Effects of Vaccinium-derived antioxidants on human health: the past, present and future

Abstract

Dietary intake of Vaccinium berries has demonstrated significant potential in preventing many risk factors associated with metabolic syndromes in the human population. In recent years, a multitude of research has shown the role of antioxidants derived from Vaccinium berries on chronic diseases such as cardiovascular disorders, diabetes, obesity, and cancer. Several studies have also investigated the effect of Vaccinium berry consumption on their ability to modulate the risk factors associated with oxidative stress, vascular function, inflammation, and lipid metabolism. Regarding cancer, studies showed that the consumption of berries reduces inflammation, inhibits angiogenesis, protects against DNA damage within the cell, and controls apoptosis and proliferation rates in malignant tumours. However, which components are responsible for the health benefits is still unclear. Reports show that whole berry consumption usually confers positive effects on human health, and the health-promoting potentials are likely due to the presence of polyphenols with antioxidant activities. Among these polyphenols, various Vaccinium berry species have been reported to contain anthocyanins and flavonoids. These two polyphenolic compounds are known to have higher antioxidant activity and are beneficial for human health. There are now several studies and human clinical trials documenting the beneficial effects of Vaccinium berries, and these findings suggest that they may be promising for preventing and treating neurodegenerative diseases. This review focuses primarily on dietary Vaccinium berries consumption effects on human health and their potential role as therapeutic agents.

1 Introduction

The eternal pursuit of finding and identifying health-promoting agents has changed how we view our food sources. We have introduced superfoods, food supplements, and nutraceuticals in developed countries, reinforcing the food industry’s further growth (European Commission, 2006). Berries represent a large group of functional foods, also popularly known as “superfoods” due to their high content of disease-preventing and health-boosting chemicals (Ferlemi and Lamari, 2016). The genus Vaccinium L. (Ericaceae) includes approximately 450 diverse species, including these main commercial crops such as highbush blueberry (V. corymbosum L.), rabbiteye blueberry (V. virgatum Aiton, formerly known as V. ashei J.M.Reade), lowbush blueberry (V. angustifolium Aiton), bilberry (V. myrtillus L.), cranberry (V. macrocarpon Aiton), and lingonberry (V. vitis-idaea L.) (Retamales and Hancock, 2018). In general, berry fruit consumption has increased in recent years. Several research papers show that the increased consumption of berries is associated with a reduced risk of disorders linked with reactive oxygen species (ROS), such as cardiovascular disorders, cancer, and other inflammatory processes (Gomes-Rochette et al., 2016). A large number of scientific research cites the effect of berry consumption in three major groups: (a) physical and mental health maintenance; (b) reduction of the rate of obesity; and (c) decreased rate of chronic diet-related diseases, e.g., cardiovascular and metabolic disorders, type II diabetes (Giampieri et al., 2015). Vaccinium berries contain high concentrations of beneficial nutrients and other bioactive phytochemicals, which has led them to become the center of attraction for researchers working on the potential role of these phytochemicals in preventing chronic diseases (Colak et al., 2016). Many research papers have shown that these active compounds, which are present in phenolic form, are associated with high antioxidant activity. Additionally, there are several studies suggesting that wild Vaccinium Berries contain higher phenolic content and antioxidant activity than cultivated berries (Braga et al., 2013; Dinstel et al., 2013; Kanget al., 2015). Phenolic compounds present in Vaccinium berries are classified into diverse groups, which include phenolic acids such as hydroxybenzoic and hydroxycinnamic acids and their derivatives, flavonoids (flavonols, flavanols, and anthocyanins, and tannins. Tannins are further sub-grouped into condensed tannins like proanthocyanidins and hydrolysable tannins (Ferlemi and Lamari, 2016). Blueberries (Vaccinium spp.) contain the highest amount of p-coumaric acid, chlorogenic acid, and other caffeic acid derivatives, which are types of hydroxycinnamic acids (Mattila et al., 2006; Määttä-Riihinen et al., 2004a; Kylli, 2010; Häkkinen et al., 1999; Taruscio et al., 2004). When it comes to flavonoids among the Vaccinium berries, lingonberries (V. vitis-idaea L.), highbush blueberries, and American cranberries (V. macrocarpon) are known to be the richest source of flavonols such as quercetin and myricetin derivatives and aglycones (Määttä-Riihinen et al., 2004b; Määttä-Riihinen et al., 2004a; Kylli, 2010; Häkkinen et al., 1999; Taruscio et al., 2004). These chemical compounds possess high antioxidant activity (Wilms et al., 2005) and play a major role in preventing many chronic diseases (Castañeda-Ovando et al., 2009; Duthie et al., 2006). However, the concentration of these compounds depends on the species, genotype, growing condition and their post-harvesting techniques (Manganaris et al., 2014; Kresty et al., 2006).

