1. FRUIT AS MEDICINE:
BLUE BERRY,
GENUS VACCINIUM
By
Kevin KF Ng, MD, PhD
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL., USA
Email:kevinng68@gmail.com
A slide presentation for HealthCare Provider Jan, 2020

2. Outline of lecture
▪ What is blueberry
▪ History
▪ Scientific classification
▪ World and US production of blueberry
▪ Nutrient and bioactive compounds
▪ Pharmacology
▪ Clinical studies
▪ Summary

3. What is a blueberry
▪ Blueberries are perennial flowering plants with blue–
or purple–colored berries.
▪ They are classified in the section Cyanococcus within
the genus Vaccinium.
▪ Vaccinium also includes cranberries, bilberries,
huckleberries and Madeira blueberries.
▪ Commercial "blueberries" – including both wild
('lowbush') and cultivated ('highbush') blueberries –
are all native to North America.
▪ The highbush blueberry varieties were introduced into
Europe during the 1930s
https://en.wikipedia.org/wiki/Blueberry

4. History of blueberry cultivation
Adapted from https://rucore.libraries.rutgers.edu/rutgers-lib/45986/PDF/1/play/

5. Top Producing Countries of Blueberry Fruit(2018)
https://www.tridge.com/intelligences/billberry/production

6. Distribution of varieties of blueberry in the United States
https://myperfectplants.com/2018/08/31/different-blueberry-bushes/
Lowbush variety Northern highbush variety Southern highbush variety Rabbiteye variety

7. Scientific classification of blueberry
https://en.wikipedia.org/wiki/Blueberry

8. Major varieties of blueberry
▪ There are five major varieties of blueberry
grown in the United States:
▪ Lowbush Vaccinium angustifolium
▪ Northern highbush Vaccinium corymbosum
▪ Southern highbush Vaccinium formosum
▪ Southern Rabbiteye Vaccinium virgatum/ashei
▪ Hybrid half-high
▪ Of these, northern highbush blueberry
varieties are the most common types of
blueberries cultivated throughout the world.
Vaccinium angustifolium

9. Differences between lowbush and highbush blueberry
Lowbush blueberry Highbush blueberry

10. Anatomy of a blueberry fruit
https://www.kitchenstories.com/en/stories/4-things-to-know-about-blueberries-plus-3-new-recipes
calyx
skin
flesh
seed

11. Nutrient composition of blueberry
https://fdc.nal.usda.gov/fdc-app.html#/food-details/341640/nutrients

12. Nutrient and phytochemical composition of blueberry
Phytochemicals
https://fdc.nal.usda.gov/fdc-app.html#/food-details/341640/nutrients

13. Classification of bioactive compounds (mg/100g ) in
blueberry fruits
https://www.researchgate.net/figure/Phenolic-composition-of-blueberry-fruits_tbl2_281167873

14. Major bioactive compounds of ripe Blueberry Fruit
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581264/
60%-90% of total polyphenols
0.3% fruit
25-495 mg%
Chlorogenic acids

15. Anthocyanin content in blueberry compared with other fruits
https://academic.oup.com/advances/advance-article/doi/10.1093/advances/nmz065/5536953

16. What is an anthocyanin and anthocyanidin?
▪ Anthocyanin is a blue, violet or red flavonoid pigment found in
plants.
▪ The main difference between anthocyanin and anthocyanidin is
that:
▪ anthocyanin is a water-soluble vacuolar pigment whereas
▪ anthocyanidin is the sugar-free counterpart of anthocyanin.
▪ the color of both anthocyanin and anthocyanidin depends on the pH.
https://pediaa.com/difference-between-anthocyanin-and-anthocyanidin/
anthocyanin

17. Structural classification of 6 most common anthocyanidins.
https://onlinelibrary.wiley.com/doi/full/10.1111/1541-4337.12024

18. Scientific studies on polyphenols in blueberries.
▪ Most polyphenol studies have been conducted using the highbush
cultivar of blueberries (V. corymbosum),
▪ The content of polyphenols and anthocyanins in lowbush (wild)
blueberries (V. angustifolium) exceeds values found in highbush cultivars.
https://en.m.wikipedia.org/wiki/Blueberry

19. Scientific studies of anthocyanins
Cells
Antimicrobial
Antioxidant
Anti-inflammatory
Anticancer
Cardiovascular protection
Anti-obesity
Anti-diabetic
Animals
Antioxidant
Anti-inflammatory
Anticancer
Vision improvement
Cardiovascular protection
Neuroprotection
Anti-diabetic
Anti-obesity
Humans
Antioxidant
Anti-inflammatory
Anticancer
Vision improvement
Cardiovascular protection
Neuroprotection
Chemoprotection
Skin improvement
https://onlinelibrary.wiley.com/doi/full/10.1111/1541-4337.12024

