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Title:
COMPOSITIONS AND METHODS FOR THE MAINTENANCE AND IMPROVEMENT OF VASCULAR HEALTH
Document Type and Number:
WIPO Patent Application WO/2024/040334
Kind Code:
A1
Abstract:
A composition for maintaining vascular health, comprising a combination of Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, and methods for preventing or treating cardiovascular disease, are provided.

Inventors:
NARWAL SAKWINDER (CA)
ANDRIC MIODRAG (CA)
GLIBETIC MARIA
Application Number:
PCT/CA2023/051084
Publication Date:
February 29, 2024
Filing Date:
August 15, 2023
Export Citation:
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Assignee:
VANA HEALTH INC (CA)
International Classes:
A61K36/736; A61K36/73; A61P9/00; A61P29/00
Foreign References:
US20090252796A12009-10-08
US20130171294A12013-07-04
US8449927B22013-05-28
US6818234B12004-11-16
Other References:
LOO ET AL.: "Consumption of chokeberry (Aronia mitschurinii) products modestly lowered blood pressure and reduced low-grade inflammation in patients with mildly elevated blood pressure", NUTRITION RESEARCH, vol. 36, 2016, pages 1222 - 1230, XP029835108, ISSN: 0271-5317, DOI: 10.1016/j.nutres.2016.09.005
SKOCZYŃSKA ANNA, JEDRYCHOWSKA I., POREBA R., AFFELSKA-JERCHA A., TURCZYN B., WOJAKOWSKA A., ANDRZEJAK R.: "Influence of chokeberry juice on arterial blood pressure and lipid parameters in men with mild hypercholesterolemia", PHARMACOLOGICAL REPORTS, POLSKA AKADEMIA NAUK, INSTYTUT FARMAKOLOGII, KRAKOW, PL, vol. 59, no. 1, 1 January 2007 (2007-01-01), PL , pages 177 - 182, XP093144783, ISSN: 1734-1140
STEVANOVIĆ VUK, PANTOVIĆ ANA, KRGA IRENA, ZEKOVIĆ MILICA, ŠARAC IVANA, GLIBETIĆ MARIA, VIDOVIĆ NEVENA: "Aronia juice consumption prior to half-marathon race can acutely affect platelet activation in recreational runners", APPLIED PHYSIOLOGY, NUTRITION, AND METABOLISM = PHYSIOLOGIE APPLIQUEE, NUTRITION ET METABOLISME, CANADIAN SCIENCE PUBLISHING, US, vol. 45, no. 4, 1 April 2020 (2020-04-01), US , pages 393 - 400, XP009553325, ISSN: 1715-5320, DOI: 10.1139/apnm-2019-0267
BELL PHILLIP, WALSHE IAN, DAVISON GARETH, STEVENSON EMMA, HOWATSON GLYN: "Montmorency Cherries Reduce the Oxidative Stress and Inflammatory Responses to Repeated Days High-Intensity Stochastic Cycling", NUTRIENTS, M D P I AG, CH, vol. 6, no. 2, CH , pages 829 - 843, XP093144784, ISSN: 2072-6643, DOI: 10.3390/nu6020829
HOWATSON G., MCHUGH M. P., HILL J. A., BROUNER J., JEWELL A. P., VAN SOMEREN K. A., SHAVE R. E., HOWATSON S. A.: "Influence of tart cherry juice on indices of recovery following marathon running ", SCANDINAVIAN JOURNAL OF MEDICINE AND SCIENCE IN SPORTS, MUNKSGAARD, COPENHAGEN, DK, vol. 20, no. 6, 1 December 2010 (2010-12-01), DK , pages 843 - 852, XP093144785, ISSN: 0905-7188, DOI: 10.1111/j.1600-0838.2009.01005.x
Attorney, Agent or Firm:
MILLER THOMSON LLP (CA)
Download PDF:
Claims:
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS: 1. A composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract. 2. The composition according to claim 1, wherein said fortified Aronia juice and said fortified tart cherry juice are in a volume ratio of 4:1. 3. The composition according to claim 1, wherein said fortified tart cherry juice and said fortified Aronia juice are in a volume ratio of up to 4.1. 4. The composition according to claim 1, wherein said Aronia juice is fortified with 100 mg to 4000 mg of Aronia extract and said tart cherry juice is fortified with 20 mg to 5000 mg of tart cherry extract per 100 mL. 5. The composition according to claim 1, wherein said Aronia juice is fortified with 2000 mg of Aronia extract and said tart cherry juice is fortified with 1500 mg of tart cherry extract per 100 mL. 6. The composition according to claim 1, further comprising one or more additional nutraceuticals selected from the group consisting of red beet extract, rosehip extract, chamomile extract, Melissa officinalis, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, cannabidiol (CBD), and a combination thereof. 7. The composition according to claim 6, wherein the one or more additional nutraceuticals comprise red beet extract, lion’s mane mushroom extract, and rosehip extract. 8. The composition according to claim 7, wherein said composition comprises 50 mg to 5000 mg of red beet extract, 100 mg to 1500 mg lion’s mane mushroom extract, and 20 mg to 5000 mg of rosehip extract per 100 mL. 53 Cardiovascular Protection.DOCX

9. The composition according to claim 7, wherein said composition comprises 1000 mg of red beet extract, 1000 mg of lion’s mane mushroom extract, and 1000 mg of rosehip extract per 100 mL. 10. The composition according to claim 6, wherein the one or more additional nutraceuticals comprise rosehip extract, chamomile extract, reishi mushroom extract, and lemon balm extract. 11. The composition according to claim 10, wherein the composition further comprises cannabidiol (CBD). 12. The composition according to claim 10, wherein said composition comprises 20 mg to 5000 mg of rosehip extract, 10 mg to 2000 mg of chamomile extract, 100 mg to 1500 mg reishi mushroom extract, and 10 mg to 4000 mg of lemon balm extract per 100 mL. 13. The composition according to claim 10, wherein said composition comprises 1000 mg of rosehip extract, 500 mg of chamomile extract, 1000 mg reishi mushroom extract, and 500 mg of lemon balm extract per 100 mL. 14. The composition according to claim 11, wherein said composition comprises 20 mg to 5000 mg of rosehip extract, 10 mg to 2000 mg of chamomile extract, 10 mg to 4000 mg of lemon balm extract, 100 mg to 1500 mg reishi mushroom extract, and 1 mg to 300 mg of cannabidiol (CBD) per 100 mL. 15. The composition according to claim 1, wherein said juices and extracts interact synergistically to enhance bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts. 16. The composition according to claim 15, wherein said juices and extracts interact synergistically to inhibit platelet aggregation and vascular inflammation. 54 Cardiovascular Protection.DOCX

17. A formulation for maintaining vascular health, comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said composition inhibits platelet aggregation and vascular inflammation. 18. The formulation according to claim 17, wherein said fortified Aronia juice and said fortified tart cherry juice are in a volume ratio of 4:1. 19. The formulation according to claim 17, wherein said fortified tart cherry juice and said fortified Aronia juice are in a volume ratio of up to 4.1. 20. The formulation according to claim 17, wherein said Aronia juice is fortified with 100 mg to 4000 mg of Aronia extract and said tart cherry juice is fortified with 20 mg to 5000 mg of tart cherry extract per 100 mL. 21. The formulation according to claim 17, wherein said Aronia juice is fortified with 2000 mg of Aronia extract and said tart cherry juice is fortified with 1500 mg of tart cherry extract per 100 mL. 22. The formulation according to any one of claims 17 to 21, wherein said formulation is formulated as a capsule, a tablet, a liquid concentrate, a liquid drink, or a powder. 23. The formulation according to any one of claims 17 to 21, wherein said formulation is formulated as a liquid drink, syrup, tonic, or jelly. 24. A method for preventing or treating cardiovascular disease in a subject, comprising administering a therapeutically effective amount of a composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said composition enhances the bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts. 25. The method according to claim 24, wherein said juices and extracts interact synergistically to inhibit platelet aggregation and vascular inflammation. 55 Cardiovascular Protection.DOCX

26. The method according to claim 24, wherein said fortified Aronia juice and said fortified tart cherry juice are in a volume ratio of 4:1. 27. The method according to claim 24, wherein said fortified tart cherry juice and said fortified Aronia juice are in a volume ratio of up to 4.1. 28. The method according to claim 24, wherein said Aronia juice is fortified with 100 mg to 4000 mg of Aronia extract and said tart cherry juice is fortified with 20 mg to 5000 mg of tart cherry extract per 100 mL. 29. The method according to claim 24, wherein said Aronia juice is fortified with 2000 mg of Aronia extract and said tart cherry juice is fortified with 1500 mg of tart cherry extract per 100 mL. 30. The method of claim 29, wherein said composition is administered at least once a day. 31. The method of claim 24, wherein said composition is administered orally in a liquid form. 56 Cardiovascular Protection.DOCX

Description:
COMPOSITIONS AND METHODS FOR THE MAINTENANCE AND IMPROVEMENT OF VASCULAR HEALTH FIELD OF THE INVENTION [0001] The present invention relates to the field of nutraceuticals and dietary supplement compositions and, in particular, to compositions comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, and methods for maintaining and improving vascular health. BACKGROUND OF THE INVENTION [0002] Heart and vascular, or cardiovascular, diseases include conditions such as arrhythmias, coronary heart disease, heart attack, high blood pressure, congenital heart defects, vascular dementia, and stroke. The World Health Organization has reported that cardiovascular diseases (CVDs) are the leading cause of death globally. An estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to heart attack and stroke. Out of the 17 million premature deaths (under the age of 70) due to non-communicable diseases in 2019, 38% were caused by CVDs. [0003] Atherosclerosis, the pathological condition often underlying CVD, is a chronic inflammatory condition involved in the initiation and perpetuation of atherosclerotic lesions, which may erode or rupture leading to clinical events such as angina, myocardial infarction, or cerebrovascular attack. Modifiable CVD risk has been associated with poor quality diet, smoking, and physical inactivity. As such, the role of diets rich in bioactive compounds in maintaining or improving cardiovascular health has been of interest; in particular, bioactive compounds with anti-inflammatory properties such as polyphenols. 1 Cardiovascular Protection.DOCX [0004] Despite the potential benefits of such bioactive compounds on the maintenance or improvement of cardiovascular health (CVH), the efficacy in their application has been limited by the limited bioavailability of such compounds when ingested. Polyphenols, specifically, are largely metabolized following ingestion, with polyphenols being metabolized in the stomach, small and large intestine, and liver. As a result, the therapeutic benefits of such compounds are never realized. [0005] The key to the therapeutic efficacy of such bioactive compounds is bioavailability and absorption of the bioactives. Specifically, bioavailability is dependent on the absorption of the micronutrients by the epithelial layer of the gut, and the chemical and biochemical transformations into epithelial cells. These processes are endogenous factors that greatly influence the bioavailability of bioactive compounds. Ensuring bioavailability is challenging due to the nature of both the bioactive compounds and the digestive tract of the consumer. As a result, the efficacy of bioactive compounds in nutraceuticals and dietary supplements, is limited at best, and unpredictable. [0006] New compositions and methods that address the shortcomings of existing nutraceuticals are, therefore, needed to realize the prophylactic and/or therapeutic effects of bioactive compounds on vascular health. [0007] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. SUMMARY OF THE INVENTION [0008] An object of the present invention is to provide compositions and methods for maintaining or improving vascular health in a subject, in particular. In accordance with one aspect of the invention, there is provided a composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract. 2 Cardiovascular Protection.DOCX In accordance with another aspect, the composition of the present invention further comprises one or more additional nutraceuticals. [0009] In accordance with another aspect of the invention, there is provided a composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, wherein said juices and extracts interact to enhance bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts. [0010] In accordance with another aspect of the invention, there is provided a composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, wherein said juices and extracts interact synergistically to inhibit platelet aggregation and vascular inflammation. [0011] In accordance with another aspect of the invention, there is provided a formulation for maintaining vascular health, comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said formulation inhibits platelet aggregation and vascular inflammation. [0012] In accordance with another aspect of the invention, there is provided a method for preventing or treating, or to aid in preventing or treating, cardiovascular disease in a subject, comprising administering a therapeutically effective amount of a composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said composition enhances the bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts. In accordance with further aspect, the said juices and extracts interact synergistically to inhibit and/or regulate platelet aggregation and to suppress vascular inflammation. 