Anthocyanins are important secondary plant metabolites, primarily occurring as glycosides of their aglycone anthocyanidins. The contents of the small edible berries are responsible for their bright colours as this pigment is evenly distributed in the epidermal tissues of the berries (Del Bo et al., 2015). The pigment in anthocyanins is water-soluble and responsible for orange, red, purple, and blue in fruits and vegetables (Delgado-Vargas et al., 2000). Anthocyanins are present in substantial quantities in glycosylated and various other forms in European cranberries (V. oxycoccus) and blueberries (Del Bo et al., 2015). European blueberries or bilberries contain fifteen anthocyanins, such as delphinidin and cyanidin monoglycosides, malvidin glycosides, petunidin, and peonidin. In the case of American cranberries, the principal anthocyanins are cyanidins, while in the case of European cranberries, it is peonidins (Norberto et al., 2013; Kaume et al., 2012; Gopalan et al., 2012; Seeram, 2008; Paredes-López et al., 2010). Similar to American cranberries, lingonberries also mainly contain cyanidin monoglycosides. Besides cyanidins, high and lowbush blueberries, lingonberries, and American cranberries contain procyanidins such as catechin and epicatechin polymers (Norberto et al., 2013; Zafra-Stone et al., 2007).

Commonly consumed Vaccinium berries have been studied for their effects on human health, but the nature and extent of their impact on humans remain vague. Hence, this article aims to provide a comprehensive overview of human clinical trials investigating the acute and chronic effects of Vaccinium berry polyphenols derived from fruits, their extracts and their derived products on inflammation, gut microbiota, diabetes, heart health, cancer, and brain activities.

2 Bioactive compounds

Plants produce numerous bioactive compounds, which belong to different classes of secondary metabolites including polyphenols, phytosterols, lipoates, carotenoids, etc. (Acquaviva et al., 2021; He et al., 2024). In berries, the most abundant bioactive compounds are phenolics, which are mostly found in leaves, fruits, and seeds but can also be present in other parts of plants. The chemical structure of the phenolic compounds carries one or more aromatic rings with one or more hydroxyl groups (Szajdek and Borowska, 2008; Nile and Park, 2014; Del Bo et al., 2015; Skrovankova et al., 2015). Phenolics are either present in free or conjugated forms with water or fat-soluble compounds (Figure 1). Conjugated forms of phenolics are predominantly present as conjugated hydroxycinnamic acids, flavonol glycosides, and anthocyanins (Määttä-Riihinen et al., 2004a). These phenolics are not species-specific but shared across the genera. Among the berry polyphenols, anthocyanins constitute a large percentage. They have a characteristic C6−C3−C6 carbon structure and are glycosylated polyhydroxy and polymethoxy derivatives of flavylium salts (Wallace, 2011). A study has reported that anthocyanins have a glycosidic structure containing more than two sugar molecules, such as galactose, arabinose, xylose, and glucose, that effectively connect with aglycon and form through the phenylpropanoid pathway. Anthocyanins have more than 600 compounds and more than 30 anthocyanidin compounds (Bilawal et al., 2021). The major phenolic compounds (anthocyanins) found in Vaccinium berries are listed in Table 1. Anthocyanins are uniquely characterized by an oxonium ion on the C ring and are highly pigmented (Pandey and Rizvi, 2009). Among these anthocyanin compounds, quercetin, myricetin and their glycosidic derivatives reach up to 30%. Anthocyanins, including procyanidins and anthocyanidins such as cyanidin, malvidin, peonidin, delphinidin, and petunidin, can account for up to 24% of all polyphenolic compounds. Phenolic acids primarily include p-coumaric acid, chlorogenic acid, caffeic acid, ferulic acid and vanillic acid. They account for up to 12% of the total polyphenols (Nemzer et al., 2022).

