Disclosures. Anthocyanins More than Nature s Colors! What are Anthocyanins? PresentaFon Outline 12/9/15. Employment

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1 Disclosures Employment Anthocyanins More than Nature s Colors! NaFonal Osteoporosis FoundaFon NaFonal Bone Health Alliance George Mason University Dr. Taylor Wallace Food & NutriFon Blog ConsulFng PepsiCo, Egg NutriFon Center, and Nestle Taylor C. Wallace, PhD, CFS, FACN George Mason University DrTaylorWallace.com Anthocyanins in Health & Disease PresentaFon Outline What are Anthocyanins? What are anthocyanins? UFlity as an alternafve to synthefc colors EsFmated populafon intakes Bioavailability issues Tissue distribufon using a animal models Eﬀects on cardiovascular disease Future research The orange- red to blue- violet pigments in many plants (anthos = ﬂower; kyanos = blue). 1

Secondary plant metabolites produced via the phenylpropanoid pathway

purple potatoes) Members of the flavonoid family (C6- C3- C6)

are acylated 27 anthocyanidins (aglycons) 6 are predominant in nature

2 Secondary plant metabolites produced via the phenylpropanoid pathway as a response to the environment. UV light Frost Soil acidity PollinaFon azractants Deter insects (e.g. purple potatoes) Members of the flavonoid family (C6- C3- C6) skeleton Their posifve charge allows them to absorb light in the visible region. > 700 anthocyanins idenffied 96% are glycosylated Approximately 50% are acylated 27 anthocyanidins (aglycons) 6 are predominant in nature and make up 90%of those idenffied to date. Adv Nutr. 2015; 6:620. R 1 and R 2 conjugafons shih λ max. AcylaFon may also shih λ max but result in a more stable compound. H O O + O H O R 1 O OH R 2 CH 2 OH Aglycon R 1 R 2 λ max Pelargonidin H H 494 nm Cyanidin OH H 506 nm Peonidin O-CH 3 H 506 nm Delphinidin OH OH 508 nm Petunidin O-CH 3 OH 508 nm Malvidin O-CH 3 O-CH nm 2

EsFmated PopulaFon Intakes EsFmated PopulaFon Intakes Average intake of anthocyanins by U.S. adults has been esfmated to be 11.6 mg/d. 31% of adults have zero intake. Top sources in the U.S. diet include: Berries Wine Grapes Red/purple vegetables 100% juice, non- citrus Yogurt J Nutr.

EsFmated PopulaFon Intakes EsFmated PopulaFon Intakes Adults who meet fruit and vegetable recommendafons set by the 2010 Dietary Guidelines consume about 34.4 to 36.0 mg/d of anthocyanins.

Toxicity has not been shown in current human intervenfon studies.

3 EsFmated PopulaFon Intakes EsFmated PopulaFon Intakes Average intake of anthocyanins by U.S. adults has been esfmated to be 11.6 mg/d. 31% of adults have zero intake. Top sources in the U.S. diet include: Berries Wine Grapes Red/purple vegetables 100% juice, non- citrus Yogurt J Nutr. 2015; 145:1239 J Acad Nutr Diet. 2012; 112(2):222. EsFmated PopulaFon Intakes EsFmated PopulaFon Intakes Adults who meet fruit and vegetable recommendafons set by the 2010 Dietary Guidelines consume about 34.4 to 36.0 mg/d of anthocyanins. J Acad Nutr Diet. 2012; 112(2):222. Amway - Phytochemical Report 2011 Toxicity and Recommended Intakes China recommends a specific proposed level of 50 mg/d but has not set a UL for anthocyanins. Toxicity has not been shown in current human intervenfon studies. In 2013, an EFSA scienffic panel concluded that currently available toxicological evidence was inadequate to establish a numerical value. AlternaFve to SyntheFc Colors Anthocyanins are stable at low ph environments. They are very unstable at neutral to higher ph ranges. Thus their use in food products has been thought to be somewhat limited. ph: 1.0 ph: 4.5 ph: 7.0 Adv Nutr. 2015; 6:620. 3

AlternaFve to SyntheFc Colors At a ph of 4.5 the ring structure opens into a chalcone (leh) and/or carbinol pseudo- base (right). This is reversible however these compounds are less stable.

