The importance of berries in the human diet

1 Introduction

A diet rich in fruit and vegetables is correlated with a high intake of bioactive and antioxidant compounds which may play an important role in preventing the development of various pathologies, such as cardiovascular disorders, cancer, diseases related to aging both at neurodegenerative and osteo-degenerative levels, as well as in exerting a high antioxidant and antimicrobial potential [1–3]. Mediterranean diet implies a high consumption of vegetables and fruits, and berries are among the most important and common fruits in this type of diet. Theyare rich in compounds that have important biological roles, such as minerals, vitamins, fibers and especially phenolic compounds with high biological activity [4].

In recent years, phenolic compounds present within these small fruits have attracted the attention of researchers, who have evaluated their potential beneficial or healthy effects with special attention to the prevention of the development of different pathologies. Therefore, in this concise review we highlighted and summarized the works of the latest 5 years on the preventive and therapeutic activities of the most common edible berries against cancer and cardiovascular diseases (CVD).

The bioactive compounds present in berries change according to the species, the cultivation method, the environmental, meteorological and genetic factors as well as the methods used for fertilization and the storage conditions and times. Among these molecules, there are tannins (proanthocyanidins, ellagic acid, ellagitannins), vitamins (C, B, A, E, K), stilbenes, carotenoids as well as different minerals. The most investigated phenolic compounds are flavonoids, among them the most representative are anthocyanins, quercetin, epicatechin, myricetin, kaempferol, isorhamnetin, epigallocatechin. Other important phenolic compounds are phenolic acids such as caffeic acid, ferulic acid, gallic acid, benzoic and cinnamic acids, p-coumaric acid, chlorogenic acid and hydroxycinnamic acid [5].

We limit our overview to the most diffused berries in Mediterranean diet which are strawberries, blueberries, blackberries and raspberries.

2 Berries and cancer

Several in vitro and in vivo studies have confirmed the antitumor effects of berries in different types of cancer, effects carried out with different mechanisms of action [6–9]. For example, a high in vitro antiproliferative activity of strawberry extracts against neuroblastoma (IMR-32, SH-SY5Y), colon adenocarcinoma (HT-29, Caco-2) cervix carcinoma (Hep-2C) [10], breast [11] and esophageal cancer [12] was demonstrated. A polyphenol-rich strawberry extract stopped breast cancer cells (A17) in G1 phase of cell cycle and modulated the genes involved in tumour invasion, an anticancer effect confirmed later also in vivo, where the extract significantly decreased the volume and the weight of the tumour mass [13]. A chronic state of redox imbalance was also seen to be related with the onset of cancer, strawberry extract was observed to improve the redox state of human liver carcinoma cells (HepG2) by modulating ROS generation, thiobarbituric acid-reactive substances production, antioxidant enzyme activity [14] and impairing mitochondrial functionality [15]. A similar modulation also occurred in the human ovarian carcinoma cells (A2780), where the strawberry extract exerted a greater antioxidant effect compared to raspberry and mulberry [16]. A high anti-tumorigenic activity was also demonstrated in vivo in CD-1 mice that had received a supplement of freeze-dried strawberries in the diet: it was observed that the incidence of colorectal cancer onset decreased markedly reducing by 64%, 75% and 44% in mice fed with 2.5%, 5% and 10% of strawberries, respectively [17].

Blueberries showed an inhibitory effect against human ovarian cancer (SKOV3 cell lines) by regulating cyclooxygenase-1 and cyclooxygenase-2 activity, two main biomarkers of this type of cancer [18]; a similar activity, for this type of berries, has also been demonstrated in vivo in lung cancer, where the extract was able to decrease the tumor onset induced in nude mice if they had received blueberries in the diet [19]. Anthocyanin and anthocyanidine extracts from blueberry fruits showed an antiproliferative and proapoptotic effects on melanoma cells (B16-F10 cells) by blocking these in the G0/G1 phase [20]. Furthermore, a greater sensitization to anticancer therapies was observed from blueberries in cervical cancer (SiHa cell line) [21] and in cisplatin-resistant human oral cancer cells [22]. A clinical study also demonstrated that a daily intake of blueberries improves plasma antioxidant capacity and reduces levels of the pro-inflammatory cytokine IL-6 associated with colorectal carcinogenesis [23].

Regarding blackberries, it has been noted that the extract exerts an anti-proliferative effect against colorectal cancer cells, by inhibiting telomerase activity [24] or by inducing apoptosis via a caspase dependent-mechanism [25]. Furthermore this extract suppressed migration and invasion of human oral cancer by inhibiting MMP-2 through the modulation of the Erk1/2 signaling pathway [26] and induced sensitization of doxorubicin-resistant cells in ovarian cancer cells [27]. The potential preventive effect of these fruits against the onset of esophageal cancer in rats has been also investigated, highlighting that the rate of tumour onset decreased markedly by modulating pathways related to oxidative stress [28, 29].