FIGURE 1

Plant phenolics were regarded as antinutritional and toxic for a long time as these compounds’ chemical nature of functioning as an inhibitor to proteolytic, lipolytic and glycolytic enzymes reduces their ability to absorb nutrients (Olas, 2018). However, the toxicity of the phenolic compounds derived from berries was generally unnoticed in the previous studies, while the benefits were observed. Apart from being a source of non-nutritive compounds such as phenolics (Singh and Basu, 2012), Vaccinium berries also contain a wide range of nutritive compounds such as simple sugars like glucose and fructose, minerals, for example, phosphorus, calcium, iron, potassium, magnesium, manganese, sodium and copper, etc. (Del Bo et al., 2015; Szajdek and Borowska, 2008). Iron and manganese are essential components of antioxidant enzymes among these above-mentioned minerals. Moreover, berries contain vitamins A and E, reducing inflammation and acting as antioxidants (Skrovankova et al., 2015). Apart from that, berries contain high concentrations of dietary fibres and low concentrations of lipids. These fibers reduce the concentration of low-density lipoproteins (LDL) in blood serum and reduce the chances of occurrence of cardiovascular and neurodegenerative diseases and cancer. All these nutritive, non-nutritive compounds, vitamins, and minerals in the Vaccinium berries synergistically affect human health (Olas et al., 2016).

Apart from the polyphenolic compounds, Vaccinium berries also contain major lipid groups such as unsaturated fatty acids, sterols, terpenoids, and others that have high biological activity. These lipids are different from those found in mammals, which is why consuming these lipids has a significant role in human metabolism (Klavins et al., 2015). The first report of the presence of lipids was investigated in cranberries (Croteau and Fagerson, 1969). Klavins et al. (2015) studied the lipid profile of blueberry, bilberry, lingonberry and cranberry grown in the wild in Latvian forests and bogs. The lipid profile revealed 111 different types of lipid fractions, including fatty acids, sterols, triterpenoids, alkanes, phenolic and carboxylic acids and carotenoids. Since then, this group of compounds has been studied in many berry species. However, there is no detailed report on lipids found in Vaccinium berries.

3 Biological activities

3.1 Overview of biological activities

Due to the response to the biotic and abiotic stresses, plants produce phytochemicals. They are also known as secondary metabolites. Like other fruits and vegetables, berries were found to be a great source of bioactive phytochemical components. Berry phytochemicals comprise bioactive components such as tannins, polysaccharides, alkaloids, vitamins, flavonoids, and other trace elements. They also contain sugar and fiber, which increases fruit taste and possesses many biological properties. In berries, these bioactive properties are directly related to the concentrations of the various phytochemicals in these fruits. Berry research has always been generally focused on their antioxidant properties. The antioxidant properties of these phytochemicals reduce oxidative damage to DNA, RNA, proteins and lipids at the cellular level by scavenging reactive oxygen species (ROS) (Bilawal et al., 2021). ROS are responsible for triggering aging and several inflammatory conditions, as well as cancer (Sosa et al., 2013; Nemzer et al., 2022). They also promote the regeneration of other antioxidants and endogenous antioxidant defense systems (Bujor et al., 2019). The imbalance between oxidants and antioxidants results in abnormalities. It produces significant ROS, including O₂^−, HO⁻, NO, and RO⁻, which interferes with the cellular processes (Bujor et al., 2019; Maya-Cano et al., 2021). These superoxide ions can convert into hydrogen peroxide (H₂O₂), which can further convert into the highly reactive hydroxyl radical (OH⁻). Hydroxyl radicals, due to their high reactivity, cause oxidative damage, including lipid peroxidation in membranes, oxidative modification of proteins, and oxidative damage to DNA (Sosa et al., 2013).