4 AlternaFve to SyntheFc Colors At a ph of 4.5 the ring structure opens into a chalcone (leh) and/or carbinol pseudo- base (right). This is reversible however these compounds are less stable. AlternaFve to SyntheFc Colors InteracFon with proteins/fat in yogurt may help them achieve higher stability in foods. Co/Ct (mg ACN Recovered) Acylated anthocyanins Non-acylated anthocyanins Berberis boliviana L. y = x Purple Carrot Extract y = x Day J Food Sci. 2010; 73(4):C238. Bioavailability Issues Bioavailability Issues Evidence from in vitro gastric and microbial fermentafon studies suggest that aher ingesfon anthocyanins are broken down either spontaneously or enzymafcally into phenolic degradafon products, which may be then further metabolized Chokeberry Bilberry Anthocyanins do appear in circulafon intact or as glucuronated, sulfoconjugated or methylated derivafves Grape Nutr Cancer. 2006; 54(1):3. Bioavailability Issues It has been previously thought that only about >0.1% of anthocyanins cross the basolateral membrane and enter circulafon. Non- acylated anthocyanins shown to be more bioavailable than the larger more complex molecules. A new 13 C- tracer study indicates that cy- 3- glu has a minimal relafve bioavailability of 12.38%. AJCN. 2013; 97:995. Bioavailability Issues Serum Metabolites C max (μmol/l) T max (h) Cy- 3- glu 0.14 ± ± 0.16 PCA + PGA* 0.72 ± ± 0.75 Phase II Conjugates of PCA 2.35 ± ± 2.46 Ferulic acid 0.94 ± ± 4.23 Hippuric acid 1.96 ± ± 4.07 *PCA, Protocatechuic acid; PGA, Phloroglucinaldehyde AJCN. 2013; 97:995. 4

Tissue DistribuFon Tissue DistribuFon Stomach is a major absorpfon site. Anthocyanins Fghtly bind to bilirubin and other proteins. 7.5% entered intesfnal Fssue. J Agric Food Chem. 2009; 57(8):3141.

2015; 6:620. Effects on Cardiovascular Disease Epidemiological studies consistently suggest an inverse relafonship of flavonoids with CVD.

2011; 93(2):336.) Highest quinfle of anthocyanin intake showed 8% reduced risk of hypertension. Iowa Women s Study (AJCN 2007;85:895.) Intake of 0.2 mg/d and ê CVD mortality.

5 Tissue DistribuFon Tissue DistribuFon Stomach is a major absorpfon site. Anthocyanins Fghtly bind to bilirubin and other proteins. 7.5% entered intesfnal Fssue. J Agric Food Chem. 2009; 57(8):3141. Anthocyanins, their metabolites and/or breakdown products cross the blood- brain barrier and have been also idenffied in various animal Fssues in vivo: Liver Kidney Vascular Fssues Brain Adv Nutr. 2015; 6:620. Effects on Cardiovascular Disease Epidemiological studies consistently suggest an inverse relafonship of flavonoids with CVD. Age- Adjusted CHD Mortality, % Mean Flavonoid Intake (mg/day) ObservaFonal Studies Nurses Health Study and Health Professionals Follow Up Study (AJCN. 2011; 93(2):336.) Highest quinfle of anthocyanin intake showed 8% reduced risk of hypertension. Iowa Women s Study (AJCN 2007;85:895.) Intake of 0.2 mg/d and ê CVD mortality. Strawberries and ê CVD mortality. Blueberries and ê CHD mortality. Arch Intern Med. 1995; 155: 381. ObservaFonal Studies Dose Response - CVD Women s Health Study (JACN 2007;26:303.) Strawberries and ê CRP. Framingham Heart Study Offspring Cohort (AJCN. 2015; 102(1):172.) Anthocyanin intake (Q1 vs. Q5) ê inflammafon score, markers of inflammafon, and insulin levels. Apples, red wine and strawberry consumpfon ê inflammafon score. QuinQle Cancer PrevenQon II NutriQon Cohort Median Intake of Anthocyanins (mg/d) Men Women All (<5.5) 1.00 (- ) 1.00 (- ) 1.00 (- ) ( ) 0.83 (0.70, 0.97) 0.79 (0.67, 0.94) 0.77 (0.69, 0.87) ( ) 0.82 (0.71, 0.96) 0.73 (0.62, 0.88) 0.77 (0.68, 0.86) ( ) 0.78 (0.67, 0.91) 0.67 (0.56, 0.80) 0.74 (0.66, 0.83) (>16.7) 0.72 ( ) 0.72 (0.61, 0.86) 0.72 (0.64, 0.80) P- trend < AJCN. 2013; 97:995. 5

