Strawberry and Human Health: Effects beyond Antioxidant Activity

Review pubs.acs.org/JAFC

Strawberry and Human Health: Effects beyond Antioxidant Activity Francesca Giampieri,† José M. Alvarez-Suarez,‡ and Maurizio Battino*,‡ †

Dipartimento di Scienze Agrarie, Alimentari e Ambientali, Università Politecnica delle Marche, Via Ranieri 65, 60131 Ancona, Italy Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche (DISCO)−Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, 60131 Ancona, Italy

‡

ABSTRACT: The usefulness of a diet rich in vegetables and fruits on human health has been widely recognized: a high intake of antioxidant and bioactive compounds may in fact play a crucial role in the prevention of several diseases, such as cancer, cardiovascular, neurodegenerative, and other chronic pathologies. The strawberry (Fragaria × ananassa Duch.) possesses a remarkable nutritional composition in terms of micronutrients, such as minerals, vitamin C, and folates, and non-nutrient elements, such as phenolic compounds, that are essential for human health. Although strawberry phenolics are known mainly for their anti-inflammatory and antioxidant actions, recent studies have demonstrated that their biological activities also spread to other pathways involved in cellular metabolism and cellular survival. This paper has the main objective of reviewing current information about the potential mechanisms involved in the effects elicited by strawberry polyphenols on human health, devoting special attention to the latest findings. KEYWORDS: strawberry, polyphenols, antioxidant capacity, cell signaling modulation, epigenetic regulation

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INTRODUCTION

should be taken into account that polyphenol antioxidant capacity has been exclusively proven in vitro and, although providing suggestive information, it is very difficult to translate these findings into in vivo actions. Moreover, polyphenol bioavailability is rather low, especially when compared to the concentrations of endogenous antioxidants, so that their real contribution to the overall cellular antioxidant capacity appears to be negligible. For these reasons, the antioxidant capacity is now beginning to be questioned and more complex mechanisms are being investigated.13 The objective of the present work is to discuss key findings from recent studies on the effects of strawberries on human health, paying particular attention to the mechanisms recently proposed that explain how polyphenols could exert their biological protective effects, beyond their mere antioxidant capacity.

The importance of diet on human health and well-being has been widely recognized all over the world. In 1991, in the United States “the 5 a day for Better Health Program” was launched to increase consumption of vegetables and fruits to an average of 5−9 servings a day, and nowadays it is one of the most widely recognized health promotion programs. In Europe, instead, the traditional Mediterranean diet has formed the basis for food consumption during the past century, originally settled on Mediterranean agronomical, pastoral, and rural archetypes. To reinforce the plant-based core of the dietary pattern, in the new Mediterranean pyramid the idea of structure of the “main meals” was launched as well as that of “frugality” and “moderateness”, because of the primary public health contest against obesity-related diseases. These changes were performed without disregarding important aspects linked with engendering, choosing, processing, and eating of foods, such as traditional, local, and ecofriendly products, biodiversity, and seasonality.1 The regular consumption of fruits and vegetables rich in antioxidants and bioactive compounds, as well as topical skin applications of polyphenols from different dietary sources, has been shown to exert a focal role in the prevention of many diseases, such as skin pathologies, various types of cancer, cardiovascular disorders, and other age-related degenerative pathologies, besides the general health benefits they provide.1−7 Berries are fruits that are rich both in nutritive compounds, including minerals, vitamins, and dietary fibers, and in nonnutritive elements, especially polyphenolic phytochemicals (phenolic acids flavonoids, tannins, and lignans).8−11 In the past few years, research on polyphenols has considerably increased, and because of the involvement of oxidative stress in the onset and development of degenerative diseases, great attention has been paid to their antioxidant properties. Previously, polyphenols’ antioxidant capacity was the most known and accepted mechanism, through which they are able to scavenge free radicals or limit their formation.12 However, it © XXXX American Chemical Society

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NUTRITIONAL COMPOSITION The strawberry (Fragaria × ananassa) is amomg the most diffused and consumed berries, in either fresh or processed forms. Because it has huge commercial and economic impacts, it can be considered unequivocally the most studied berry from nutritional, genomic, or agronomic points of view. Its high contents of vitamin C and folates (Table 1) confer a remarkable nutritional composition, which is enriched also by a vast variety of phenolic constituents8−10,14,15 (Figure 1; Table 2). Flavonoids, mainly anthocyanins, are the major class of these compounds (Figure 2), the best known strawberry polyphenolic compounds. In this regard, several studies have confirmed that anthocyanins represent the most quantitatively Special Issue: 2013 Berry Health Benefits Symposium Received: August 10, 2013 Revised: January 23, 2014 Accepted: January 23, 2014

