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FLORIDA DEPARTMENT OF CITRUS
1
Staying on Trend: The Powerful
Flavonoid Consumers Need
Navindra P. Seeram, Ph.D.
Bioactive Botanical Research Laboratory
Outline
1. Introduction– Florida Department of Citrus
– Dr. Navindra Seeram*
2. Overview– Plant Natural Products:
Flavonoids & Polyphenols
– Role of Flavonoid-Rich Plant Foods in Human Health and Disease
3. Orange Juice and Hesperidin– Published human studies
supporting health effects
4. Summary & Conclusions
*Dr. Seeram is an Associate Professor in the
Department of Biomedical and Pharmaceutical
Sciences, College of Pharmacy, University of Rhode
Island. Dr. Seeram received an honorarium for the sole
purpose of this presentation and has no other conflicts
of interest of note.
Plant Medicines
• Plants have been used as medicines by ancient
cultures for centuries e.g. Traditional Chinese
Medicine, Ayurveda, etc.
• The WHO estimates 80% of developing countries
currently use plants as basis of medicinal systems
• Used as foods, extracts, teas, tinctures, herbs and
spices, etc.
Examples of Pharmaceuticals from Plants
Salicin, constituent of willow bark;Aspirin: acetyl derivative
Dietary Plant PolyphenolsStilbenes
Resveratrol
OH
HO
OH
Phenolic polymers
OH
OHOC
OO
O
OO
O
OCOC
COOC
HO
HO
HOOH
OHOH
OHHO
HOHO
HO
HO
Casuariin
Ellagitannins
Proanthocyanidin
HO O
OH
OH
Procyanidin trimer(flavanol)
OH
OH
HO O
OH
OH
OH
OH
HO O
OH
OH
OH
OH
Isoflavonoid
Coumestans
Daidzein
Isoflavone
s
Coumestrol
HO O
OOH
O
HO O
OOH
Flavonoids
Flavones
Flavonols
Flavanones
Flavanols (Catechins)
Anthocyanins
HO O
OOH
OH
Apigenin
HO O
OOH
OH
OH
Quercetin
HO O
OOH
OH
Naringenin
HO O
OHOH
OH
OH
(+)-Catechin
HO O
OH
OH
OH
Cyanidin
+
OH
Phenolic acids
Cinnamic acid
COOH
COOH
OCH3
Ferulic acid
HOOH
OHO
HO
HH
H
O OH
OH
O
Chlorogenic acid
Lignans
HO
OH
OH
OCH3
OH
Secoisolariciresinol
H3CO
Examples of Polyphenol-Rich Plants
• Grape Seed & Red Wine
Extracts & Resveratrol
• Green Tea
Flavanols/Catechins
• Cranberry & PACs
Green Tea
Extract
Grape Seed
Extract
Citrus Fruits and Hesperidin
Hesperidin Dietary
Supplement Hesperidin
Powder Supplement
• Flavonoid found in citrus fruits and juices: lemon, lime,
grape fruit, and oranges (blond and blood)
• ‘Hesperidium’ = ‘modified berry with leathery rind’
• Isolated in 1828 from white inner layer of citrus peels
• 26-44 mg/100 mL pure orange juice (source: Phenol-Explorer)
• Also found in some other plants e.g. peppermint, Welsh
onion (a type of scallion)
What is Hesperidin?
• Flavanones– Naringenin– Hesperetin– Neohesperidose (Nh)– Rutinose (Ru)
• Polymethoxylated flavones– Nobiletin– Tangeretin– Apigenin– Luteolin– Diosmetin
• Flavonols– Quercetin– Kampferol
• Flavanone glycosides– Narirutin– Naringin– Hesperidin– Neohesperidin
Citrus Flavonoids*
*Anthocyanins found in red grapefruit & blood orange
Nutrient-Rich 100% Orange Juice (OJ)
EXCELLENT SOURCE
>20% Daily Value
• Vitamin C
• Calcium (fortified juices)
• Vitamin D (fortified juices)
GOOD SOURCE
10-19% Daily Value
• Potassium
• Folate
• Thiamin8 oz.