High Quality RCTs High Quality RCTs InhibiFon of cholesterol ester transfer protein in dyslipidemic subjects.

individuals over a 12- week period. Healthy populafon (markers in normal range) Threshold effect? AJCN. 2009; 90:485. J Nutr. 2009; 139:2266.

No significant effects on HDL Baseline status was in higher range (~46 mg/dl) SystemaFc Review 10 included RCTs (12 manuscripts) tesfng the effects of purified anthocyanins and/or

Lipid profiles Triglycerides Blood pressure Consistent decrease in LDL among unhealthy individuals or those with elevated markers. Evid Based Complement Alternat Med. 2014. ArFcle 217451.

6 High Quality RCTs High Quality RCTs InhibiFon of cholesterol ester transfer protein in dyslipidemic subjects. Elderberry extract anthocyanins (500 mg/d) did not affect plasma levels of inflammatory biomarkers, vascular reacfvity, plasma lipid profiles, or glucose concentrafons in an RCT of 57 individuals over a 12- week period. Healthy populafon (markers in normal range) Threshold effect? AJCN. 2009; 90:485. J Nutr. 2009; 139:2266. High Quality RCTs Whortleberry anthocyanins (45 mg/d) significantly decreased total cholesterol, LDL, and triglycerides over 4- wk among hyperlipidemic individuals. No significant effects on HDL Baseline status was in higher range (~46 mg/dl) SystemaFc Review 10 included RCTs (12 manuscripts) tesfng the effects of purified anthocyanins and/or anthocyanin- rich extracts on markers of cardiovascular disease. Lipid profiles Triglycerides Blood pressure Consistent decrease in LDL among unhealthy individuals or those with elevated markers. Evid Based Complement Alternat Med ArFcle Nutrients. (Under Review) SystemaFc Review MechanisFc Data No significant effects lipid profiles, triglycerides and blood pressure in healthy individuals; however, trends of improvement among subjects in the treatment group were noted. Lipid PeroxidaQon Endothelial FuncQon AnQ- inflammatory AcQvity Anthocyanins in CVD ProtecQon from DNA Cleavage Enzyme InhibiQon Membrane Strengthening Capillary Fragility & Permeability Cytokine ProducQon Nutrients. (Under Review) 6

Mechanism Intracellular ROS CorrelaFon concentrafon of serum

Pre- supplementafon with anthocyanins on intracellular ROS in human

Dichloroﬂuorescein assay used to measure ROS induced damage.