20. Measurement of antioxidant activity
▪ Oxygen radical absorbance capacity: ORAC
▪ Cellular antioxidant activity: CAA
▪ Total phenolic content
free radicalantioxidant

21. A recent advancement in the measurement of antioxidant
activity in foods is the cellular antioxidant activity (CAA) assay
http://www.wildblueberries.com/health-research/antioxidants/

22. Damaging effects of free radicals: oxidative stress
▪ Production of free radicals in the human body:
▪ Effects of free radicals in the human body:
▪ Cardiovascular disease
▪ Cancer
▪ Aging process
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/

23. Antioxidant and Anti-Inflammatory Effects of Blueberry Anthocyanins
on Human Retinal Capillary Endothelial Cells (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842687/

24. Anthocyanin Supplementation Improves Endothelial Function in
Hypercholesterolemic Individuals (2011)
Levels of plasma anthocyanins (A), cGMP (B), and FMD (C) before and after (12 wks) capsule ingestion (n = 12).
Brachial artery flow-mediated dilation (FMD
http://clinchem.aaccjnls.org/content/57/11/1524

25. Effects of different anthocyanin treatments on cell viability in
Human Retinal Capillary Endothelial Cells (HRCECs)
exposed to high glucose for 24 and 48 h
∗ and ∗∗ indicate P < 0.05 and P < 0.01, respectively, compared to each NG group; #, ##,
and ### indicate P < 0.05, P < 0.01, and P < 0.001, respectively, compared to each HG group.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842687/

26. Blueberry and Mulberry Juice Prevent Obesity Development
in Mice (2013)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797064/
Body weight Liquid intake

27. Blueberry and Mulberry Juice Prevent Obesity Development
in Mice (2013)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797064/
Leptin Insulin HOMA-IR Adiponectin

28. Blueberry inhibits growth of breast cancer cells (2011)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862148/
weight % proliferation % apoptosis

29. Blueberry as a Potential Radiosensitizer for Treating
Cervical Cancer (2017)
▪ Cervical cancer (CC) is a leading cause of death in women worldwide.
▪ Radiation therapy (RT) for CC is an effective alternative, but its toxicity remains challenging.
▪ Blueberry is amongst the most commonly consumed berries in the United States. It has been
shown that resveratrol, a compound in red grapes, can be used as a radiosensitizer for prostate
cancer.
▪ In this study, we found that the percentage of colonies, PCNA expression level and the OD value of
cells from the CC cell line SiHa were all decreased in RT/Blueberry Extract (BE) group when
compared to those in the RT alone group.
▪ Furthermore, TUNEL+ cells and the relative caspase-3 activity in the CC cells were increased in the
RT/BE group compared to those in the RT alone group.
▪ The anti-proliferative effect of RT/BE on cancer cells correlated with downregulation of pro-
proliferative molecules cyclin D and cyclin E. The pro-apoptotic effect of RT/BE correlated with
upregulation of the pro-apoptotic molecule TRAIL.
▪ Thus, BE sensitizes SiHa cells to RT by inhibition of proliferation and promotion of apoptosis,
suggesting that blueberry might be used as a potential radiosensitizer to treat CC.
https://link.springer.com/article/10.1007/s12253-017-0319-y

30. Gut microbiota modulation accounts for the neuroprotective
properties of anthocyanins (2018)
• High-fat (HF) diets are thought to disrupt the profile of the gut microbiota in a manner that
may contribute to the neuroinflammation and neurobehavioral changes observed in obesity.
• we hypothesize that by preventing HF-diet induced dysbiosis it is possible to prevent
neuroinflammation and the consequent neurological disorders.
• Anthocyanins are flavonoids found in berries that exhibit anti-neuroinflammatory properties
in the context of obesity.
• Here, we demonstrate that the blackberry anthocyanin-rich extract (BE) can modulate gut
microbiota composition and counteract some of the features of HF-diet induced dysbiosis.
• In addition, we show that the modifications in gut microbial environment are partially linked
with the anti-neuroinflammatory properties of BE.
• Through fecal metabolome analysis, we unravel the mechanism by which BE participates in
the bilateral communication between the gut and the brain.
• BE alters host tryptophan metabolism, increasing the production of the neuroprotective
metabolite kynurenic acid.
• These findings strongly suggest that dietary manipulation of the gut microbiota with
anthocyanins can attenuate the neurologic complications of obesity, thus expanding the
classification of psychobiotics to anthocyanins.
https://www.nature.com/articles/s41598-018-29744-5