Various methods have been used to determine the antioxidant activity of Vaccinium berries. Among them, the Folin-Ciocalteu method, the copper ion reducibility assay (CUPRAC), the ferric ion reducibility assay (FRAP), the DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical scavenging method, and the ABTS method were mostly used in the scientific literature (Bujor et al., 2019). Goyali et al. (2013) examined the oxidative capacity of lowbush blueberry (V. angustifolium). It was found that the total phenolic content (TPC) value ranged from 34.2 to 42.7 mg GAE/g FW, total flavonoid content (TFC) from 12.7 to 22.3 mg CE/g FW, and proanthocyanidin content (PAC) from 4.7 to 6.5 mg CE/g FW in the greenhouse-grown and their cutting counterparts. In another study on half-high blueberries, results of the biochemical assays of the greenhouse-grown and somatic embryogenesis-derived plants revealed that TPC varied from 0.26 to 0.46 GAE/g lw, TFC varied from 7.93 to 11.65 CE/g lw, and antioxidant activity (AA) varied from 0.08 to 14.85 GAE/g lw. The results showed that the propagation method and genotype impact the phenols and flavonoids in the leaves (Ghosh et al., 2018). A study on V. oxycoccos and V. macrocarpon compared the AA by the Folin-Ciocalteu method. It was found that polyphenol quantity in V. macrocarpon was 296.3 mg/100 g fresh weight while in V. oxycoccos, it was 288.5 mg/100 g fresh weight. However, DPPH revealed that V. oxycoccos had a stronger antioxidant potential (16.4 μmol TE/g FW) than V. macrocarpon varieties (13.08 μmol TE/g FW), which led to the inference that the concentration of resveratrol in the analyzed samples of both the species that may have an impact on the AA of the varieties (Borowska et al., 2009). The antioxidant capacity of the Vaccinium species has been tested in in-vivo studies as well. A study was conducted on male Drosophila melanogaster to analyze the anti-aging effect of anthocyanins derived from the bilberry extracts. It was reported that the administration of anthocyanin extracts at the concentrations of 2.5, 5.0 and 10.0 mg/mL extended the life of the flies by 9.16%, 11.90% and 6.88%, respectively, compared to the control sample (Zhang and Dai, 2022). Several pieces of research show that the effect of phytochemicals derived from Vaccinium berries is directly associated with their anticancerous activities (Juranić and Žižak, 2005). Not only anticancerous properties, but numerous studies have shown that all these components are believed to hold a broad spectrum of biomedical functions, including anti-inflammatory, antimicrobial, antiviral and antioxidant properties (Figure 2) (Puupponen-Pimia et al., 2004; Seeram, 2008; Skrovankova et al., 2015). Due to their health-promoting activities, these berries are highly recommended for the human diet, as their antioxidant effects have been explored in several in vitro and in vivo studies (Juranić and Žižak, 2005; Skrovankova et al., 2015) (Table 2).

FIGURE 2

Studies have reported that adding fruits to our diet reduces the risk of chronic diseases like cancer, type II diabetes, obesity, and cardiovascular disorders (Skrovankova et al., 2015). It was revealed that dietary intake of flavonoids is associated with a lowered risk of all-cause mortality (Liu et al., 2017), including CVD. However, it is important to understand that all subclasses of flavonoids are not equally involved with cardioprotection, as there is a huge gap between flavonoids’ bioavailability and bioactivity. Anthocyanins, a subclass of flavonoids, are one of the main phytochemicals present in Vaccinium berries. It was found that anthocyanins have a greater bioavailability than was previously estimated (Czank et al., 2013). Several in-vitro studies have shown that anthocyanins are as bioactive as their parent compounds and sometimes even more (Amin et al., 2015; Keane et al., 2016). Anthocyanins are known to stimulate anti-inflammatory, anti-atherogenic, antioxidant and vasodilatory actions (Castaneda-Ovando et al., 2009; Edwards et al., 2015; Wang et al., 1999). Not only that but there is also a growing body of evidence revealing that dietary inclusion of anthocyanins improves in vivo vascular health (Fairlie-Jones et al., 2017; Jennings et al., 2012) as they have a potential underlying mechanism of augmenting endothelial-derived nitric oxide (NO) bioavailability. It was found that anthocyanins can directly or indirectly increase NO availability either by upregulating endothelial nitric oxide synthase and L-arginine pathways or via optimizing nitrate-nitrite-NO pathway and reducing NO degradation by their antioxidant activities (Edwards et al., 2015; Rocha et al., 2014). NO is an important molecule as it regulates endothelial homeostasis. Anthocyanin displays strong antioxidant activities, and foods high in anthocyanin have been shown to improve endothelial function (Rodriguez-Mateos et al., 2013). Research on the effect of flavonoid intake on mortality showed that intake of anthocyanidins is positively correlated with decreased risk of CVD mortality (Summary relative risk = 0.89, 95% CI: 0.83, 0.95) when tested amongst 5 cohorts (Grosso et al., 2017). All the available research done in vitro and in vivo on antioxidant and anticancerous properties of Vaccinium berries has advanced our understanding of their effects on human health and diseases. Therefore, the current review comprehensively summarizes what is currently known about the medicinal potential of these berries.

