDP-glucuronosyltransferases, and aldehyde dehydrogenases 52. Treatment of Nrf2^–/– mice and WT mice with the green tea component epigallocatechin gallate, and the flavonoid curcumin revealed the capacity of these polyphenols to activate phase II detoxifying enzymes through the Nrf2 pathway 53, 54. Also, curcumin supplementation in WT mice resulted in increased expression of the detoxification enzymes glutathione-S-transferase, glutathione reductase, epoxide hydrolase, HO-1, catalase, and NQO1 in the liver, small intestine, and kidney tissues, which did not occur in Nrf2^–/– mice (Table 1) 54. Likewise, exposure to arsenic-containing dust and sulforaphane resulted in increased expression of Nrf2, as well as its target genes NQO1, γGCS, and HO-1 in lung tissue of WT mice but not Nrf2 knockout mice (Table 1) 55. An elegant study in EpRE-luc reporter mice indicated that a combination extract made of coffee, thyme, broccoli, rosemary, turmeric, and red onion induced EpRE-mediated luciferase in lung and adipose tissue, indicating the important role of these dietary bioactives with respect to their NRf2/EpRE-inducing properties in an intact organism 56. This study also showed that treatment with dietary plant extracts led to a significant higher induction of the Nrf2 pathway as compared with pure compounds, indicating combinatorial effects of compounds found in whole foods 56. It is interesting to see, therefore, that significant effects on the antioxidant response in human intervention studies are found in studies applying interventions with combined bioactives foods or food components (Table 1) 57, 58.

Interesting new research has revealed that a combination of dietary unsaturated fatty acids and nitrates may give rise to a range of electrophilic nitro-fatty acids. These compounds can covalently bind to Keap1, leading to an induced expression of phase II gene expression, as well as inhibiting the enzyme soluble epoxide hydrolase 59, 60. Inhibition of the sEH enzyme prevents hydrolysis of the enzymes’ substrate epoxyeicosatrienoic acids, leading to accumulation of these potent anti-inflammatory and vasodilatory compounds. In Cys521Ser sEH redox-dead knock in mice, which are resistant to inhibition of sEH activity by electrophilic lipids, dietary intervention with linoleic acid and nitrite did not affect sEH activity, whereas the same diet reduced sEH activity in WT mice 60.

3.2 The HSR

Another important integrated stress signaling pathway triggered by endogenous stimuli or environmental stresses is the HSR. This is an ordered response to a loss of proteostatic control due to a wide array of acute and chronic stress conditions including heat, metabolic dysregulation, electrophiles, and exposure to inflammatory derived reactive species 61. HSR is regulated at the transcriptional level by HSFs, primarily by HSF1. The principal mechanism of activation of HSF1 is incompletely understood, but it is known that HSF1 is tethered by heat shock protein (HSP)90 in the cytoplasm in an inactive state. HSP70 and its co-chaperone HSP40 also suppress HSF1 activity. Upon activation, HSF1 undergoes multistep processing involving posttranslational modifications, nuclear enrichment, trimerization, and binding to heat shock elements (HSEs). This results in the induction of a number of HSPs each identified by molecular mass, e.g. HSP27, HSP40, HSP60, HSP70/HSP72, and HSP90 (Fig. 2). Many of the proteins function as chaperones, proteases, or other proteins essential for protection of the cell against proteotoxic stress 62, 63.

HSPs are stress sensors that are believed to play a critical role in the development of cardiovascular disease, insulin sensitivity, and longevity. Indeed, transgenic mice overexpressing HSP70 are protected against the damaging effects of ischemia 64, and high levels of human HSP70 have been associated with a low coronary artery disease risk, independent of traditional risk factors 65. Also, experimentally elevated levels of HSP72 specifically in muscle or globally in mice by genetic or pharmacologic means conferred protection against diet- and leptin-induced obesity and insulin resistance 66, while mice lacking HSP72 display glucose intolerance and skeletal muscle insulin resistance 67. Cellular stress resistance against inflammatory and metabolic stresses appeared critical for disease prevention and longevity in certain models. For example, upregulating proteostasis activities by the HSF-1 transcription factors resulted in an increased longevity of worms harboring misfolding-prone proteins 68. Although regulation of HSP proteins may not affect longevity in humans, it is believed that restoring or maintaining proteostasis should increase quality of life by delaying the onset or decreasing the impact of cardiovascular disease or type 2 diabetes 61.

Dietary compounds may have the potential to upregulate the HSR, although evidence is only available from a limited amount of in vivo studies (Table 1). Structure–activity relationships have shown that HSP induction requires the presence of a reactive α,β-unsaturated carbonyl group that can form Michael adducts with cellular nucleophilics, and to covalently bind to cysteine residues of proteins 69. We showed that cis9, trans11-conjugated linoleic acid, a fatty acid present in the lipid fraction of meat, milk, and dairy products or other foods derived from ruminant animals, significantly increased levels of five different posttranslationally modified forms of hepatic HSP70 in Apoe^–/– mice. This increase coincided with a reduction in atherosclerotic plaque formation, a reduced inflammatory response, and improved insulin sensitivity 40. In the rat insulinoma cell line INS 1E, the plant phenolic, caffeic acid, the flavanone naringenin from citrus fruits, and the flavonol quercetin from fruits and vegetables induced Hsp70 gene expression, indicating a possible role of these phenolics in β cell survival during glucotoxicity 70. In high-fat diet streptozotocin induced type 2 diabetic rats, dietary naringin, a flavonoid from grapefruit, significantly decreased insulin resistance and dyslipidemia, in addition to increasing protein levels of HSP27 and HSP72 in the pancreas, liver, and kidney 32. It has been proposed that activation of HSP72 protects against obesity-induced hyperglycemia, hyperinsulinemia, and insulin resistance by inhibition of c-jun amino terminal kinase activation and κΒ kinase, which are critical inflammatory kinases in the development of insulin resistance and type 2 diabetes 66.

