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).

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.

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).

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).

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.

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).

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).

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.