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1 Introduction

Generally, fruits and vegetables contain high levels of compounds and nutrients that may have beneficial effects on human health. For example, fruits and vegetables contain high levels of polyphenols that exhibit high antioxidant properties. Though a direct correlation between the antioxidant properties of fruit polyphenolic compounds and inhibition of cancer cell growth has not been conclusively proven, evidence suggests high levels of dietary fruits could reduce the incidence of cancer. Thus, other mechanisms apart from antioxidant effects may be responsible for observed antitumor effects of fruits and vegetables. For example, the polyphenolic compounds could inhibit certain enzymes that promote cell proliferation or promote activities of enzymes that induce cell death. However, it should be noted that the exact mechanism for the anticancer effects of fruits and vegetable polyphenols is yet to be fully determined. The effects could be direct action on cellular metabolism or indirect through stimulation of the immune system.

Epidemiological studies have also shown that increased consumption of soluble fiber in fruits has an inverse relationship with blood pressure in postmenopausal women. Specifically, fruit fiber consumption is directly related to plasma level of 16α-hydroxyestrone, a metabolite of the hormone 17β-estradiol, which is known to decrease with menopause. 16α-hydroxyestrone is a potent antioxidant that can increase production of prostacyclin (a vasodilator) at twice the rate of 17β-estradiol, endothelial nitric oxide synthase gene expression, nitric oxide production, and proliferation of vascular endothelial cell.

The polyphenolic compounds in fruits and vegetables have also been associated with blood pressure reducing effects, which is believed to occur through inhibition of angiotensin converting enzyme (ACE), a principal causative factor for hypertension. Specifically, the flavanol ­epicatechin and related oligomeric compounds (procyanidins) have ACE-inhibitory properties, in vitro. Among the oligomers, the tetramer is the most potent in vitro ACE inhibitor, though bioavailability and real effect in vivo remains to be demonstrated.

The following sections will illustrate potential beneficial effects on human health that has been reported for specific fruits and vegetables.

2 Ellagic Acid

One of the most common plant polyphenols called ellagic acid (Fig. 6.1) has been studied for potential health benefits, especially in relation to anticancer properties. Ellagic acid is an abundant polyphenol found in various fruits such as strawberry, raspberry, black currants, and grapes.

Fig. 6.1
figure 1

Chemical structure of ellagic acid

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2.1 Ellagic Acid and Cancer

One of the most common plant polyphenols called ellagic acid has been shown to exhibit antiproliferative and antioxidant properties during in vitro and in vivo tests. The antiproliferative properties of ellagic acid are related to ability to inhibit binding of some carcinogens to DNA, which can prevent induction of carcinogenesis. Similar to other antioxidant polyphenolic compounds, ellagic acid can reduce oxidative stress in cell culture models through radical-scavenging activities to produce chemoprotective effects. However, ellagic acid has been shown to have antagonistic effects against catechins, when present together. The potential chemopreventive properties of ellagic acid have generated interest in its use for modulating human health. Using a randomized controlled trial that involved 19 patients with carotid artery stenosis, it was found that pomegranate juice, which is high in ellagic acid, has potential benefits because of the observed reductions in blood pressure and carotid artery wall thickness. In prostate cancer patients undergoing chemotherapy, the use of ellagic acid supplementation reduced the rate of chemotherapy-associated loss of white blood cells, though there was no improvement in overall or progression-free survival of patients with prostate cancer. In male hamsters with 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) tumors, addition of ellagic acid to the diet led to significant suppression of the carcinoma. In fact, at 0.4% inclusion of ellagic acid in the diet, the rate of tumor incidence was zero, though there was a slight incidence of hyperplasia. The mechanism of action involved attenuation of the Wnt/β-catenin pathway by ellagic acid. The Wnt signaling pathway is a network of proteins that play important roles in pathogenesis by promoting embryogenesis and carcinogenesis. β-Catenin is a subunit of the cadherin protein complex and is an integral component of the Wnt signaling pathway. β-Catenin functions as part of the protein complex that constitute adherens junctions, which are required for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. β-Catenin is also important for transmitting the contact inhibition signal that stops cell division when the epithelial sheet formation is complete. Therefore, suppression of the Wnt signaling pathway can be used to suppress carcinogenesis and prevent progression and intensity of tumor pathology. Within the Wnt signaling pathway, expressions of Fz, Dvl-2, and GSK-3β were significantly high in DMBA-treated hamsters but were attenuated when ellagic acid was present in the diet. The nuclear expression of β-catenin was suppressed but that of cytosol was enhanced with ellagic acid supplementation. But nuclear translocation of the cytosolic β-catenin, which is required for activation of downstream target genes and signaling cascades, was attenuated because the required GSK-3β was present in low levels during ellagic acid supplementation. It should be noted that the Wnt signaling pathway is normally activated by binding of Wnt ligands to frizzled receptors (Fz), recruitment of cytoplasmic phosphoprotein disheveled (Dvl), and disruption of glycogen synthase kinase 3β (GSK-3β)-containing multiprotein complex. Thus, ellagic acid suppressed Wnt signaling pathway activation through attenuated expressions of Fz, Dvl-2, and GSK-3β. The DMBA-treated hamsters also showed increased expression of nuclear factor kappa B (NF-κB), which was suppressed when ellagic acid was present in the diet. The increased expression of NF-κB was due to the downregulated activity of inhibitory kappa B (IκB); IκB expression was increased by ellagic acid to prevent NF-κB activation. Ellagic acid supplementation increased the level of cellular apoptosis through upregulation of the expression levels of proapoptotic molecules like caspase 3 and 9. Moreover, attenuation of the Wnt and NF-κB pathways is known to enhance apoptotic cell death. Overall, it is evident that ellagic acid supplementation blocks or interrupts the functional cross talk between Wnt and NF-κB signaling pathways in HBP carcinomas, which leads to apoptotic cell death and prevention of carcinogenesis. Therefore, increased consumption of fruits and vegetables with high contents of ellagic acid may be beneficial for cancer prevention. Moreover, ellagic acid could be regarded as a potential compound for the formulation of anticancer foods and nutraceuticals.