4 How can we intervene to improve resilience and maximize health?

Consumption of plant-based foods and beverages rich in phytochemicals is epidemiologically associated with a decreased risk of chronic and age-related disease development 71-73, although mechanisms of protection remain unclear. Much attention has focused on polyphenols that have powerful antioxidant activities in vitro as they scavenge a wide range of reactive oxygen, nitrogen and chlorine species, and chelate metal ions capable of promoting oxidation 11. However, many of these in vitro results may be artifactual due to the rapid oxidation of polyphenolic compounds in cell culture media, generating H₂O₂ and quinones/semiquinones 11, 74. Furthermore, some of the observed antioxidant effects in vitro may be less relevant in vivo, simply because plasma concentrations of polyphenols are usually very low, rarely exceeding 1 μmol/L. Moreover, polyphenols are rapidly metabolized in the liver and by colonic bacteria, and many of the metabolites are believed to have decreased antioxidant activity 75.

A large number of human intervention studies have been performed to assess the antioxidant effects of dietary polyphenols in vivo. Perhaps, the most important outcomes to consider would be urinary F₂-isoprostanes and oxidized LDL, which are currently the most reliable in vivo disease biomarkers of lipid peroxidation 76. However, there is limited evidence that polyphenol-rich products modify these biomarkers in humans 47, 74, and furthermore, a causal relationship between these biomarkers and cardiovascular health has not yet been established 47. In addition, there is no substantive evidence that increased intakes of the classic dietary antioxidants vitamin C, vitamin E, and β-carotene decrease levels of oxidative damage in well-nourished people 11, despite their well-known antioxidant capacity preventing either polyunsaturated fatty acid oxidation or other events driven by free radicals 9. Beneficial effects of antioxidant vitamin supplementation on primary or secondary prevention of mortality in healthy participants and patients with various diseases also are equivocal 77. Indeed, β-carotene and vitamin E seem to increase mortality, although it should be said that many studies used pharmacological, rather than dietary doses 78. Consequently, it is unlikely that any potentially beneficial bioactive effects of polyphenols and certain vitamins are ascribed to direct antioxidant effects.

Instead, as we show in this review, transcriptional gene regulation may be more important in vivo, and the action of dietary bioactives, especially polyphenols, may indeed go beyond their antioxidant capacity 14. Indeed, enhancing resilience through moderate exposure to pro-oxidants, which can be obtained through the diet, may confer protection in a much more effective way by increasing the production of protective enzymes and proteins through regulation of the ARE-regulated and/or the HSRs. The resilience response would offer enhanced endogenous protection against any subsequent chemical and/or oxidative stress that may arise. Indeed, the resilience response is not just the intrinsic capacity of a system to respond to a stress. It is a system that can be “tuned” by external factors, such as habitual intake of moderate concentrations of dietary pro-oxidant molecules. In this respect, it is interesting to note that new therapeutic drugs based on a resilience response, such as SOD and GPx1 mimetics, are being developed to alleviate complications in diabetic patients who suffer from a decline in cellular antioxidant defenses 79.

5 Conclusion

Emerging new research suggests that exposure to the right dietary pro-oxidant molecules, in the right concentrations, and on a regular basis, can cause a sustained increase in cellular levels of protective enzymes, or enhanced resilience products. Increasing levels of such products by dietary means may protect against the damage induced by oxidative stress challenges, and increase health, although current evidence obtained from human intervention studies is not sufficient to design dietary strategies based on pro-oxidant capacity. Thus, analyzing levels of enhanced resilience products, such as enzyme activity levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase, plasma levels of HSPs, urinary levels of epoxyeicosatrienoic acids, and expression of Nrf2 genes, as a measure of the strength of a person's physiological resilience, may be more effective than conventional disease biomarkers to establish the efficacy by which dietary compounds affect the “health” of an individual. Assessing the role of dietary pro-oxidants (rather than antioxidants) in the maintenance of health (rather than reduction of disease) may therefore improve our understanding of the protective mechanisms that underlie the beneficial effects of specific food bioactives. Ultimately, the use of novel resilience markers and signatures could significantly improve our ability to prove the efficacy by which pro-oxidant dietary bioactives improve lifelong health, as well as targeting those with lowest resilience as a way to make best use of limited healthcare resources.

Acknowledgments

This research is funded by the Scottish Government's Rural and Environment Science and Analytical Services Division.

The authors have declared no conflict of interest.

