Blueberry

Last Updated: September 28 2022

Blueberries are a fruit that contain a lot of molecules called anthocyanins. These antioxidant compounds are often supplemented for their ability to improve cognition.

Blueberry is most often used for.

1.

Sources and Composition

1.1

Sources

Vaccinium (of the family Ericaceae) is a genus of berry making plants which contain a few common classes of berries, with the particular section of this genus (Vaccinium cyanococcus) being those plants which bear blueberries. There are several species of plants which bear blueberries, including:

  • Rabbiteye blueberry (Vaccinium ashei[1][2] and Vaccinium virgatum[3] are both called this)
  • Lowbush blueberry (Vaccinium angustifolium[4])
  • Northern highbush blueberry (Vaccinium corymbosum[5])
  • Wild Bog blueberry (Vaccinium uliginosum[6])
  • Andean blueberry (Vaccinium floribundum[7])
  • Colombian blueberry (Vaccinium meridionale[8])

Other sections include the European blueberry or 'Bilberry' (Vaccinium myrtillus[9]), Natsuhaze (Vaccinium oldhamii[10]), Shashanbo (Vaccinium bracteatum[11]), and cranberries (Vaccinium oxycoccus, of which oxycoccus refers to a subgenus[12]), while some other berries that just happen to be blue-ish in color sometimes falsely carry the blueberry name such as neotropical blueberry (Anthopterus wardii[13]).

The vaccinum family of plants is a fruit bearing family of plants, and the section of this family known as cyanococcus is known to produce blueberries. There are a few species of plants of which blueberries are interchangeably referred to

Blueberries are known to have a high anthocyanin content which confers relatively potent antioxidant potential[14][15] which has been noted to collectively confer about 85% of total antioxidant capacities of blueberries (the rest coming from other flavonoids).[15] The anthocyanin content is variable (changes depending on species of blueberry and analytic technique) but is in the range of 42-187.3mg/g (4.2-18.7%) dry weight[16][17][18][19][20][21][22] and within batch can vary two-fold.[23]

The fruits themselves (not dehydrated powder) tend to have a 201.4-402.8mg/100g range (0.2-0.4%) of anthocyanins,[23] they are mostly rich in the two anthocyanins malvidin and delphinidin.[24][23]

The anthocyanins seem to be stored in the peels (693-8814.9mg/100g dry weight) to a larger degree than the fruit (93.8-528.6mg/100g), and correlate with color of the berries (the darker blue-purple being associated with more anthocyanins).[25]

Blueberries are essentially a source of anthocyanin compounds, similar to other dark berries. They are definitely a respectable source of anthocyanin compounds, but not the highest among darker berries

1.2

Composition

Blueberry extracts (dehydrated blueberry powder) tend to contain:

  • Malvidin as 3-O-glucoside (1,290mcg/g[26]), 3-O-β-glucopyranoside (6.26mcg/g[27]), 3-O-galactoside, 3-O-arabinoside, and both 3-O-(6″-acetyl)galactoside and 3-O-(6″-acetyl)glucoside.[23] Malvidin comprises 43.7% of total anthocyanins, with 3-O-galactoside being 24.1% of total anthocyanins[23]
  • Delphinidin as 3-O-glucoside (98.00mcg/g[26]), 3-O-β-glucopyranoside (69.9mcg/g[27]), 3-O-(6″-acetyl)glucoside, and 3-O-arabinoside.[23] Delphinidin comprises 30.2% of total anthocyanins[23]
  • Cyanidin as 3-O-glucoside (153mcg/g[26] or 1% of anthocyanins[23]), 3-O-β-glucopyranoside (12.2mcg/g[27]), 3-O-rutinoside (65.10mcg/g[26]), 3-O-(6″-acetyl)glucoside, 3-O-galactoside, and 3-O-arabinoside.[23] Cyanidin comprises 13.6% of total anthocyanins[23]
  • Petunidin as 3-O-β-glucopyranoside (34.7mcg/g[27]), 3-O-galactoside, 3-O-arabinoside, and 3-O-(6″-acetyl)glucoside. Petunidin totals 10% of total anthocyanins[23]
  • Peonidin as 3-O-β-glucopyranoside (2.6mcg/g[27]) and 3-O-galactoside (1.5% total anthocyanins)[23]
  • Pelargonidin as 3-O-glucoside (219mcg/g[26]) although elsewhere it was found to not significantly contribute to anthocyanin content[23]

Blueberries possess all six anthocyanin compounds, although it appears to be a good source of malvidin and delphinidin in particular and a moderate source of cyanidin and petuidin. Peonidin and pelargonidin are not highly present in the fruits, as they correlated more with red pigmentation (strawberries) than with blue-black