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dx.doi.org/10.1021/jf405455n | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry

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Table 1. Nutrient Composition of Fresh Strawberriesa (Adapted from U.S. Department of Agriculture50) proximates and carbohydrates water (g) energy (kcal) protein (g) ash (g) total lipid (g) carbohydrate (g) sugars (g) sucrose (g) glucose (g) fructose (g) dietary fiber (g) a

90.95 32.00 0.67 0.40 0.30 7.68 4.89 0.47 1.99 2.44 2.00

mineral content calcium (mg) iron (mg) magnesium (mg) phosphorus (mg) potassium (mg) sodium (mg) zinc (mg) copper (mg) manganese (mg) selenium (μg)

vitamin content 16.00 0.41 13.00 24.00 153.00 1.00 0.14 0.048 0.39 0.40

vitamin C (mg) thiamin (mg) riboflavin (mg) niacin (mg) pantothenic acid (mg) vitamin B6 (mg) folate (μg) choline (mg) vitamin A, RAE (μg) lutein + zeaxanthin (μg) vitamin E, α-tocopherol (mg) vitamin K, phylloquinone (μg)

58.80 0.02 0.02 0.39 0.13 0.05 24.00 5.70 1.00 26.00 0.29 2.20

Amount in 100 g of strawberry.

Figure 1. Chemical structures of the major polyphenolic compounds present in strawberries.

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shape, and firmness of the fruit, as well as its taste and aroma in different berry species. Only recently, strawberry nutritional value has been seriously studied and also requested as an added value by consumers, stimulating researchers to implement new breeding and biotechnological programs: for example, the increase of antioxidant compounds in commercial strawberries using wild germplasm as genetic material is a valid alternative to provide greater intake of healthy compounds even with a lower fruit consumption.18,19 In this regard, only a few groups have demonstrated the correlation between the antioxidant and phenolic contents related to different genotypes, as well as the contribution of wild species to the bioactive compound contents in new genotypes.20−22 These studies stressed the great importance of genetic background on antioxidant and chemical profiles of the strawberry. In fact, total antioxidant capacity and all classes of compounds tested, such as total phenols, flavonoids, anthocyanins, vitamin C, and folates, were significantly different according to their different genotypes. An online postcolumn antioxidant detection system adopted to evaluate the individual tribute of strawberry compounds to the total antioxidant capacity of the fruits also highlighted that vitamin C usually contributed >30% to the total antioxidant capacity in any cultivars and selections, whereas pelargonidin-3glucoside contributed to the antioxidant capacity approximately 25% to nearly 40% of the eluting compounds depending on the cultivars tested.20 Moreover, one of the advanced selections of the Marche Polytechnic University strawberry breeding program, obtained from a cross between a wild and cultivated species, was demonstrated as the most important genotype because of the highest total antioxidant capacity and total phenolic content, confirming once again the important role of the genetic background.

Table 2. Concentrations of the Main Phenolic Compounds in Strawberries (Data Obtained from Aaby et al.15) group

compound

concentration (mg/100 g FW)

anthocyanins

cyanidin-3-glucoside pelargonidin-3-glucoside pelargonidin-3-rutinoside cyanidin-3-malonylglucoside pelargonidin-3-malonylglucoside

1.10 25.30 1.10 0.40 6.00

flavonols

quercetin glycosides kaempferol glycosides

1.81 0.84

flavan-3-ols

(+)-catechin proanthocyanidins procyanidin dimers procyanidin trimers

4.50 9.10 7.90

ellagitannins

agrimoniin ellagic acid

8.80 0.52

ellagic acid glycosides

ellagic acid penthoside, ellagic acid deoxyhexoside, methylellagic acid deoxyhexoside

