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

nseeram@uri.edu

Dr. Tami Turner Florida Department of Citrus

TTurner@citrus.myflorida.com