2.2 Ellagic Acid and Cardiovascular Health

Ellagic acid has also been shown to have potential ameliorative effects on cardiac damage as evident by the protection of cardiomyocytes during drug-induced myocardial necrosis. Rats that did not receive ellagic acid showed neutrophil-infiltrated necrotic cardiac muscle fibers, whereas ellagic acid-pretreated rats had reduced myocardial necrosis with less edema and reduced neutrophil infiltration. In fact, hearts from the ellagic acid-pretreated rats had less edema and infarction with an almost normal myocardial architecture. The undesirable drop in blood pressure that accompanies myocardial infarction was significantly attenuated by ellagic acid treatment, with values that were very similar to normal rats. Oral administration of ellagic acid also significantly reduced oxidative stress markers such as C-reactive protein, plasma homocysteine, and lipid peroxides that are associated with myocardial infarction. Thus, ellagic acid has both antioxidant and anti-inflammatory properties. In contrast, cardiac levels of antioxidant enzymes such as superoxide dismutase and catalase as well as level of plasma antioxidant molecules such as α-tocopherol and vitamin C were significantly enhanced by ellagic acid treatment. In addition, the severity of heart damage as measured by leakage of cardiac enzymes such as ­troponin-I, creatine kinase, and lactate dehydrogenase was significantly attenuated by treatment of the rats with ellagic acid prior to induction of myocardial infarction. Also important is the ability of ellagic acid to protect cardiomyocyte mitochondria during myocardial necrosis. The cardiomyocyte has a very high energy demand that is dependent on ATP from mitochondria oxidative phosphorylation; therefore, mitochondria damage could have significant negative effects on beat-by-beat contraction and relaxation of cardiac muscles. In addition to the antioxidant effects (increased antioxidant enzymes and reduced lipid peroxidation), ellagic acid pretreatment (7.5 and 15 mg/kg body weight) of rats led to increased activities of tricarboxylic acid enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and α-keto glutarate dehydrogenase), which enhanced ATP formation when compared to the control rats that received no ellagic acid. The mitochondria of myocardial-infracted control rats contained high levels of cholesterol, free fatty acid, and triglycerides, all of which were significantly reduced as a result of pretreatment with ellagic acid prior to induction of myocardial infarction. High level of cholesterol in particular is undesirable in the mitochondria as it affects membrane fluidity and permeability to ions. During myocardial infarction, there is elevated level of mitochondria Ca2+, which stimulates excessive production of reactive oxygen species and ultimately cell death. Rats that were provided oral administration of ellagic acid prior to induction of myocardial infarction had significantly reduced levels of Ca2+ in the cardiomyocyte mitochondria probably due to modulation of ion pumps. It is estimated that dietary consumption about 1.05 g of ellagic acid per day in the form of ellagic acid-rich fruits and vegetables (strawberries, raspberry, pomegranates, etc.) may be enough to produce these protective antioxidant and ATP-generating effects as seen during ellagic acid treatment of myocardial infarction.