6 References

1 Constitution of the World Health Organisation 2006. http://www.who.int/governance/eb/who_constitution_en.pdf
Google Scholar
2Daar, A. S., Singer, P. A., Persad, D. L., Pramming, S. K. et al., Grand challenges in chronic non-communicable diseases. Nature 2007, 450, 494–496.
10.1038/450494a
CAS PubMed Web of Science® Google Scholar
3Lopez, A. D., Mather, C. D., Ezzati, M., Jamison, D. T., Murray, C. J. L. (Eds.), Global Burden of Disease and Risk Factors, World Bank, Washington DC 2006.
10.1596/978-0-8213-6262-4
Web of Science® Google Scholar
4Huber, M., Knottnerus, J. A., Green, L., van der Horst, H. et al., How should we define health?. BMJ 2011, 343, d4163.
10.1136/bmj.d4163
PubMed Web of Science® Google Scholar
5Rockstrom, J., Steffen, W., Noone, K., Persson, A. et al., A safe operating space for humanity. Nature 2009, 461, 472–475.
10.1038/461472a
CAS PubMed Web of Science® Google Scholar
6 What is health? The ability to adapt. Lancet 2009, 373, 781.
10.1016/S0140-6736(09)60456-6
PubMed Google Scholar
7McEwen, B. S., Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging. Metabolism 2003, 52, 10–16.
10.1016/S0026-0495(03)00295-6
CAS PubMed Web of Science® Google Scholar
8Vasan, R. S., Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 2006, 113, 2335–2362.
10.1161/CIRCULATIONAHA.104.482570
PubMed Web of Science® Google Scholar
9Forbes-Hernandez, T. Y., Giampieri, F., Gasparrini, M., Mazzoni, L. et al., The effects of bioactive compounds from plant foods on mitochondrial function: a focus on apoptotic mechanisms. Food Chem. Toxicol. 2014, 68, 154–182.
10.1016/j.fct.2014.03.017
CAS PubMed Web of Science® Google Scholar
10Martindale, J. L., Holbrook, N. J., Cellular response to oxidative stress: signaling for suicide and survival. J. Cell. Physiol. 2002, 192, 1–15.
10.1002/jcp.10119
CAS PubMed Web of Science® Google Scholar
11Halliwell, B., Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?. Arch. Biochem. Biophys. 2008, 476, 107–112.
10.1016/j.abb.2008.01.028
CAS PubMed Web of Science® Google Scholar
12Wu, R. P., Hayashi, T., Cottam, H. B., Jin, G. et al., Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 2010, 107, 7479–7484.
10.1073/pnas.1002890107
CAS PubMed Web of Science® Google Scholar
13Kansanen, E., Jyrkkanen, H. K., Levonen, A. L., Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. Free Radic. Biol. Med. 2012, 52, 973–982.
10.1016/j.freeradbiomed.2011.11.038
CAS PubMed Web of Science® Google Scholar
14Chiva-Blanch, G., Visioli, F., Polyphenols and health: moving beyond antioxidants. J. Berry Res. 2012, 2, 63–71.
CAS Google Scholar
15Rodrigo, R., Prieto, J. C., Castillo, R., Cardioprotection against ischaemia/reperfusion by vitamins C and E plus n-3 fatty acids: molecular mechanisms and potential clinical applications. Clin. Sci. 2013, 124, 1–15.
10.1042/CS20110663
CAS PubMed Web of Science® Google Scholar
16Bak, M. J., Ok, S., Jun, M., Jeong, W. S., 6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice. Molecules 2012, 17, 8037–8055.
10.3390/molecules17078037
CAS PubMed Web of Science® Google Scholar
17Robb, E. L., Winkelmolen, L., Visanji, N., Brotchie, J. et al., Dietary resveratrol administration increases MnSOD expression and activity in mouse brain. Biochem. Biophys. Res. Commun. 2008, 372, 254–259.
10.1016/j.bbrc.2008.05.028
CAS PubMed Web of Science® Google Scholar
18Ushakova, T., Melkonyan, H., Nikonova, L., Mudrik, N. et al., The effect of dietary supplements on gene expression in mice tissues. Free Radic. Biol. Med. 1996, 20, 279–284.
10.1016/0891-5849(95)02040-3
CAS PubMed Web of Science® Google Scholar
19Liu, W., Wang, J., Zhang, Z., Xu, J. et al., In vitro and in vivo antioxidant activity of a fructan from the roots of Arctium lappa L. Int. J. Biol. Macromol. 2014, 65, 446–453.
10.1016/j.ijbiomac.2014.01.062
CAS PubMed Web of Science® Google Scholar
20Tsai, C. F., Hsu, Y. W., Ting, H. C., Huang, C. F. et al., The in vivo antioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae). Food Chem. 2013, 136, 1337–1344.
10.1016/j.foodchem.2012.09.063
CAS PubMed Web of Science® Google Scholar
21Rodriguez-Gutierrez, G., Duthie, G. G., Wood, S., Morrice, P. C. et al., Alperujo extract, hydroxytyrosol and 3,4-dihydroxyphenylglycol are bioavailable and have antioxidant properties in vitamin-E deficient rats—a proteomics and network analysis approach. Mol. Nutr. Food Res. 2012, 56, 1137–1147.