0.58

cinnamic acid conjugates

coumaroyl hexoses cinnamoyl glucose

5.40 5.00

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BIOAVAILABILITY AND METABOLISM OF PHENOLIC COMPOUNDS In recent years it has become extremely important to comprehend the absorption, metabolism, and excretion of phenols after dietary intake, as proof of the possible diseasepreventing and health-promoting effects of strawberry phenolic phytochemicals continues to pile up. In general, most dietary phenols are assimilated in the intestine: indeed, after ingestion, flavonoids, in the form of glycoside conjugates, reach the brush border of the small intestine epithelial cells where they are hydrolyzed by lactase phloridizin hydrolase, leading to the release of aglycone, which is then enabled to pass into the same cells by passive diffusion as a result of its increased lipophilicity.9,10,23,24 Another way by which glucoside conjugates are hydrolyzed is represented by a cytosolic β-glucosidase within the epithelial cells, after transportation of polar glucoside into the epithelial cells: it has been suggested that this can occur probably thanks to the active Nadependent GLUT-1.9,10,23,24 Aglycones resulting from this type of hydrolysis can suffer two different fates: (i) they can return into the lumen of the small intestine, possibly with the involvement of members of the ATP-binding family of transporters, or (ii) they can be processed in glucuronide, methylated metabolites, and/or sulfate, through the corresponding action of UDP-glucuronosyltransferases, catechol-Omethyltransferases, and sulfotransferases, and pass into the bloodstream.9,10,23,24 They then quickly approach the liver: here, they can undergo phase II metabolism and pass to the systemic circulation; they can also move back to the small intestine thanks to bile excretion.

Figure 2. The most common phenolic compounds identified in strawberries. Data obtained from Aaby et al.15

important phenolic compounds present in strawberries and that the pelargonidin and cyanidin derivates are the most representative ones.2,9,10,16 They have different properties (e.g., photoprotective, antioxidant, anti-inflammatory, anticarcinogenic, antimutagenic) and can also modulate enzymatic pathways; this is the way some of them may act in the prevention of oxidative stress-related diseases. Moreover, the daily intake of anthocyanins is very consistent and considered the most consumed group of phenolic compounds in the human diet: it has been estimated that the daily intake may reach 12.5 mg/day in the United States.17 Nowadays, it is known that fruit nutritional composition varies very considerably as a consequence of different pre- and postharvest factors, with the genetic background playing a major role in determining strawberry nutritional traits. For these reasons, breeding and biotechnological programs have focused their attention on ameliorating the productivity, aspect, C



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All flavonoids that are not taken up in the small intestine pass into the colon and are processed by colonic microflora, which halve conjugating fractions; the resultant aglycones are transformed into phenolic acids and hydroxycinnamates that sometimes are assimilated, reaching the hepatic tissue; in the liver they can undergo phase II metabolism before being excreted in urine.9,10,23,24 Anthocyanins. Results from the few presently known investigations concerning anthocyanin bioavailability in humans demonstrate that these compounds are very exiguously absorbed: usually about 0.1% of the eaten amounts, or even less, has been found in urine within 24 h of consumption; lower concentrations have been detected in plasma.9,10,23,24 The characteristics of both the anthocyanidin structure and the sugar moiety influence the limited absorption and excretion of anthocyanins. Indeed, anthocyanins do not seem to suffer wide metabolism to glucuronide derivates, unlike what happens to other flavonoids. In the stomach, the acid pH maintains anthocyanins in the stable flavylium cation form, so that a limited quantity can be quickly assimilated from the stomach after intake, through a mechanism which could implicate bilitranslocase.9,10,23,24 The other part of anthocyanins reaches the small intestine, where they are converted into some neutral pH forms of anthocyanins: hemiketals, chalcones, and quinonoids. Such compounds appear to be just partially assimilated in the jejunum and undergo wide conjugation reactions, mostly in the liver but also in the kidney and in the intestine. Indeed, consistent quantities of ingested anthocyanins avoid absorption in the upper small intestine and pass into the colon, where they are exposed to a microbiota able to largely modify their molecular entity, breaking glycosidic linkages and heterocycle; colonic bacteria further convert the aglycones resulting from this process into smaller phenolic acids, such as protocatechuic acid for cyanidin-based anthocyanins or 4hydroxybenzoic acid for pelargonidin-based anthocyanins.9,10,23,24 Ellagitannins. In the past decade, only a few studies have focused on the pharmacokinetics of dietary ellagitannins, especially after a single dose intake of red and black raspberries, walnuts, and pomegranate juice.9,10,23,24 A complex picture emerged showing that ellagitannins are absorbed in the jejunum, where they are hydrolyzed to ellagic acid thanks to the neutral pH environment. Ellagic acid appears to be moved across the enterocyte apical membrane and rapidly transformed into methyl or dimethyl conjugated by catechol o-methyl transferase and presumably glucuronidated by UDP-glucuronosyltransferases. Afterward, ellagic acid metabolites undergo hepatic phase II biotransformations, producing a puzzling group of conjugated forms characterized by fast kinetics of plasma appearance and urinary excretion once they have entered the systemic circulation.9,10,23,24 In any case, within the intestinal lumen, most ellagitannins are subjected to microbiota transformation, resulting in the production of derivatives commonly known as urolithins (urolithins A−D). These metabolites are preferentially absorbed as their lipophilicity increases and, in the enterocyte and hepatocyte, further undergo phase II biotransformations, giving a combination of urolithin metabolites. For example, urolithin A 3-O-glucuronide and urolithin B 3-O-glucuronide are the major components found in plasma, whereas urolithin A and C glucuronides are present in urine.9,10,23,24 Finally, it should be taken into account that the different colonic microbiota of different subjects are responsible for the