3.2 Anti-inflammatory effect

Inflammation is known as the first line of defense in animals in response to the attack of pathogens, allergens, or any kind of tissue injury. As a result of the inflammatory response, macrophages, which are part of our immunity system, release inflammatory mediators such as interleukins, nitric oxide (NO), tumour necrosis factor-α (TNF-α), and prostaglandin (PGE2) (Joseph et al., 2014). Usually, overexpression of such mediators is associated with a response to type II diabetes, cancer, and cardiovascular diseases (CVDs) (Joseph et al., 2016). Over the years, much-accumulated data on pre-clinical studies of mice shows that Vaccinium berries, such as blueberries, reduce adiposity while increasing insulin sensitivity and decreasing inflammatory responses (Land Lail et al., 2021). A study on blueberries and blackberries disclosed that a daily dietary intake of 9–18.9 mg/kg BW of phenolic extract reduced cholesterol in blood plasma and metabolic dysfunctions induced by high-fat diet (HFD) in C57BL/6J mice (Joseph et al., 2016). Another study showed that the continuous intake of Nordic wild blueberries with HFD (45% fat) for 12 weeks slows down weight gain because of obesity-induced inflammation in C57BL/6 (Mykkänen et al., 2014). Similarly, HFD mixed with blueberry powder for 12 weeks helped to restore innate immune response and T-cell proliferation in HFD-induced obese mice (Lewis et al., 2018). This also shows that consuming an adequate quantity of blueberry with an HFD may target the crucial factors in immune response and inflammation. A study in macrophages (RAW 264.7) revealed that blueberry anthocyanin reduced the expressions of two cytokines, such as Tumor necrosis factor α (TNFα) and Interleukin 1β (IL-1β), after 3 h of treatment by suppressing the NF-kB pathway expression (Lee et al., 2014). A study on V. floribundum revealed that phenolic extract of the berries reduced lipid accumulation and inhibited the production of anti-inflammatory response-inducing enzymes such as PGE2, NO, COX-2, and iNOS in macrophages (LPS-RAW 264.7) (Schreckinger et al., 2010). The antioxidant and anti-inflammatory effects correlate with phenolic content in berries being dependent on the species, varieties, and geographical location (Grace et al., 2014).

3.3 Maintenance of gut microbiota and antimicrobial and antiviral activities

Dietary consumption of berries is also known to help grow bacteria in the gut. Berries contain polyphenols, which promote symbiotic bacteria, reducing dysbiosis disorders (Pap et al., 2021). Phenolics and flavonoids present in the berries are also found to be effective against pathogenic bacteria and fungi (Kranz et al., 2020). The human gut microbiota consists of viruses, bacteria, fungi, protozoa, and archaebacteria (Burgos-Edwards et al., 2020). A berry diet can promote the growth of beneficial microbiota and inhibit negative bacterial populations in the gut. Studies have shown that black raspberries and Vaccinium berries, such as blueberries and lingonberries, help increase the growth of Lactobacillus and some of their subspecies, the population of Bifidobacterium, and help in slowing down obesity-related problems (Pap et al., 2021). A study revealed that cranberry juice has a strong activity against co-adhesion and co-aggregation of oral plaque bacteria (Gupta et al., 2015). In another study, several types of berry extracts, including lingonberry (V. vitis-idaea), bilberry (V. myrtillus), were found to have antibacterial effects against commonly found pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus (Tian et al., 2018). Berry and leaf extracts of lingonberry have shown maximum anti-microbial effects against S. aureus (strain ATCC-25923) and MRSA (clinical) oral cavity isolates (Kryvtsova et al., 2020). Research done on Romanian blueberry (var. Elliot) showed that minimum inhibitory concentration of leaf extract was discovered to be highly effective against bacterial strains such as S. aureus, Escherichia faecalis, Rhodococcus equi, E. coli, and Klebsiella pneumoniae and a few Candida fungal strains, such as C. albicans, C. zeylanoides, and C. parapsilosis (Ștefanescu et al., 2020).