10.1002/mnfr.201100808
CAS PubMed Web of Science® Google Scholar
22Cho, B. O., Ryu, H. W., Jin, C. H., Choi, D. S. et al., Blackberry extract attenuates oxidative stress through up-regulation of Nrf2-dependent antioxidant enzymes in carbon tetrachloride-treated rats. J. Agric. Food Chem. 2011, 59, 11442–11448.
10.1021/jf2021804
CAS PubMed Web of Science® Google Scholar
23Gao, S., Duan, X., Wang, X., Dong, D. et al., Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem. Toxicol. 2013, 59, 739–747.
10.1016/j.fct.2013.07.032
CAS PubMed Web of Science® Google Scholar
24Diamanti, J., Mezzetti, B., Giampieri, F., Alvarez-Suarez, J. M. et al., Doxorubicin-induced oxidative stress in rats is efficiently counteracted by dietary anthocyanin differently enriched strawberry (Fragaria x ananassa Duch.). J. Agric. Food Chem. 2014 [Epub ahead of print].
10.1021/jf405721d
Web of Science® Google Scholar
25Newsome, B. J., Petriello, M. C., Han, S. G., Murphy, M. O. et al., Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes. J. Nutr. Biochem. 2014, 25, 126–135.
10.1016/j.jnutbio.2013.10.003
CAS PubMed Web of Science® Google Scholar
26Chowdhury, R., Dutta, A., Chaudhuri, S. R., Sharma, N. et al., In vitro and in vivo reduction of sodium arsenite induced toxicity by aqueous garlic extract. Food Chem. Toxicol. 2008, 46, 740–751.
10.1016/j.fct.2007.09.108
CAS PubMed Web of Science® Google Scholar
27Rajesha, J., Murthy, K. N., Kumar, M. K., Madhusudhan, B. et al., Antioxidant potentials of flaxseed by in vivo model. J. Agric. Food Chem. 2006, 54, 3794–3799.
10.1021/jf053048a
CAS PubMed Web of Science® Google Scholar
28Wang, B. S., Huang, G. J., Lu, Y. H., Chang, L. W., Anti-inflammatory effects of an aqueous extract of Welsh onion green leaves in mice. Food Chem. 2013, 138, 751–756.
10.1016/j.foodchem.2012.11.106
CAS PubMed Web of Science® Google Scholar
29Mueller, K., Blum, N. M., Mueller, A. S., Examination of the anti-inflammatory, antioxidant, and xenobiotic-inducing potential of broccoli extract and various essential oils during a mild DSS-induced colitis in rats. ISRN Gastroenterol. 2013, 2013, 710856.
10.1155/2013/710856
PubMed Google Scholar
30Wagner, A. E., Will, O., Sturm, C., Lipinski, S. et al., DSS-induced acute colitis in C57BL/6 mice is mitigated by sulforaphane pre-treatment. J. Nutr. Biochem. 2013, 24, 2085–2091.
10.1016/j.jnutbio.2013.07.009
CAS PubMed Web of Science® Google Scholar
31Ushida, Y., Talalay, P., Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases: relevance to ethanol intolerance. Alcohol Alcohol 2013, 48, 526–534.
10.1093/alcalc/agt063
CAS PubMed Web of Science® Google Scholar
32Sharma, A. K., Bharti, S., Ojha, S., Bhatia, J. et al., Up-regulation of PPARgamma, heat shock protein-27 and -72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br. J. Nutr. 2011, 106, 1713–1723.
10.1017/S000711451100225X
CAS PubMed Web of Science® Google Scholar
33Wiegand, H., Wagner, A. E., Boesch-Saadatmandi, C., Kruse, H. P. et al., Effect of dietary genistein on Phase II and antioxidant enzymes in rat liver. Cancer Genomics Proteomics 2009, 6, 85–92.
CAS PubMed Google Scholar
34Afonso, M. S., de O Silva, A. M., Carvalho, E. B., Rivelli, D. P. et al., Phenolic compounds from Rosemary (Rosmarinus officinalis L.) attenuate oxidative stress and reduce blood cholesterol concentrations in diet-induced hypercholesterolemic rats. Nutr. Metab. 2013, 10, 19.
10.1186/1743-7075-10-19
CAS Web of Science® Google Scholar
35Senggunprai, L., Kukongviriyapan, V., Prawan, A., Kukongviriyapan, U., Consumption of Syzygium gratum promotes the antioxidant defense system in mice. Plant Foods Hum. Nutr. 2010, 65, 403–409.
10.1007/s11130-010-0200-6
CAS PubMed Web of Science® Google Scholar
36Lee, Y. M., Gweon, O. C., Seo, Y. J., Im, J. et al., Antioxidant effect of garlic and aged black garlic in animal model of type 2 diabetes mellitus. Nutr. Res. Pract. 2009, 3, 156–161.
10.4162/nrp.2009.3.2.156
PubMed Web of Science® Google Scholar
37Mohd, E. N., Abdul Kadir, K. K., Amom, Z., Azlan, A., Antioxidant activity of white rice, brown rice and germinated brown rice (in vivo and in vitro) and the effects on lipid peroxidation and liver enzymes in hyperlipidaemic rabbits. Food Chem. 2013, 141, 1306–1312.