3 Cardiovascular Protection.DOCX BRIEF DESCRIPTION OF THE DRAWINGS [0013] These and other features of the invention will become more apparent in the following detailed description in which reference is made to the appended drawings. [0014] Figure 1 presents an illustration of the systemic effects resulting from the enhanced bioavailability and absorption of the polyphenol gut metabolites elicited by the composition according to embodiments of the present invention. [0015] Figure 2 is a graph presenting changes in diastolic blood pressure across three time points (baseline (T0), 3 weeks (T1) and 3 months (T2) of aronia (chokeberry)/tart cherry core formulation consumption). The graph represents results of repeated measures ANOVA of normalized data, presented as relative change from T0. **p<0.01, compared to T0; #, p<0.05, compared to T1. [0016] Figure 3 presents changes in total body water of right leg (A), left leg (B), Intracellular water of right leg (C), left leg (D), extracellular water of right leg (E) and left leg (F) across three time points (baseline (T0), 3 weeks (T1) and 3 months (T2) of aronia (chokeberry)/tart cherry core formulation consumption). The graphs represent repeated measures ANOVA analysis of normalized data, presented as relative change from T0. **p<0.01, compared to T0; #, p<0.05, compared to T1. [0017] Figure 4 presents the effect of 3-month long core formulation consumption on markers of endothelial dysfunction. Results presented as median with 25-75 percentiles (box) and 10-90 percentile range (whiskers), before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD risk. n=15-17 subjects; data analyzed by Wilcoxon signed-rank test for non-normal data distribution. ***, p<0.001; ns, p>0.05. [0018] Figure 5 presents the effect of 3-month long core formulation consumption on intestinal permeability. Results presented as mean ± standard error of the mean, before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD 4 Cardiovascular Protection.DOCX risk. n=17 subjects; data analyzed by paired t-test for normally distributed data. ***, p<0.001. [0019] Figure 6 presents the effect of 3-month core formulation consumption on oxidative stress/antioxidant defense parameters. Results presented as mean ± standard error of the mean for normally distributed data or as median with 25-75 percentiles (box) and 10-90 percentile range (whiskers) for non-normal distribution, before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD risk. n=17 subjects; data analyzed by paired t-test or Wilcoxon signed-rank test. All data are not statistically significant, p>0.05. [0020] Figure 7 presents an illustration of the study design conducted to assess the acute effects of the core formulation. [0021] Figure 8 presents a schematic representation of platelet function assessments. [0022] Figure 9 are graphs presenting the acute effects of consuming core formulation (CF) and its components on markers of platelet aggregation with leukocytes after ex vivo stimulation with a suboptimal concentration (0.5^M) of adenosine diphosphate (ADP): Figure 9A is a graph presenting percentage of platelet-neutrophil aggregates (PNA) in the total population of neutrophils, Figure 9B is a graph presenting density of platelets in platelet-neutrophil aggregates, Figure 9C is a graph presenting percentage of platelet- monocyte aggregates (PMA) in the total population of monocytes, Figure 9D is a graph presenting density of platelets in platelet-monocyte aggregates, Figure 9E is a graph presenting relative number of platelets per platelet-monocyte aggregate (binding index, BI) calculated as % of aggregates in the total population of monocytes x mean fluorescence intensity (MFI)/100. Results are presented relative to the maximal platelet response (ADP 20^M), and depicted as mean ± standard error of the mean (SEM), n=4-6, data analyzed by paired sample t-tests for normally distributed data, or Wilcoxon signed-rank test for non- normal data distribution, * p<0.05; compared to 0h. AJ-Aronia juice, AE-Aronia extract, TCJ-tart cherry juice, TCE-tart cherry extract. 5 Cardiovascular Protection.DOCX [0023] Figure 10 are graphs presenting the acute effects of consuming core formulation (CF) and its components on markers of platelet activation after ex vivo stimulation with a suboptimal concentration (0.5^M) of adenosine diphosphate (ADP): Figure 10A is a graph presenting percentage of GPIIbIIIa-positive platelets in the total number of collected platelets; Figure 10B is a graph presenting relative number of GPIIbIIIa on the surface of antigen-positive platelets (platelet activation index, PAI, calculated as % of GPIIbIIIa- platelets x mean fluorescence intensity (MFI)/100, Figure 10C is a graph presenting percentage of P-selectin-positive platelets in the total number of collected platelets Figure 10D is a graph presenting relative number of P-selectin on the surface of antigen-positive platelets. Results are presented relative to the maximal platelet response (ADP 20^M), and depicted as mean ± standard error of the mean (SEM), n=5-6, data analyzed by paired sample t-tests for normally distributed data, or Wilcoxon signed-rank test for non-normal data distribution, * p<0.05; compared to 0h. AJ-Aronia juice, AE-Aronia extract, TCJ-tart cherry juice, TCE-tart cherry extract. [0024] Figure 11 are graphs presenting the acute effects of consuming core formulation (CF) and its components on markers of platelet aggregation with leukocytes in the basal state: Figure 11A is a graph presenting percentage of platelet-neutrophil aggregates (PNA) in the total population of neutrophils, Figure 11B is a graph presenting density of platelets in platelet-neutrophil aggregates, Figure 11C is a graph presenting percentage of platelet- monocyte aggregates (PMA) in the total population of monocytes, Figure 11D is a graph presenting density of platelets in platelet-monocyte aggregates, Figure 11E is a graph presenting relative number of platelets per platelet-monocyte aggregate (binding index, BI) calculated as % of aggregates in the total population of monocytes x mean fluorescent intensity (MFI)/100. Results are presented relative to the maximal platelet response (ADP 20^M), and depicted as mean ± standard error of the mean (SEM), n=4-6, data analyzed by paired sample t-tests for normally distributed data, or Wilcoxon signed-rank test for non- normal data distribution, * p<0.05; compared to 0h. AJ-Aronia juice, AE-Aronia extract, TCJ-tart cherry juice, TCE-tart cherry extract. 6 Cardiovascular Protection.DOCX [0025] Figure 12 are graphs presenting the acute effects of consuming core formulation (CF) and its components on markers of platelet activation in the basal state: Figure 12A is a graph presenting percentage of GPIIbIIIa-positive platelets in the total number of collected platelets Figure 12B is a graph presenting relative number of GPIIbIIIa on the surface of antigen-positive platelets (platelet activation index, PAI, calculated as % of GPIIbIIIa- platelets x mean fluorescence intensity (MFI)/100), Figure 12C is a graph presenting percentage of P-selectin-positive platelets in the total number of collected platelets; Figure 12D is a graph presenting relative number of P-selectin on the surface of antigen-positive platelets. Results are presented relative to the maximal platelet response (ADP 20^M), and depicted as mean ± standard error of the mean (SEM), n=5-6, data analyzed by paired sample t-tests for normally distributed data, or Wilcoxon signed-rank test for non-normal data distribution, * p<0.05; compared to 0h. AJ-Aronia juice, AE-Aronia extract, TCJ-tart cherry juice, TCE-tart cherry extract. [0026] Figure 13 are graphs presenting the effect of 3-month long core formulation consumption on markers of vascular inflammation and cell adhesion/migration. DETAILED DESCRIPTION OF THE INVENTION [0027] Polyphenols are micronutrients found in a wide range of food sources that have gained particular attention for their antioxidant properties and their role in the prevention of various diseases associated with oxidative stress, such as cancer and cardiovascular and neurodegenerative diseases. Polyphenols, which constitute the active substances found in many medicinal plants, have also been found to modulate the activity of a wide range of enzymes and cell receptors. [0028] More than 8,000 types of polyphenols have been identified. They can be further categorized into 4 main groups: (i) flavonoids which account for around 60% of all polyphenols and include quercetin, kaempferol, catechins, apigenin, fisetin, proanthocyanidins, and anthocyanins; (ii) phenolic acids which account for around 30% of 7 Cardiovascular Protection.DOCX all polyphenols and include stilbenes and lignans; (iii) polyphenolic amides which include capsaicinoids and avenanthramides; and (iv) other polyphenols which include resveratrol, ellagic acid, ellagitannins, resveratrol, urolithin A, curcumin, and lignans. [0029] As with all micronutrients, however, the health effects of polyphenols depend on their bioavailability. There are a number of factors that affect the absorption of polyphenols, in particular, metabolism of the polyphenols by intestinal and hepatic enzymes, catabolism of polyphenols and the production of active metabolites by intestinal microflora, and intestinal absorption, all affect the absorption of polyphenols and the polyphenol metabolites. Accordingly, in various embodiments, nutraceutical compositions are described that unexpectedly enhance the bioavailability of polyphenols and the polyphenol gut metabolites. Without being bound by theory, it is contemplated that polyphenols and the polyphenol gut metabolites are made more bioavailable in compositions that include pure fruit juice that has the full spectrum of fruit sugars, nutrients, vitamins and minerals to aid in nutrient metabolism by intestinal microflora, such as Coriobacteriia (Eggerthellaceae). [0030] In certain embodiments, the nutraceutical compositions of the present invention enhance antioxidant bioavailability in the gut by combining nutrient-rich and polyphenol- high Aronia and tart cherry juice. According to further embodiments, the nutraceutical compositions comprise Aronia and tart cherry juices that are further fortified with Aronia and tart cherry extract which together enhance polyphenol bioavailability. In certain embodiments, the nutraceutical compositions comprise a combination of Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract. [0031] Enhanced bioavailability of polyphenols leads to an increase in the final active metabolites produced by gut bacterial species and subsequent intestinal absorption of the polyphenol gut metabolites. In this regard, it is believed that the nutraceutical compositions described herein alter the gut’s vascular wall to enhance absorption of micronutrients and bioactive phytochemicals. 