3 Raspberries

The aqueous extract of red raspberries was obtained from a homogenate of the fruits that has been passed through a 0.2-μm filter. Antioxidant and anticancer effects of the filtered raspberry fruit extract was tested using stomach, colon, pancreatic, and breast cancer cell lines as well as other in vitro assays. All the cell lines showed susceptibility to berry extract-induced death, but the colon and stomach cancer cells were more susceptible than the breast cancer cells. Though all the cell lines were susceptible to vitamin C-induced cell death, the breast cancer cells were the most susceptible to this compound. It was evident that the antioxidant properties of vitamin C played a very strong role in the susceptibility of breast cancer and pancreatic cancer cells to berry extract-induced cell death. Though apoptotic death was not observed, cells that were treated with berry extract showed condensation of nucleus materials (chromatin) in addition to disorganization of the cytoskeletal structure. Thus, the berry extract had negative effects on cellular organization, which may have led to the observed cell death. It has been suggested that autophagy (catabolic degradation of cellular components) may play a role in the berry extract-induced death of the cancer cells.

4 Cherries

These are fruits of the Prunus genus within the Rosaceae family and typical examples include sweet cherry (P. avium) and tart cherry (P. cerasus). The fruits are rich in nutrients such as vitamin C, carotenoids, various polyphenolic compounds (especially anthocyanins), and fiber. Anthocyanins are glycosides of anthocyanidins and are compounds responsible for the red-purple color of sweet cherries. Some of the health benefits associated with cherry consumptions are described as follows.

4.1 Cardiovascular Effects

Most of the evidence for the health benefits of cherries has come from in vitro and animal studies. For example, an extract of tart cherry seed was found to improve regular heart beat and led to reduced cardiac damage in rat hearts that have been subjected to ischemic injury. Exposure of bovine artery cells to cyanidin-3-glycoside (an anthocyanin) from cherry led to increase production of nitric oxide (NO), the vasodilatory agent. In addition to the upregulation of NO, there was decreased inflammation and reduced foam cell formation, which lowers the risk for development of atherosclerosis. Cyanidin-3-glycoside also reduced the level of cholesterol in macrophages and associated foam cells, which is an indication of ability of this cherry glycoside to lower the risk of cardiovascular disease.

4.2 Anti-inflammatory Effects

It is a well-known fact that low-grade inflammation can enhance the potential for development of various chronic diseases such as obesity, arthritis, kidney malfunction, cardiovascular disease, diabetes, and cancer. One of the main demonstrated effects of cherry components is the inhibition of cyclooxygenases (COX), the enzymes responsible for inflammatory response. Cyanidin and malvidin have the greatest anti-inflammatory effects among the cherry nutrients. Cyanidin (Fig. 6.2) is particularly very effective as an anti-inflammatory agent, which is probably because the structure contains a hydroxyl group on the B-ring. The extra hydroxyl group provides additional electrons that can be used to scavenge free radicals in addition to stabilizing the polyphenolic ring through increased ability to form resonance structures. In fact, cherry anthocyanins can inhibit COX-1 as much as 60% of the inhibitory level demonstrated by medications such as ibuprofen and naproxen while inhibition of COX-2 is actually higher than those exhibited by these medications. Cherry extracts (40 mg/kg) reduced the level serum tumor necrosis factor alpha (TNFα) and prostaglandin E2 (PGE2) in mice arthritis model, suggesting the potential use in treatment of this inflammatory condition. And in a human intervention trial that fed 280 g of sweet cherries daily for 4 weeks to healthy adults, there were significant reductions in the level of serum C-reactive protein, suggesting reduced inflammatory status when compared to baseline condition. What was more interesting is the increase in serum C-reactive protein when the intervention with cherries was terminated, which indicates that substances in the fruit were responsible for the observed anti-inflammatory effects.