3.4 Antidiabetic effect

Diabetes mellitus (DM) is a chronic disease which is associated with other lethal diseases, including hypertension, obesity, cardiovascular diseases, and hyperlipidemia. DM is classified into type I and type II; among these, type II contributes to more than 90% of all diabetes globally (Batool et al., 2021; Skyler et al., 2017). According to the World Health Organization (WHO), 108 million in 1980 and 422 million in 2014 were living with diabetes. A report done by Cho and co-workers in 2018 revealed that 451 million adults were diagnosed globally with diabetes, and it was predicted to reach up to 693 million by 2045 (Cho et al., 2018). Either form of DM is known to increase the risk of serious chronic illnesses such as blocking heart and blood vessels and affecting kidneys, eyes and nerve functions. This is due to the high blood sugar level, which affects and damages the nerves and the blood vessels controlling these organs. Blockage of the heart and blood vessels may also cause complications like CAD and stroke (Edirisinghe and Burton-Freeman, 2016). Not only CAD but CVD is also known to be the prime cause of death in patients with DM (Grundy et al., 1999). Several researchers have investigated and supported the idea that berry polyphenols have an antidiabetic effect, which is usually associated with glucose homeostasis. Glucose homeostasis can be regulated in an insulin-dependent and independent manner. Polyphenols derived from berries have been studied for years for their effects on insulin-dependent glucose metabolism. This can be achieved by regulating insulin secretion via modulating pancreatic-cell function and peripheral tissue sensitivity (Edirisinghe and Burton-Freeman, 2016). It was found that Canadian blueberry extracts increased 3H-thymidine incorporation in TC-tet cells and increased cell proliferation by 2.8-fold (Martineau et al., 2006). In another study, it was seen that dietary supplementation of freeze-dried whole blueberry powder in a double-blinded and placebo-controlled sensitivity had antidiabetic effects in obese, nondiabetic, and insulin-resistant human participants (p < 0.05) when administered for over 6 weeks and reported to improve insulin sensitivity (Stull et al., 2010). In diabetic C57b1/6J mice, feeding them a blueberry diet also displayed antidiabetic activity. Blueberry fraction enriched with phenolics and anthocyanin, in addition to Labrasol (a pharmaceutically acceptable self-micro emulsifying drug delivery system), was reported to lower raised blood glucose levels when fed to diabetic C57b1/6J mice. The hypoglycemic effect of the concoction was equivalent to that of metformin, a well-known antidiabetic drug (Grace et al., 2009). A study on postprandial healthy women showed that the administration of either whole lingonberries or extracts reduced sucrose-induced postprandial glucose and insulin concentrations throughout the first 30 min of consumption. Furthermore, it was seen that during the second-hour post-intake, the concentration declined slowly but improved the overall glycemic profile (p < 0.05). Additionally, the investigation showed that whole berries and extracts stopped the sucrose-induced late postprandial hypoglycemic response and the compensatory free fatty acid recovery (Torronen et al., 2012). Schell et al. (2017) experimented with the anti-diabetic activities of cranberry extract in T2D and revealed that administration of dried cranberry significantly improved the postprandial glucose excursion. These situations revealed that the increasing incidence of DM and its associated diseases can be controlled with a Vaccinium berry-rich diet.

3.5 Cardioprotective effect

Several studies have shown a strong connection between berry-derived anthocyanins and cardiovascular health. Clinical studies such as the Kuopio Ischemic Heart Disease Risk Factor Study for a follow-up of around 13 years revealed a considerably lowered risk of CVD-associated death among men who had a significantly higher quartile of berry intake (>408 g/day) than men with the lowest intake (<133 g/day) (Basu et al., 2010). Although these results positively impacted CVD risk factors, the models also showed an inverse correlation between the intake of fruits, berries, and vegetables and serum haptoglobin in blood, an inflammation marker (Rissanen et al., 2003). A large group of postmenopausal women (n = 34,489) contributing to a CVD mortality study associated with blueberry intake for a 16-year follow-up period at Iowa Women’s Health Study found that consumption of blueberries once a week significantly decreased coronary heart disease mortality using an age-and energy-adjusted model (Mink et al., 2007). The most significant conclusion drawn from all these clinical studies was that dietary inclusion of berries in everyday diet might decrease LDL oxidation and lipid peroxidation, reduce plasma glucose or total cholesterol, and increase HDL cholesterol and plasma or urinary antioxidant capacity (Basu et al., 2010). As a high content of plasma glucose, lipids, and lipid oxidation have been associated with coronary artery disease (CAD), these researchers suggested that edible berries, including berries from the Vaccinium family, can be consumed to reduce the risk factors of CAD significantly (Krentz, 2003; Gupta et al., 2009). It was further shown that the regular inclusion of berries in the diet also reduces the postprandial metabolic and oxidative stresses, which are also associated with CAD (O’Keefe et al., 2008). Cranberry has been proven to be very effective against several health issues, including the management of systolic blood pressure in healthy men (Ruel et al., 2008). Another study showed that cranberry extract positively affects lipid profiles in subjects with type I or II DM (Lee et al., 2008). Various other studies showed that consuming blueberries and cranberries significantly decreases postprandial oxidative stress, specifically lipid peroxidation (Pedersen et al., 2000; Kay and Holub, 2002; Mazza et al., 2002; Ruel et al., 2005; Ruel et al., 2006). Many studies suggest the inverse correlation of flavonoid (specifically anthocyanin) intake with the occurrence of CVD and the elevated risk factors involved with CVD (Cassidy et al., 2011; Jennings et al., 2012; McCullough et al., 2012). Berry polyphenols positively affect the lipid profile and endothelial function of the blood vessels by reducing blood pressure and platelet accumulation (Pojer et al., 2013; Rodriguez-Mateos et al., 2014a; Rodriguez-Mateos et al., 2014c). Not only that, but their antioxidant and anti-inflammatory activities also support cardiovascular health (Rodriguez-Mateos et al., 2014a; Pojer et al., 2013). Not only the berry extracts from fresh or frozen fruits but baked goods with lowbush blueberries (V. angustifolium) exhibited similar effects on endothelial function (FMV) as with the drink made with freeze-dried blueberry powder (Rodriguez-Mateos et al., 2014b). All this available research suggests that dietary inclusion of berries can potentially be used as a therapy for pre-hypertension and hypertension management (Basu et al., 2010). However, none of these clinical trials were found to interfere with biomarkers responsible for inflammation, except in one case, it was found that cranberry juice supplementation substantially decreases adhesion molecules in healthy volunteers (Ruel et al., 2008).