serving
LESSER AMOUNTS
<10% Daily Value
Magnesium
Vitamin B6
Vitamin A
Niacin
• Is the most commonly consumed and commercially produced food product that contains Hesperidin
• Hesperidin is naturally found in the pulp & peel and thus is ‘extracted’ into 100% OJ during its production
• 100% juice contains no added sugar
• 100% juice can help all ages meet daily fruit intake recommendations
Also…100% OJ
SOURCE: What We Eat in America, NHANES 2009-2010, available online at
https://health.gov/dietaryguidelines/2015-scientific-report/data-table-4.asp
Health Benefits of 100% OJ & Hesperidin
• Cardiometabolic:
endothelial function, blood
pressure and vascular
health
• Glucose homeostasis &
blood sugar control
• Immune system
• Cognition
• Gut health: anti-
inflammatory effects in
colon
Animal vs. Human Clinical Studies
HumansRodentsCell-Culture
What happens when we consume food
bioactives?
• Absorption
• Distribution
• Metabolism
• Excretion
Flavonoid Bioavailability & Metabolism
Phase I + II metabolism
EnterohepaticCirculation
LiverBile
Small intestine
Peripheral Tissues
Kidneys
Urine
Blood Circulation
Colon Microflora
Feces
Oral
Ingestion
Small Intestine
Phase II Conjugation: Glucuronidation; Sulfation; Methylation
Review of Published Human Studies
with 100% OJ and/or Hesperidin
Cardiovascular: Vasodilation & BP
OJ and Hesperidin
increased blood flow.
OJ was more potent
than Hesperidin in
acute vasodilation
suggesting synergistic
effects of compounds
in OJ.
-Morand et al. Am J Clin Nutr. 2011;93(1):73-80.
“Hesperidin contributes to the vascular
protective effects of OJ in healthy volunteers.”
CDP= control + placebo CDH= control + Hesperidin
Cardiovascular: Coagulant
Both OJ and red OJ
decreased pro-coagulant
activity of whole blood.
Since the flavonoid and
nutrient content of
blond OJ and red OJ
were similar, the authors
concluded the effect of
OJ is independent of its
anthocyanin content (as
previously
hypothesized).
-Napoleone et al. Thrombosis Res. 2013;132(2):288-292.
Effect of OJ intake on whole blood (WB) procoagulant
activity without (A), with TNFa (B) or with LPS (C)
Cardiovascular: Endothelial FunctionALL of the OJ drinks attenuated the adverse effects of high-fat meals on
endothelial function measured by a smaller reduction in blood flow
compared to the control.
-Rendeiro et al. Br J Nutr. 2017;116(12):1999-2010.
Control
Cardiovascular: Endothelial Function
All OJ drinks
sustained plasma
nitrite levels
-Rendeiro et al. Br J Nutr. 2017;116(12):1999-2010.
No dose-response relation was observed suggesting 100%
OJ containing 128 mg flavanones is sufficient (potentially
obtainable w/in recommended intakes) to attenuate effects
of high fat intake on vascular function.
Inflammation/Immune/Genetic
• 500 mL OJ or Hesperidin (146 mg) changed white blood
cell gene expression to an anti-inflammatory and anti-
atherogenic profile.
- Milenkovic et al. PLoS One. 2011;6(11):e26669.
• 500 mL OJ vs. isocaloric drink with or without Hesperitin
daily x 1 month did not affect immune system.-Perche et al. Clin Nutr 2014; 33(1):130-135
• Increased total antioxidant capacity of whole blood with
200ml 3/d x 4wk of OJ. -Constans J, et al. Clin Nutr. 2015;34(6):1093-1100
CognitionRandomized, double-blind, cross-over study in 24 healthy
overweight men (30-65 yr) evaluated 240 mL of flavanone-
rich OJ (272 mg) compared to an energy-matched placebo
consumed on different days separated by a 2-week
washout.
-Alharbi et al. Eur J Nutr. 2016;55(6):2021-2029.
Psychomotor speed
improved in OJ group
and was higher than
placebo at 2 and 6 hrs
Cognition
Flav-rich OJ attenuated
diminishing subjective
alertness over time compared
to placebo
-Alharbi et al. Eur J Nutr. 2016;55(6):2021- 2029.