consistent interindividual variability in the in vivo production of these metabolites, which makes the ellagitannin metabolism even more complex to explain.23,24 Proanthocyanidins. Results obtained in the few presently known investigations on the bioavailability of proanthocyanidins in the polymeric forms demonstrate that they are not absorbed to any degree.23,24 Indeed, when they reach the large intestine unaltered, they are usually processed by colonic microbiota, leading to the production of an extensive range of phenolic acids such as 3-(3-hydroxyphenyl)propionic acid and 4-O-methylgallic acid; these metabolites pass into the circulatory system and are eliminated through the urine.23,24 Only two investigations have found low levels of proanthocyanidin dimers in human plasma,23,24 suggesting that polymerization greatly impairs intestinal absorption. According to this evidence, it is thought that the biological effects of proanthocyanidins are usually ascribed not to their direct action but to the activity of their metabolites, even though there is still little detailed information regarding this issue.

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STRAWBERRY EFFECTS ON HUMAN HEALTH Overcoming the Gap between in Vitro and in Vivo Studies. As known, polyphenols are among the most important and best known bioactive compounds present in fruits, especially berries. In the past few years, several investigations have been carried out to delineate the biological activity that these compounds exert in the maintenance of wellbeing and in the prevention of a huge variety of chronic pathologies (Table 3). Although berries are one of the most antioxidant-rich foods, and although the potential efficacy of polyphenols is currently receiving ample attention, most of the literature data are still obtained from in vitro studies. In this regard, one of the most interesting research areas focuses on the in vitro effects of polyphenols in skin well-being. Skin is always open to a diversity of chemical, genotoxic, and environmental agents that contribute to aging, disease, and carcinogenesis. A wide array of polyphenols from different dietary sources possess substantial skin protective effects, which has raised increasing interest in their systemic and topical applications for skin protection. Much of this interest concerns the antioxidant properties of polyphenols. A recent paper analyzed the in vitro protective capacity of an anthocyanin-rich strawberry extract on human dermal fibroblasts exposed to UVA radiation.2 UV-A radiation penetrates the dermis, causing oxidative damage by generating reactive oxygen species (ROS). In this study, incubation for 24 h with 0.5 mg/mL strawberry extracts led to photoprotective activity in human dermal fibroblasts subjected to UV-A radiation, with an increase in cellular viability and a decrease in DNA damage in a doseresponsive manner when compared to control cells. Yin et al.3 obtained similar results: they found that 1 mg of quercitrin, a glycosylated form of quercitin, in mouse epidermal cells decreased ROS generation induced by UV-B irradiation and restored catalase expression and glutathione/glutathione disulfide ratio, leading to a reduction of oxidative DNA damage and apoptosis and to protection of the skin from inflammation. Likewise, another recent study4 assessed the inhibitory effects of two powerful plant-based phenolic antioxidants (i.e., ferulic and caffeic acids) at different concentrations of 3.75, 7.5, 15, and 30 μM, on UV-A-induced cytotoxicity in human keratinocyte cells, evaluating the recovery of the antioxidant defense system. Results showed that ferulic and caffeic acids upregulated activities and mRNA expression of catalase and D