3.6 Anticancerous effect

Among all the other healthy eating habits, including berries in the everyday diet is one of the most promising ways to prevent cancer (Baby et al., 2018). Phytochemicals present in the berry extracts influence genome stability at several stages, such as malignant transformation, initiation modulation, promotion and progression of cancer (Duthie, 2007). In general, berry extracts combat carcinogenesis in animal models. However, when exposed to chemical carcinogens, blueberry extracts did not protect animal models. DNA damage was noticed in the tumours, and there was no evidence of a reduction in the proliferation rate of the cancerous cells or size of the tumours when pre- or co-treated with blueberry extract. These results further suggested that despite having higher antioxidant capacity than other berry species, blueberries are deficient in one or more cryoprotective phytochemicals, preventing chemically induced cancer in the animal model (Aziz et al., 2002).

It was reported that the growth of the HT-29 cell lines in colon cancer was significantly inhibited using phenolics, such as anthocyanins and flavonols extracted from cranberry juice (Desrouillères et al., 2020). In another study, lingonberry-derived quercetin and procyanidin-A2 displayed anticancerous activity against colon (HT-29), melanoma (IGR39), and renal (CaKi-1) cancer. It was also observed that quercetin demonstrated the best anticancerous activity against renal cell carcinoma (CaKi-1) (Vilkickyte et al., 2020). Fermented catechol extracted from fermented Rabbiteye blueberry (V. virgatum) extract along with Lactiplantibacillus plantarum (CK10) resulted in inducing apoptosis and inhibiting HeLa cell multiplication after 24–72 h of administration (Ryu et al., 2019). Various flavonol compounds such as kaempferol, quercetin, and genistein acid extracted from bilberry or European blueberry (V. myrtillus) demonstrated cytotoxic effects against HCT-116 colon cancer cells. This study further showed that kaempferol had better anticancerous activity than other flavonols, inducing apoptosis by preventing apoptosis proteins (IAPs) inhibitors (Sezer et al., 2019). Extracts from Vaccinium-berries such as blueberry, bilberry, cranberry, and lingonberry contain anthocyanins and ellagic acid, which are known to exhibit anticarcinogenic activities (Seeram, 2008). Other reports suggest that cranberry extracts and press cake can significantly inhibit cell growth in breast, prostate, skin, brain and liver cancer cases by stopping the G1 stage of the cell cycle and initiating apoptosis (Sun et al., 2002; Sun and Liu, 2006). Additionally, bilberry extracts were found to induce programmed cell death in patients with leukemia (Katsube et al., 2003). Extracts of several fruits, including blueberries, blackcurrant, black chokeberries, and raspberries, showed a strong antagonistic effect on the proliferation of breast cancer cell line MCF-7 and the colon cancer cell line HT29 and reduced their growth by up to 74% (Olsson et al., 2004).