10.1016/j.foodchem.2013.03.086
CAS PubMed Web of Science® Google Scholar
38Wang, H. H., Hung, T. M., Wei, J., Chiang, A. N., Fish oil increases antioxidant enzyme activities in macrophages and reduces atherosclerotic lesions in apoE-knockout mice. Cardiovasc. Res. 2004, 61, 169–176.
10.1016/j.cardiores.2003.11.002
CAS PubMed Web of Science® Google Scholar
39Wagner, A. E., Boesch-Saadatmandi, C., Dose, J., Schultheiss, G. et al., Anti-inflammatory potential of allyl-isothiocyanate–role of Nrf2, NF-(kappa) B and microRNA-155. J. Cell. Mol. Med. 2012, 16, 836–843.
10.1111/j.1582-4934.2011.01367.x
CAS PubMed Web of Science® Google Scholar
40de Roos, B., Rucklidge, G., Reid, M., Ross, K. et al., Divergent mechanisms of cis9, trans11-and trans10, cis12-conjugated linoleic acid affecting insulin resistance and inflammation in apolipoprotein E knockout mice: a proteomics approach. FASEB J. 2005, 19, 1746–1748.
CAS PubMed Web of Science® Google Scholar
41Xie, C., Kang, J., Burris, R., Ferguson, M. E. et al., Acai juice attenuates atherosclerosis in ApoE deficient mice through antioxidant and anti-inflammatory activities. Atherosclerosis 2011, 216, 327–333.
10.1016/j.atherosclerosis.2011.02.035
CAS PubMed Web of Science® Google Scholar
42Macedo, L. F., Rogero, M. M., Guimaraes, J. P., Granato, D. et al., Effect of red wines with different in vitro antioxidant activity on oxidative stress of high-fat diet rats. Food Chem. 2013, 137, 122–129.
10.1016/j.foodchem.2012.10.017
CAS PubMed Web of Science® Google Scholar
43Sharmila, G., Bhat, F. A., Arunkumar, R., Elumalai, P. et al., Chemopreventive effect of quercetin, a natural dietary flavonoid on prostate cancer in in vivo model. Clin. Nutr. 2014, 33, 718–726.
10.1016/j.clnu.2013.08.011
CAS PubMed Web of Science® Google Scholar
44Keum, Y. S., Khor, T. O., Lin, W., Shen, G. et al., Pharmacokinetics and pharmacodynamics of broccoli sprouts on the suppression of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: implication of induction of Nrf2, HO-1 and apoptosis and the suppression of Akt-dependent kinase pathway. Pharm. Res. 2009, 26, 2324–2331.
10.1007/s11095-009-9948-5
CAS PubMed Web of Science® Google Scholar
45Wiegand, H., Boesch-Saadatmandi, C., Regos, I., Treutter, D. et al., Effects of quercetin and catechin on hepatic glutathione-S transferase (GST), NAD(P)H quinone oxidoreductase 1 (NQO1), and antioxidant enzyme activity levels in rats. Nutr. Cancer 2009, 61, 717–722.
10.1080/01635580902825621
CAS PubMed Web of Science® Google Scholar
46Choi, C. S., Chung, H. K., Choi, M. K., Kang, M. H., Effects of grape pomace on the antioxidant defense system in diet-induced hypercholesterolemic rabbits. Nutr. Res. Pract. 2010, 4, 114–120.
10.4162/nrp.2010.4.2.114
CAS PubMed Web of Science® Google Scholar
47Hollman, P. C., Cassidy, A., Comte, B., Heinonen, M. et al., The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established. J. Nutr. 2011, 141, 989S–1009S.
10.3945/jn.110.131490
CAS PubMed Web of Science® Google Scholar
48Chen, C. H., Sun, L., Mochly-Rosen, D., Mitochondrial aldehyde dehydrogenase and cardiac diseases. Cardiovasc. Res. 2010, 88, 51–57.
10.1093/cvr/cvq192
CAS PubMed Web of Science® Google Scholar
49Chandiramani, N., Wang, X., Margeta, M., Molecular basis for vulnerability to mitochondrial and oxidative stress in a neuroendocrine CRI-G1 cell line PLoS One 2011, 6, e14485.
10.1371/journal.pone.0014485
CAS PubMed Web of Science® Google Scholar
50Visioli, F., Wolfram, R., Richard, D., Abdullah, M. I. et al., Olive phenolics increase glutathione levels in healthy volunteers. J. Agric. Food Chem. 2009, 57, 1793–1796.
10.1021/jf8034429
CAS PubMed Web of Science® Google Scholar
51Chan, K., Kan, Y. W., Nrf2 is essential for protection against acute pulmonary injury in mice. Proc. Natl. Acad. Sci. USA 1999, 96, 12731–12736.
10.1073/pnas.96.22.12731
CAS PubMed Web of Science® Google Scholar
52Reisman, S. A., Yeager, R. L., Yamamoto, M., Klaassen, C. D., Increased Nrf2 activation in livers from Keap1-knockdown mice increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species. Toxicol. Sci. 2009, 108, 35–47.
10.1093/toxsci/kfn267
CAS PubMed Web of Science® Google Scholar