8 Cardiovascular Protection.DOCX [0032] According to certain embodiments, the nutraceutical compositions result in an increase in n3 and a decrease in n6 polyunsaturated fatty acids (PUFAs) in endothelium and vascular wall cell membranes. In further embodiments, the components of the nutraceutical compositions interact synergistically to ultimately lead to increased cell membrane fluidity through phospholipid restructuring. According to certain embodiments, this restructuring of the vascular wall cell membrane further enhances the intestinal absorption of micronutrients and bioactive phytochemicals. [0033] In further embodiments, the nutraceutical compositions described herein result in stabilization of the permeability of the gut wall thereby reducing the loss of polyphenol gut metabolites, and thus increasing the amount of bioactive components to be absorbed by the gut epithelium and underlying vasculature. In certain embodiments, the nutraceutical compositions result in the lowering of zonulin production that modulates the permeability of tight junctions between cells of the gut wall to stabilize gut wall permeability. [0034] In certain embodiments, the compositions of the present invention are combined with additional nutraceuticals to enhance their absorption. According to embodiments of the present invention, the compositions comprise Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, and further in combination with additional nutraceuticals. It is contemplated that the additional nutraceuticals can include any nutraceutical of interest. In certain embodiments, the nutraceutical compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with one or more extracts. The one or more extracts can include, for example, red beet extract, rosehip extract, chamomile extract, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, resveratrol extract, quercetin extract, fisetin extract, berberine extract, urolithin A, NMN, Ca-AKG, spermidine extract, TMG, and/or cannabidiol (CBD). [0035] According to certain embodiments, the compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with, for example, red beet extract, lion’s mane mushroom extract, and/or 9 Cardiovascular Protection.DOCX rosehip extract. In other embodiments, the compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with, for example, one or more of rosehip extract, chamomile extract, lemon balm extract, reishi mushroom extract, and/or cannabidiol (CBD). [0036] Compositions of the present invention, comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, are therefore contemplated in certain embodiments for use as an absorption-enhancing carrier for micronutrients and bioactive phytochemicals derived from nutraceutical extracts. In some embodiments, the present invention provides for the use of the fortified Aronia and tart cherry juice composition prior to consumption of nutraceutical extracts. In other embodiments, the present invention provides for the use of the fortified Aronia and tart cherry juice composition as a carrier for additional nutraceutical extracts. [0037] According to further embodiments, the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract, unexpectedly interact to reduce the expression of cell adhesion molecules (CAMs) associated with vascular disorders and microvascular dysfunction, including one or more of E-selectin, L-selectin, P-selectin glycoprotein ligand- 1 (PSGL-1), ALCAM-1, ICAM-2, and ICAM-1. In this way, according to embodiments described herein, the compositions comprise components that synergistically interact to inhibit platelet aggregation and stabilize vascular endothelium by suppressing the expression of vascular inflammatory markers. Definitions [0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. 10 Cardiovascular Protection.DOCX [0039] As used herein, the term “about” refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to. [0040] The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.” [0041] As used herein, the words “comprising” (and grammatical variations thereof, such as “comprise” and “comprises”), “having” (and grammatical variations thereof, such as “have” and “has”), “including” (and grammatical variations thereof, such as “includes” and “include”) or “containing” (and grammatical variations thereof, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. [0042] The term “nutraceutical(s)” as used herein refers to a substance that is a food or a part of a food, such as an extract, and contains phytochemicals that are able to induce medical and health benefits. [0043] The term “polyphenols” as used herein refers to the group of plant-derived phytochemicals that can be generally categorized into four main groups: flavonoids, phenolic acids, stilbenes, and lignans. The term “polyphenol gut metabolites” as used herein refers to the polyphenol metabolites of the gut microbiota. [0044] The term “subject” as used herein refers to both human and non-human animals. [0045] The term “attenuate”, “inhibit”, “treat”, and “reduce” and grammatical variations thereof, as used herein, refer to a measurable decrease in a given parameter or event. [0046] The term “preventing” as used herein refers to reducing the risks associated with developing a disease, including reducing the onset of the disease. The term “prevention” or “prophylaxis” may be used herein to refer to an individual known to be at high risk of 11 Cardiovascular Protection.DOCX developing a disease or in a population at large for maintaining good health, for example, maintaining vascular health. [0047] The term “vascular” as used herein refers to the entire vascular system, including the heart, and the term “vascular health” is inclusive of the cardiovascular health and/or coronary health. [0048] It is contemplated that any embodiment discussed herein can be implemented with respect to any method or composition of the invention, and vice versa. FORTIFIED ARONIA AND TART CHERRY JUICE [0049] The present invention discloses a composition which comprises Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract. According to embodiments, the combination of the extracts with the corresponding juice enhances the bioavailability of the polyphenol gut metabolites. In further embodiments, the combination of the extracts with the corresponding juice unexpectedly provides a synergistic effect to reduce the expression of cell adhesion molecules (CAMs) associated with vascular disorders and microvascular dysfunction, including one or more of E-selectin, L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), ALCAM-1, ICAM-2, and ICAM-1. In this way, according to embodiments described herein, the compositions comprise components that interact to inhibit platelet aggregation and vascular inflammation. The composition may also comprise additional nutraceutical extracts, wherein said composition enhances the absorption of micronutrients from the additional nutraceutical extracts. Fortified Aronia Juice [0050] Aronia, also known as chokeberry, is known to contain very high concentrations of polyphenols having antioxidant and radical scavenging properties. Aronia is a deciduous shrub which belongs to the plant family Rosaceae. Within the genus Aronia several species and hybrids are known, such as Aronia melanocarpa (black chokeberry), Aronia arbutifolia (red chokeberry), and Aronia x prunifolia (purple chokeberry). In certain embodiments, the 12 Cardiovascular Protection.DOCX Aronia extract and juice originate from an Aronia species which is pharmaceutically and nutraceutically acceptable or is a mixture of different pharmaceutically or nutraceutically acceptable Aronia species. Aronia species that may be used include, but are not limited to A. melanocarpa, A. arbutifolia, and A. x prunifolia. According to other embodiments, the extract and juice are from Aronia melanocarpa. In a preferred embodiment of the present invention, the extract and juice are from Aronia melanocarpa rubinia. [0051] The polyphenol content may vary depending on the maturity of the Aronia berries and the growing conditions of the plant. According to embodiments, the Aronia plant and fruit may be obtained from various parts of the world, including northern Europe and North America. In an exemplary embodiment, the Aronia extract and juice are derived from the fruit of A. melanocarpa, which may contain between 500 to 2000 mg of polyphenol per 100 mL of juice. In certain embodiments, the polyphenol content is between 400 to 900 mg per 100 mL of juice. In further embodiments, the polyphenol content is between 600 to 900 mg per 100 mL of juice. [0052] The Aronia extract may be derived from the whole fruit or from parts of the fruit. For example, according to embodiments, the extract may be produced from the pomace of the fruit, fresh fruit, dried fruit, or fruit juice. The Aronia extract may be obtained according to any suitable extraction method. In certain embodiments, the Aronia extract is prepared by ultrasound, microwave, and pressure assisted extraction. In other embodiments, the Aronia extract is prepared by solvent (ethanol) extraction and the solvent evaporated according to methods known in the art to produce a dry, water-soluble, extract. [0053] The Aronia juice may be prepared from the whole fruit or from parts of the fruit. In certain embodiments, the Aronia juice is prepared from the whole fruit in order to retain the full spectrum of fruit sugars, nutrients, vitamins and minerals found in the whole fruit juice. The Aronia juice may be obtained according to any suitable juice extraction method. For example, the Aronia juice can be prepared by known methods of steam extraction, hot press extraction, cold press extraction, with or without macerating enzyme treatment. In certain embodiments, the Aronia juice is prepared at low temperatures to maintain the integrity of 13 Cardiovascular Protection.DOCX the micronutrients and phytochemicals in the juice. According to embodiments, the Aronia juice is prepared by cold press extraction. In further embodiments, the whole Aronia fruit is pressed without heat to allow the release of polyphenols and other berry bioactives from the berry skin. In further embodiments, the Aronia juice is further pasteurized or sterilized at low temperatures. [0054] According to embodiments of the present invention, the Aronia juice is fortified with Aronia extract. In certain embodiments, the Aronia extract is a liquid concentrate and is combined with the Aronia juice. In other embodiments, the Aronia extract is a dry powder that is dissolved in the Aronia juice. In embodiments of the present invention, the fortified Aronia juice comprises from at least about 100 mg to about 4000 mg of Aronia extract per 100 mL of Aronia juice. In other embodiments, the fortified Aronia juice comprises from at least about 200 mg to about 3500 mg, from at least about 300 mg to about 3000 mg, from at least about 400 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, and from at least about 700 mg to about 1000 mg of Aronia extract per 100 mL of Aronia juice. According to certain embodiments, the fortified Aronia juice comprises about 500 mg of Aronia extract per 100 ml of Aronia juice. In other embodiments, the fortified Aronia juice comprises about 1,000 mg to about 3,000 mg of Aronia extract per 100 ml of Aronia juice. [0055] In certain embodiments, the fortified Aronia juice of the present invention comprises Aronia extract in a concentration from at least about 1 mg/mL to about 40 mg/mL, from about 2 mg/mL to about 35 mg/mL, from about 3 mg/mL to about 30 mg/mL, from about 4 mg/mL to about 25 mg/mL, and from about 6 mg/mL to about 15 mg/mL. Fortified Tart Cherry Juice [0056] Tart cherry, sour cherry, or also referred to as dwarf cherry, is a species of Prunus in the subgenus Cerasus of the plant family Rosaceae. Tart cherries have been shown to be a source of several beneficial micronutrients, particularly vitamin C, anthocyanins, and 14 Cardiovascular Protection.DOCX melatonin. According to certain embodiments, the Serbian Oblacinska variety of tart cherry is identified as a suitable variety of tart cherry juice and/or extract. [0057] The tart cherry extract may be derived from the whole fruit or from parts of the fruit. For example, according to embodiments, the extract may be produced from the pomace of the fruit, fresh fruit, dried fruit, or fruit juice. The tart cherry extract may be obtained according to any suitable extraction method. In certain embodiments, the tart cherry extract is prepared by ultrasound, microwave, and pressure assisted extraction. In other embodiments, the tart cherry extract is prepared by solvent (ethanol) extraction and the solvent evaporated according to methods known in the art to produce a dry, water-soluble, extract. [0058] The tart cherry juice may be prepared from the whole fruit or from parts of the fruit. In certain embodiments, the tart cherry juice is prepared from the whole fruit in order to retain the full spectrum of fruit sugars, nutrients, vitamins and minerals found in the whole fruit juice. The tart cherry juice may be obtained according to any suitable juice extraction method. For example, the tart cherry juice can be prepared by known methods of steam extraction, hot press extraction, cold press extraction, with or without macerating enzyme treatment. In certain embodiments, the tart cherry juice is prepared at low temperatures in order to maintain the integrity of the micronutrients and phytochemicals in the juice. According to embodiments, the tart cherry juice is prepared by cold press extraction. In further embodiments, the whole tart cherry fruit is pressed without heat to allow the release of polyphenols and other bioactives from the skin of the fruit. In further embodiments, the tart cherry