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polyphenols,5 quercetin,6 and resveratrol7 have shown an antiinflamatory effect associated with the control of signal transduction, with the reduced expression of pro-inflammatory proteins (i.e., COX-2), inducible tumor necrosis factor-α (TNF-α), and nitric oxide synthase. These findings indicate that polyphenols may have protective effects on dermal cells in vitro, suggesting that these compounds could be helpful in protecting human dermal cells against several of the toxic agents to which the skin is frequently exposed. Nevertheless, in vitro studies are often carried out in experimental conditions not comparable with the in vivo situation. Thus, it should be mandatory to endorse the potential health-promoting results of strawberry in vivo studies, especially in human studies. With these critical points taken into account, in recent years several studies have been carried out in vivo, in both physiological and pathological conditions, selecting strawberry varieties particularly rich in phytochemical compounds, mainly anthocyanins. For instance, in the feeding trial on rats we are currently carrying out in our laboratory, we are evaluating the possible role of strawberries in ameliorating the aging process.25 In general, after 2 months of 15% strawberry consumption, a reduction of physiological oxidative damage has been observed at tissue, cellular, and subcellular levels as well as an enhancement in antioxidant biomarkers and an amelioration of lipid profile. A strawberry-enriched diet has also determined the reduction of oxidative stress in liver mitochondria, improving the animals’ functionality and respiratory performance. These results agree with a recent feeding trial on old rats,26 which demonstrated that the intake of polyphenols (75 mg/kg body weight) resulted in a decrease of ROS production, an enhancement of antioxidant defense, and the prevention of age-related mitochondrial respiratory impairment. Similarly, Laurent et al.27 found that moderate oral supplementation of a red grape polyphenol extract improved the general antioxidant status of aged rats, increasing the biogenesis of mitochondria and decreasing age-dependent autophagy in gastrocnemius of the old animals. Interestingly, we obtained the same results when oxidative stress was induced by doxorubicin administration, a very toxic drug that alters DNA and produces free radicals at a very high rate. In particular, in the rat, strawberry supplementation seems to be able to give protection against oxidative injury induced by doxorubicin in plasma, lymphocytes, or liver at tissue, cellular, and subcellular levels. Our findings agree with the data obtained by Choi et al.,28 who demonstrated that dietary supplementation with anthocyanin-rich bilberry extract (500 mg/kg body weight) was effective in reducing doxorubicin-induced oxidative damage and in improving antioxidant defense as well as in restoring hemoglobin levels and bone marrow cell and red blood cell counts, in both rats and mice. Again, another recent study29 on rats showed that diet supplementation with grain rich in phenolic acids led to a decrease of oxidative status and of doxorubicin-induced liver inflammation and to a concomitant enhancement in antioxidant enzyme activities. These results confirm the possible health benefit of bioactive compounds in vivo against oxidative stress, also in physiological conditions characterized by a higher level of oxidative stress produced by aging or in pathological situations caused by the administration of oxidant agents. Other in vivo studies16,30 have recently shown that polyphenols may have a preventive function counteracting the progress of gastric ulcerations, erosions, and cancer. That is why an in vivo trial16 on rats was carried out to examine the

Table 3. Effects of Dietary Polyphenols effects UV

refs

in vivo decrease of intracellular ROS concentration increase of antioxidant enzyme activities

3, 5

increase of cell viability reduction of DNA damage decrease of intracellular ROS concentration increase of antioxidant enzyme activities reduction of proinflammatory proteins reduction of TNF-α

2 2 3, 4

increase of antioxidant defense reduction of oxidative stress increase of mitochondrial respiratory performance decrease of age-related autophagy

25, 26 25, 26 25, 27

reduction of ulcer index decrease of gastric lipid peroxidation increase of antioxidant defense reduction of suppression of MMP-2 activity inhibition of phosphorylation of mitogen-activated protein kinases

16 16, 29, 30 16, 29, 30 30

decrease of gastric lipid peroxidation increase of antioxidant defense reduction of suppression of MMP-2 activity inhibition of phosphorylation of mitogen-activated protein kinases

30 30 30, 31

reduction of inflammation inhibition of platelet aggregation improvement of endothelial function improvement of plasma lipid profile increase of LDL resistance to oxidation increase in plasma antioxidant capacity reduction of myocardial infarction risk

33, 36, 33, 37, 35, 37, 33, 41, 37, 38, 32−34 33, 37,

demethylation of tumor suppressor genes induction of cell cycle arrest and apoptosis suppression of suppressing tumor

45, 46, 49

3, 5

in vitro

aging

gastric pathological conditions

3, 4 6, 7 6, 7

in vivo

27

in vivo

30

in vitro

cardiovascular disease

cancer

30, 31

in vivo 43 38 38 42 42 38

in vitro

45, 47, 48 46

glutathione peroxidase as well as γ-glutamate cysteine ligase mRNA and glutathione concentrations in irradiated cells. However, many other recent studies5−7 have shown new insights in the molecular mechanisms responsible for the healthful effects of polyphenols in skin application, beyond the antioxidant capacity. According to these findings, the potency of polyphenols to protect skin against harmful agents could be due to their capacity of altering signal transduction and epigenetic regulation of gene expression. For instance, green tea E