Fig. 6.2
figure 2

Typical chemical structure of cyanidins showing the A, B, and C skeletal ring arrangement

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4.3 Anticancer Effects

The anticancer effect of cherries is probably due to several nutrients such as fiber, ascorbic acid, carotenoids, and even the anthocyanins. While the levels of non-anthocyanin compounds are small and may be present in insufficient quantity within the fruit to produce anticancer effects, additive (synergistic) effects may contribute to increased potency against tumor development. However, the main anticancer compound in cherries is believed to be the anthocyanins and dark-red fruits will have higher levels than light-red fruits. Cherry diet, anthocyanins, and cyanidin have all been shown to reduce the number of cecal tumors but not colon tumors during mice feeding experiments, which suggest that the polyphenolic compounds may only be bioavailable in the cecum where it exerts antitumor properties. Antioxidant effects of cherry anthocyanins may also be a mechanism involved in the antitumor effects since cyanidin and the glycoside have shown protective effects on DNA cleavage when tested in cancer cell lines. Another mechanism proposed include evidence from cell culture, which showed that cherry anthocyanins induced apoptosis through arrest of the G2/M growth cycle. Cherry cyanidin also act as anticancer agent through increased radical-scavenging activity and inhibition of xanthine oxidase (enzyme that generates reactive oxygen species) activity. Other mechanisms include ability of cherry ­nutrients to inhibit epidermal growth factor (EGF), and specifically, cyanidin can promote cellular differentiation, which reduces the risk for formation of malignant cells. Inhibition of EGF is particularly important since presence of this protein enhances cellular differentiation, proliferation, and ultimately survival. Therefore, by inhibiting EGF (probably through protein-polyphenol complex formation), cherry anthocyanins and anthocyanidins can enhance apoptosis and limit survival of tumor cells.

4.4 Antidiabetic Effects

The role of cherries as antidiabetic agents is believed to be due primarily to the antioxidant properties, high fiber content, and blood glucose-reducing properties exhibited by the fruit nutrients. This is because diabetes and associated symptoms is related to poor glucose utilization in addition to oxidative stress. Therefore, antioxidant compounds in cherries such as anthocyanins and quercetin may be able to reduce the risk of diabetes onset as well ameliorate pathological symptoms that occur during disease progression. In addition to antioxidant role, the cherry anthocyanins and anthocyanidins have been shown to reduce insulin resistance and glucose intolerance. In animal model of hyperglycemia, addition of cherry anthocyanins to the feed led to reductions in blood glucose. Insulin production can be enhanced in response to various glucose loads by pretreatment with cherry anthocyanins and anthocyanidins, which facilitates reduction in blood glucose levels. Moreover, sweet cherries has a lower glycemic index (22) and is a better fruit snack for diabetic patients when compared to high glycemic index fruits such as peach (42), plum (39), grapes (46), and apricot (57).

5 Grape Seed

Grape seeds contain several polyphenolic components, especially the proanthocyanidins or condensed tannins that are considered to possess health-promoting properties. In vitro work has showed that the ethanolic extract of grape seed can inhibit activity of some lipid-metabolizing enzymes such as pancreatic lipase (PL), lipoprotein lipase (LPL), and hormone-sensitive lipase (HSL). PL is responsible for lipid digestion, specifically breakdown of dietary triglycerides into free fatty acids and 2-monoacyl glyceride, all of which contribute to increase weight of adipose tissue and indirectly, obesity. Inhibition of PL by grape seed extract (GSE) could limit gastrointestinal breakdown of dietary triglycerides, reduce fatty acid absorption (triglycerides are not absorbable) and may contribute to reduced adipose tissue weight. LPL hydrolyzes lipoproteins to release triglycerides, which are then stored in adipocytes; therefore, LPL activity also contributes to obesity development. GSE also showed high level of LPL inhibition, which may contribute to reduced availability of triglycerides and reduced adipocyte storage. HSL hydrolyzes adipocyte fats and releases free fatty acids (FFA) into the blood circulatory system; high levels of plasma FFA is believed to induce insulin resistance and development of metabolic syndrome. Therefore, the ability of GSE to inhibit HSL activity may be used as a means of reducing plasma FFA content and reduce the risk of developing metabolic syndrome. Despite these potential health benefits, animal and human trials are required to validate bioactive properties of grape seed polyphenolic compounds as agents for preventing obesity and metabolic syndrome.