Endothelial DysfuncQon Inducible nitric oxide synthase (inos)

Narrowing) Neuronal nitric oxide synthase (nnos) Plaque Rupture & Clot

adherence and aggregafon Inﬂammatory leukocyte recruitment Vascular

Endothelium- dependent vasorelaxafon (enos acfvafon) of rat aorta (J

7 Mechanism Intracellular ROS CorrelaFon concentrafon of serum anthocyanins and ORAC (i.e. anfoxidant acfvity) in male subjects. Pre- supplementafon with anthocyanins on intracellular ROS in human endothelial cells. Dichloroﬂuorescein assay used to measure ROS induced damage. Mechanism AnFoxidant AcFvity J Nutr Biochem 2002;13:282. J Agric Food Chem. 2002; 50:7731. Mechanism Endothelial FuncFon Mechanism Nitric Oxide Synthases Endothelial DysfuncQon Inducible nitric oxide synthase (inos) InﬂammaFon Endothelial nitric oxide synthase (enos) Stenosis (Abnormal Narrowing) Neuronal nitric oxide synthase (nnos) Plaque Rupture & Clot FormaFon Occlusion Mechanism enos VasodilaFon Platelet acfvafon, adherence and aggregafon Inﬂammatory leukocyte recruitment Vascular oxidant stress Mechanism enos Delphinidin and Black Currant Extract Endothelium- dependent vasorelaxafon (enos acfvafon) of rat aorta (J Nutr Biochem 2002;13:282; Jpn J pharmacol 2002;89:29.) Cy- 3- glu UpregulaFon of enos in bovine endothelial cells. Phosphorylates enos and enhances its acfvity (Hypertension 2004;44:217.) J Agric Food Chem. 2002; 50:

$B 30 inos activity (pmol/min/mg of protein) 20 10 * # # # # 0 0 11 22 45 90 Anthocyanin fraction of blackberry extract ( g/ml) AMG Nitric Oxide 2006;15:30. Brit J Pharmac 2006;149:283.$ . Mechanism MCP- 1 Conclusions Anthocyanins reduce microvascular endothelium vulnerability to oxidafve and inflammatory insults.

. Mechanism MCP- 1 Conclusions Anthocyanins reduce microvascular endothelium vulnerability to oxidafve and inflammatory insults.

As research confnues to expand we need to consider how to appropriately translate findings into dietary guidance and public policy. J Nutr Biochem 2002;13:282.

8 Mechanism inos Mechanism VEGF Blackberry anthocyanins inhibit inos acfvity in murine macrophages. Anthocyanins inhibit platelet- derived vascular endothelial growth factor (VEGF) in vitro. B 30 inos activity (pmol/min/mg of protein) * # # # # Anthocyanin fraction of blackberry extract ( g/ml) AMG Nitric Oxide 2006;15:30. Brit J Pharmac 2006;149:283.. Mechanism MCP- 1 Conclusions Anthocyanins reduce microvascular endothelium vulnerability to oxidafve and inflammatory insults. Although research is emerging, the current literature collecfvely supports that consumpfon of anthocyanin- rich diets may help to maintain a healthy vascular system. As research confnues to expand we need to consider how to appropriately translate findings into dietary guidance and public policy. J Nutr Biochem 2002;13:282. Final Thoughts Final Thoughts InflammaFon is a part of the immune response network that is essenfal, but can be damaging when sustained! Can anthocyanins, their metabolites and/or breakdown products accumulate in certain Fssues over Fme? What amount of anthocyanins are needed to achieve opfmal vascular health? Dose response human intervenfon studies. 8

9 Future Research Cross- secfonal study of NHANES to look at anthocyanin intake and markers/endpoints of CVD. Thank You! Taylor C. Wallace, PhD, CFS, FACN Phone: Website: Small (n=40) 8- week crossover controlled feeding study with blackberries. Lipid profiles and markers of CVD Energy expenditure 9

Dr. Pran Kishore Deb Dr. Balakumar Chandrasekaran Assistant Professor Pharmaceutical Medicinal Chemistry Faculty of Pharmacy, Philadelphia

Dr. Pran Kishore Deb Dr. Balakumar Chandrasekaran Assistant Professor Pharmaceutical Medicinal Chemistry Faculty of Pharmacy, Philadelphia University-Jordan Email: pdeb@philadelphia.edu.jo 1 Learning Outcomes