53Shen, G., Xu, C., Hu, R., Jain, M. R. et al., Comparison of (-)-epigallocatechin-3-gallate elicited liver and small intestine gene expression profiles between C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Pharm. Res. 2005, 22, 1805–1820.
10.1007/s11095-005-7546-8
CAS PubMed Web of Science® Google Scholar
54Shen, G., Xu, C., Hu, R., Jain, M. R. et al., Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol. Cancer Ther. 2006, 5, 39–51.
10.1158/1535-7163.MCT-05-0293
CAS PubMed Web of Science® Google Scholar
55Zheng, Y., Tao, S., Lian, F., Chau, B. T. et al., Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response. Toxicol. Appl. Pharmacol. 2012, 265, 292–299.
10.1016/j.taap.2012.08.028
CAS PubMed Web of Science® Google Scholar
56Balstad, T. R., Carlsen, H., Myhrstad, M. C., Kolberg, M. et al., Coffee, broccoli and spices are strong inducers of electrophile response element-dependent transcription in vitro and in vivo—studies in electrophile response element transgenic mice. Mol. Nutr. Food Res. 2011, 55, 185–197.
10.1002/mnfr.201000204
CAS PubMed Web of Science® Google Scholar
57Howard, J., Jones, G. L., Oliver, C., Watson, K., Dietary intake of antioxidant supplements modulate antioxidant status and heat shock protein 70 synthesis. Redox Rep. 2002, 7, 308–311.
10.1179/135100002125000857
CAS PubMed Web of Science® Google Scholar
58Bohn, S. K., Myhrstad, M. C., Thoresen, M., Holden, M. et al., Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers. BMC Med. 2010, 8, 54.
10.1186/1741-7015-8-54
CAS PubMed Web of Science® Google Scholar
59Freeman, B. A., Baker, P. R., Schopfer, F. J., Woodcock, S. R. et al., Nitro-fatty acid formation and signaling. J. Biol. Chem. 2008, 283, 15515–15519.
10.1074/jbc.R800004200
CAS PubMed Web of Science® Google Scholar
60Charles, R. L., Rudyk, O., Prysyazhna, O., Kamynina, A. et al., Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase. Proc. Natl. Acad. Sci. USA 2014, 111, 8167–8172.
10.1073/pnas.1402965111
CAS PubMed Web of Science® Google Scholar
61Balch, W. E., Morimoto, R. I., Dillin, A., Kelly, J. W., Adapting proteostasis for disease intervention. Science 2008, 319, 916–919.
10.1126/science.1141448
CAS PubMed Web of Science® Google Scholar
62Akerfelt, M., Morimoto, R. I., Sistonen, L., Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 2010, 11, 545–555.
10.1038/nrm2938
CAS PubMed Web of Science® Google Scholar
63Richter, K., Haslbeck, M., Buchner, J., The heat shock response: life on the verge of death. Mol. Cell 2010, 40, 253–266.
10.1016/j.molcel.2010.10.006
CAS PubMed Web of Science® Google Scholar
64Radford, N. B., Fina, M., Benjamin, I. J., Moreadith, R. W. et al., Cardioprotective effects of 70-kDa heat shock protein in transgenic mice. Proc. Natl. Acad. Sci. USA 1996, 93, 2339–2342.
10.1073/pnas.93.6.2339
CAS PubMed Web of Science® Google Scholar
65Zhu, J., Quyyumi, A. A., Wu, H., Csako, G. et al., Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1055–1059.
10.1161/01.ATV.0000074899.60898.FD
CAS PubMed Web of Science® Google Scholar
66Chung, J., Nguyen, A. K., Henstridge, D. C., Holmes, A. G. et al., HSP72 protects against obesity-induced insulin resistance. Proc. Natl. Acad. Sci. USA 2008, 105, 1739–1744.
10.1073/pnas.0705799105
CAS PubMed Web of Science® Google Scholar
67Drew, B. G., Ribas, V., Le, J. A., Henstridge, D. C. et al., HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes 2014, 63, 1488–1505.
10.2337/db13-0665
CAS PubMed Web of Science® Google Scholar
68Hsu, A. L., Murphy, C. T., Kenyon, C., Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 2003, 300, 1142–1145.
10.1126/science.1083701
CAS PubMed Web of Science® Google Scholar
69Santoro, M. G., Heat shock factors and the control of the stress response. Biochem. Pharmacol. 2000, 59, 55–63.
10.1016/S0006-2952(99)00299-3
CAS PubMed Web of Science® Google Scholar
70Bhattacharya, S., Oksbjerg, N., Young, J. F., Jeppesen, P. B., Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells. Diabetes Obes. Metab. 2014, 16, 602–612.
10.1111/dom.12236
CAS PubMed Web of Science® Google Scholar
71Hertog, M. G., Feskens, E. J., Hollman, P. C., Katan, M. B. et al., Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993, 342, 1007–1011.
10.1016/0140-6736(93)92876-U
CAS PubMed Web of Science® Google Scholar
72Lin, J., Rexrode, K. M., Hu, F., Albert, C. M. et al., Dietary intakes of flavonols and flavones and coronary heart disease in US women. Am. J. Epidemiol. 2007, 165, 1305–1313.