The immunomodulatory potential of grape seed proanthocyanidins (GSP) have also been studied and shown to potentiate antitumor effects in mice inoculated with Sarcoma 180 cells. The GSP had no direct cytotoxic effect on the tumor cells, but the antitumor effect was potentiated through stimulation of humoral and cellular immune response. This was evidenced by the increased thymus and spleen weight in addition to enhanced lymphocyte transformation, lysosomal enzyme activity, phagocytic capability of peritoneal macrophages, and production of tumor necrosis factor alpha (TNF-α) in GSP-treated mice. The increased weight of the thymus and spleen is reflective of activated immune response, which suggests that GSP could enhance an animal’s immune system in order to attack and kill the tumor cells. High level of macrophage phagocytosis can promote tumor cell destruction while at the same time enhance production of TNF-α, a cytokine that can induce apoptotic tumor cell death.

6 Blueberries

The seeds of the Vaccinium plant are particularly very rich in phenolic compounds such as flavonoids, hydroxycinnamic acids, anthocyanins, and proanthocyanidins. The health benefits of blueberry consumption are associated mainly with the potent antioxidant properties of these polyphenolic constituents. For example, blueberry consumption is reported to protect against inflammation, improve cognitive functions, and attenuate disease progression of obesity/adiposity. Dietary supplementation of a high-fat mice diet with purified blueberry anthocyanins led to decreases in body and adipose tissue weights in addition to lower plasma levels of triglycerides, cholesterol, and leptin. There were also improvements in fasting blood glucose levels in addition to enhanced pancreatic β-cell function (insulin-producing cells found in the islets of Langerhans). The observed beneficial effects were not due to differences in food consumption as mice on blueberry and control diets had similar food intakes. But blueberry juice was not as effective as the purified anthocyanins except for the effect on reducing leptin levels. The lower efficacy of blueberry juice in reducing adiposity is probably due to attenuation of absorption of the bioactive anthocyanin molecules by other nutrients (sugars, polysaccharides, and lipids) present in the juice. In a separate experiment, freeze-dried whole blueberry powder did not reduce body or adipose tissue weight but improved insulin sensitivity and glucose homeostasis in mice. Mice that consumed the blueberry-supplemented diet had reduced adipocyte death, which was accompanied by downregulated gene expressions of TNF-α, IL-10, and CD11c (a surface marker for macrophages). This is significant because dead adipocytes cause an increase in the levels of proinflammatory cytokines such as MCP-1, TNF-α, and IL-10 due to the increased influx of macrophages. Thus, the blueberry extract was effective in reducing sensitivity and inflammation (attenuated cytokine levels plus decreased influx of macrophages to the adipose tissue) that is associated with obesity.

However, the antiobesity ability of the blueberry juice was substantially improved through biotransformation of the polyphenols with Serratia vaccinii, a bacteria present in the microflora of blueberry fruits. The biotransformed blueberry juice had increased phenolic content and antioxidant activities, but the negative effect on food intake may be responsible for the observed decreases in body weight gain, abdominal fat pads, and liver weight. Following chronic administration of the biotransformed juice to diabetic mice, there were reduced levels of plasma glucose and insulin levels, but adiponectin (an adipocytokine) level increased. The effect on adiponectin is significant because this cytokine have been shown to reverse insulin resistance in obese mice and can reduce muscle triglyceride levels through increased catabolism of free fatty acids. The biotransformed blueberry juice was also tested as an antioxidant agent for the protection of the nervous system and as potential therapeutic agent for the management of neurodegenerative diseases. The biotransformed juice significantly increased the activity of antioxidant enzymes (catalase and superoxide dismutase) and protected neurons against H2O2-induced cell death in a dose-dependent manner. The positive effects were associated with upregulation of mitogen-activated protein kinase (MAPK) family of enzymes such as p38 and c-Jun N-terminal kinase (JNK) as well as with the protection against H2O2-induced cell death through downregulation of extracellular signal-regulated kinase (ERK1/2) and MAPK/ERK kinase (MEK1/2) activities.