juice is further pasteurized or sterilized at low temperatures. [0059] According to embodiments of the present invention, the tart cherry juice is fortified with tart cherry extract. In certain embodiments, the tart cherry extract is a liquid concentrate and is combined with the tart cherry juice. In other embodiments, the tart cherry extract is a dry powder that is dissolved in the tart cherry juice. In embodiments of the present invention, the fortified tart cherry juice comprises from at least about 100 mg to about 5000 mg of tart cherry extract per 100 mL of tart cherry juice. In other embodiments, the fortified tart cherry 15 Cardiovascular Protection.DOCX juice comprises from at least about 50 mg to about 4500 mg, from at least about 150 mg to about 3000 mg, from at least about 375 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, and from at least about 700 mg to about 1000 mg of tart cherry extract per 100 mL of tart cherry juice. According to certain embodiments, the fortified tart cherry juice comprises about 1,000 mg to about 3,000 mg of tart cherry extract per 100 mL of tart cherry juice. [0060] In certain embodiments, the fortified tart cherry juice of the present invention comprises tart cherry extract in a concentration from at least about 1 mg/mL to about 50 mg/mL, from about 0.5 mg/mL to about 25 mg/mL, from about 5 mg/mL to about 20 mg/mL, from about 6 mg/mL to about 15 mg/mL, and from about 7 mg/mL to about 10 mg/mL. Fortified Aronia and Tart Cherry Juice [0061] According to embodiments, the composition of the present invention is prepared by combining the Aronia-extract-fortified Aronia juice and the tart cherry-extract-fortified tart cherry juice. In embodiments of the present invention, the composition comprises a volume ratio of fortified Aronia juice to fortified tart cherry juice in a 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 volume ratio. According to certain embodiments, the composition comprises a volume ratio of fortified Aronia juice to fortified tart cherry juice in a 1:1, 2:1, or 4:1 volume ratio. [0062] In other embodiments, the composition comprises a volume ratio of fortified tart cherry juice to fortified Aronia juice in a 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 volume ratio. According to certain embodiments, the composition comprises a volume ratio of fortified tart cherry juice to fortified Aronia juice in a 1:1, 2:1, or 4:1 volume ratio. [0063] According to embodiments of the present invention, the composition of Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice comprises from at least about 100 mg to about 4000 mg of Aronia extract and from at least about 20 mg to about 5000 mg of tart cherry extract per 100 mL. In other embodiments, the composition comprises from at least about 200 mg to about 3500 mg, from at least about 16 Cardiovascular Protection.DOCX 300 mg to about 3000 mg, from at least about 400 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, or from at least about 700 mg to about 1000 mg of Aronia extract per 100 mL, and from at least about 50 mg to about 4500 mg, from at least about 150 mg to about 3000 mg, from at least about 375 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, or from at least about 700 mg to about 1000 mg of tart cherry extract per 100 mL. In certain embodiments, the composition comprises about 2000 mg of Aronia extract and about 1500 mg of tart cherry extract per 100 mL. ADDITIONAL MICRONUTRIENTS AND BIOACTIVE PHYTOCHEMICALS [0064] According to embodiments of the present invention, it is contemplated that the combination of Aronia and tart cherry extracts with the corresponding juice provides a synergistic effect that enhances the bioavailability of polyphenol and/or polyphenol gut metabolites, and enhances absorption of micronutrients and bioactive phytochemicals. In certain embodiments, the composition of Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract may also comprise additional nutraceutical extracts. In certain embodiments, the additional extracts comprise additional polyphenols. In other embodiments, the additional extracts comprise bioactive agents that further support vascular health. In other embodiments, the additional extracts comprise bioactive agents having activities that complement vascular health. It is contemplated that the increased absorption of the micronutrients and bioactive phytochemicals, when combined with the composition of fortified Aronia and tart cherry juice, results in an enhanced beneficial effect. Additive Micronutrients and Bioactive Phytochemicals [0065] The additional micronutrients and bioactive phytochemicals may be provided as one or more active compounds from the group of vitamins, minerals, and trace minerals. The additional micronutrient and bioactive phytochemicals may be provided in synthetic or plant-derived form. In preferred embodiments, the additional micronutrients and bioactive phytochemicals comprise polyphenols. In further embodiments, the additional 17 Cardiovascular Protection.DOCX micronutrients and bioactive phytochemicals are provided as one or more nutraceutical extracts. For example, but not limited thereto, the additional micronutrients and bioactive phytochemicals may be provided as any one or more of the following nutraceutical extracts. Beetroot Extract [0066] Beetroot extract has a high nitrate and antioxidant (betanin) content. Beetroot extract may increase in vivo nitric oxide (NO) bioavailability, enhance endothelial function, improve blood flow and enhance physical performance, as well as combat damaging reactive oxygen species. Rosehip Extract [0067] Rosehip extract has a particularly high vitamin C, carotenoid (lycopene), and polyphenol content, which are all beneficial in fighting inflammation and protecting the immune system from viral and bacterial infection. Chamomile Extract [0068] Chamomile extract is traditionally used for its calming effects and is thought to aid in combating depression and anxiety with its unique content of apigenin, an antioxidant that promotes sleepiness, improves sleep quality and reduces insomnia. In addition, chamomile extract is thought to improve gastrointestinal and cardiovascular health, and lower blood pressure. Lemon Balm Extract [0069] Lemon balm (Melissa officinalis) is a powerful herb from the mint family that is thought to reduce stress and anxiety, and improve mood and sleep quality. Lemon balm extract is high in flavonoids, phenolic compounds, as well as antioxidants such as rosmarinic and gallic acid, which all help to combat inflammation, promote gastrointestinal health and boost cognitive function. 18 Cardiovascular Protection.DOCX Lion’s Mane Mushroom Extract [0070] Lion’s mane mushroom is a medicinal mushroom believed to offer a range of health benefits, including reduced inflammation and improved cognitive and heart health. Reishi Mushroom Extract [0071] Reishi mushroom is a polypore fungus belonging to the genus Ganoderma (Ganoderma lucidum) and is considered to be a medicinal mushroom in many Asian cultures for its health-promoting effects. Reishi mushroom is thought to have immunomodulatory, renoprotective, anti-inflammatory, and hepatoprotective properties. Natural Wild Species Parsley Extract [0072] The two main groups of parsley are curly leaf (i.e.,P. crispum crispum group; syn. P. crispum var. crispum) and Italian, or flat leaf (i.e., P. crispum neapolitanum group; syn. P. crispum var. neapolitanum). Of these, the neapolitanum group more closely resembles the natural wild species. It contains a variety of B vitamins including B-5 and B- 2. Parsley may also contain more vitamin K than any other herb since it has more than 1300 percent of the recommended daily intake. Parsley can be used to treat conditions like: water edema, high blood pressure, digestion. Cannabidiol (CBD) [0073] CBD, particularly from hemp, has a variety of vitamins and minerals such as vitamins A, C, E and B complex, as well as zinc, potassium, iron, calcium, essential amino acids, and omega 3 and 6 fatty acids. CBD has been reported to reduce anxiety, stress and depression, as well as improve sleep quality, pain management and overall wellness. [0074] According to embodiments of the present invention, the composition of Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice, further includes one or more additional nutraceuticals selected from red beet extract, rosehip extract, chamomile extract, Melissa officinalis, lemon balm extract, lion’s mane mushroom extract, 19 Cardiovascular Protection.DOCX reishi mushroom extract, parlsley, cannabidiol (CBD), or any combination of these extracts. In certain embodiments, the one or more additional nutraceutical extracts are added to the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in the following ranges, from at least about 50 mg to 5000 mg of red beet extract, from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 10 mg to 3000 mg of Melissa officinalis, from at least about 10 mg to 4000 mg of lemon balm extract, from at least about 100 mg to 1500 mg of lion’s mane mushroom extract, from at least about 100 mg to 1500 mg of reishi mushroom extract, and/or from at least about 1 mg to 300 mg of cannabidiol (CBD) per 100 mL. [0075] In further embodiments, the composition includes one or both of the additional nutraceutical extracts selected from red beet extract, lion’s mane mushroom extract, and/or rosehip extract. In certain embodiments, the composition includes from about 50 mg to 5000 mg of red beet extract, and/or from about 20 mg to 5000 mg of rosehip extract, and/or from about 100 mg to 1500 mg of lion’s mane mushroom extract per 100 mL. In other embodiments, the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition, further includes about 1000 mg of red beet extract, and/or about 1000 mg of rosehip extract, and/or about 1000 mg of lion’s mane mushroom extract, and/or about 300-1000 mg of wild form of parsley extract per 100 mL. [0076] According to other embodiments of the present invention, the Aronia-extract- fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition further includes one or more additional nutraceutical extracts that comprise one or more of rosehip extract, chamomile extract, reishi mushroom extract, and lemon balm extract. In certain embodiments, the one or more additional nutraceutical extracts are added to the Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in the following ranges, from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 100 mg to 1500 mg of reishi mushroom extract, and/or from at least about 10 mg to 4000 mg of lemon balm 20 Cardiovascular Protection.DOCX extract per 100 mL. In further embodiments, the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition, further includes about 1000 mg of rosehip extract, 700 mg of chamomile extract, 1000 mg of reishi mushroom extract, and/or 500 mg of lemon balm extract, and/or about 300-1000 mg of wild form of parsley extract per 100 mL. [0077] In certain embodiments, the formulation comprises Aronia-extract-fortified Aronia juice, tart cherry-extract-fortified tart cherry juice, with at least about 50 mg to 5000 mg of red beet extract, about 20 mg to 5000 mg of rosehip extract, about 10 mg to 2000 mg of chamomile extract, and 100 mg to 1500 mg of lion’s mane mushroom extract per 100 mL. In other embodiments, the formulation comprises Aronia-extract-fortified Aronia juice, tart cherry-extract-fortified tart cherry juice, with at least about 10 mg to 2000 mg of chamomile extract, at least about 10 mg to 4000 mg of lemon balm extract, at least about 100 mg to 1500 mg of reishi mushroom extract per 100 mL. [0078] According to certain embodiments of the present invention, the additional nutraceuticals added to the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition further includes cannabidiol (CBD). The CBD is added to the composition, according to certain embodiments, in an amount that ranges from at least about 1 mg to 300 mg per 100 mL. [0079] In certain embodiments, the Aronia-extract-fortified Aronia juice and tart cherry- extract-fortified tart cherry juice composition includes one or more of from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 10 mg to 4000 mg of lemon balm extract, from at least about 100 to 1500 mg of reishi mushroom extract, from at least about 300 to1000 mg of wild form of parsley, and from at least about 1 mg to 300 mg of cannabidiol (CBD) per 100 mL. [0080] In further embodiments, the Aronia-extract-fortified Aronia juice and tart cherry- extract-fortified tart cherry juice composition further includes one or more additional nutraceuticals selected from about 100mg to 2,000mg of resveratrol extract, about 100mg to 21 