  • Carotenoids (totalling 2140mcg/100g in bilberries) including lutein (1530+/-24mcg/100g), Neoxanthin (79.6+/-1.5mcg/100g), violaxanthin (100.8+/-2.4mcg/100g), zeaxanthin (20.4+/-0.3mcg/100g), Antheraxanthin (49.2+/-0.9mcg/100g), and β-carotene (365.0+/-5.0mcg/100g)[28]
  • Resveratrol at 3.83mcg/g[26] and its analogue Pterostilbene[29] at 0.59mcg/g[26]
  • Catechin (74.1-190mcg/g[26] total, with 14.8mcg/g (+)-catechin and 59.3mcg/g (-)-catechin[27])
  • Procyanidins (15.28+/-0.51mg/g[30]) of mostly B-type configuration[17] in a 2:1 catechin:epicatechin ratio[30]
  • Quercetin (23.90mcg/g[26]) as 3-O-rutinoside (31+/-1nmol/g), 3-O-galactoside (368+/-36nmol/g), 3-O-glucoside (155+/-15nmol/g), and 3-O-arabinoside (75+/-2.3nmol/g)[15]
  • Chlorogenic acid as main phenolic acid (96.5% of phenolic acids)[23] with total phenolic acids reaching up to 3% of weight[31]
  • Ferulic acid (7.38mcg/g[26] or 0.9% of total phenolic acids[23])
  • Vanillic acid at 104mcg/g[26]
  • p-coumaric acid at 1.4% total phenolic acids[23]
  • Caffeic acid at 1.2% total phenolic acids[23]
  • Vitamin C at 115+/-4nmol/g[15]

Other compounds include the stilbene compounds (resveratrol and pterostilbene) and the catechins, the latter of which can be structured into chains called procyanidins. There are some other trace phenolic acids and a low vitamin C content (relative to other fruits)

The leaves of blueberries also possess some bioactive components, including:

  • Chlorogenic acid (64mg/g dry leaf weight[32])
  • Hyperoside (8.58mg/g dry leaf weight[32])
  • Procyanidins, mostly A2 (catechin and epicatechin)[33] comprising 11.3% of the leaf weight[34] and catechin/epicatechin glycosides[33]
  • Cinchonain Ia and Ib (extension units of the procyanidins)[34]
  • Vaccinin A[34]

There is a negligient anthocyanin content in the leaves, as evidenced by the lack of blue-red pigmentation. The leaves are also known to be bioactive in regards to fat metabolism[35][36] and blood pressure[37] although most of the information on this page does not refer to leaf extracts (instead referring to the berries).

Water extracts of the leaves also appear to be biologically active, particularly because of the procyanidin and catechin content as well as other polyphenolics (such as chlorogenic acid and quercetin glycosides). They do not have a significant anthocyanin content like the berries do

1.3

Structure

Anthocyanins are a class of bioflavonoid which are characterized by having a 2-phenylbenzopyrylium (flavylium cation) skeleton with added hydroxyl or methoxy groups. Relative to other flavonoids, they are different as the oxygen in their backbone is highly polar.

Anthocyanins are relatively unique flavonoids that are found in fruits and vegetables of the dark blue to black coloration range, with a few expections being those that are rich in pelargonidin (which is red, and thus found highly in strawberries)

The term procyanidin (interchangeable with 'proanthocyanidin') is used to refer to dimers or larger compounds composed of catechin molecules; commonly seen in food products or supplements that also have a catechin content such as cocoa extract, grape seed extract, or pycnogenol. Despite being named proanthocyanidins, they have no relation to the anthocyanins.

When looking at the procyanidin component of blueberries (compounds consisting of multiple catechin units), it seems that while 8.4-11.9% of catechins are not bound in procyanidin structure (monomers) that there are mostly dimers (18.0-32.1%) with less trimers (7.6-11.2%), hexamers (6.9-15.8%), and heptamers (5.9-16.6%) in blueberries.[19]

Due to the large procyanidin content of blueberries, there may be more catechins that previously detected and noted. The monomers (catechins not in procyanidin configuration) consist of around one tenth of total catechins and the most prevalent procyanidin is a B-type dimer

1.4

Properties

Freeze drying has been found to reduce total anthocyanin content by 3.9%,[23] which is not an overly large amount as anthocyanins can inherently vary two-fold in blueberries.[23] Various phenolics acids (ferulic, vanillic, etc.) experience a 1.9-fold increase upon freezing.[23]

Blanching berries (usually prior to processing) does not appear to inherently alter anthocyanin content (increase in the content of chlorogenic acid and other phenolic acids)[38] and may reduce the losses in other forms of treatment.[39][40] Furthermore, blanched berry produts appear to have a 25% increased bioavailability of anthocyanins when compared to control berries.[38]

Heat treatment of anthocyanin containing berries (as puree) for 20 minutes as increasing temperatures (20-70°C range) is able to reduce anthocyanin count by 21%.[41]

Freezing technically reduces anthocyanins, but this is likely too small of a reduction to matter. Heat treatment is more likely to reduce anthocyanin content when it is prolonged, and blanching not only protects anthocyanins but may make them more bioavailable

Prolonged storage of freeze-dried blueberry powder reduces the anthocyanin content of the powder in a temperature dependent manner, with low losses near room temperature (3% loss at 25°C over 14 days) and higher losses in heat (80°C causing 85% loss within three days),[42] the half-life of decay at 25°C was 139 days.[42]

Refrigeration of heat-treated anthocyanins results in degradation,[43] with 60 days of storage at 31°C causing complete elimination of anthocyanins (despite other polyphenolics being preserved).[44]

In cold storage, blueberries are either stable or experience small increases in anthocyanin content and total antioxidant capacity.[45][46]