7 Strawberry

The health benefits of strawberry fruits have been associated with the very high contents of vitamin C, manganese, folate, and phenolic compounds, all of which contribute to improving oxidative status. The fruits also contain mostly the soluble form of dietary fiber, which can slow digestion and absorption of nutrients and enhance regulation of plasma blood sugar and insulin levels. The fiber in strawberry fruits can provide satiating and calorie-reduction effects, which contributes to reduced caloric intake. The seed oil is very high (∼72%) in polyunsaturated fatty acids that can provide health benefits associated with consumption of omega-3 fatty acids. While the contributions of strawberry to healthy lipid consumption may be low due to the fact that the lipids are present only in the seeds, regular intake of the fruit could still make it a good source of essential fatty acids. However, the major bioactive components in strawberry are the polyphenolic compounds that include flavonoids (mainly anthocyanins), phenolic acids (hydroxybenzoic acid and hydroxycinnamic acid), lignans, hydrolysable tannins (ellagitannins and gallotannins), and condensed tannins (proanthocyanidins or procyanidins). The most important polyphenolic compounds are the anthocyanins (up to 800 mg/kg fresh fruit), which are responsible for most of the red color of strawberry fruits. Several (up to 25) strawberry fruit anthocyanin pigments have been reported, but the major one is pelargonidin-3-glucosides that includes pelargonidin-3-malonyl-glucoside, cyanidin-3-glucoside, and pelargonidin-3-rutinoside. Interest in strawberry fruits as functional foods has increased recently due to the reported bioactivities of the procyanidins, especially their role as antioxidant, antimicrobial, antiallergic, and antihypertensive agents. The main potential health benefits of strawberry anthocyanins are related to their antioxidant properties, especially ability to scavenge free radicals and prevent oxidative damage to blood lipids and DNA.

Strawberry glycosides can be absorbed intact or in the aglycone form after hydrolysis by β-glycosidases in the intestine. During absorption, the anthocyanins are conjugated with glucuronic acid such that the main metabolite present in the urine is pelargonidin-glucuronide as evident from human feeding studies. Pelargonidin-glucuronide was highest in the urine within the first 12 h of strawberry consumption and decreased thereafter. In humans that consumed strawberry fruits, serum lipoperoxidation was significantly decreased by 20% up to 22 h post-consumption. The ratio of 8-oxo-2′-deoxyguanosine (8-oxo-dG) to deoxyguanosine (dG) was decreased following strawberry consumption and returned to baseline values during the washout period when strawberry was withdrawn from the diet. 8-Oxo-dG is an oxidized dG product, and a high ratio reflects high level of DNA oxidation.

7.1 Anticancer Effects of Strawberry Fruits

Various cell culture and animal experiments have demonstrated the potential of strawberry fruits as anti-proliferation agents and in reducing the induction or disease progression of cancerous tumors. In a human feeding trial, formation of a carcinogen (N-nitrosodimethylamine) was shown to be reduced by 70% when strawberries were consumed immediately after intake of a diet rich in nitrates and amines. While the actual mechanism has not been elucidated, it is possible that the soluble fiber and polyphenolic compounds and carotenoids in strawberries bind and reduce availability of the carcinogen precursors. The presence of ellagic acid has been shown to be associated with the in vitro and in vivo chemopreventive abilities of strawberries as anticarcinogenic agents at the initiation and post-initiation stages of tumor development. Strawberry anthocyanins and tannins have also been shown to possess in vitro and in vivo antitumor properties when tested against various human cancer cell types. The mechanism of action of strawberry polyphenols is believed to be through their antioxidant properties, which inhibits mutagenesis and cancer initiation. These antioxidant properties include stimulation of antioxidant enzymes, decreased oxidative DNA damage, inhibition of carcinogen-induced DNA adduct formation, enhancement of DNA repair, and scavenging of reactive oxygen species. In addition to antioxidative effects, the strawberry polyphenols can also act as anticancer agents by promoting apoptosis and inhibiting angiogenesis, cell-cell communications, cell-cycle arrest, and inflammation. Modulation of other cell signaling pathways such as cell proliferation and differentiation that is associated with cancer progression is also believed to be potential modes of action. For example, pretreatment of mouse epidermal cells with strawberry extracts had a dose-dependent suppression of activator protein-1 and nuclear factor kappa B activity that is normally induced by cancer-promoting agents like ultraviolet-B or O-tetradecanoylphorbol-13-acetate. Thus, the strawberry extract was able to inhibit proliferation and transformation of cancer cells and the associated signal kinase pathways. Other potential but yet to be elucidated mechanisms of cancer inhibition by strawberry includes induction of phase II-detoxifying enzymes, reduction in bioavailability of carcinogens, as well as inhibition of metalloproteinases and other enzymes involved in cancer metastasis.