Cardiovascular Protection.DOCX 1,000mg of quercetin extract, about 100mg to 1,000mg of fisetin extract, 100mg to 3,000mg of berberine extract, about 100mg to 3,000mg of urolithin A, about 100mg to 3,000mg of NMN, about 100mg to 3,000mg of Ca-AKG, about 10mg to 3,000mg of spermidine extract, and/or about 100mg to 3,000mg of TMG. FORMULATIONS [0081] The Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition can be formulated as a nutritional supplement for oral consumption. According to certain embodiments, the formulation comprises the Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition as described herein, formulated as an oral supplement. In other embodiments, the formulation comprises the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition in combination with one or more additional nutraceutical extracts as described herein, formulated as an oral supplement. In further embodiments, the formulation comprises the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in combination with one or more additional polyphenol-containing extract. [0082] The composition according to the present invention may be formulated in a liquid form, i.e., for example in the form of solutions, dispersions, emulsions and gels, or in a solid form. In certain embodiments, the composition is formulated as a capsule, a tablet, a liquid concentrate, a liquid drink, or a powder. According to other embodiments, the composition is formulated as a liquid drink, syrup, tonic, or jelly. In further embodiments, the composition is formulated as an edible solid or an edible semi-solid. In certain embodiments, the formulation is a powder reconstituted into potable liquid (i.e. water, etc.). [0083] In some embodiments, additional components can be added to the formulation to provide colour, flavour, texture, scent, etc. In some embodiments, the formulation comprises additional components that act as preservatives or stabilize one or more of the ingredients. 22 Cardiovascular Protection.DOCX METHODS AND USE [0084] Also within the scope of the invention are methods for treating and/or preventing and/or aiding the treatment and/or prevention of diseases and/or conditions associated with adhesive interactions modulated by cell adhesion molecules. In certain embodiments, the methods comprise treating an existing medical condition, for example, high blood pressure or atherosclerosis, by affecting the pathology of the disease or the symptoms associated therewith. In other embodiments, the methods comprise preventing or reducing the risks associated with developing a disease, for example, high blood pressure or atherosclerosis. In certain embodiments, the method comprises the prevention or prophylaxis of vascular health in an individual known to be at high risk of developing a disease. In other embodiments, the methods comprise maintaining good vascular health in a subject. [0085] Diseases and/or conditions associated with adhesive interactions modulated by cell adhesion molecules include atherosclerosis, hypertension, coronary heart disease (CHD), cerebrovascular disease, heart attack, stroke, peripheral vascular disease and kidney failure. Also included are methods for inhibiting platelet aggregation, monocyte adhesion and proliferation of vascular smooth muscle, reducing blood pressure, reducing thrombosis, and modulating oxidative stress. [0086] The methods comprise administering to a subject, an amount of the composition effective to treat, prevent, or aid in the treatment or prevention, or achieve at least the beneficial effect of inhibiting platelet aggregation. The methods may further comprise determining the effectiveness of the treatment by, for example, determining plasma levels of CVD biomarkers, including cell adhesion molecules and/or platelet aggregation and/or platelet activation. [0087] The composition may be administered to a healthy subject for prophylactic purposes or to a subject in need of a treatment or having at least one of the risk factors associated. Any individual having at least one of the risk factors associated with vascular health problems is a subject for administration of the compositions described herein. 23 Cardiovascular Protection.DOCX Populations of subjects who are susceptible to developing vascular health problems will be apparent to one skilled in the art. [0088] A method of enhancing absorption of a polyphenol into the blood of a subject is also provided. The method, which in essence enhances the bioavalability of polyphenols that are beneficial for the subject, comprises administering to the subject an Aronia-extract- fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition. [0089] The effective amount may be determined by a person skilled in the art using the guidance provided herein and the general knowledge in the art. It will be appreciated that the amount to be administered depends on the subject to be treated taking into account age, weight and other personal conditions. The treatments/preventive administration may be continued as a regimen, e.g., daily, monthly, bimonthly, biannually, annually, or in some other regimen, as determined by the skilled medical practitioner for such time as is necessary. Preferably, the composition is administered daily, most preferably two or three times a day, for example, morning and evening to maintain the levels of the effective compounds in the body of the subject. To obtain the most beneficial results, the composition may be administered for at least about 30 to about 60 days. These regimens may be repeated periodically. [0090] According to some embodiments, the composition is taken at least once a day for 1 week to 12 months. In other embodiments, the composition is taken at least once a day for 1, 2, 3, or 4 weeks. In further embodiments, the composition is taken at least once a day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. [0091] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any way. 24 Cardiovascular Protection.DOCX EXAMPLES EXAMPLE 1: PRELIMINARY STUDY TO IDENTIFY THE SYSTEMIC EFFECT OF FORTIFIED ARONIA-TART CHERRY FORMULATION [0092] The ability of the fortified aronia-tart cherry formulation (“core formulation”) to enhance bioavailability and absorption of polyphenol gut metabolites was first assessed in a preliminary study of the systemic effects resulting from daily consumption of the core formulation over a period of 3 months. [0093] The formulation consisted of aronia also known as chokeberry (Aronia melanocarpa) and tart cherry (Prunus cerasus) mother juices combined in a 4:1 ratio (volume/volume) enriched with polyphenol-rich dry extracts from both of these fruits, total of 1000 mg od polyphenols. [0094] The parameters observed in this preliminary study include: blood count parameters, markers of kidney and liver function, anthropometric parameters, blood pressure, metabolic parameters (blood lipid profiles, blood sugar), markers of cardiovascular risk, intestinal permeability, inflammatory biomarkers, antioxidant defense parameters and erythrocyte fatty acid profiles. These parameters were monitored to identify the systemic effects resulting from prolonged consumption of the core formulation which reflect the bioavailability and absorption of the polyphenols. Methods i) Study participants and treatment [0095] Participants included in this study were subjects of both sexes (11 men and 6 women), mean age 43.8±2.2, with no diagnosed cardiovascular disease (CVD), with an elevated body mass index (BMI≥ 25) or abdominal obesity (waist circumference above ≥94 cm for men, ≥80 cm for women), with or without: blood pressure above optimal values (SBP/DBP ≥ 120/80 mm Hg), elevated triglycerides (≥1.7 mmol/L or ≥150 mg/dL), elevated 25 Cardiovascular Protection.DOCX LDL cholesterol (> 2.6 mmol/L or > 100 mg/dL), elevated total-cholesterol (≥5.0 mmol/L or ≥193 mg/dL) and reduced HDL-cholesterol (men < 1 mmol/L, women < 1.3 mmol/L). Study participants were not on special dietary regimens (e.g., vegan and vegetarian) and did not report allergy or intolerance to berries or chokeberry/tart cherry formulation components. [0096] The study participants were instructed to consume a daily dose of 60 ml of core formulation after breakfast. During the study, participants were asked to maintain their habitual diet and physical activity but abstain from berries and berry-derived products other than the test drink and avoid excess amounts of other polyphenol rich-foods and alcohol. To determine baseline dietary intake, trained staff conducted structured interviews with study subjects and collected data using a food frequency questionnaire and repeated 24-hour dietary recalls. Adherence to dietary restrictions was monitored by regular contact with members of the research team and unannounced 24-hour dietary recall checks. ii) Sample collection and processing [0097] Venous blood was drawn in the morning (8:00-9:00 a.m.) after an overnight fast, at three time points: before the consumption (Baseline, T0), after 3-weeks (short-term, T1), and after 3 months (long-term, T2) of core formulation consumption. Blood was collected into the appropriate sample tubes and further processed to obtain serum and plasma samples. Biochemical parameters were determined in fresh serum samples using the clinical biochemistry analyzer. Plasma samples were used to evaluate intestinal permeability and inflammatory parameters by ELISA assays. Whole blood was used to assess hematological parameters by the hematology analyzer and the antioxidant defense parameters by commercial kits. Erythrocyte fatty acid profiles in the total lipid pool were determined by gas chromatography. 26 Cardiovascular Protection.DOCX Results i) Dietary intake assessments. [0098] Dietary data were collected for two non-consecutive days within the baseline evaluation (T0), follow-up assessment, i.e., during the consumption of the provided juice (T1), and at the end of the study period (T2). Dietary assessment was based on the average values derived from repeated reports for each study point to better estimate intra-individual dietary variability over the study continuum. [0099] The results of this dietary intake analysis revealed that there was no statistically significant difference between the estimated energy and macronutrient intake with reference to the baseline assessment (Table 1). These results confirm that the dietary changes were unchanged during supplement intervention and are no reason for any biological effects. Table 1. Changes of the mean dietary intake estimates over the three time-points of the study ii) Hematological parameters [00100] The hematological parameters assessed include leukocyte count and differential, erythrocyte count, platelet count, hemoglobin concentration, hematocrit (packed cell volume), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC). 27 Cardiovascular Protection.DOCX [00101] As shown in Table 2, daily consumption of core formulation induced a significant increase in MCH (the average quantity of hemoglobin in a red blood cell) and MCHC values (the content of hemoglobin per unit volume in red blood cells) over time, with significant changes observed between baseline (T0) and 3 months (T2) as well as 3-week (T1) and 3- month time points. Moreover, the observed changes in MCH remained significant when subjects were stratified according to gender (T0 vs. T2, p=0.023 for men, p=0.045 for women). Thus, these data suggest potential benefits of core formulation consumption on variables associated with anemia and the health of the hemoglobin in the blood. Table 2. The effect of 3-month core formulation consumption on hematological parameters 28 Cardiovascular Protection.DOCX [00102] Kidney function was assessed for ability to perform normal functions like clearing waste products (serum urea (BUN), creatinine, uric acid levels) and maintaining the electrolyte balance (serum sodium, potassium, and chloride levels). [00103] The consumption of core formulation for 3 months significantly reduced serum uric acid levels by 9% compared to baseline (T0 vs. T2, p=0.004). Serum concentrations of this parameter have been previously shown to positively correlate with the development of various diseases, including hypertension, metabolic syndrome, and diabetes mellitus. As presented in Table 3, the core formulation consumption did not induce significant alterations in other evaluated kidney function parameters. Table 3. The effect of 3-month core formulation consumption on parameters of kidney function iv) Liver function parameters [00104] Liver function was assessed by observing how well the liver is performing its regular function like producing protein (serum albumin, total protein levels) and clearing bilirubin, as well as the measurement of enzymes that liver cells release in response to 29 Cardiovascular Protection.DOCX damage, including serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH). [00105] The consumption of core formulation during 3 months did not significantly affect any of the evaluated parameters of liver function (Table 4). Together with kidney function data, these results support the safety of long-term consumption of core formulation for human health. Table 4. The effect of 3-month core formulation consumption on parameters of liver function v) Anthropometric parameters and blood pressure [00106] Height was measured to the nearest 0.5 cm using a SECA stadiometer, and waist and hip circumferences were measured to the nearest 0.1 cm using a measuring tape. Body composition was evaluated using bioelectrical impedance analysis (BIA) – InBody 770 (Inbody Co., LTD, Seoul, Korea). During measurements, subjects wore typical athletic clothing and removed all metal jewelry. Subjects stood on the platform of the device barefoot with the soles of their feet on the electrodes and grasped the unit's handles with their thumb and fingers to maintain direct contact with the electrodes. They remained still for ~1 min with elbows fully extended, and their shoulder joint abducted to approximately a 30-degree angle. 