Exposure to high oxygen environments does not appear to negatively affect the anthocyanin content of blueberries, instead also causing a slight increase.[47]

Blueberries lose their anthocyanin content with prolonged storage after heat treatment, although this can be attenuated greatly by keeping them in cool conditions (room temperature is associated with slight degradation, refrigeration much less). Prolonged cold storage or exposure to oxygen seems to support their structure and may enhance anthocyanin content

The pomace of blueberries (skins, pulp residue, and seeds left after pressing juice) appears to still retain a fair bit of anthocyanin and procyanidin compounds which are heat resistant at 40°C over three days (albeit degraded in a temperature-dependent manner above 60°C)[48] and, while bound to fibers in the pomace, can be released during acid hydrolysis.[49] Blueberry pomace is likely to be used as an industrial additive for flavoring or colorants due to it being deemed a 'waste product' and cheap.[50][51]

A byproduct of making blueberry juice, the pomace, can be used as an additive to functional foods as colorant or flavoring. It will likely retain biological potency if used in this manner unless thoroughly heat treated

1.5

Fruits versus Supplementation

It has been noted that an oral intake of approximately 2% blueberry lysophilized powder in the diet of rats (which is about 400mg per rat or 1g/kg[52]) is equivalent to oral intake of 0.16g/kg in humans or, for a 150lb human, 10.9g. As 400mg blueberry powder is equivalent to 4,400mg fresh blueberries (water weight inclusive), then 10.9g of the powder is approximately 120g of blueberries.

Studies that use an oral intake level of about 2% blueberry powder in rats is equivalent to an average human consuming 11g of a powdered blueberry supplement of 120g of fresh berries

2.

Longevity

2.1

Caloric Restriction

Dietary supplementation of polyphenolics (a mixture of blueberry at 2%, pomegranate at 0.3%, and the green tea catechin EGCG at 155mcg/kg) alongside caloric restriction appears to augment the pro-longevity effects of said caloric restriction (enhancing the median lifespan from a 37% increase to a 46%)[53] which was hypothesized to be due to the polyphenolics suppressing neuronal inflammation which was unregulated in caloric restriction control.[53]

3.

Pharmacology

3.1

Digestion and Absorption

Anthocyanins appear to undergo slightly degradation in saliva (with aglycones being more susceptable than glycosides), which appears to be mediated by salivary bacteria.[54]

The bioavailability of anthocyanins (regardless of source) tends to be in the range of 1.7-3.3%.[55]

3.2

Serum

Anthocyanins have been confirmed to be absorbed from the intestines[56] and oral ingestion of 720mg anthocyanins (as glycosides) in older women has been noted to increase serum anthocyanins to 97.4nM (with a range of 55.3-168.3nM at a Tmax of 71.3m.[57]

In otherwise healthy men consuming 300mg fresh berries (348mg anthocyanins), plasma anthocyanins have been noted to reach 13.7+/-10.7nM after one hour and 18.7+/-6.4nM after two hours.[58]

Blueberry juice consumption (1,000mL) has also been confirmed to be a bioavailable source of Quercetin, increasing plasma quercetin from a baseline level of 28.8nM to 79.2nM but a very minimal effect on plasma vitamin C (from 58μM to 61μM).[59]

3.3

Metabolism

Blueberry tannin structures have been noted to be metabolized into smaller phenolic acids via the bacteria Lactobacillus plantarum (expresses tannase) such as phenyllactic acid, hydroxylactic acid, and 3,4-dihydroxyphenylpropionic acid.[60] This bacteria is found in a variety of fermented food products, and can survive in the human intestinal tract and thus these metabolites may be biologically relevant.

4.

Neurology

4.1

Pharmacokinetics

500µg/mL of blueberry extract, used in in vitro studies, appears to correlate to a 1% dietary intake of blueberry in rats, or 200mg per rat (500mg/kg)[52] with a 2% dietary intake (also commonly used in rat studies) correlating to 400mg per rat or 1g/kg oral intake (in regards to the dehydrated powder).[52]

4.2

Glutaminergic Neurotransmission

NDMA receptor dependent long term potentiation (LTP) is a process that is known to be involved in memory formation[61] and its decline with aging known to (in part) underlie memory loss,[62] particularly spatial memory formation.[61][63] This hypoactivity is thought to be due to both less receptor expression[64][65] and less stimuli to activate signalling.[66]

Supplementation of 1.8% blueberry water extract in the diet of aged rats over eight weeks is able to restore LTP in the hippocampus back to the level of young control rats[67] although it did not appear to restore levels of the NMDA receptor subunits that were impaired in aged rats, although it could increase NR2B phosphorylation.[67]

This is likely a general mechanisms rather than one specific for glutaminergic receptors, since other parameters that are reduced during aging (dopamine release, GTPase activity, and Ca45 buffering) are known to be restored to youthful levels alongside memory enhancement.[68]

The decline in NMDA receptor function seen with aging appears to be restored to the levels of youthful controls with daily ingestion of blueberry extracts

4.3

Appetite

In diabetic rats, supplementation of blueberry juice appears to attenuate the diabetes-induced hyperphagia (which resulted in less weight gained).[69] Other studies using rats and blueberries in the dosage range of 1-3% do not find significant alterations in food intake.[35]