7.2 Cardiovascular Effects of Strawberry Fruits

Initial data relating strawberry consumption to decreased risk of cardiovascular diseases came from the epidemiological study that involved overweight postmenopausal women. Increased level of strawberry consumption had an inverse relationship with cardiovascular disease (CVD) mortality after a 16-year follow-up. However, another study that involved a population with modest median strawberry consumption (1–3 servings per week) did not find any significant effect on the risk of CVD. But women who consume at least 2 strawberry servings in a week had significantly reduced risk of CVD when compared to those who do not consume strawberries. Therefore, the relationship between strawberry consumption and CVD risk reduction is related to the amount of the fruit that is consumed on a regular basis. A plausible mechanism of action of strawberry in reducing the risk of CVD is through the antioxidant properties of the fruit’s constituents, especially polyphenolic compounds and vitamin C. In animal experiments, addition of strawberry fruits to the diet was shown to increase plasma antioxidant status with decreases in malondialdehyde formation. The strawberry group also had less DNA damage in the mononuclear blood cells, suggesting a strong antioxidative protective effect. In humans, long-term consumption of strawberries had significant effects of increasing LDL peroxidation lag time as well as increased erythrocyte resistance to oxidative damage. Strawberry polyphenolic compounds, especially anthocyanins, can act as antioxidants to protect lipid oxidation because they can be translocated into lipoprotein domains and cell membranes where interaction with lipid bilayers enhances protection of unsaturated fatty acids effects against oxidative agents. Within the vascular system, strawberry anthocyanins are incorporated into the endothelial cells and can be translocated into the cytosol. The presence of anthocyanins prevents oxidative damage to the endothelial cells and helps to preserve structure and function of the vascular system. In human intervention trials, daily consumption of dried strawberry extract or supplement led to reductions in plasma cholesterol and lipid (LDL) oxidation, thus supporting the ability of strawberry constituents to reduce in vivo oxidative stress. Another effect of strawberry is inhibition of α-glucosidase and α-amylase, which could enhance plasma glucose management by reducing starch digestion. Strawberry may also enhance blood pressure reduction because the fruit’s extracts can inhibit angiotensin converting enzyme, a key enzyme involved in blood pressure elevation.

8 Blackberry

The high antioxidant plus anti-inflammatory capacities of blackberry polyphenolic extracts (mostly anthocyanins) has also been demonstrated, and there have also been various reports of the potential use as medicinal agents to reduce the risk of cancer and cardiovascular diseases. Using carbon tetrachloride (CCl4)-induced oxidative stress in rats, oral administration of blackberry extract led to attenuated levels of hepatic lipid peroxidation with increased activities of antioxidant enzymes such as superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and catalase (CAT). In the liver, CCl4 is converted to trichloromethyl free radical (•CCl3) by cytochrome P450 and then to trichloromethyl peroxide (Cl3COO−), both of which are highly reactive species. Hepatic damage is subsequently caused when •CCl3 or Cl3COO− attack and damage cellular components like nucleic acids, proteins, and unsaturated lipids. The attack on unsaturated lipids leads to formation of lipid peroxides, which breaks down into malondialdehyde (MDA), a common indicator of lipid peroxidation. Hepatic level of MDA was significantly increased by CCl4 treatment but was reduced in rats that received the blackberry extract, which indicates ability of the polyphenols to scavenge the CCl4-derived free radicals and prevent lipid peroxidation. During hepatic injury, as can be caused by high level of free radical species, there is increased cell membrane permeability that causes increased release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) into the blood. The CCl4-induced free radical-mediated hepatic damage was attenuated by oral administration of the blackberry extract as indicated by reduced levels of serum AST and ALT. Molecular mechanism involved in the antioxidant effects of the blackberry extract involved upregulation of expression levels of nuclear factor E2-related factor 2 (Nrf2) and nuclear factor E2-dependent antioxidant enzymes such as SOD, GPx, and heme oxygenase-1 (HO-1). Nrf2 is an activating factor for the synthesis of antioxidant enzyme proteins because it positively regulates their mRNA expression. Therefore, blackberry polyphenolic extract-induced increase in the level of Nrf2 led to upregulated expression and protein synthesis of antioxidant enzymes, which enhanced hepatic antioxidant capacity.