30 Cardiovascular Protection.DOCX [00107] As shown in Table 5, daily consumption of chokeberry/tart cherry core formulation induced significant changes in diastolic blood pressure, total body water of right and left leg, and intra and extra-cellular water of right and left leg over time. Table 5. The effects of consumption of chokeberry/tart cherry formulation on body composition and blood pressure [00108] Consumption of chokeberry/tart cherry core formulation significantly decreased diastolic blood pressure after 3 months (T0 vs. T2, p=0.006; T1 vs. T2, p=0.041), while only three weeks of consumption had an insignificant but clearly noticeable downward trend (Figure 2). 31 Cardiovascular Protection.DOCX [00109] Values of total body water of the right (T0 vs. T2, p=0.002; T1 vs. T2, p=0.012) and left leg (T0 vs. T2, p=0.001; T1 vs. T2, p=0.017) were significantly lower after 3 months consumption compared to both baseline and 3-week time points (Figure 3A, B). Similar lowering effects were observed for intracellular water in right (T0 vs. T2, p=0.003; T1 vs. T2, p=0.010) and left leg (T0 vs. T2, p=0.001; T1 vs. T2, p=0.010) (Figure 3C, D). Additionally, the observed values after 3-month long consumption were also significantly lower for extracellular water in both legs (Figure 3E, F) when compared to both baseline and 3 weeks of consumption (right leg: T0 vs. T2, p=0.002; T1 vs. T2, p=0.015; left leg: T0 vs. T2, p=0.004, T1 vs. T2, p=0.026). vi) Metabolic markers and blood markers of CVD risk [00110] Certain blood biomarkers were assessed. Blood biomarkers of CVD risk include fibrinogen, homocysteine, and C-reactive protein (CRP) levels. [00111] After a 3-month long consumption of core formulation, there was a significant decrease in serum HbA1c levels that reflect an average blood glucose content for the last two to three months (Table 6, T1 vs. T2, p=0.028). Similarly, there was a significant reduction in serum homocysteine levels, a blood marker of CVD risk (Table 7, T1 vs. T2, p=0.021). By contrast, chronic consumption of core formulation consumption did not induce significant modulations in serum glucose levels, lipid profiles (Table 6), and levels of other evaluated blood markers of CVD risk (Table 7) in studied subjects. 32 Cardiovascular Protection.DOCX Table 6. The effects of 3-week core formulation consumption on metabolic markers Table 7. The effects of long-term core formulation consumption of core formulation on blood markers of CVD risk vii) Parameters of endothelial dysfunction and inflammation [00112] The markers of endothelial dysfunction that were monitored include: vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), endothelin-1 (ET-1) and inflammation: tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6). [00113] Consumption of core formulation for 3 months significantly reduced plasma ICAM-1 levels by 11.8% compared to baseline (p=0.0005) and lowered plasma VCAM-1 33 Cardiovascular Protection.DOCX levels by 14.6%, although without statistical significance (p=0.1514) (Figure 4). The levels of another marker of endothelial dysfunction, ET-1, and markers of inflammation TNFα and IL-6 were below the assay detection limit for the majority of evaluated samples (both before and after 3-month long core formulation consumption, data not shown). viii) Intestinal permeability (evaluated as zonulin plasma levels) [00114] The long-term consumption of core formulation for 3 months significantly reduced plasma zonulin levels, a marker of intestinal permeability, by 28.5% compared to baseline (p=0.0002, Figure 5). ix) Parameters of oxidative stress/antioxidant defense [00115] Oxidative stress/antioxidant defense was evaluated as 1) activities of enzymes involved in antioxidant protection: glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT); and 2) index of lipid peroxidation determined as thiobarbituric acid-reactive substances (TBARS) expressed as malondialdehyde (MDA) equivalents. [00116] Following the consumption of core formulation for 3 months, there was a slight reduction in catalase and SOD activities in erythrocytes, however, not statistically significant (p=0.086 and p=0.092, respectively) (Figure 6). Furthermore, there were no significant changes in the relative activity of GPx (p=0.7819), and index of lipid peroxidation (MDA equivalent levels) tended to be significantly reduced (p=0.074). Data from the literature show that polyphenols exert high antioxidant action in vitro. Thus, a decrease in antioxidant enzyme activities and lipid peroxidation index observed in this study could be a result of direct antioxidant effects of core formulation’s polyphenols and their metabolites, which could reduce oxidative stress and consequently lower the need for the activity of antioxidant enzymes and lipid peroxidation. 34 Cardiovascular Protection.DOCX Preliminary conclusions [00117] Figure 1 illustrates the systemic effects observed with consumption of the core formulation. A significant reduction in junctional protein levels, ICAM-1 (a marker of endothelial dysfunction) and plasma zonulin, suggest that long-term consumption of the aronia/tart cherry core formulation improved intestinal permeability leading to tighter cell junctions and less water and nutrient loss. The resulting systemic effects of this were further shown by a significant effect on the total, intra and extracellular water in both legs and lowered diastolic blood pressure, suggesting potential anticellulite and blood pressure modulating effects of the studied formulation. The test drink also showed increased variables associated with anemia and the health of the hemoglobin in the blood (MCH, MCHC) and reduced uric acid levels, a parameter associated with the development of hypertension, metabolic syndrome, and diabetes mellitus. Furthermore, reduced serum levels of CVD risk biomarker homocysteine, and lowered long-term blood glucose levels, were observed. The polyphenol-rich core formulation also showed a tendency to modulate oxidative stress/antioxidant defense. EXAMPLE 2: ACUTE EFFECT OF FORTIFIED ARONIA-TART CHERRY FORMULATION ON PLATELET FUNCTION [00118] Platelets play an important role in hemostasis and thrombosis, as well as in the development of atherosclerosis, which is a major cause of cardiovascular diseases (CVD). The involvement of platelets in these events is a consequence of their activation, mediated by various physiological and pathophysiological factors, and their subsequent interaction with leukocytes, other platelets and endothelial cells. Platelets may interact with these cells directly through adhesion molecules such as P-selectin and GPIIbIIIa on the surface of activated platelets to form aggregates. [00119] Disturbed platelet function has been shown to discriminate between healthy and individuals at high risk for CVD, and its major hallmarks are platelet hyperactivation (a higher number of activated platelets in basal state or in response to agonists ex vivo), and 35 Cardiovascular Protection.DOCX hyperreactivity (increased response to suboptimal concentrations of agonists). Furthermore, increased platelet-leukocyte aggregates (neutrophil/monocytes) formation has been reported in subjects with hypertension, diabetes, metabolic syndrome, ischemic heart disease and stroke. Therefore, elevated platelet activation and aggregation with leukocytes are increasingly regarded as a biomarker of CVD risk and a potential target for CVD prevention and treatment. [00120] Plant foods and their bioactive compounds have been suggested to exert protective effects against CVD, which may be partly attributed to their effect on platelet function. Moreover, in the guidance document on the scientific requirements for health claims related to antioxidants, oxidative damage and cardiovascular health (updated in 2018), the European Food Safety Authority’s Panel on Dietetic Products, Nutrition and Allergies states that the reduction in platelet aggregation could be considered a beneficial physiological effect, which further supports the research of the potential effects of different foods and their bioactive compounds on platelet function towards maintaining good cardiovascular health. [00121] The objective of this study was to evaluate the potential acute effects of consuming core formulation and its components on platelet function, assessed as the expression of platelet activation markers (P-selectin and GPIIbIIIa) and platelet-monocyte and platelet- neutrophil aggregate formation in the whole blood of subjects in both basal state and after the ex vivo exposure to a suboptimal concentration of platelet agonist. The core formulation consisted of chokeberry (Aronia melanocarpa) and tart cherry (Prunus cerasus) mother juices combined in a 4:1 ratio (volume/volume) and enriched with polyphenol-rich dry extracts from both fruits. Based on the preliminary studies suggesting an enhanced bioavailability of polyphenols with consumption of the core formulation, we hypothesized that combining a dry extract with the mother juice of the same fruit will be more effective on markers of platelet function compared to extract alone and, more importantly, that the mixture of two mother juices and their corresponding dry extracts will exert the most pronounced effect on these parameters. 36 Cardiovascular Protection.DOCX Methods i) Study design and treatments [00122] This study included six apparently healthy, non-smoking men, aged 39.00 ± 1.67 (mean ± SEM), with an elevated body mass index (BMI>25). Study participants were not on special dietary regimens (e.g., vegan and vegetarian) and did not report allergy or intolerance to berries or chokeberry/tart cherry formulation components. Their health status was estimated based on their medical history and standard blood tests. [00123] Volunteers visited the research center five times (Figure 7). Each visit corresponded to the evaluation of the effect of a different test drink on platelet function, with a washout period of around a week between the visits. Study participants were asked to abstain from consuming alcohol, berry fruits, berry-derived products (e.g., juices and jams) and regularly consumed polyphenol-rich drinks such as tea and coffee for 72 hours before each blood collection to reduce the impact of background diet on platelet function. They were also asked to refrain from working out a day before blood collection. Adherence to these restrictions was monitored by contact with members of the research team. [00124] At each visit, participants were asked to rest for at least 20 minutes before the first blood sampling, performed in the morning (8:30-9:30 a.m.) after an overnight fast (0h time point). Venipuncture was performed using the 21-gauge needle and no tourniquet. Whole blood was collected in sodium citrate (3.2%)-coated tubes and used immediately, according to standardized protocols for blood collection in platelet analyses. After the first blood collection, participants consumed 60 ml of a test drink, followed by a slice of white toast and a cup of water (60 ml). The second blood collection for platelet function analyses was performed after 2 hours (2h time point). This time point was selected in accordance with data from the literature showing that polyphenols and their metabolites can be present in circulation at considerable levels by 2 hours after consuming different polyphenol-rich food sources. Participants spent the 2 hours between two blood collections at the research center in a seated rest. 37 Cardiovascular Protection.DOCX [00125] During the study, all participants consumed five different study drinks: 1) Core formulation - CF — Aronia and tart cherry mother juices combined in a 4:1 ratio (volume/volume) and enriched with polyphenol-rich dry extracts from both fruits (1 g/60 ml each), 2) Aronia mother juice mixed in a 4:1 ratio (volume/volume) with water and enriched with Aronia dry extract (1 g/60 ml) — AJ+AE, 3) Aronia dry extract (1g/60 ml water) — AE 4) Tart cherry mother juice combined in a 1:4 ratio (volume/volume) with water and enriched with tart cherry extract (1 g/60 ml) — TCJ+CE, 5) Tart cherry extract (1g/60 ml water) — TCE [00126] Participants signed informed consent before their enrollment in the study, which was conducted following the principles of the Helsinki Declaration. ii) Evaluated parameters [00127] Investigated parameters included markers of: a) platelet activation — the expression of P-selectin and GPIIbIIIa activation markers on platelets b) platelet-leucocyte aggregation—platelet-neutrophil and platelet-monocyte aggregates in the population of neutrophils and monocytes, respectively [00128] These parameters were explored in the whole blood in the basal state and in response to suboptimal (0.5μM) and optimal concentration (20 μM, maximal response) of agonist adenosine diphosphate (ADP), all assessed at two time points: before consuming each test drink (0h) and 2 hours after consumption (2h) (Figure 8). 