The addition of 50g fresh blueberries to a test meal has failed to significantly alter the satiety rating of the meal in humans.[70]

Although it is possible to reduce appetite secondary to the insulin sensitizing effects of blueberry ingestion, the lone human study using 50g of blueberries alongside a meal failed to find an effect

4.4

Neuroinflammation

In vitro, blueberries have shown anti-inflammatory effects via reducing the release of inflammatory biomarkers (TNF-α and COX2) from activated microglia,[71] which respond to inflammatory signals and contribute to some pathological conditions of cognitive decline.[72] Nitric oxide production is reduced at the concentration of 1-2mg/mL,[26] although some isolated compounds of blueberry are more potent (20-30μM of malvidin-3-O-glucoside and 10-30μM pterostilbene).[26] Elsewhere, a more potent inhibitory effect has been noted (IC50 of 100μg/mL with no more potency at 250-500μg/mL[71]) despite this dose being ineffective elsewhere.[26]

In cells exposed to TNF-α (proinflammatory molecule that can cause oxidation[73] via NADPH oxidase activation[74] from sphingolipids[75]), 5μg/mL of blueberry extract can reduce oxidation to near control levels without affecting basal oxidation;[6] this was attributed to the nonpolar fragment with poor direct antioxidant capabilities, and is thought to be due to inhibiting the NADPH oxidase enzyme from assembling in the plasma membranes[6] which is required for NADPH oxidase functioning.[76]

In vitro, blueberries appears to be able to suppress microglia activation in response to inflammatory stressors such as LPS. This occurs in a concentration range that is able to be achieved via dietary intake or supplementation, and may be related to NADPH oxidase inhibition (similar to spirulina)

NF-kB mRNA has been shown to be normalized despite kainic acid administration when blueberries are ingested at 2% of the diet over 8 weeks[77] and the increase in NF-kB seen with aging[78] appears to be attenuated with blueberry at the same dose over 4 months.[52]

Blueberries have been noted to decrease microglial activation (in response to kainic acid) when consumed in the diet of rats at 2% of the diet over 8 weeks, to about halfway between kainic acid control and true control.[77]

Neuroprotective effects against inflammation have been noted in rats with oral ingestion of blueberries daily in the diet

4.5

Neurogenesis

Blueberry ingestion has been noted to augment a kainic acid induced increase in IGF-1 at 2% of the diet over 8 weeks, without inherent effect on rats not administrated kainic acid.[77]

Dietary supplementation of 2% blueberry (179.0mcg/g anthocyanins and 74.1mcg/g flavanols) as well as either the anthocyanins or flavanols in isolation at the same dose was able to increase brain BDNF levels with no influence on pro-BDNF, and the anthocyanin group increased BDNF mRNA levels (81% in the hippocampus).[27] This has been confirmed to occur in otherwise healthy young rats as well at 2% of the diet as blueberries.[79]

4.6

Memory and Learning

Isolated pterostilbene has been noted to improve cognition in aged rats when fed in the diet at 0.004-0.016% over 12-13 weeks, with the improvements correlating with hippocampal concentrations of pterostilbene.[80] Similar benefits have been found with 2% blueberries in the diet, although this study attributed the observed benefit to anthocyanins.[81]

Cognitive impairments by kainic acid as assessed by water maze have been noted to be attenuated with 2% blueberry in the diet over 8 weeks in rats[77] and the cognitive decline (object recognition task) in aged rats appears to be normalized to young control at the same dose.[52]

In aged rats given 2% blueberries or the anthocyanin equivalent (179mcg/g), the improvements in spatial memory and attention performance were increased to an equal degree.[27] This study also noted that oral ingestion of flavanol compounds (59.3mcg/g (+)-catechin in the feed and 14.8mcg/g (-)-catechin) was comparable efficacious,[27] and the increase in cognition seen in older rats with blueberry ingestion at 2% of the diet correlates with CREB phosphoryation and BDNF production.[82]

In studies on cognitive decline, the addition of either blueberries to the diet or isolated blueberry components is able to reverse or at least attenuate the changes seen in cognition

One study in otherwise healthy young rats given 2% of the diet as blueberries (approximately 11.2mg/kg anthocyanins and 4.61mg flavanols daily) for seven weeks noted improvements in spatial memory formation associated with activation of ERK1/2 and CREB as well as increased levels of BDNF.[79]

An improvement in spatial memory formation has been confirmed in otherwise healthy young rats given blueberry daily

In twelve elderly humans with age-related memory decline, concord grape juice (6-9mL/kg, anthocyanin content not disclosed) daily for 12 weeks was associated with an improvement of verbal learning with nonsignificant benefits in spatial and verbal recall[83] and a later study using similar dosing in a similar population found cognitive benefit with wild blueberry juice (428-598mg anthocyanins daily) as assessed by verbal memory tests.[84]

Anthocyanins as well as blueberry juice itself have been demonstrated to improve cognition in elderly humans

5.