3.7 Neuroprotective activity

There is much evidence supporting that oxidative stress of reactive oxygen species (ROS) in cells is responsible for the progression of neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease (Lim et al., 2024), and berry-derived antioxidants were effective against neurodegenerative diseases (Nile and Park, 2014). Berry antioxidants also demonstrate neuroprotective activities, and several studies have shown that phenolic components from the Vaccinium species have anti-inflammatory and neuroprotective effects. In a study done with blueberry and lingonberry, brain-derived cell cultures from rats were found to be significantly tolerant against glutamate excitotoxicity when treated with blueberry extracts for 24 h. However, lingonberry (V. vitis-idaea L.) extracts failed to provide any protection against it. Additionally, leaf extracts of blueberry and lingonberry displayed significant neuroprotective effects, while among the fruits, only blueberry fruits showed neuroprotection on the same brain cells (Vyas et al., 2013). That is why further work has been done to investigate the neuroprotective activity of blueberry leaf extract in microglial cells derived from mice. Microglial cells are the brain’s first line of defence cells; glutamate or α-synuclein was administered to microglial cells to induce an inflammatory response. The cells were treated with blueberry fruit and leaf extracts, which decreased cell death and reduced inflammation after 24 h. This result further points to the fact that a blueberry-rich diet, with leaves or fruits, can protect against neurodegenerative disorders (Debnath-Canning et al., 2020). Over the years, studies have suggested that the inclusion of blueberries in a regular diet may help with age-related and oxidative stress, which are responsible for declined brain function (Wang et al., 2005; Krikorian et al., 2010). Another report suggested that a blueberry-supplemented diet can improve behavioural deficits associated with age or a high-fat diet (Carey et al., 2014). Overproducing ROS and reactive nitrogen species (RNS) free radicals cause aging and neurodegenerative diseases. Cortical cell cultures derived from neonatal rat pups were intoxicated with glutamate for 24 h, and it was seen that glutamate was responsible for morphological disruptions such as increased formation of dark punctae and disruption of cell bodies. Glutamate-treated cells were administered with lingonberry and blueberry leaf and fruit extract. They were found that, while lingonberry fruits failed to provide any protection from glutamate toxicity, the leaf extracts from both the berries and blueberry fruit extract displayed no cell death in the presence of glutamate (Kalidindi, 2014).

It was found that aged rats fed with blueberries have shown a reduction of ischemia-induced apoptosis in brain cells which is due to their capability of interacting with ROS and RNS, which accumulated during the ischemic phase in the central nervous system (Wang et al., 2005; Andres-Lacueva et al., 2005). Krikorian et al. (2010) reported in older humans that improved memory capabilities were detected by increased synaptic plasticity as a result of microglial modulation of the microglia-neuron crosstalk through the increase of the expression of CX3CR1 receptor was associated with a blueberry rich diet (Meireles et al., 2016). Memory loss is often associated with oxidative damage to lipids, proteins, and nucleic acids. Oxidative damage to all three can disrupt neural function. It was seen that bilberry extract was significantly effective against oxidative damage by decreasing lipid peroxides and increasing superoxide dismutase activity in the brain. Additionally, it was found that long-term supplementation of bilberry extract in the diet of the OXYS rats prevented learning and memory deficits (Rahman, 2007; Uttara et al., 2009). These findings specifically signify the effect of Vaccinium berry antioxidants on the neuroprotection of brain function.

4 Conclusion

Several in vitro and in vivo studies now indicate that berries positively impact human health by acting as strong anticancer and antioxidant agents. They are an ideal dietary source of bioactive components and could play a role in reducing cancer risk. The unique phytochemical constituents in berries act individually or synergistically to provide protection against several health disorders, including cancer and CADs. It is evident from this review that a lot has been done in this direction, but much more needs to be done to pinpoint the molecular mechanisms associated with the most beneficial phytochemicals that make up these nutritious fruits. The review summarizes the effects of bioactive compounds present in Vaccinium berries and their function against cardiovascular and neurodegenerative diseases. It was seen that measurable criteria like total anthocyanin or total phenolic content and total antioxidant content may also be associated with the effectiveness of health benefits. Overall, more in vivo data are required to understand the mechanisms of action, while more human clinical trials using different parameters such as gender, age, and any pre-existing condition should be performed such new information on the bioactive components of berries can be revealed, and the existing information could be validated. Also, using berry phenolic compounds as antimicrobial agents provides many possibilities for use in the food and medical industry. It will also be a very interesting topic for future research priority by developing new ways for berry compounds to avoid and manage antibiotic-resistant infections. In addition to the phenolic compounds, phytosterols are well-known for their antioxidant activities. Epidemiological and experimental reports suggest that they help reduce cholesterol and potentially protect against several types of cancer. Furthermore, berry lipids are also used in many commercial products. These ignited a general interest in studying these compounds in depth to understand their potential application in cosmetics, pharmacy and the food industry.

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