38 Cardiovascular Protection.DOCX Assessment of platelet activation: [00129] At both 0h and 2h after the consumption of each test drink, one sample of diluted whole blood (1:10 in HEPES-Tyrode buffer (HTB)) was treated with the suboptimal concentration of ADP (0.5μM), one with optimal concentration (20μM) and one with HTB (basal state), and labeled with monoclonal antibodies (antiCD61-PerCP (platelet identifier), antiCD62P-PE (P-selectin) and PAC1-FITC (GPIIbIIIa)) for 15 min in the dark at RT, fixed with 1% p-formaldehyde and analyzed on FACS Calibur flow cytometer (BD Bioscience, USA). [00130] Platelet activation markers were expressed as 1) the percentage and 2) mean fluorescence intensity (MFI) of P-selectin and GPIIbIIIa-positive platelets in the total number of collected platelets (20000). The first parameter corresponds to the percentage of activated platelets in the total population of platelets and the latter is a measure of the density of P-selectin or GPIIbIIIa per platelet. These two parameters were used to calculate the "platelet activation index"(PAI) (PAI = % x MFI / 100), which indicates the relative number of P-selectin and GPIIbIIIa on the surface of antigen-positive platelets. All data are presented relative to maximal platelet response (stimulation with 20μM ADP). Assessment of platelet aggregation: [00131] At both 0h and 2h after the consumption of each test drink, one undiluted whole blood sample was treated with the suboptimal concentration of ADP (0.5μM), one with optimal concentration (20μM), and one with HTB (basal state) and labeled with antibodies (antiCD61-FITC (platelet identifier), antiCD11b-PE (neutrophil identifier) and antiCD14- PerCP (monocyte identifier)) for 20 min in the dark at RT, lysed with Lysing solution, washed two times in HTB, fixed with 1% p-formaldehyde and analyzed on FACS Calibur flow cytometer. [00132] Platelet aggregation with monocytes and neutrophils was expressed as a percentage of aggregates in the total population of monocytes (1000) and neutrophils (10000) as well as MFI in platelet-monocyte and platelet-neutrophil aggregates, which provided the relative 39 Cardiovascular Protection.DOCX measure of a density (average number per aggregate) of platelets in these aggregates. All data are presented relative to maximal platelet response (stimulation with 20μM ADP). [00133] The effects of each study drink on evaluated markers of platelet function were evaluated by paired sample t-tests for normally distributed data, or Wilcoxon signed-rank tests for non-normal data distribution (0h vs. 2h time points). Differences between study drinks’ effects were also evaluated by paired sample t-tests/ Wilcoxon signed-rank tests and are presented whenever the within treatment effect was or tended to be statistically significant (p<0.05). Results i) Study participants’ characteristics. [00134] Six apparently healthy, non-smoking male volunteers, between 32 and 44 years old, were recruited to investigate the effect of core formulation and its components on platelet function. Characteristics of study participants are presented in Table 8. Volunteers had an elevated BMI (≥ 25 kg/m 2 , overweight/obese) and abdominal obesity (waist-hip ratio ≥ 0.9). Systolic and diastolic blood pressure values were within the higher normal blood pressure category (130-139 and/or 85-89mmHg) according to the European Society of Cardiology and the European Society of Hypertension. Assessed hematological and biochemical parameters of volunteers were within reference ranges for gender and age (Table 8). Table 8. Characteristics of recruited volunteers Characteristics of volunteers Values * Reference value Age (years) 39.00 ± 1.67 N/A Height (cm) 184.00 ± 2.86 N/A Body weight (kg) 104.25 ± 4.20 N/A BMI (kg/m 2 ) 31.3 ± 1.02 <25 11 Waist-hip ratio 1.02 ± 0.03 <0.9 11 Systolic blood pressure (mmHg) 132.86 ± 3.26 120-129 10 Diastolic blood pressure (mmHg) 85.36 ± 3.82 80-84 10 HGB (g/L) 159.62 ± 5.44 138 - 175 HCT (L/L) 0.47 ± 0.01 0.415 - 0.53 40 Cardiovascular Protection.DOCX MCV (fL) 89.15 ± 1.75 83-97.2 MCH (pg) 30.27 ± 0.81 27.4-33.9 MCHC (g/L) 339.33 ± 3.23 320-370 RCB (x 10 12 /L) 5.27 ± 0.12 4.34-5.72 WBC (x 10 9 /L) 6.25 ± 0.63 3.5-10.0 PLT (x 10 9 /L) 205.25 ± 19.69 140-450 TC (mmol/L) 5.10± 0.25 3.90- 5.20 LDL-c (mmol/L) 3.22 ± 0.24 < 3.4 HDL-c (mmol/L) 1.36 ± 0.09 >1.03 Triglycerides (mmol/L) 1.17 ± 0.13 0.46-1.70 *Results are shown as mean ± SEM (standard error of the mean), n=6. ALT, Alanine transaminase; AST, Aspartate transaminase; BMI, Body mass index; HCT, Hematocrit; HDL-c, High-density lipoprotein cholesterol; HGB, Hemoglobin; LDH, Lactate dehydrogenase; LDL-c, Low-density lipoprotein cholesterol; MCH, Mean corpuscular hemoglobin; MCHC, Mean corpuscular hemoglobin concentration; MCV, Mean corpuscular volume; PLT, Platelet count; RBC, Red blood cells; TC, Total cholesterol; WBC, White blood cells. ii) Effects of core formulation and its components on markers of platelet aggregation after responding to platelet agonist. [00135] CF significantly reduced the proportion of platelet-neutrophil aggregates by 11.4% in the whole blood of volunteers after the ex vivo stimulation with the suboptimal concentration of platelet agonist (0h: 70.45±8.88% vs.2h: 62.39±6.84%, p=0.032) (Figure 9A), and this effect tended to be significant when compared to TCJ+TCE treatment (CF: ^= -8.06±2.12 vs. TCJ+TCE: ^=0.68±2.99, p=0.084) (Table 9). Consumption of CF also tended to lower the percentage of platelet-monocyte aggregates by 38.5% after responding to platelet agonist (0h: 58.76±9.19 vs.2h: 36.13±1.31, p=0.081) (Figure 9C), and this effect showed a trend towards being different when compared to the effects of CF components (CF: ^= -22.63±8.72 vs. AJ+AE: ^= -8.04±7.79, p=0.051; vs. TCE: ^= -3.47±8.54, p=0.091). Moreover, CF significantly reduced the relative number of platelets in platelet- monocyte aggregates by 41.3% (0h: 37.71±7.20 vs.2h: 22.14±4.34, p=0.026) (Figure 9E) 41 Cardiovascular Protection.DOCX — calculated as % of aggregates in the total population of monocytes x MFI/100 (binding index). Unlike CF, its components did not significantly affect assessed markers of either platelet aggregation with monocytes or neutrophils after ex vivo stimulation with the platelet agonist (Figure 9). Table 9. The effects of study drinks on markers of platelet activation and aggregation with leukocytes 0 .5^M ADP Basal state Chan e from Chan e from * 2 9 4 0 9 8 6 1 9 0 0 0 7 1 3 1 2 8 6 7 42 Cardiovascular Protection.DOCX AJ+AE -11.77±8.06 0.464 -3.41±2.66 0.475 0124 4 4 4 3 9 2 1 2 7 6 2 0 1 7 7 0 5 9 Results e t-tests for normal significant, compared to core formulation (CF). AJ+AE vs. AE and TCJ+TCE vs. TCE, nonsignificant. AJ-Aronia juice, AE- Aronia extract, TCJ-tart cherry juice, TCE-tart cherry extract. iii) Effects of core formulation and its components on markers of platelet activation after responding to platelet agonist [00136] Regarding the assessed platelet activation markers, CF significantly reduced the percentage of GPIIbIIIa-positive platelets by 6.8% after the ex vivo stimulation with the platelet agonist (0h: 96.84±0.97% vs.2h: 90.29±2.75%, p=0.034) (Figure 10A). Similarly, AJ+AE significantly reduced the percentage of GPIIbIIIa-positive platelets by 6.7% (0h: 43 Cardiovascular Protection.DOCX 83.23±1.40% vs.2h: 77.67±2.73%, p=0.025) as well as the relative number of this receptor on activated platelets by 17.32% (0h: 62.64±1.55% vs.2h: 51.79±2.42%, p=0.028) (Figure 10A, B). Moreover, this treatment lowered the percentage of P-selectin positive platelets by 14.1% (0h: 58.45±2.06% vs.2h: 50.21±2.96%, p=0.027), and tended to reduce the relative number of this antigen on the surface of activated platelets by 16.2% (0h: 48.15±2.57% vs. 2h: 40.33±2.41%, p=0.051) (Figure 10C, D). Conversely, when provided alone, AE induced weaker and statistically non-significant changes in the assessed markers of platelet activation (Figure 10). [00137] TCE significantly attenuated the percentage of P-selectin positive platelets by 14.2% (0h: 62.53±3.00% vs. 2h: 53.67±3.94%, p=0.012) (Figure 10C) and reduced the relative number of this receptor on activated platelets by 20% (0h: 52.97±2.64% vs. 2h: 42.36±3.79%, p=0.045). Combining TCE with TCJ induced significant and more pronounced decreases in these parameters, with the reduction of 20.7% observed for the percentage of P-selectin-positive platelets (0h: 55.04±3.30% vs.2h: 43.65±3.07%, p=0.033), and of 29.2% for the relative number of P-selectin on activated platelets (0h: 46.15±3.85% vs.2h: 32.67±3.81%, p=0.025) (Figure 10C, D). iv) Effects of core formulation and its components on markers of platelet activation and leukocyte-aggregate formation in the basal state [00138] CF significantly lowered the proportion of platelet-monocyte aggregates by 38.1% in the whole blood of volunteers in the basal state (0h: 36.54±5.80% vs.2h: 22.63±2.09%, p=0.027) (Figure 11C), and this effect was significant when compared to TCE (CF: ∆= - 15.60±84.81 vs. TCE: ∆= -0.75±5.51, p=0.021). In addition to CF, TCJ+TCE also reduced the percentage of platelet-monocyte aggregates in the basal state by 14.8% (0h: 30.07±3.86% vs. 2h: 25.64±2.74%, p=0.036), while other components did not significantly affect this parameter (Figure 11C). CF also showed a trend toward reducing the relative number of platelets in platelet-monocyte aggregates by 47.8% (0h: 18.33±7.99% vs.2h: 9.58±2.00%, p=0.080) (Figure 11D), and this effect tended to be significant when compared to TCE (CF: 44 Cardiovascular Protection.DOCX ∆= -10.02±8.00 vs. TCE: ∆= 1.38±4.52, p=0.064). None of the treatments significantly affected platelet-neutrophil aggregation (Figure 11A, B). [00139] Regarding the platelet activation in the basal state, no significant effect was observed either for CF or its components (Figure 12). Discussion and concluding remarks i) Platelet Aggregation (Anti-Inflammatory Signaling) - Acute effects of individual ingredients of the core formulation [00140] Regarding the evaluated markers of platelet activation, the core formulation significantly reduced the percentage of GPIIbIIIa-positive platelets after responding to ADP. In contrast, individual core formulation components reduced the relative number of GPIIbIIIa on activated platelets, the percentage of P-selectin positive platelets and the relative number of P-selectin on activated platelets. These results demonstrate the capacity of the core formulation in significantly modulating platelet-leucocyte aggregate formation in baseline conditions and in response to adenosine diphosphate (ADP), a potent platelet agonist stored in platelets’ dense granules and released upon their activation. Aggregation of platelets with monocytes and neutrophils is the initial step in atherogenesis, and the percentage of platelet-leukocyte aggregates is regarded as a marker of CVD risk. Acute consumption of core formulation significantly reduced the percentage of platelet-neutrophil aggregates, reduced the percentage of platelet aggregates with monocytes, and significantly lowered the relative number of platelets in platelet-monocyte aggregates after