Cardiovascular Health

5.1

Cardiac Tissue

A higher dietary intake of anthocyanins is associated with less risk for myocardial infarction in young and middle-aged women.[85]

There appears to be a protective effect on cardiac lesions induced by myocardial infarction when bluberry is supplemented at 2% of the rat diet for three months preceding experimental infarction[86] and one year of daily blueberry supplementation at 2% of the rat diet following an experimental myocardial infarction showed protective effects as mortality was reduced by 22% in the blueberry group relative to placebo without influencing blood pressure nor heart rate.[87]

In vitro, blueberry extract at 100μg/mL shows protective effects against ischemic injury, the protective effect and the antioxidant effects were nitric oxide dependent and abolished by L-NAME.[8] Blueberry extract was found to upregulate eNOS activity in ischemic cardiac tissue.[8]

It appears that blueberry supplementation causes an increase in the threshold required for mitochondrial permeability transition (MTPt) to around 24% at 2% of the diet.[86] MTP is increased by reactive oxygen species[88] and involved in increasing mitochondrial permeability and cell death by causing an influx of molecules into the mitochondria,[89][90] and the increased threshold seen with blueberry ingestion[86] makes it more difficult for a stressor to cause cell death via MTP.

Blueberry has protective effects against myocardial infarction in both a preventative and rehabilitative manner, which is associated with both nitric oxide metabolism and making it more difficult for a stressor to increase MTP and cause cellular death

5.2

Blood Flow and Pressure

In rats fed blueberries (fermented with Lactobacillus plantarum to break down tannins into smaller compounds) or the isolated molecules that were produced after fermentation (phenylactic acid, hydroxylactic acid, and 3,4-dihydroxyphenylpropionic acid) failed to reduce the hypertension caused by L-NAME.[60] Elsewhere, blueberries have been found to reduce blood pressure in hypertensive rats (spontaneously hypertensive rats) at 2-3% of the diet[91] which has been replicated elsewhere.[92]

There are possible interactions with potassium channels (as an opener, similar to minoxidil) and hydrogen sulfide metabolism with blueberry juice.[93]

In animals, blueberry appears to be effective in reducing the blood pressure of spontaneously hypertensive rats although if the rats are treated with L-NAME (nitric oxide inhibitor) the benefits are prevented, suggesting blueberry is working vicariously through nitric oxide metabolism

300g fresh berries (348mg anthocyanins) has failed to influence blood flow, heart rate, or nitric oxide concentrations following acute administration.[58] In persons at risk for cardiovascular disease, 50g of freeze-dried blueberries (350g berry equivalent; 1624mg phenolics and 742mg anthocyanins) daily for eight weeks is able to reduce both systolic (6%) and diastolic (4%) blood pressure.[94] In postmenopausal women with pre-existing pre- or stage 1 hypertension, 11 g of freeze-dried blueberries twice daily for 8 weeks (22 g per day containing 186 mg phenolics and 103 mg anthocyanins) reduced systolic (5%) and diastolic (6%) blood pressure as well as reducing brachial-ankle pulse wave velocity (PWV), while not affecting carotid-femoral PWV.[95]

Preliminary human evidence suggests that freeze-dried blueberry powder may be able to reduce blood pressure by around 5%.

5.3

Lipoproteins

Anthocyanins appear to be able to prevent the oxidation of LDL cholesterol in vitro[96][97] with malvidin being the most potent anthocyanin[96] yet blackberries being more potent than blueberries (despite the high malvidin percentage of the latter) due to more overall anthocyanins.[97]

In vitro studies suggest the direct free radical scavenging effects can reduce the rate of lipoprotein oxidation

Oral ingestion of 75g of fresh berries (1.3% anthocyanins) alongside a standardized meal has been noted to delay lipoprotein oxidation in vivo when measured at three hours after the meal[98] and in persons at risk for cardiovascular disease daily intake of 742mg anthocyanins over eight weeks is associated with a 27% reduction in LDL oxidation.[94]

Appears to be active following oral ingestion of berries

Oral consumption of 22.5g blueberry extract (1462mg phenolics and 668mg anthocyanins) daily for six weeks in obese and insulin resistant persons failed to significantly alter HDL-C, LDL-C, or total cholesterol[99] and these lipid biomarkers are unaffected with 724mg of anthocyanins daily for eight weeks in persons at risk for cardiovascular disease.[94]

5.4

Triglycerides

In guinea pigs fed a high cholesterol diet and 8% blueberries by weight, blueberry ingestion failed to influence serum triglycerides despite reducing hepatic triglycerides (50% attenuation).[100] This inefficacy of blueberries on serum triglycerides extends to other animals such as rats.[35]

Oral consumption of blueberry (1462mg phenolics and 668mg anthocyanins) over six weeks in obese and insulin resistant persons has failed to reduce triglycerides[99] and in persons at risk for cardiovascular disease there is still no change in triglycerides.[94]

5.5

Atherosclerosis

Ingestion of 1% of the mouse diet as blueberries appears to be able to delay progression of atherosclerotic lesions in ApoE-/- mice without apparent changes in lipoprotein and triglyceride levels.[101]

6.

