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Adherence to a ‘Mediterranean diet’ has been shown to be beneficial to human health. Fruit and vegetables represent some of the main components of the Mediterranean diet and their role has been increasingly considered in the process of preventing or reducing the risk of chronic degenerative diseases, such as cerebrovascular or coronary heart disorders, cancer and neurodegenerative diseases. To investigate the beneficial effect of these dietary compounds, two EU‐funded projects were conducted during the last 10 years. Their results from experimental models suggest that dietary anthocyanin enrichment is beneficial against a number of ischemic and degenerative conditions. On the other hand, human studies demonstrated that anthocyanin supplementation can counteract the inflammatory response to stress conditions, such as a fatty meal. Moreover, an intervention trial in patients with breast cancer undergoing radiotherapy is presently testing the possible beneficial effect of the administration of a product enriched in anthocyanins on the inflammatory response to radiation and on its consequent skin toxicity, as well as on systemic low‐grade inflammation reaction.
Adherence to a ‘Mediterranean diet’ has been shown to be beneficial to human health. A population‐based, prospective investigation involving more than 22000 adults in Greece showed that greater adherence to the traditional Mediterranean diet is associated with a significant reduction in total mortality 1. Sofi et al. 2 systematically reviewed all the prospective cohort studies that had analysed the relation between adherence to a Mediterranean diet, mortality and incidence of chronic diseases in a primary prevention setting and concluded that each two‐point increase in a 9‐point score reflecting the adherence to a Mediterranean diet is associated with a significant improvement in health status, as seen by a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and incidence of Parkinson's disease and Alzheimer's disease (13%). These results seem to be clinically relevant for public health, in particular for promoting a Mediterranean‐like dietary pattern for primary prevention of major chronic diseases. Large epidemiological studies show that a Mediterranean diet significantly reduces the risk of cardiovascular disease (by about −25%), of the same order of magnitude as pharmacological interventions 1, 2.
Fruit and vegetables represent some of the main components of the Mediterranean diet. The role of plant‐based foods has been increasingly considered to prevent or reduce the risk of chronic degenerative diseases: in particular, dietary flavonoids have been associated with a reduction in cerebrovascular disorders and coronary heart disease (CHD).
In the 1990s, Renaud and de Lorgeril discussed the so‐called ‘French paradox’: given a correlation between dairy fat consumption in diet and coronary heart disease mortality, reported from ecologic studies, inhabitants of France were observed to be outliers, with lower than expected levels of CHD. When age‐standardized death rate for CHD in different countries and consumption of dairy fats was corrected for wine consumption, data concerning the French population were again compatible with the correlation 3. The ‘French paradox’, although derived from observational data, had the merit of stimulating a great deal of research (3260 citations – according to Google Scholar – from 1992 to January 2016), improving the knowledge on the beneficial effects of wine and some of its non‐alcoholic components preventing cardiovascular disease and other chronic disorders.
An experimental contribution of our group to this issue was an original study in rats reproducing the French paradox and supporting its hypothesis 4. An artificial plastic loop was inserted into the abdominal aorta of rats. This loop became occluded in about 80 hours. Compared to animals fed a standard diet, rats fed a cholesterol‐rich diet experienced a several‐fold increase in lipid plasma levels with a concomitant significant increase in thrombotic tendency, measured as shortening of the occlusion time of the vascular prosthesis, and as platelet adhesion. Alcohol‐free red wine supplementation to rats almost completely reverted the prothrombotic effect of the cholesterol‐rich diet without changing the blood lipid levels. This experiment supports the concept that, despite dyslipidemia, intake of wine or of its non‐alcoholic components is able to protect individuals at risk from ischemic events 4.
Different mechanisms have been investigated to explain the beneficial effects of bioactive polyphenols, of which the Mediterranean diet is particularly rich. It is generally agreed that these effects are mediated, at least in part, by antiplatelet and antioxidant activities of polyphenols, both contributing to downregulate the inflammatory response to injury 5, 6, 7, 8. The possible role on vascular function of resveratrol and of other non‐alcoholic components of wine has recently been reviewed 9.
Among polyphenols, anthocyanins belong to the bioactive family of compounds called flavonoids and are responsible for the red, purple, and blue colours of wine and many fruits, vegetables, cereal grains and flowers. These compounds are found in high amounts in blackcurrants, raspberries, aubergines, blood orange juice and blueberries. Although there are no clear indications for specific recommendations on the amount of flavonoids to consume on a regular basis, there is growing agreement that these bioactive compounds have beneficial effects on chronic diseases.
The need to provide sound mechanistic bases for the reported beneficial effect of these dietary compounds, prompted an interdisciplinary group of European investigators to start a joint venture which resulted in a ten‐year collaboration through two subsequent EU‐funded projects: FLORA (FLavonoids and related phenolics for healthy living using ORally recommended Antioxidants) and ATHENA (AnTHocyanin and polyphenol bioactives for Health Enhancement through Nutritional Advancement), respectively in the 6th (STREP 007130; from 2005 to 2009) and in the 7th (FP7‐KBBE‐2009‐3; from 2010 to 2015) Framework Programs (http://athena‐flora.eu). Both projects focused their attention on the possible health beneficial effects of anthocyanins.