responding to a suboptimal dose of ADP. Interestingly, individual core formulation components did not induce statistically significant changes in these parameters after ADP stimulation, suggesting significant synergistic effects of the core formulation components in modulating platelet-leucocyte aggregate formation. [00141] Platelet activation/aggregation response to low doses of ADP has been reported as a parameter with the predictive value for cardiovascular events. Consequently, the observed changes in platelet response to suboptimal levels of ADP could be regarded as beneficial for 45 Cardiovascular Protection.DOCX cardiovascular health. The core formulation also significantly lowered the percentage of platelet-monocyte aggregates in baseline conditions. Since increased platelet activity and consequent aggregation in the baseline conditions also correlates with CVD risk level, this observed effect of the core formulation in baseline conditions further proposes its potentially protective effects against CVD. [00142] Regarding the evaluated markers of platelet activation, the core formulation significantly reduced the percentage of GPIIbIIIa-positive platelets after responding to ADP. In contrast, individual core formulation components, in addition to attenuating this parameter (AJ+AE), reduced the relative number of GPIIbIIIa on activated platelets (AJ+AE), the percentage of P-selectin positive platelets (AJ+AE, TCJ+TCE, TCE) and the relative number of P-selectin on activated platelets (TCJ+TCE, TCE). GPIIbIIIa and P- selectin are markers of platelet activation that also directly mediate platelet interactions with other cells. P-selectin is stored in platelet α granules and translocates to the surface only in response to their activation to mediate initial contact with neutrophils and monocytes. On the other hand, GPIIb/IIIa is a receptor for fibrinogen that mediates platelet-platelet and platelet-leukocyte aggregation. In this study, the observed changes in these platelet activation parameters were more pronounced when fruit extracts were combined with their corresponding mother juices. Individual core formulation components did not affect platelet activation, as the only significant reduction in the percentage of GPIIbIIIa-positive platelets was observed after consuming the core formulation itself. The effects of the individual core formulation components on platelet activation have a synergistic effect that could only be detected after being combined, since the extent of formation of these aggregates is directly dependent on platelet activation. [00143] In conclusion, this study showed the capacity of the core formulation to significantly modulate parameters of platelet activation and their aggregation with leukocytes. Interestingly, the statistically significant reductions in platelet aggregation with leukocytes after responding to platelet agonist were observed only upon CF consumption and not after the intake of its individual components. Platelet aggregation with leukocytes is 46 Cardiovascular Protection.DOCX an essential step in the development of atherosclerosis that precedes CVD, and these aggregates are considered an even more reliable marker of CVD risk compared to platelet activation. Therefore, the results from this study suggest the potentially beneficial effects of combining individual core formulation components into one formula in maintaining cardiovascular health. EXAMPLE 3: EFFECT OF FORTIFIED ARONIA-TART CHERRY FORMULATION ON CELL ADHESION AND INFLAMMATION [00144] The objective of this study was to evaluate the potential effects of 3 month-long everyday consumption of the core formulation on human health. This formulation consisted of chokeberry (Aronia melanocarpa) and tart cherry (Prunus cerasus) mother juices combined in a 4:1 ratio (volume/volume) and enriched with polyphenol-rich dry extracts from both of these fruits. Methods i) Study participants and treatment [00145] Participants included in this study were subjects of both sexes (11 men and 6 women), mean age 43.8±2.2, with no diagnosed cardiovascular disease (CVD), with an elevated body mass index (BMI≥ 25) or abdominal obesity (waist circumference above ≥94 cm for men, ≥80 cm for women), with or without: blood pressure above optimal values (SBP/DBP ≥ 120/80 mm Hg), elevated triglycerides (≥1.7 mmol/L or ≥150 mg/dL), elevated LDL cholesterol (> 2.6 mmol/L or > 100 mg/dL), elevated total-cholesterol (≥5.0 mmol/L or ≥193 mg/dL) and reduced HDL-cholesterol (men < 1 mmol/L, women < 1.3 mmol/L). Study participants were not on special dietary regimens (e.g., vegan and vegetarian) and did not report allergy or intolerance to berries or chokeberry/tart cherry formulation components. [00146] The study participants were instructed to consume a daily dose of 60 ml of core formulation (chokeberry and tart cherry mother juices (4:1, v/v) enriched with polyphenol- rich dry extracts from both fruits) after breakfast. Study treatments were provided in dark 47 Cardiovascular Protection.DOCX bottles and participants were asked to keep them in the refrigerator to preserve polyphenol stability. Compliance with the study beverage supplementation was assessed by collecting empty bottles on the last day of the intervention. During the study, participants were asked to maintain their habitual diet and physical activity but abstain from berries and berry- derived products other than the test drink and avoid excess amounts of other polyphenol rich-foods and alcohol. [00147] Participants were fully informed about the study protocols and signed informed consent before their enrollment in the study, which was conducted following the principles of the Helsinki Declaration. ii) Sample collection and processing [00148] Venous blood was drawn in the morning (8:00-9:00 a.m.) after an overnight fast, at three time points: before the consumption (Baseline, T0), after 3-weeks (short-term, T1), and after 3 months (long-term, T2) of core formulation consumption. Blood was collected into EDTA-coated tubes and further processed to obtain plasma samples. Plasma samples were used to evaluate cell markers of vascular inflammation using Legendplex assays with fluorescence-encoded beads. Samples were analyzed by flow cytometry. iii) Evaluated parameters [00149] For the additional analysis of the effects of regular, long-term consumption of core formulation for 3 months on human health, the following parameters were evaluated: 1) Markers of vascular inflammation: myoglobin, calprotectin (MRP8/14), lipocalin A (NGAL), matrix metallopeptidase 2 (MMP-2), osteopontin (OPN), myeloperoxidase (MPO), serum amyloid A (SAA), insulin-like growth factor- binding protein 4 (IGFBP-4), vascular cell adhesion molecule 1 (VCAM-1), matrix metallopeptidase 9 (MMP-9), cystatin C. 48 Cardiovascular Protection.DOCX 2) Cell adhesion molecules that mediate interactions between cells and cells and extracellular matrix and are essential in processes like cell adhesion, migration and inflammation. Assessed adhesion molecules included: platelet endothelial cell adhesion molecule (PECAM-1), activated leukocyte cell adhesion molecule (ALCAM-1), epithelial cellular adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), E-selectin, P-selectin, L-selectin, Intercellular Adhesion Molecule 1 (ICAM-1), ICAM-2, ICAM-3, P-selectin glycoprotein ligand-1 (PSGL- 1), and CD44. Results [00150] The results of the analyses are given in the Table 10 and Figure 13. Consumption of core formulation for 3 months significantly reduced plasma levels of cell adhesion molecules E-selectin, L-selectin, PSGL-1, ALCAM-1 and ICAM-2 compared to baseline. Core formulation also tended to reduce ICAM-1 as well MMP-2, myoglobin and SAA. The levels of MRP8/14, PECAM-1, EpCAM, NCAM and ICAM-3 were mainly below detection limit of the assay. Table 10. The effect of 3-month long core formulation consumption on markers of vascular inflammation and cell adhesion/migration (ng/ml) Baseline 3 months p-value Myoglobin 108.10±14.48 75.18±9.58 0.063 Matrix metallopeptidase 2 (MMP- 2 ) 116.19 (44.43) 103.01 (33.19) 0.068 Matrix metallopeptidase 9 (MMP- 9 ) 250.43±46.96 ns Lipocalin A (NGAL) 63.92 (47.49) ns Osteopontin (OPN) 23.49 (13.81) 18.54 (17.71) ns Myeloperoxidase (MPO) 22.84 (10.32) 20.30(5.34) ns Serum Amyloid A (SAA) 744.23±123.11 556.35±84.48 0.073 Insulin-like growth factor-binding 295.53 protein 4 (IGFBP-4) (241.84) 244.18 (336.57) ns Vascular cell adhesion molecule 520.83 (VCAM-1) (246.01) 388.23 (288.04) ns 49 Cardiovascular Protection.DOCX Cystatin C 291.29 ( 132.21) 239.58 (149.75) ns L -selectin 5992.78 ± 4351.36 ± 5 42.82 306.71 0.022 E-selectin 48.99(32.96) 23.84(14.84) 0.024 P-selectin 17.94 (22.44) 11.31 (17.90) ns P-selectin glycoprotein ligand-1 ( PSGL-1) 13.16±1.16 7.98±0.97 0.005 Activated leukocyte cell adhesion m olecule (ALCAM-1) 146.59 (88.09) 63.26 (74.14) 0.003 CD44 318.61(161.23) 264.14 (117.87) ns Intercellular Adhesion Molecule 1 ( ICAM-2) 87.37 (41.64) 61.28 (50.07) 0.039 Intercellular Adhesion Molecule 1 I CAM-1 5.91 (3.93) 2.19 (2.55) 0.057 Results presented as mean ± standard error of the mean for normally distributed data, or median (interquartile range) for non-normal distribution, before and after 3 months of core formulation consumption in subjects of both sexes at increased CVD risk. n=13-17 subjects; Data were analyzed by paired t-test for normal data distribution or Wilcoxon signed-rank test for non-normal data distribution. Conclusion i) Endothelial Function & Cardiovascular Health - Long Term Consumption and the Effects on Cardiovascular Health [00151] Long-term consumption of the core formulation significantly lowered diastolic blood pressure, blood pressure-modulating effects. Furthermore, it reduced serum levels of CVD risk biomarker homocysteine, lowered long-term blood glucose levels, and improved intestinal permeability by reducing plasma zonulin (ZO-1) levels. The polyphenol-rich core formulation also showed a tendency to modulate oxidative stress/antioxidant defense. [00152] Chronic, long-term consumption of core formulation was safe for human consumption and induced improvement in digestion. Most study participants enjoyed consuming test drink and noted that they would like to continue consumption after the study. 50 Cardiovascular Protection.DOCX [00153] Moreover, consumption of core formulation for 3 months significantly reduced plasma levels of cell adhesion molecules E-selectin, L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), ALCAM-1 and ICAM-2 compared to baseline, and an induced a marked, albeit statistically insignificant, reduction in ICAM-1. The core formulation also showed a tendency to reduce other vascular inflammation markers including serum amyloid A (SAA), myoglobin, and MMP-2, whose increased levels have been associated with inflammation and CVD. [00154] Core formulation ingredients are extensively metabolized by the gut microbiota and have increased bioavailability by crossing the gut/blood barrier. Moreover, these ingredients mediate the interaction between cells through cell adhesion molecules (CAMs), which are cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM) and are broadly recognized as markers of inflammation and CVD risk. Increased CAM cell surface expression and plasma levels have been linked to cardiovascular disease. Our analysis showed the potency of chronic consumption of the chokeberry/tart cherry core formulation to significantly reduce the expression of several cell adhesion molecules (CAMs). [00155] These results suggest beneficial, anti-inflammatory and vessel-protective effects of long-term consumption of core formulation in preserving the CVH and in the subjects at increased CVD risk. In addition, our data suggest that the regular use of the core formulation, where the polyphenol rich extracts are reconstituted in their original juice form, has a potent role regulating many molecular pathways involved in blood flow, atherosclerosis and inflammation that underlie the mechanisms of endothelium damage. [00156] The disclosures of all patents, patent applications, publications and database entries referenced in this specification are hereby specifically incorporated by reference in their entirety to the same extent as if each such individual patent, patent application, publication and database entry were specifically and individually indicated to be incorporated by reference. 51 Cardiovascular Protection.DOCX [00157] Although the invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention. All such modifications as would be apparent to one skilled in the art are intended to be included within the scope of the following claims. 52 Cardiovascular Protection.DOCX