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Figure 3. Mechanisms proposed for strawberry polyphenol modulation on normal and cancer cells. Abbreviations: Nrf2, nuclear factor-erythroid 2related factor 2; PPARs, peroxisome proliferator-activated receptors; AMPK, 5′-adenosine monophosphate-activated protein kinase; Sirt1, sirtuin 1; ROS, reactive oxygen species; ATP, adenosine triphosphate.

status in young and middle-aged subjects. In young healthy volunteers, total antioxidant capacity and vitamin C concentration in serum were significantly enhanced after the consumption of 300 g of strawberries (fresh fruit).32 A concomitant decrease in oxidative biomarkers both in urine and in plasma was found after the consumption of 500 g of strawberries for 1 month.33,34 Either oxidant-untreated or treated erythrocytes displayed improved protection to hemolysis as well as a highly reduced percentage of mortality and an increased proportion of metabolic activity in ex vivo mononuclear cells treated with H2O2 after consumption of 500 g of strawberries for 2 weeks.35 Among the mechanisms of action implicated in the antioxidant effects of strawberry consumption, a reduction in DNA oxidative damage and an improvement of DNA repair capacity could be involved. Nowadays, it is generally accepted that obesity and oxidative stress may be present at younger ages and persistent exposure to systemic inflammation could result in the onset and development of cardiovascular disease (CVD). Evidence suggests that the addition of polyphenol-rich foods in the diet may improve CVD risk factors, inhibiting inflammation and platelet aggregation and ameliorating endothelial function, plasma lipid profile, and free radical scavenging, thus increasing LDL resistance to oxidation. In overweight and obese children,36 a short-term blueberry consumption, consisting of the weekly intake of 375 g of fresh blueberries during 8 weeks, resulted in enhanced antioxidant capacity of plasma and in a concomitant reduction of inflammation and oxidative stress markers, whereas in dyslipidemic subjects anthocyanin consumption37 (about 160 mg twice daily for 12 weeks) was found to increase HDL-cholesterol concentrations and to decrease LDL-cholesterol concentrations and cholesteryl ester

strawberry protective and antioxidant effects toward ethanolinduced gastric mucosa damage. Strawberry consumption (40 mg/day/kg body weight) was able to protect against the deleterious role of ethanol, to significantly increase antioxidant enzyme activities, and to diminish, at the same time, gastric lipid peroxidation. Also, the percent of inhibition of ulcer index significantly correlated with total anthocyanin content. These results agree with those obtained in a recent study in rats,30 where the administration of different concentrations of anthocyanins (5, 25, or 50 mg/kg body weight) from black rice bran was shown to significantly protect against gastric ulcer induced by a nonsteroidal anti-inflammatory drug, decreasing ROS levels and inhibiting lipid peroxidation, enhancing the antioxidant enzymes activities and attenuating the suppression of matrix metalloproteinase-2 (MMP-2) activity. Similarly, in another study31 supplementation of different anthocyanin amounts (12.5, 25, 50, 100, or 200 μg/mL) exerted an antiinflammatory effect in gastric epithelial cells infected by Helicobacter pylori, decreasing ROS concentration and inhibiting the phosphorylation of mitogen-activated protein kinases as well as the translocation of nuclear factor-κB. On the basis of this evidence, the potential of polyphenols could be taken into account for preventing/treating chronic subacute gastric lesions. The intake of a diet rich in bioactive compounds could prevent and/or ameliorate pathological states of the stomach as well as attenuate gastric mucosal damage, thereafter curing or diminishing ulcer formation, side effects of subacute chronic alcohol intake, nonsteroid anti-inflammatory-related gastritis, or H. pylori treatment. The most significant outcomes of polyphenol supplementation in human studies32−37 have addressed the possible variations in both cellular and plasma markers of antioxidant F



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also confirmed that a protracted consumption of strawberries is associated with a general improvement of the serum lipid profile in young subjects, through a reduction of total cholesterol, LDL-C, and triglyceride levels.33 To summarize, polyphenols have different biological effects on metabolically active tissues, affecting insulin sensitivity, inflammation, lipid metabolism, and obesity, which could be switched on by PPAR activation, through Nrf2, reducing different phenotypic risk factors connected with the risk for type 2 diabetes and metabolic syndrome. Finally, another possible mechanism to explain all of these polyphenol effects on health is the activation of the AMPk/ SIRT1 (5′-adenosine monophosphate-activated protein kinase/ sirtuin 1) signaling cascade that can lead to an increase in cellular metabolism, mitochondrial biogenesis and functionality, and antioxidant defense and to a concomitant decrease of ROS levels and inflammation. However, this is a new area of study that has begun to be investigated for elucidating the mechanisms and strawberry compounds implicated in these responses. Effects beyond Antioxidant Capacity: 2. Possible Role in Cancer Prevention and Treatment. The fact that polyphenols extend their properties beyond antioxidation up to cell signaling modulation gives an interesting insight into their potential anticancer properties. In the past few years, polyphenol antioxidant capacity has been taken into account as one of the outstanding mechanisms of action in inhibiting mutagenesis and cancer initiation, by means of their capacity to scavenge ROS, activate antioxidant enzymes, prevent carcinogen-induced DNA adduct formation, enhance DNA repair, and reduce overall oxidative DNA injury44 (Figure 3). Whereas antioxidation certainly has a pivotal function in polyphenols’ anticancer effectiveness, several recent investigations have also supported their function as modulators of cellular processes connected with cancer growth: in vitro and in vivo evidence indicates in fact that phenolics may modulate cell signaling in the cancer cell by inhibiting proliferation of these cells through the demethylation of tumor suppressor genes,45 inducing cell cycle arrest and apoptosis45 and suppressing tumor angiogenesis.46 A recent study47 on PC-3 prostate cancer cells revealed that polyphenol-rich tea extracts at different concentrations (0.4, 0.8, 1.2, 1.6, or 2.0 mg/mL) inhibited cell proliferation, induced apoptosis, and provoked reduction of the mitochondrial membrane potential and ATP level decrease, whereas resveratrol metabolites (at 10, 20, and 30 μM) were reported to inhibit colon cancer cell growth and cause an accrual of cells in the S phase, inducing DNA damage and the apoptotic process.48 Similarly, Link et al.49 found that curcumin (7.5−10 μM) exerted chemopreventive effects, inducing DNA methylation at selected loci, rather than fully methylated sites in colorectal cancer cells, and that DNA methylation changes were obtained through analogous modifications in gene expression at either up- or down-regulated genes. Unfortunately, investigations devoted to the mechanisms underlying the anticancer efficacy of berry polyphenols are still limited. Recently, Wang et al.45 reported that different concentrations of anthocyanins present in black raspberries canceled activity as well as protein expression of DNA methyltransferase enzymes, demethylated promoters of CDKN2A, and SFRP2, SFRP5, and WIF1 by inhibiting cell proliferation and inducing apoptosis in colorectal cancers. We are presently assaying the in vitro effects of strawberry polyphenols on a murine mammary cancer cell line N201/1A that expresses high levels of human epidermal growth

transfer protein activity in plasma. Similarly, Cassidy et al.38demonstrated that, in young or middle-aged women, a reduced risk for myocardial infarction was associated with elevated anthocyanin intake. Another study33 showed that the daily consumption of 500 g of strawberries for 1 month in young healthy volunteers was associated with a general improvement of the serum lipid profile of the subjects, through a reduction of total cholesterol, LDL-C, and triglyceride levels, indicating that some of the constituents of the fruit, such as vitamin C and anthocyanins, may favorably affect the plasma lipid profile. In this study, the intent was also to determine platelet basal activation in healthy subjects after strawberry consumption, as a preventive factor against CVD through a diet rich in antioxidants. Although the majority of platelets remained in the resting state after treatment, as expected, a significant decrease was found in the number of activated platelets during the strawberry supplementation period compared to baseline values, indicating a favorable effect of strawberry treatment on platelet function. Therefore, according to the data obtained in these studies, polyphenols seem to exert in vivo effects in the prevention of CVD risk, explaining in part the protective role of a diet abundant in vegetables and fruits in preventing CVD and other chronic diseases mediated by oxidative stress. Effects beyond Antioxidant Capacity: 1. Possible Role in Chronic Metabolic Disorders. All of the beneficial effects that polyphenols exert in vivo on human health may not depend only on direct antioxidant properties. In fact, polyphenols are processed by the body as xenobiotics, stimulating the stress-related cell signaling pathways, which results in an increased expression of cytoprotective genes (Figure 3). Recently, it was found that polyphenols might increase gene transcription of nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor that binds to the antioxidant response element (ARE) and regulates enzymes involved in antioxidant functions or detoxification.39 In this way, polyphenols may give antioxidant protection in an indirect way with the activation endogenous defense systems, mainly with the modulation of the expression of some antioxidant enzymes, and this fact may partly explain the increase in antioxidant enzymes found in in vivo studies. Another important mechanism that should be taken into account besides the antioxidant capacity is the effect that polyphenols indirectly exert on peroxisome proliferatoractivated receptors (PPARs), through Nrf2 activation.40 PPARs are transcriptional factors that manage insulin sensitivity, glucose homeostasis, fatty acid oxidation, and lipid metabolism in general, so that their agonists are employed for treating metabolic syndrome, cardiovascular diseases, and hyperlipidemia. In this regard, a polyphenol-rich fraction from amla fruit (Emblica officinalis Gaertn.) in concentrations of 40 or 10 mg/kg body weight per day for 100 days was reported to improve age-related hypertriglyceridemia in young and old rats by stimulating liver PPARα expression,41 whereas 1% of phenols and anthocyanins from cherries was found to decrease, in rat, hyperinsulinemia fasting blood glucose, hyperlipidemia, and fatty liver by enhancing hepatic PPARα mRNA and hepatic PPAR-α target acyl-CoA oxidase mRNA activity.42 Similarly, the daily consumption of chokeberries (100 and 200 mg/kg body weight) led to a decrease in glycemia, cholesterol, LDLcholesterol, triglycerides, and epididymal fat as well as to a reduction in plasma TNF-α and interleukin-6 levels and an upregulation of the gene expression of PPARγ mRNA levels.43 We G