10.1093/aje/kwm016
PubMed Web of Science® Google Scholar
73Geleijnse, J. M., Launer, L. J., Van der Kuip, D. A., Hofman, A. et al., Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am. J. Clin. Nutr. 2002, 75, 880–886.
10.1093/ajcn/75.5.880
CAS PubMed Web of Science® Google Scholar
74Halliwell, B., Rafter, J., Jenner, A., Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects?. Antioxidant or not? Am. J. Clin. Nutr. 2005, 81, 268S–276S.
10.1093/ajcn/81.1.268S
CAS PubMed Web of Science® Google Scholar
75Rechner, A. R., Kuhnle, G., Hu, H., Roedig-Penman, A. et al., The metabolism of dietary polyphenols and the relevance to circulating levels of conjugated metabolites. Free Radic. Res. 2002, 36, 1229–1241.
10.1080/246-1071576021000016472
CAS PubMed Web of Science® Google Scholar
76 EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). SCIENTIFIC OPINION: Guidance on the scientific requirements for health claims related to antioxidants, oxidative damage and cardiovascular health. EFSA J. 2011, 9, 2474.
10.2903/j.efsa.2011.2474
Google Scholar
77Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. et al., Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev. 2012, 3, CD007176.
PubMed Web of Science® Google Scholar
78Goodman, M., Bostick, R. M., Kucuk, O., and Jones, D. P., Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radic. Biol. Med. 2011, 51, 1068–1084.
10.1016/j.freeradbiomed.2011.05.018
CAS PubMed Web of Science® Google Scholar
79Rochette, L., Zeller, M., Cottin, Y., Vergely, C., Diabetes, oxidative stress and therapeutic strategies. Biochim. Biophys. Acta 2014, 1840, 2709–2729.
10.1016/j.bbagen.2014.05.017
CAS PubMed Web of Science® Google Scholar
80Tabassum, H., Parvez, S., Rehman, H., Banerjee, B. D. et al., Catechin as an antioxidant in liver mitochondrial toxicity: inhibition of tamoxifen-induced protein oxidation and lipid peroxidation. J. Biochem. Mol. Toxicol. 2007, 21, 110–117.
10.1002/jbt.20167
CAS PubMed Web of Science® Google Scholar
81Garg, R., Gupta, S., Maru, G. B., Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis 2008, 29, 1022–1032.
10.1093/carcin/bgn064
CAS PubMed Web of Science® Google Scholar
82Dietz, B. M., Hagos, G. K., Eskra, J. N., Wijewickrama, G. T. et al., Differential regulation of detoxification enzymes in hepatic and mammary tissue by . Mol. Nutr. Food Res. 2013, 57, 1055–1066.
10.1002/mnfr.201200534
CAS PubMed Web of Science® Google Scholar
83Wang, R., Paul, V. J., Luesch, H., Seaweed extracts and unsaturated fatty acid constituents from the green alga Ulva lactuca as activators of the cytoprotective Nrf2-ARE pathway. Free Radic. Biol. Med. 2013, 57, 141–153.
10.1016/j.freeradbiomed.2012.12.019
CAS PubMed Web of Science® Google Scholar
84Kropat, C., Mueller, D., Boettler, U., Zimmermann, K. et al., Modulation of Nrf2-dependent gene transcription by bilberry anthocyanins in vivo. Mol. Nutr. Food Res. 2013, 57, 545–550.
10.1002/mnfr.201200504
CAS PubMed Web of Science® Google Scholar
85Rezaei-Moghadam, A., Mohajeri, D., Rafiei, B., Dizaji, R. et al., Effect of turmeric and carrot seed extracts on serum liver biomarkers and hepatic lipid peroxidation, antioxidant enzymes and total antioxidant status in rats. Bioimpacts 2012, 2, 151–157.
PubMed Google Scholar
86Alvarez-Suarez, J. M., Dekanski, D., Ristic, S., Radonjic, N. V. et al., Strawberry polyphenols attenuate ethanol-induced gastric lesions in rats by activation of antioxidant enzymes and attenuation of MDA increase. PLoS One 2011, 6, e25878.
10.1371/journal.pone.0025878
CAS PubMed Web of Science® Google Scholar
87Xu, J., Yang, F., An, X., Hu, Q., Anticarcinogenic activity of selenium-enriched green tea extracts in vivo. J. Agric. Food Chem. 2007, 55, 5349–5353.
10.1021/jf070568s
CAS PubMed Web of Science® Google Scholar
88Jimenez-Escrig, A., Dragsted, L. O., Daneshvar, B., Pulido, R. et al., In vitro antioxidant activities of edible artichoke (Cynara scolymus L.) and effect on biomarkers of antioxidants in rats. J. Agric. Food Chem. 2003, 51, 5540–5545.
10.1021/jf030047e
CAS PubMed Web of Science® Google Scholar
89McWalter, G. K., Higgins, L. G., McLellan, L. I., Henderson, C. J. et al., Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J. Nutr. 2004, 134, 3499S–3506S.