31. Determinant factors of the oral bioavailability of
bioactive anthocyanins
Modified from https://www.hindawi.com/journals/jo/2017/7351976/fig1/

32. Current reports of pharmacokinetics of anthocyanins in humans
after oral dose of 68-1,300 mg
‫٭‬https://www.sciencedirect.com/science/article/abs/pii/S1756464613001370
‫٭‬

33. Bioavailability study with radio-labelled anthocyanin
in humans (2019)
▪ After ingestion, anthocyanins are converted to a large number of products via
chemical events, human and microbial metabolism.
▪ Within 6 h after humans ingested 13C-labeled anthocyanin, substantial 13C-labeled
CO2 was detected in exhaled breath, which demonstrated rapid and complete
anthocyanin catabolism.
▪ >50% of the 13C still remained in the body after 48 h .
▪ Anthocyanins and their phase 2 metabolites persist in urine long after anthocyanin
intake , probably due to their transport in bile .
▪ Due to the catabolic action of gastrointestinal microflora on anthocyanins and other
food polyphenolics, phenolic acid products are very abundant in the large intestine .
https://academic.oup.com/advances/advance-article/doi/10.1093/advances/nmz065/5536953

34. Population studies on effects of blueberries in
chronic diseases (2019)
▪ Cardiovascular disease
▪ Prediabetes and Type 2 diabetes
▪ Neurodegenerative diseases
▪ Vision and Eye Health
▪ Blueberries, Anthocyanins, and Food Processing
https://academic.oup.com/advances/advance-
article/doi/10.1093/advances/nmz065/5536953

35. Meta-analysis: Hierarchy of evidence in clinical studies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049418/

36. Meta-analysis: Hierarchy of evidence in clinical studies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049418/

37. The effect of blueberries on preventing and improving
type 2 diabetes in obese and insulin-resistant adults.(2016)
* Studies that used bilberries.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187542/

38. Meta-analysis of effects of berries products consumption on
lipid parameters compared with control arms. (2016)
https://www.nature.com/articles/srep23625/figures/1

39. Effects of blueberry supplementation on blood pressure:
a systematic review and meta-analysis of randomized clinical trials (2017)
https://www.semanticscholar.org/paper/Effects-of-blueberry-supplementation-
on-blood-a-and-Zhu-Sun/95c81a21615be0022ccf9c8031686bd162e3dfda
SBP
DBP

40. Blueberry Supplementation Improves Memory in
Older Adults (2010)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850944/
Data show significantly improved performances for both the V-PAL, p = 0.009, and CVLT recall, p = 0.04.

41. Blueberry as a Potential Radiosensitizer for Treating
Cervical Cancer (2017):
Evidence from tumor mediators
https://link.springer.com/article/10.1007/s12253-017-0319-y

42. Common uses of blueberries
▪ Fresh fruits
▪ Dried fruit
▪ Juice powder
▪ Concentrate Powder (50:1)
▪ Juice.
▪ Smoothie
▪ Cakes
▪ Consumer goods:
▪ Jellies
▪ Jams
▪ Pies
▪ Muffins
▪ Wines

43. Antioxidant activity of blueberry fruit is impaired by
association with milk (2008)
https://www.sciencedirect.com/science/article/abs/pii/S0891584908007454

44. Some delicious blueberry cuisine

45. Pesticides in blueberries:
Environmental Working Group's "Dirty Dozen"
▪ Blueberries are a popular fruit because they're
high in antioxidants which have been tied to
protective health benefits.
▪ In total, domestic blueberries tested positive for
42 different pesticide residues, and 73 percent of
the blueberries contained two or more pesticides.
https://www.cbsnews.com/pictures/pesticides-in-produce-environmental-working-groups-dirty-dozen/3/

46. Side effects and safety
▪ When taken by mouth: Blueberry fruit is LIKELY SAFE for
most people when consumed in the amounts found in
food.
▪ Blueberry may enhance the effects of anti-diabetic
medications.
▪ There is not enough scientific information to determine
an appropriate range of doses for blueberry.

47. Summary
▪ Blueberry is a flowering plant with blue or purple fruits.
▪ It is native to North America but cultivated since 1911.
▪ Anthocyanin flavonoids account for 60% to 90% of the
total polyphenolics in ripe blueberries.
▪ Clinical studies show that blueberries are beneficial for
patients with diabetes, hypertension, hyperlipidemia
and cancer.
▪ The bioavalability of anthocyanins is about 1% and the
beneficial effects of blueberries may be due to the
metabolites produced by the microbiome in large
intestine.

48. ANY QUESTION?
Please contact
Kevin KF Ng, MD, PhD
Email: kevinng68@gmail.com
48