Non-significant trends
(p=0.09) for improvement in
global score for OJ, whereas
placebo declined
Cognition-Kean RJ, et al. Am J Clin Nutr. 2015;101(3):506-514.
Global cognitive function was
significantly better following
consumption of 500mL of flav-
rich OJ compared to low-flav
OJ
Executive function z-score
(combining all tests) was
higher in flav-rich OJ but did
not reach statistical
significance
Prospective cohort in Italy (45 -64yr), 14 year follow-up
• Increased flavanone intake decreased CV risk score and
changes in CV risk score over time
• Higher flavanone intake associated with a 52% lower
cardiovascular events and 41% lower all-cause mortality
(HR 0.48 (0.29, 0.77) and HR 0.59 (0.40, 0.85) p<0.005, adjusted models)
-Ponzo et al. J Trans Med. 2015;13(1):218
Epidemiological studies - Cardiovascular
Nurses' Health Study and NHSII - Higher urinary flavononeswere significantly associated with a 39% lower T2D risk in the short-term follow-up. (OR 0.61 (0.39, 0.98; p-trend 0.03)
-Sun et al. J Nutr. 2015;145(6):1280- 1288.
Korean National Health and Nutrition Examination Survey Males with impaired fasting glucose consumed significantly less hesperidin and total flavanones than males with normal fasting blood glucose. (energy, macronutrient, vitamin C intake did
not differ)
-Yeon et al. Clinica Chimica Acta. 2015;439(Suppl C):225-230.
Epidemiological studies - Diabetes
Nurse’s Health Study and NHSII
Incidence of depression was 10% lower in women with
higher intake of flavanones. (HR 0.90 (0.85-0.96), p-trend 0.0007)
A weekly serving of citrus fruit or a daily serving of citrus fruit
& citrus juices lowered depression incidence by 7 – 15%.
(fruit HR 0.93 (0.88, 0.99); fruit & juices HR 0.85 (0.75, 0.97), p-trends ≤0.05)
Epidemiological studies - Depression
-Chang et al. Am J Clin Nutr. 2016;104(3):704-714.
Kinetics & Metabolism
In-vitro digestion of orange fruit, homogenized orange fruit, and OJ pasteurized (flash vs. normal). Although the whole and homogenized fruit had more flavanones, carotenoids and vitamin C, the liberation and bioavailability was much greater for all compounds in the processed OJ.
-Aschoff et al. J Agric Food Chem. 2015;63(2):578-587.
In a randomized, cross-over study in 12 adults, no differences in urinary excretion of Hesperidin from OJ vs whole orange, although whole fruit had 2.3x higher amounts of flavanones. Authors state possible saturation occurs with absorption OR whole fruit matrices inhibit absorption.
-Aschoff et al. Mol Nutr Food Res. 2016;60(12):2602-2610.
No difference in absorption or excretion of flavanones
from OJ versus whole orange fruit in a randomized
crossover study of 20 healthy adults.
In adults consuming OJ only, individual variation in urinary
excretion was very large (0-59%). No effects of BMI, sex, or
contraceptive use associated with the variation in
flavanone excretion.
-Brett et al. Br J Nutr. 2009;101(5):664-675
Kinetics & Metabolism
Male endurance athletes consumed 500 mL OJ 1 time
during training and again when training was stopped for
1 week.
Bioavailability of Hesperidin metabolites from OJ
(measured by urinary excretion) was greater during
training compared to when training ceased.
-Pereira-Caro et al. Am J Clin Nutr. 2017; 106(3):791-800.
Kinetics & Metabolism
Summary & Conclusions
• Several human studies
support the cardiovascular
beneficial effects of 100% OJ
and Hesperidin
• Also other biological effects
include: glucose regulatory,
cognition, anti-oxidant and
anti-inflammatory effects
• Hesperidin contributes to
the health benefits of 100%
OJ
FLORIDA DEPARTMENT OF CITRUS
Acknowledgment & Questions
Visit FDOC at Booth #2022
Dr. Navindra SeeramUniversity of Rhode Island
Dr. Tami Turner Florida Department of Citrus