A very interesting activity is related to black raspberries: they have a chemotherapy preventive effect by modulating the gut microbiota and increasing the demethylation of SFRP2 in the onset of colon and oral cancers in mice [30–32]. The antiproliferative effect of this type of berries was confirmed in human hepatocellular carcinoma (HepG2 and Huh7 cell lines), where red raspberries were able to block cell growth by PTEN/AKT pathway [33].

Furthermore, the preventive effect of raspberry has also been demonstrated at clinical level: in patients previously subjected to surgery for oral carcinoma, the administration of raspberry was able to decrease the main inflammation biomarkers [34].

3 Berries and cardiovascular disease

Scientific evidence has been found on the effect of berries also on CVD and related disorders or causes (like diabetes1 and 2, dyslipidaemia, metabolic syndrome, obesity). Also, in this case the ways in which the bioactive compounds act are different; most of these are related to their antioxidant activity [35]. Platelet aggregation is one of the most common disorders in CVD: strawberry extract reduced platelet aggregation activity by the inhibition of inflammatory mediator of atherosclerosis (sP-selectin, sCD40L, RANTES, and IL-1β) [36] and of thrombus formation [37].

It was observed that in diabetic mice fed with freeze-dried strawberries in the diet, there was a clear reduction of the typical markers of vascular inflammation and a significant decrease in lipid peroxidation and blood pressure [38]. Clinical studies have also been carried out in recent years that confirmed the beneficial effect of dietary supplementation of strawberry powder on parameters of vascular health in obese adolescent males [39], but it was also demonstrated a preventive effect against CVD in healthy nonobese subjects: strawberries associated with a normal diet in fact significantly decreased plasma cholesterol levels [37, 40].

Lipotoxicity-induced endothelial dysfunction is an important complication of diabetic patients: it has been observed that the pre-treatment of human aortic endothelial cells (HAECs) with blueberry metabolites was able to prevent the damage caused by palmitate [41] and ameliorate endothelial inflammation in diabetic endothelial cells (ECs) by restoring cell surface glycosaminoglycan [42]. Also, the exposure to some substances, mostly fine particulates, can increase the risk of developing CVD, in particular increasing the risk of myocardial infarction especially through mechanisms linked to inflammation and oxidative stress [43]. It was observed that blueberry extract administered to rats subsequently exposed to fine particulate (PM 2.5) was able to decrease cardiac injury biomarkers as well as the expression of inflammatory cytokines and apoptosis of cardiomyocyte [44]. Doxorubicin can induce cardiac damage, too, especially increasing the oxidative stress of cardiomyocytes (H9c2): it has been observed that a pre-exposure of these cells with a blueberry extract reduced the damage induced by oxidative stress and the rate of apoptosis [45]. In addition, in rats with a diet supplemented with blueberry, plasma levels of nitric oxide, iNOS and COX-2 decreased significantly, as well as the levels of IL-6, TNFα and NF-κB in the liver and in the fatty tissue of rats [46]. Furthermore, in hypercholesterolemic rats, this kind of diet was able to reduce total cholesterol, LDL and triglyceride levels, also decreasing arterial lesions at histopathological level [47]. Beneficial effects of blueberry on the metabolic syndrome have also been demonstrated in a clinical study in adults with metabolic syndrome, where supplementation of blueberries improved endothelial parameters [48] and ameliorated biomarkers of cardiometabolic function [49]. Other clinical studies have demonstrated that the consumption of freeze-dried blueberry improved arterial stiffness and blood pressure in post-menopausal women with stage 1 hypertension [50] and reduced postprandial hyperglycaemia in patients with type 2 diabetes, which is a significant risk factor for CVD [51]. A beneficial effect was also confirmed in young female smokers, where the blueberries supplementation improved blood pressure and peripheral arterial function [52].

Finally, in induced senescence vascular smooth muscle cells (VSMCs), raspberry polyphenol extract reduced the activation of angiotensin II and ROS levels, increasing instead the activity of superoxide dismutase [53]. In obese diabetic mice or rats supplemented with raspberries, a decrease of marker levels of oxidative stress and inflammation has been observed [54] together with a decrease in the weight gain, preventing or delaying the development of heart disease [55]. Also for raspberry, some clinical studies have been carried out and they have confirmed that the supplementation of this small fruit in the diet of patients suffering from metabolic syndrome increases the number of circulating endothelial progenitor cells and improves arterial stiffness, also lowering the levels of IL-6 and TNFα [56]; moreover, in healthy males the consumption of raspberries improved the endothelial function, increasing the flow-mediated dilation [57].

4 Conclusion

In this concise review the beneficial effects of berries as a dietary supplement have been highlighted. In the last 5 years, many in vitro, in vivo and clinical studies have shown that these small fruits play a key role in the prevention of two of the most widespread and deadly diseases in the world, exerting their activity in different ways, thus confirming the beneficial role that they have on human health.

Conflict of interest

The authors declare no conflict of interest.