Interactions with Glucose Metabolism

6.1

Carbohydrate Absorption

Isolated anthocyanins (albeit not from blueberry) have previously been linked to inhibiting α-glucoside with an IC50 below 200mM with pelargonidin based glycosides having an IC50 of 4.6mM,[102] and procyanidins are known to be capable of inhibiting these enzymes as well (as is seen with Pycnogenol).[103]

Isolated components of blueberries have previously been linked to inhibiting enzymes of carbohydrate absorption

Blueberries have an inhibitory effect on α-amylase with inhibition between 5.06-24.01% and a more potent inhibitory effect on α-glucoside with 90.42-92.83% inhibition (44.3-109.1mg/L anthocyanin concentration)[104] with the exact potency of the berries correlating highly with the anthocyanin and phenolic content[25] and in the best case scenario being comparable to arcabose.[105]

The potency of blueberries seem less than that of red berries, apparently due to the soluble tannin component.[106]

Blueberries show inhibitory effects on enzymes of carbohydrate absorption, with more potency against α-glucoside than α-amylase. This inhibition is dose-dependent and correlated with the anthocyanin content, with darker berries or parts of the berries with higher anthocyanin content (peels) having more inhibitory potential

Oral ingestion of 50g fresh blueberries mixed into pancakes (compared to control pancakes) failed to significantly affect postprandial glucose absorption (both max value and AUC were unaltered)[70] and high dose anthocyanin supplementation (100g berries conferring 1,200mg anthocyanins) has failed to reduce the postprandial spike in blood glucose, instead being associated with a slight increase 3-4 hours after ingestion.[107]

6.2

Blood glucose

While one study using blueberry leaves (50mg myricetin and 50mg chlorogenic acid per 300mg supplemental leaf extract) in type II diabetics has reported a reduction in blood glucose from 143+/-5.2mg/L to 104+/-5.7mg/L (28%),[108] other studies using blueberry fruits have failed to note reductions in blood glucose in persons with insulin resistance[99] or persons at risk for cardiovascular disease.[94]

6.3

Insulin Sensitivity

Consumption of 22.5g blueberry extract (1462mg phenolics and 668mg anthocyanins) daily for six weeks in obese but non-diabetic adults with insulin resistance was able to improve insulin sensitivity by more than 10% in two-thirds of participants, with an average group mean improvement of 22.2+/-5.8% (placebo 4.9+/-4.5%).[99] A failure to benefit insulin sensitivity has been noted elsewhere in persons who were not insulin resistant.[94]

7.

Fat Mass and Obesity

7.1

Mechanisms

In rat adipocytes (3T3-F442A), 150-250mg/mL of blueberry polyphenols is able to suppress the differentiation of fat cells and dose-dependently reduce lipid accumulation (27-74%).[109]

Blueberry polyphenols at doses of up to 250mg/mL have failed to significantly increase lipolysis.[109]

Very high concentrations (likely not relevant to oral supplementation) can suppress fat cell differentiation, but even this inpractically high concentration is not able to increase lipolysis

Blueberry supplementation to obese rats appears to modify PPAR content in both adipose and skeletal muscle towards more glucose uptake and fat oxidation.[110]

Influences on PPARs may beneficially influence both fat cell differentiation and glucose uptake

7.2

Interventions

Blueberry appears to be able to improve glucose tolerance and handling in the body, and even in interventions where weight is loss (naturally aids in glucose tolerance) it cannot fully explain the actions of blueberries.[69]

The bioaccumulation of macrophages in adipose tissue (body fat) tends to lead to specific insulin resistance in adipose tissue as well as some other comorbidities of obesity,[111][112] and can lead to excessive adipocyte death.[113][114] Supplementation of blueberries in the diet has been confirmed to reduce macrophage infiltration via reducing levels of the protein it uses to adhere to tissues (MCP-1)[115] and supplementation of 4% of the diet as blueberry powder (contributing 2.7% of total calories and 3.1% total anthocyanins in the diet) over 8 weeks in obese mice fully prevented the reductionin insulin sensitivity in adipose tissue seen with the high fat diet.[116]

Along the lines of inflammatory accumulation, supplementation of an 8% diet to obese rats with metabolic syndrome has resulted in reductions in several inflammatory biomarkers such as CRP (13.1% reduction in serum levels), TNF-α (25.6% reduced circulating levels, 52-59% reduced expression), IL-6 (14.9% reduced serum levels, 64-65% reduced expression), and NF-kB activity (reduced expression in the liver and adipose by 25% and 65%, respectively).[117]

When looking at the insulin sensitivity of fat cells, there appears to be a protective effect of blueberry ingestion on the development of insulin resistance. This appears to be secondary to an anti-inflammatory effect, by preventing macrophages from getting inside adipose tissue

Despite apparent improvements in insulin sensitivity, weight gain and fat cell size as well as adipokines (leptin and adiponectin) are not affected by blueberry supplementation.[116] Adiponectin has been noted to be increased up to 24.1% in the serum obese rats (its expression increased by 25%)[117][69] and leptin decreased[118] with blueberry juice or purified anthocyanins, and while other studies have noted a failure to prevent weight gain associated with 10% blueberry powder to rats[119] several studies using blueberry juice or purified anthocyanins (equivalent to the feeding of blueberry powder) seem to find an attenuated rate of fat gain during obesogenic diets in diabetic[69] and high fat fed rats.[119][118]

The adipokines (Leptin and adiponectin mostly) appear to be altered in an anti-obesogenic manner with consumption of blueberries in animals that are likely to have a large degree of adipose inflammation, while there does not appear to be a per se effect on these adipokines (without attenuating inflammation, no changes are noted)

Although there have been failures for the fruit extracts themselves to reduce fat mass[116][119] there are some studies noting efficacy;[110] it is unsure what underlies the differences in the observed results.