10.1093/jn/134.12.3499S
CAS PubMed Web of Science® Google Scholar
90Mahn, K., Borras, C., Knock, G. A., Taylor, P. et al., Dietary soy isoflavone induced increases in antioxidant and eNOS gene expression lead to improved endothelial function and reduced blood pressure in vivo. FASEB J. 2005, 19, 1755–1757.
10.1096/fj.05-4008fje
CAS PubMed Web of Science® Google Scholar
91Ibrahim, W. H., Habib, H. M., Chow, C. K., Bruckner, G. G., Isoflavone-rich soy isolate reduces lipid peroxidation in mouse liver. Int. J. Vitam. Nutr. Res. 2008, 78, 217–222.
10.1024/0300-9831.78.45.217
CAS PubMed Web of Science® Google Scholar
92Kapravelou, G., Martinez, R., Andrade, A. M., Lopez, C. C. et al., Improvement of the antioxidant and hypolipidaemic effects of cowpea flours (Vigna unguiculata) by fermentation: results of in vitro and in vivo experiments. J. Sci. Food Agric. 2014 [Epub ahead of print].
PubMed Web of Science® Google Scholar
93Kim, S., Lee, H. G., Park, S. A., Kundu, J. K. et al., Keap1 cysteine 288 as a potential target for diallyl trisulfide-induced Nrf2 activation. PLoS One 2014, 9, e85984.
10.1371/journal.pone.0085984
PubMed Web of Science® Google Scholar
94Ho, C. Y., Cheng, Y. T., Chau, C. F., Yen, G. C., Effect of diallyl sulfide on in vitro and in vivo Nrf2-mediated pulmonic antioxidant enzyme expression via activation ERK/p38 signaling pathway. J. Agric. Food Chem. 2012, 60, 100–107.
10.1021/jf203800d
CAS PubMed Web of Science® Google Scholar
95Camargo, A., Pena-Orihuela, P., Rangel-Zuniga, O. A., Perez-Martinez, P. et al., Peripheral blood mononuclear cells as in vivo model for dietary intervention induced systemic oxidative stress. Food Chem. Toxicol. 2014, 72C, 178–186.
10.1016/j.fct.2014.07.024
CAS Web of Science® Google Scholar
96Pena-Orihuela, P., Camargo, A., Rangel-Zuniga, O. A., Perez-Martinez, P. et al., Antioxidant system response is modified by dietary fat in adipose tissue of metabolic syndrome patients. J. Nutr. Biochem. 2013, 24, 1717–1723.
10.1016/j.jnutbio.2013.02.012
CAS PubMed Web of Science® Google Scholar
97Nakagawa, F., Morino, K., Ugi, S., Ishikado, A. et al., 4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs. Biochem. Biophys. Res. Commun. 2014, 443, 991–996.
10.1016/j.bbrc.2013.12.085
CAS PubMed Web of Science® Google Scholar
98Jahangiri, A., Leifert, W. R., Kind, K. L., McMurchie, E. J., Dietary fish oil alters cardiomyocyte Ca2+ dynamics and antioxidant status. Free Radic. Biol. Med. 2006, 40, 1592–1602.
10.1016/j.freeradbiomed.2005.12.026
CAS PubMed Web of Science® Google Scholar
99Ottestad, I., Vogt, G., Retterstol, K., Myhrstad, M. C. et al., Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br. J. Nutr. 2012, 108, 315–326.
10.1017/S0007114511005484
CAS PubMed Web of Science® Google Scholar
100Magbanua, M. J., Roy, R., Sosa, E. V., Weinberg, V. et al., Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PLoS One 2011, 6, e24004.
10.1371/journal.pone.0024004
CAS PubMed Web of Science® Google Scholar
101Oliveras-Lopez, M. J., Molina, J. J., Mir, M. V., Rey, E. F. et al., Extra virgin olive oil (EVOO) consumption and antioxidant status in healthy institutionalized elderly humans. Arch. Gerontol. Geriatr. 2013, 57, 234–242.
10.1016/j.archger.2013.04.002
CAS PubMed Web of Science® Google Scholar
102Pereira, A. C., Dionisio, A. P., Wurlitzer, N. J., Alves, R. E. et al., Effect of antioxidant potential of tropical fruit juices on antioxidant enzyme profiles and lipid peroxidation in rats. Food Chem. 2014, 157, 179–185.
10.1016/j.foodchem.2014.01.090
CAS PubMed Web of Science® Google Scholar
103Breinholt, V. M., Nielsen, S. E., Knuthsen, P., Lauridsen, S. T. et al., Effects of commonly consumed fruit juices and carbohydrates on redox status and anticancer biomarkers in female rats. Nutr. Cancer 2003, 45, 46–52.
10.1207/S15327914NC4501_6
CAS PubMed Web of Science® Google Scholar
104Nair, S., Barve, A., Khor, T. O., Shen, G. X. et al., Regulation of Nrf2- and AP-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in prostate of Nrf2-knockout or C57BL/6J mice and PC-3 AP-1 human prostate cancer cells. Acta Pharmacol. Sin. 2010, 31, 1223–1240.
10.1038/aps.2010.147
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume59, Issue7

July 2015

Pages 1229-1248

Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress