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New findings of oxidative stress biomarkers in nutritional research

Kochlik, Bastiana,b,*; Grune, Tilmana,b,c,d; Weber, Danielaa,b,*

Current Opinion in Clinical Nutrition and Metabolic Care: September 2017 - Volume 20 - Issue 5 - p 349–359
doi: 10.1097/MCO.0000000000000388
ASSESSMENT OF NUTRITIONAL AND METABOLIC STATUS: Edited by Dwight E. Matthews and Kristina Norman

Purpose of review The aim of this article is to present a brief overview of recently published articles assessing oxidative stress markers in nutritional studies.

Recent findings Intervention and observational studies were carried out in both, healthy subjects and patients and describe the association of foodstuffs as well as isolated nutrients with biomarkers of oxidative stress. The results from human intervention studies on healthy participants and patients are controversial. Long-term interventions (>8 weeks) seem to be more effective than short-term or single-dose interventions. Results are difficult to compare because not only the methods used, also the assessed biomarkers and outcomes were very diverse. In addition, studies vary in the compounds and doses used, duration, participants and so on. Different biomarkers (damaged molecules together with antioxidants from different compartments) should be assessed to evaluate the true ‘redox-status’ of an individual and the impact of a nutritional intervention.

Summary Both observational and interventional studies performed in healthy participants and patients show possible beneficial effects of nutrients and foodstuffs by improving oxidative stress markers and antioxidant enzyme activities. Biomarkers should be standardized to allow better comparison of results of antioxidant intervention studies.

aDepartment of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE)

bNutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal

cGerman Center for Diabetes Research (DZD), Munich

dGerman Center for Cardiovascular Research (DZHK), Berlin, Germany

*Bastian Kochlik and Daniela Weber contributed equally to the article.

Correspondence to Daniela Weber, Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE), Nuthetal, Germany. Tel: +49 33200 88 2358; e-mail: Daniela.Weber@dife.de

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

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INTRODUCTION

Oxidative stress has been studied extensively in various model systems, animals and humans as it is known to play a crucial role in the aging process and in numerous age-related diseases [1]. As the term oxidative stress was defined as the imbalance between oxidants and antioxidants in favor of the former, the common perception was that intervention studies with antioxidants would help to maintain or restore this balance and thus, positively influence health status. However, the evidence from clinical trials has been controversial [2]. It is important to note that the revised definition of oxidative stress not only comprises the before-mentioned imbalance but also the shift in redox signaling that may have detrimental but also positive effects [3].

Reactive oxygen and nitrogen species are produced constantly as by-products of normal metabolism. When oxidant production increases or when antioxidants are not sufficient or effective then the oxidants overwhelm the antioxidant defense and can damage a wide range of biomolecules and thus, influence physiological processes. To counteract oxidative damage, endogenous (enzymatic) antioxidant defense mechanisms act together with exogenous antioxidants such as diet-derived polyphenols, vitamins, and so on [1].

The aim of this review is to give an overview of recent findings assessing oxidative stress in observational studies and nutrition-related interventions in healthy participants and patients.

Box 1

Box 1

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CURRENT STATE OF RESEARCH

A literature search was performed on PubMed on 8 March 2017 (Fig. 1). The aim was to obtain a detailed overview on recent human studies dealing with oxidative stress and nutrition. All abstracts were studied and those publications excluded which did not relate to either of the search terms ‘oxidative stress’ and ‘nutrition’. For sake of brevity, we excluded publications studying children, pregnant women, cancers, polycystic ovary syndrome and hepatitis.

FIGURE 1

FIGURE 1

Our search results are divided into observational studies (Table 1: nine results; [4–12]) and intervention studies and within these we separated healthy participants (Table 2: 14 results; [13–26]) from patients (Table 3 : 22 results; [27–30,31▪,32–44,45▪,46,47▪,48]).

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

Table 3

Table 3

For this review, we focus on major chronic diseases such as overweight and obesity, type 2 diabetes mellitus (T2D), hyperlipidemia, coronary heart disease, cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), rheumatoid arthritis (RA), mild cognitive impairment (MCI), Parkinson's disease, major depressive disorder (MDD) and kidney diseases such as chronic kidney disease (CKD), renal failure and renal transplant recipients (Fig. 2).

FIGURE 2

FIGURE 2

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BIOMARKERS OF OXIDATIVE STRESS

There are different ways to estimate the ‘oxidative stress status’ of a person. One can analyze the free radicals, damaged/oxidized biomolecules, or antioxidants (Fig. 2). The quantification of reactive species/free radicals such as hydrogen peroxide (H2O2), superoxide anion radical (O2 ●−), nitric oxide (NO), is difficult as they are highly reactive and have a short half-life. Therefore, samples must be rapidly prepared and analyzed which is not always given in clinical practice and research.

Widely accepted biomarkers of oxidative damage include isoprostanes, 8-hydroxy-deoxyguanosine (8-OHdG), protein carbonyls, 3-nitrotyrosine, lipid hydroperoxides and malondialdehyde (MDA) which can be measured as thiobarbituric acid reactive species (TBARS). Commercially available kits exist as well as more sophisticated laboratory methods.

Antioxidant capacity comprises assays termed total antioxidant capacity (TAC), total antioxidant status, biological antioxidant potential, oxygen radical absorbance capacity (ORAC), or ferric reducing antioxidant potential, just to name a few. Many studies described here applied these capacity assays. A multitude of assays exist, but unfortunately none of them are universal. They have been controversially discussed elsewhere (refer to Ref. [49▪] for more details). The difficulty with these assays is that they only consider the ‘quenching potential’ of the sample itself against an artificial radical source used for the specific assay. Most of the antioxidant activity in plasma comes from uric acid; thus, a high uric acid concentration may lead to misinterpretation of assay results. For an excellent review on this topic see Laguerre et al. [50].

For the measurement of antioxidant enzyme activities such as those of superoxide dismutase (SOD), catalase (CAT) or glutathione peroxidase (GPx) activity commercially available kits exist. The direct measurement of endogenous antioxidants such as uric acid, glutathione (reduced GSH/oxidized GSSG) and total thiols, and nutritional antioxidants such as ascorbic acid and lipid-soluble micronutrients is relatively easy and commonly carried out in human studies.

Nutrition-derived protection against oxidative stress and thus, prevention of several diseases seems to be an easy way to maintain health and quality of life. Current findings of the influence of nutrients and foodstuffs on oxidative stress underpin this suggestion, yet with a few limitations.

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Observational studies

Nine observational studies analyzing the intake and status of various vitamins, lycopene and foods showed an influence on oxidative stress as well as associations with age and different disease (Table 1). These studies focused on persons with metabolic syndrome (MetS), T2D, CVD, MCI, CKD and fatty liver disease.

The antioxidants ascorbic acid, vitamin E and lycopene seem to be connected to MetS etiology. Patients with MetS had both, significantly lower plasma vitamin A, C and E concentrations and a significantly higher prevalence in vitamin deficiencies than the healthy control subjects [4]. A correlation between vitamin intake and blood concentrations was not found in MetS patients, but in healthy subjects for vitamin E and C, although there were no differences in the consumed amount between both groups. When dividing MetS patients according to their lycopene status into high (0.626 μmol/l), medium (0.374 μmol/l) and low (0.204 μmol/l) lycopene groups, a significantly improved mortality outcome was shown for subjects with higher lycopene levels [5].