When looking at interventions measuring fat gain over time, blueberry juice and purified anthocyanins appear to exert a minor anti-obese effect which is less reliably seen with the whole fruits.

8.

Exercise and Skeletal Muscle

8.1

Interventions

Consumption of blueberries in a smoothie 10 and 5 hours before exercise (as well as immediately after and 12 and 36 hours afterwards; five drinks in total with each consisting of 200g berries and 96.6mg anthocyanins) is able to speed up the recovery of power following eccentric leg extensions, but does not appear to influence muscle soreness nor fatigue during the workout.[120]

9.

Skeleton and Bone Mass

9.1

Interventions

Consumption of blueberries in the diet of pre-pubertal female rats was effective in preventing menopausal bone loss later in life, despite supplementation not continuing for that time.[121] This was thought to be due to enhancing peak bone growth (a common preventative strategy that is targeted towards youth[122]) and related to a reduced rate of cellular senescence[121] and increase osteoblastic growth in young rats.[123]

10.

Interactions with Hormones

10.1

Estrogen

5% of the diet as blueberries to rats bearing estrogen-responsive tumors has been noted to reduce the protein content of the CYP1A1 enzyme[124] which was associated with delaying the onset of tumors by 28.5%, slightly less potent than blackberries.[124] This reduction in CYP1A1 activity has been confirmed elsewhere at 2.5% of the diet, although blueberries again underperformed relative to blackberries[125] which is thought to be due to the higher content of ellagic acid.[124][125][126]

The ellagic acid metabolites have previously been noted to act as selective estrogen receptor modulators (SERMs)[127] and this property has been noted with anthocyanins as well, as anthocyanin aglycones can induce signalling through estrogen receptors yet reduce the signalling of estradiol.[128] Despite these mechanisms, supplementation of blueberries at 2.5% of the diet does not alter the ability of estrogen to signal through its receptors (both ERα and ERβ) suggesting it requires too high a concentration.[125]

Blueberry ingestion may reduce CYP1A1 expression, although all studies currently have been conducted in rats bearing mammary tumors. The actual potential interactions of blueberry at the level of the receptor (acting as a SERM) likely do not apply to oral supplementation

11.

Interactions with Oxidation

11.1

Mechanisms

Anthocyanins have been noted to directly sequester superoxide radicals,[129][130] hydroxyl radicals,[130] lipid peroxides[130][131] and lipid peroxidation induced by copper,[132] and the nitric oxide free radical.[133] This antioxidant capacity of blueberries appears to occur intracellularly at very low concentrations (less than 1µg/mL anthocyanin concentration)[134] which suggests that they are active despite the poor oral absorption.

Anthocyanins have the capacity to directly scavenge free radicals

Ingestion of blueberries (35g or 75g fresh berries) alongside breakfast noted that the higher dose was associated with a higher plasma antioxidant capacity as well as increased urate and vitamin c concentrations.[98]

Oral intake of low doses of berries does appear to confer antioxidant effects to humans within 3 hours after ingestion

The actions of the enzyme NADPH oxidase require it to gather in the membrane of a cell where it localizes with its subunits,[76] and then it can produce superoxide radicals and contribute to oxidation;[74] this enzyme is activated by various proinflammatory cytokines such as TNF-α[73] and inhibiting it can reduce NADPH oxidase dependent oxidation (from inflammatory signals). Blueberries have been noted to inhibit this enzyme, and a fraction of the berry that is nonpolar (not anthocyanins) appears to be able to do this despite having a poor direct antioxidative effect.[6]

Components of blueberries may also inhibit NADPH oxidase, which would reduce the oxidation produced from an overactive immune system

11.2

Antioxidant Enzymes

Blueberry has been noted to induce nuclear accumulation of Nrf2 in a cancer model of DMBA-induced carcinogenesis[135] and studies that measure overall protein content note a normalization of Nrf2 levels (1.5% for 8 weeks) in instances of liver damage where it is abnormally elevated[136] and 0.6% for 21 days may increase Nrf2 mRNA in otherwise healthy rats.[137]

Antioxidant enzymes including SOD, Glutathione peroxidase, and catalase (reduced by DMBA toxin) have been noted to be preserved with blueberry (200mg/kg)[135] and the reduction seen in hepatic fibrosis also abrogated.[136] Upregulation of these enzymes is known to be secondary to activation of Nrf2[138][139] as well as NADPH quinone oxidoreductase 1 (NQO1).[140]

Blueberry appears to interact with the transcription factor Nrf2 (which regulates the antioxidant response element of the genome), and secondary to this it may increase levels of antioxidant enzymes. This may be a more indirect way to promote antioxidant defense

11.3

Irradiation

75μg/mL of blueberry anthocyanins or procyanidins have both been shown to reduce UV-induced DNA damage in cellular cultures.[141]