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ABBREVIATIONS USED Nrf2, nuclear factor-erythroid 2-related factor 2; AMPK, 5′adenosine monophosphate-activated protein kinase; Sirt1, sirtuin1; CVD, cardiovascolar disease; MMP, matrix metalloproteinase; TNF-α, tumor necrosis factor-α; ARE, antioxidant response element; PPARs, peroxisome proliferator-activated receptors

factor receptor 2 (HER-2) oncoprotein. HER2 expression in breast cancer has usually been considered an interesting therapeutic goal because it is frequently linked to an aggressive phenotype and poor prognosis. We have found that after strawberry treatment (corresponding to 2.5 μg of anthocyanins/mL), tumor cells that express the oncogene show higher levels of apoptosis at lower extract concentrations compared to tumor cells without the oncogene. This may mean that the N202/1A cells are more sensitive at lower extract concentrations, as demonstrated by the high apoptosis rate. Furthermore, strawberry treatment results in an increase in intracellular ROS and in an impairment of glycolysis and mitochondrial functionality in cells that express the oncogene compared to cells without the oncogene. Probably, there is a mechanism linked to the apoptotic pathway and cellular metabolism through the strawberry extract that can affect tumor cell viability, especially of the N202/1A cell line, which overexpresses the HER-2/neuoncogene. We obtained similar results also in an in vivo trial, on transgenic mice expressing the HER-2/neu oncogene (line FVB/N 233 neu-NT), supplemented for 4 months with 15% strawberries. A reduction of the number and size of metastases, as well as their propagation in the lung, was observed in animals fed strawberries compared to the control group. These findings lead to the conclusion that polyphenols, when investigated for their antitumoral effects, target distinct signaling mechanisms, therefore emphasizing the urgency of additional research to highlight the pathways involved in the anticancer effects of strawberries and to characterize the bioactive compounds that may play a fundamental role against cancer. In conclusion, strawberry fruits possess a remarkable nutritional composition due to their high content of micronutrients such as folates, minerals, and vitamins, and are also a rich source of phenolic constituents. Currently, evidence on the biological activity of polyphenolic compounds is growing. Many mechanisms have been proposed to explain how polyphenols exert their biological protective effects, which, for several years, have been often ascribed mainly to their antioxidant capacity. However, this view is now challenged by recent findings, and more complex actions are being investigated. Recent findings have demonstrated that, besides antioxidant and anti-inflammatory capacities, phenolics may engage with cellular signaling flow, controlling the action of transcription factors and subsequently affecting the expression of those genes involved in cellular metabolism and cellular survival. Further in vivo investigations are required to translate the evidence obtained in vitro into actual outcomes in vivo and to understand the factors and mechanisms regulating the bioefficacy of strawberry phytochemicals.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*(M.B.) Phone: +39 071 2204646. Fax: +39 071 2204123. Email: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are indebted to M. Glebocki for extensive editing of the manuscript. H



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Strawberry and Human Health: Effects beyond Antioxidant Activity

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