Dietary pattern and individual compounds also showed associations with oxidative stress and antioxidant capacity in patients with T2D and MCI. In diabetic vegetarians and omnivores, vitamin B12 (VB12) levels above 250 pmol/l were significantly associated with higher antioxidant enzyme activities and lower oxidative stress and the VB12 status correlated negatively with oxLDL [6]. In newly diagnosed T2D patients, some dietary ingredients showed effects on 8-OHdG and glutathione reductase [7]. Seaweed and dairy intake were negatively associated with 8-OHdG, whereas vegetable and fruit intake were positively associated with glutathione reductase. MCI patients consumed more red meat and less fish, and had significantly lower plasma vitamin E and TAC and higher MDA than healthy subjects [8]. However, plasma retinol, flavonoids, GSH, erythrocyte enzyme activities (SOD, CAT, GPx, glutathione-S-transferase (GST) and glutathione reductase) and urinary 8-OHdG were not different.

The association between vitamin B metabolites and oxidative stress may also play an important role in CVD and CKD. Newly diagnosed CVD patients had significantly lower levels and intake of folate, vitamin B6 (VB6) and VB12, and thus significantly higher homocysteine compared with healthy subjects [9]. In addition, CVD patients had significantly lower GSH and TAC levels and significantly higher oxidative stress. Regarding CKD, it was shown that significantly higher MDA, homocysteine and TAC, and lower folate, VB6 and enzyme activities were found in CKD patients [10]. In CKD and healthy patients, there was no association of B-vitamins with MDA and antioxidant capacities, although there was a significant association between CKD risk and homocysteine, folate, VB6, MDA, GST and SOD [10].

In addition, elevated oxidative stress, measured as different forms of oxidized lipoprotein fractions was associated with an increased risk for developing fatty liver, one risk factor for cardiovascular events [11▪].

An observational study showed associations between antioxidant lipid-soluble micronutrients and age in 2118 healthy men and women (35–75 years), especially the inverse association between lycopene and age was of interest since it remained even after adjusting for significant cofactors (country, season, cholesterol, sex, smoking status, BMI and dietary habits) [12].

Observational studies published in the last 12 months may give some hints on associations between nutrition and oxidative stress in healthy and diseased populations. Results demonstrated beneficial effects of antioxidants, vitamins and foodstuffs on biomarkers of oxidative stress, antioxidant enzymes and disease outcome. However, as observational studies cannot allow drawing conclusions on the cause and effect relationship, intervention studies are needed to prove the relevance of antioxidants for human health.

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Interventions with foodstuffs in healthy participants

Single doses of green tea had no or only little effect on different biomarkers [13–15], whereas an intervention for 6 months showed improved GSH and ascorbic acid and significantly decreased TBARS [16]. One study using pomegranate juice in athletes demonstrated reduced MDA and protein carbonyls after a 3-week intervention [17]. After the same study duration with black currant nectar, subjects on the intervention-arm had stable ORAC levels after exercise while ORAC was significantly decreased in the placebo group compared with baseline [18]. For onion juice [19], mushrooms [20] and a phenolic alkaloid found in oat [21], an improvement in TAC was observed in healthy subjects. A single dose of blueberries together with cigarette smoking had no effect on ascorbic acid, aminothiol and endogenous as well as oxidatively induced DNA damage in blood cells [22]. Improved lipid hydroperoxides, plasma and urinary isoprostanes were observed after subjects received plant sterol-enriched soy milk for 4 weeks [23], and one single intervention with a functional food-cookie containing different sources of fiber and probiotics led to an improved peroxidation of leukocyte index in a crossover study in 10 healthy subjects [24].

Despite these findings, foodstuffs consist of a multitude of substances which act together to exert their functions; therefore, it is difficult to trace the function back to only one ingredient.

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Interventions with antioxidants in healthy participants

Only few studies were carried out with single antioxidants in healthy participants (Table 2). Sarmiento et al. [25] used ubiquinol and was able to show that 3 weeks of supplementation had positive effects on isoprostanes, 8-OHdG and oxidized LDL, as well as vitamin E, coenzyme Q9, Q10, and CAT. By contrast, supplementation with ascorbic acid for 12 weeks did not lead to any significant improvement [26].

These findings show how difficult it is to show changes after the administration of foodstuffs or single antioxidants in healthy subjects. If one assumes that healthy participants possess a balanced antioxidant/oxidant ratio, then intervention studies in patients should show beneficial effects (Table 3 ).

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Interventions with foodstuffs in patients

Supplementation of 21 overweight and obese participants with pomegranate extract (containing polyphenols, anthocyanins and tannins) for 30 days resulted in statistically significantly reduced MDA compared with placebo and baseline [27].

The administration of grape pomace and omija fruit ethanol extracts [grape and omija (GO)] containing phenolic compounds for 10 weeks showed beneficial effects on antioxidant enzyme activities and oxidative stress compared with the placebo group [28]. The intervention increased SOD activity compared with baseline; GPx and glutathione reductase activities were also significantly increased compared with baseline and placebo by high-GO supplementation, whereas TBARS and H2O2 declined significantly in the high-GO group.

Diabetic patients consuming chamomile tea (containing sesquiterpenic and phenolic compounds) for 8 weeks had statistically significant higher TAC levels, SOD, GPx and CAT activity and lower MDA than placebo patients and compared with baseline [29]. Improved biomarkers were also observed in hyperlipidemic participants, in which the consumption of polyphenol-enriched virgin olive oil had a greater effect than olive oil alone, shown in statistically significantly decreased 8-OHdG and increased SOD activity [30]. The trace element selenium (Se), a central component of GPx enzymes was administered over 6 months in form of a Brazilian nut, providing approximately 288.75 μg Se/day. This resulted in significantly increased Se levels and GPx activity in 20 MCI patients compared with MCI-controls [31▪]. In another form of neurodegeneration, namely Parkinson's disease, the urate-adjusted administration of inosine for 24 months led to a statistically significant higher plasma antioxidant capacity compared with placebo [33].

Patients with knee osteoarthritis who consumed Burdock root tea (containing phenolic acid and flavonoids) daily for 42 days had a significant decline in oxidative stress and an increase in antioxidant enzyme activities and TAC compared with baseline and controls [32]. Dietary sesamin (a major lignan in sesame seeds) supplementation for 6 weeks in women with RA resulted in statistically significantly increased TAC and decreased MDA compared with baseline and to the placebo group [34].

The use of synbiotic bread (Lactobacillus sporogenes and inulin) for 8 weeks in diabetic patients resulted in reduced MDA but had no effect on TAC, CAT and total GSH [35]. In contrast, another study found no effects on isoprostanes and GPx by supplementing synbiotics to CKD patients for 6 weeks [36]. Beneficial effects on GSH in MDD patients were observed after an 8-week supplementation with probiotic capsules (mixture of bacteria) [37], whereas no improvements on oxidative stress status were seen in women with RA after a probiotic intervention (only Lactobacillus casei) for the same duration [38]. Fish oil was also used in patients with RA [39] and in obese and overweight women [40]. However, there was no change in isoprostanes and quercetin after a 10-week supplementation period with a flavonoid-fish oil mix containing also catechin, ascorbic acid, niacinamide and folic acid in 48 obese and overweight women [40]. The supplementation with fish oil and evening primrose lead to conflicting results. In the fish oil group TBARS and GSH increased, whereas H2O2 decreased. In the fish oil and evening primrose group, TBARS and SOD increased. Thus, these supplementations lead to an improvement in antioxidant activity but also to an increase in lipid peroxidation products [39].

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Interventions with antioxidants in patients

One publication describes T2D patients on an N-acetylcysteine intervention. After 2 weeks, there were no differences in concentrations of GSH, GSSG, TBARS or isoprostanes compared with baseline [41].

n-3 fatty acids and coenzyme Q were administered to patients with CKD [42]. After 8 weeks, these patients had significantly reduced isoprostanes. Supplementation with conjugated linoleic acid and vitamin E for 8 weeks in obese patients with NAFLD resulted in increased TAC as well as reduced MDA [43]. Vitamin E supplementation for 8 weeks did not influence MDA and NOx concentrations in patients with T2D [44]. The same was true for a 1-year supplementation with astaxanthin in renal transplant recipients which had no effect on isoprostanes [45▪]. Selenium intervention for 8 weeks significantly increased TAC in patients with T2D and coronary heart disease [46]. Isoprostanes, GSH/GSSG and 2′,7′-dichlorofluorescin oxidation were improved in a cross-sectional study in T2D patients receiving ascorbic acid for 4 months [47▪]. Vitamin D supplementation for 8 weeks, however, led to significantly improved TAC and GSH in patients with MDD [48].

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DISCUSSION

Recent findings in both observational and intervention studies show possible beneficial effects of single nutrients and also foodstuffs on oxidative stress biomarkers and disease outcome. These effects were observed in healthy participants as well as in patients.

Some intervention studies were not able to show any beneficial effect of nutritional supplements on biomarkers of oxidative stress. These studies used green tea catechins, blueberries together with smoking, astaxanthin, ascorbic acid together with exercise, synbiotics, probiotics, fish oil together with evening primrose and vitamin E. That these trials failed to demonstrate an improvement after nutritional intervention most likely has several reasons. For instance, the duration of few days or weeks might not have been sufficient or the number of participants was not large enough to reach statistical significance. Durations of the studies described here ranged from single over short-term interventions (2–6 weeks), and some trials were carried out over 1–2 years.

An intervention with only one nutrient or food may not be enough to influence biomarkers of oxidative stress. On the other hand, multiple compound-interventions do not allow distinguishing between effects of one single compound and may lead to difficulties in the interpretation of results, as seen in the grape pomace and omija fruit ethanol extract intervention. Furthermore, some studies describe only measuring one biomarker of oxidative stress or only single biomarkers were changed after intervention which reduces the informative value of the study.

A balanced oxidant/antioxidant ratio is the result of a healthy diet and lifestyle, genetics, environment and many other factors. Possible confounders such as dietary intake, nutrition and physical activity should be taken into account to exclude possible influences of these lifestyle factors. In addition to this, when assessing oxidative stress it is of utmost importance to consider damaged molecules together with antioxidants form different compartments, for example cellular and plasma antioxidants but also water-soluble and lipid-soluble antioxidants to approximate the true ‘redox-status’ of an individual. This is especially necessary as there is no such thing as the ‘gold standard’ for analyzing oxidative stress in human studies. Reliable conclusions on the effect of an intervention cannot be drawn if only one biomarker is measured. Especially, in observational studies and nutritional intervention, it is necessary to use different biomarkers as the oxidative stress status of an individual is not only influenced by one specific antioxidant applied but also by the individual's demographics, anthropometrics, health status, lifestyle and so on.

It is noteworthy that some studies analyzed biomarkers in specimen which are not recommended, for example glutathione in plasma instead of red blood cells or MDA in serum instead of plasma. Thus, the sample type should always be considered when carrying out and when interpreting such intervention studies.

Studies regarding dietary patterns such as the Mediterranean Diet are missing in this review and thus a statement about potential new effects cannot be made. Although it is already known that there are beneficial effects of some dietary patterns on oxidative stress biomarkers there is still need to generate and expand information related to disease.

Future studies must ensure an adequate sample size, duration (long-term) and control of lifestyle factors and to measure various biomarkers of oxidative stress to confirm results.

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CONCLUSION

Current studies demonstrated that there are beneficial influences of single nutrients (vitamins and phenolic compounds) and foodstuffs (fruits and vegetables) on an individual's ‘oxidative stress status’; however, further research regarding the nutritional impact on oxidative stress, being a main driver in aging and metabolic impairments, is worthy. More focus should take place in studies concerning dietary patterns and lifestyle, both being responsible for a healthy life.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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Keywords:

intervention study; nutrition; observational study; oxidative stress

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