Cardiovascular disease (CVD), such as hypertension and atherosclerosis, is the leading cause of global death. Endothelial dysfunction (ED) is a strong predictor for most CVD making it a therapeutic target for both drug and nutrition interventions. It has been previously shown that polyphenols from wine and grape extracts possess vasodilator activities, due to the increased expression and phosphorylation of the endothelial nitric oxide synthase (eNOS), and consequent vasodilator nitric oxide (NO) production. This is vital in the prevention of ED, as NO production contributes to the maintenance of endothelial homeostasis. Moreover, polyphenols have the ability to inhibit reactive oxygen species (ROS), which can cause oxidative stress, as well as suppress the upregulation of inflammatory markers within the endothelium. However, while the majority of the research has focused on red wine, this has overshadowed the potential of other nutritional components for targeting ED, such as the use of berries. Berries are high in anthocyanin flavonoids a subtype of polyphenols with studies suggesting improved vascular function as a result of inducing NO production and reducing oxidative stress and inflammation. This review focuses on the protective effects of berries within the vasculature.

Anthocyanins are a subgroup of flavonoid polyphenols previously investigated for improving cardiovascular health and preventing the development of endothelial dysfunction. However, their poor bioavailability raises the question of whether the observed biological activity is due to their metabolites. Phenolic metabolites can reach higher plasma concentrations and can persist in the circulation for periods much longer than their original anthocyanin form; therefore, the biological activity and health promoting effects of anthocyanins may differ from their metabolites. To address this, recent studies have facilitated different cell models, in vivo studies and explored physiologically relevant concentrations to better understand their mechanisms of action. The criteria were chosen based on previous reports demonstrating that anthocyanins can improve endothelial function via modulation of the Akt-endothelial nitric oxide synthase pathway and transcription factors Nrf2 and NF-κB, which made it critical to assess the phenolic metabolites’ modes of action via these pathways. This review demonstrates how phenolic metabolites differ in bioactivity from their precursor anthocyanin, demonstrating improved endothelial function in response to inflammatory mediators at concentrations that are tolerated in vivo. The review highlights the crucial need for further studies to focus on improving the bioavailability of metabolites in isolation and explore the effect of metabolites in mixtures.

Coronavirus disease 2019 (COVID‐19) pandemic has been triggered by the severe acute respiratory syndrome coronavirus (SARS‐CoV‐2). Although recent studies demonstrate that SARS‐CoV‐2 possibly does not directly infect endothelial cells (EC), the endothelium may be affected as a secondary response due to the damage of neighboring cells, circulating pro‐inflammatory cytokines, and/or other mechanisms. Long‐term COVID‐19 symptoms specifically nonrespiratory symptoms are due to the persistence of endothelial dysfunction (ED). Based on the literature, anthocyanins a major subgroup of flavonoid polyphenols found in berries, have been well researched for their vascular protective properties as well as the prevention of cardiovascular disease (CVD)‐related deaths. Elderberries have been previously used as a natural remedy for treating influenza, cold, and consequently cardiovascular health due to a high content of cyanidin‐3‐glucoside (C3G) a major anthocyanin found in the human diet. The literature reported many studies demonstrating that EE has both antiviral and vascular protective properties that should be further investigated as a nutritional component used against the (in)direct effect of SARS‐CoV‐2 in vascular function. Practical applications While previous work among the literature looks promising and builds a suggestion for investigating elderberry extract (EE) against COVID‐19, further in vitro and in vivo research is required to fully evaluate EE mechanisms of action and its use as a supplement to aid current therapies.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): De Montfort PhD funded scholarship scheme Introduction During the early stages of atherosclerosis, monocytes attach to endothelial cells (EC) before differentiating into macrophages causing the accumulation of foam cells and plaque growth. NF-κB and vascular cell adhesion molecule 1 (VCAM-1) are some of the main mediators in EC that are involved in the monocyte adhesion process. Elderberry extract (EE) are rich in anthocyanins a subclass polyphenol with vascular-protective properties. Purpose The main of aim of this study is to examine if EE can prevent TNF-α induced inflammation and monocyte adherence to EC. Methods Primary Human Umbilical Vein Endothelial Cells (HUVEC) were pre-treated for 1-h and stimulated with or without TNF-α 10 ng/ml for western blot. Cell lysates from the treated cells were then subjected to Western blotting and probed for total and phospho-NF-κB. For monocyte adherence cells were pre-treated for 24-h, then stimulated with/or without TNF-α 10 ng/ml for 24-h. Fluorescently labelled THP-1 cells were then added to the HUVECs for an additional 30 minutes, and samples were measured in a fluorescence plate reader. Cells were put through flow cytometry for measuring reactive oxygen species (ROS) using DCFHFDA assay or VCAM-1 levels using Anti-CD106. Results An increase in ROS production and NF-κB phosphorylation was found after stimulation TNF-α 10 ng/ml (p = 0.01). However, cells pre-incubated with EE (50 μg/ml) for 1-hour before TNF-α stimulation caused a reduction in ROS as well as inhibition of NF-κB phosphorylation (p < 0.01). TNF-α 10 ng/ml increased the monocyte adherence to the HUVECs by a 2-fold although, EE prevented TNF-α monocyte adherence (mean value, 589.7 vs 408 p = 0.0033). This was associated with suppressed VCAM-1 expression found in the EE pre-treatment with TNF-α (p = 0.02). Discussion Our Preliminary data demonstrates that EE, can prevent monocytes binding onto EC potentially by inhibiting TNF-α induced NF-κB and VCAM-1 levels. Our findings postulate that NF-κB and VCAM-1 could be the direct link for targeting the prevention of monocyte adherence to EC, although this would need confirmation by blocking key cellular signalling pathways to confirm its role. This preliminary data suggests that EE and potentially other polyphenols could be a useful strategy for targeting the initial stages of atherosclerosis.

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