11.4

DNA Repair

DNA repair enzymes have been noted to be upregulated with blueberry extract (200mg/kg), with a potency greater than astaxanthin (15mg/kg) and ellagic acid (0.4mg/kg) but lesser than chlorophyllin (4mg/kg)[135] which may be secondary to Nrf2 activation.[142]

DNA damage has been noted to be reduced in humans following consumption of blueberry extract (15g powder conferring 375mg anthocyanins) for six weeks as assessed by less formamidopyrimidine DNA glycosylase (FPG)–sensitive sites (24.2%) and H2O2 induced damage (19.8%)[143] and over four weeks of 1,000mL of a blueberry drink DNA damage has been noted to be reduced in healthy controls (20% less oxidative damage).[59]

Following acute oral ingestion of 300g fresh blueberries (348mg anthocyanins and 727mg phenolic acids) to otherwise healthy male subjects in the form of a gel (in order to mask placebo) noted that a single oral dose of blueberries was able to reduce H2O2 induced DNA damage from 51.7% to 42.7%.[58] However, the reduced DNA damage was very transient and disappeared after two hours[58] and other studies using 200g of a mixed berry desert daily for two weeks have failed to find a significant change in basal DNA damage.[144]

Appears to reduce DNA damage, and may do so after a single dosage. This appears to occur following higher doses of blueberries in otherwise healthy humans, but it is short lived and may not be practically relevant

12.

Inflammation and Immunology

12.1

Virology

The phenolics of blueberries may possess anti-influenza properties in vitro.[10]

12.2

Exercise Immunology

Oral ingestion of 250g fresh berries daily for six weeks (and a single dose of 375g taken one hour before exercise) in well trained runners subject to 2.5 hours of moderate intensity exercse (72% VO2 max) is able to increase serum IL-10 relative to control and increase natural killer cell count by 76-122%, although other immune cells (leukocytes, neutrophils, monocytes, and both T and B lymphocytes) and cytokines (IL-1ra, IL-6, IL-8) were unaffected.[145] IL-6 has been found to be unaffected elsewhere with exercise in untrained persons[120] and is unaffected in sedentary persons at risk for cardiovascular disease.[94]

Appears to enhance natural killer cell content when taken prior to exercise or in the diet routinely

13.

Interactions with Organ Systems

13.1

Liver

In studies assessing liver fat, oral supplementation of blueberries to the diets of rats appears to cause a dose-dependent reduction in hepatic fat accumulation.[35]

Reductions in liver fat can occur independently of any changes in serum triglyceride, which blueberry supplementation does not appear to significantly influence.[100][35]

May reduce liver fat accumulation despite its inefficacy in reducing circulating triglycerides

The oxidative stress induced by diethylnitrosamine is able to be attenuated with high dose blueberry supplementation in rats (5-10% of the diet)[146] and blueberry juice has been noted to reduce fibrosis induced by CCL4 over 8 weeks when consumed at 15g/kg daily.[147]

13.2

Kidneys

Supplementation of 2% blueberries in the diets of hypertensive rats is able to improve glomerular filtration rate and reduce renovascular resistance secondary to improving blood pressure; these changes are thought to be due to antioxidant properties of the blueberries as improvements in oxidative biomarkers in the kidneys were noted.[91]

The conditional reduction of blood pressure with blueberry supplementation or ingestion is known to be able to improve kidney function

14.

Nutrient-Nutrient Interactions

14.1

Spirulina

Spirulina is a highly efficacious antioxidant compound due to the C-phycocyanin component, with 0.1-0.33% of the diet as spirulina being more neuroprotective than a diet of 2% blueberries acutely albeit the opposite trend at 4 weeks afterwards.[148][149]

Blueberry and Spirulina are both neuroprotective, although spirulina appears to be significantly more protective when measured acutely while blueberries may be more rehabilitative

NT-020 is a combination of polyphenols from blueberry, green tea catechins, carnosine (from beta-alanine) and Vitamin D[150][151] and this combination supplement appears to be synergistic with spirulina in enhancing stem cell proliferation (CD34+ derived bone marrow cells). Although the exact molecule(s) mediating the synergism are not known, it was calculated at being 50% greater than the additive benefits.[152] The mechanism of synergism appeared to be via spirulina suppressing TNF-α induced suppression of stem cell proliferation, while some other agent was able to induce stem cell proliferation (and worked better when TNF-α could not act).[152] NT-020 overall is known to do this[153][154] in a synergistic manner itself[150] with all bioactives being somewhat active (hypothesized to be secondary to reducing oxidative stress[150]).

Although NT-020 (of which contains blueberry) is synergistic with spirulina in enhancing neurogenesis, it is not clear which of the bioactives (or whether a combination thereof) is required for this synergism

14.2

Vinegar

Blueberries fermented in alcohol followed shortly by acetic acid fermentation (vinegar, which is also inhernetly bioactive[155]) resulting in a fruit vinegar of 5.6% blueberry and 59.14% acetic acid failed to activate hepatic genes involved in fat metabolism (PPARα, CPT-1 and ACO) despite pomegranate vinegar doing so.[156] This synergism was thought to be due to the ellagic acid and punicalagin content, both of which are not present in blueberries.

No demonstratable synergism with blueberries and vinegar after fermentation, despite pomegranate showing good synergism

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