Several European groups, coordinated by the John Innes Centre, Norwich, UK, participated in the project, with expertise ranging from plant physiology and genetics to preparation of foods enriched in anthocyanins, from analytical measurements of anthocyanins in food and biological matrices to cell biology, from experimental animal models of disease to human intervention studies. The main foods enriched in anthocyanins developed and tested in the projects were: tomatoes, obtained by genetic engineering 10, oranges (either rich or not in anthocyanins, red and blond, respectively) selected from different varieties 11, and corn (either rich or not in anthocyanins, black and yellow, respectively) obtained by classical breeding 12.
The possible protective effects of anthocyanin enrichment was tested in different experimental models: tomatoes were shown to extend lifespan in cancer‐prone mice 10; in other experiments, the size of an experimental myocardial infarction was significantly reduced in rats fed anthocyanin‐rich corn 13; supplementation with orange juice (rich in anthocyanins) reduced body weight gain and fat accumulation in mice, through mechanisms involving resistance to high fat diet‐induced obesity and transcriptional reprogramming 14, and counteracted liver steatogenesis in mice with diet‐induced obesity 15.
Our group contributed to the project first by the development and validation of a highly sensitive analytical LC–MS method to detect the main anthocyanin metabolites in biological fluids 16. Through this method the bioavailability of anthocyanin metabolites was monitored both in the above‐mentioned experimental models and in humans.
In healthy volunteers, four‐week ingestion of red orange juice resulted in measurable urine levels of the three main metabolites, namely delphinidin‐3‐glucoside, cyanidin‐3‐glucoside and cyanidin‐3‐(6‐malonylglucoside), reaching a plateau level after the first week of ingestion 17. An expected high inter‐individual absorption of the flavonoids was observed by the measurement of the plasma concentrations vs. time curve of anthocyanins in healthy volunteers after single administration of two‐fold concentrated 500 ml of red orange juice; measurable urinary excretion of the same metabolites was also reported, and the same considered as markers of anthocyanin bioavailability in subsequent human studies 17.
In healthy human volunteers chronic consumption of orange juice, rich (or not) in anthocyanins, did not affect platelet activation nor cell inflammation markers of cardiovascular disease 17, but decreased the procoagulant activity of whole blood: the latter effect was similar for both orange juices, either rich or not in anthocyanins, suggesting a role for antioxidants different from that of anthocyanins 18.
A single portion of orange juice in human volunteers was also effective in preventing the post‐prandial inflammatory response to a standardized fatty meal 19: the latter was previously shown to induce an acute, significant and reversible inflammation status, characterized by increased platelet and leukocyte counts and increased myeloperoxidase degranulation of granulocytes, all representative of an oxidative stress condition 20.
On the basis of these experiments, one could argue that the post‐prandial condition, following a frequent fatty meal consumption, is a phenomenon that may lead to chronic low‐grade inflammation and to a complex series of events (including endotoxemia) that may initiate and develop atherothrombosis 21. Thus, a life‐long adherence to a Mediterranean dietary pattern might favourably modulate low grade inflammation and reduce the risk to initiate and develop atherothrombosis 8, 22, 23, 24.
Moving from healthy subjects to patients, an observational study performed at the Catholic University in Campobasso reported that, in breast cancer patients, moderate wine consumption may have a protective effect on skin toxicity induced by radiotherapy, attributing this effect to the possible antioxidant effect of polyphenols contained in wine 25.
This observation, together with the experience gathered in studies on the anti‐inflammatory effects of anthocyanins, prompted us to design an intervention trial in patients with breast cancer undergoing radiotherapy. The aim was to test the possible beneficial effect of the administration of a product enriched in anthocyanins on the inflammatory response to radiation and consequent skin toxicity, as well as systemic inflammation reaction, as evaluated by plasma biomarkers.
The synopsis of the protocol of the study, a randomized, placebo‐controlled, double blind, monocentric evaluation, including 300 patients, is reported in the Supporting Information Table S1 (ClinicalTrials.gov ID: NCT02195960). The trial is ongoing and will be completed in the coming months.
The principal achievement of the FLORA and ATHENA research projects has been to include anthocyanins among the health‐promoting dietary polyphenols that are effective in offering cardioprotection, protection against cancer and limitation of weight gain from obesity‐inducing, high‐fat diets, in preclinical studies with animals.
As human studies are more complex than experimental ones, the observed beneficial effects cannot be immediately translated into improvement of risk biomarkers for chronic disease in healthy volunteers, unless stress systems, such as the fatty meal, are used.
It is hoped that clinical intervention trials in subjects with risk factors or in patients undergoing a chronic inflammatory injury will provide the validation in humans of the health beneficial effects of the dietary modulation we have discussed.
All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: 1. no support from any organization for the submitted work; 2. no financial relationships with any organization that might have an interest in the submitted work in the previous three years; 3. no other relationships or activities that could appear to have influenced the submitted work.
This paper is dedicated to the memory of our radiotherapy colleague Cinzia Digesù, MD. This work was partially supported by the European Commission 7th Framework Programme ATHENA project (contract no. 245121). The authors wish to thank professor Cathie Martin, Norwich (UK), coordinator of the FLORA and ATHENA projects, and professor Chiara Tonelli, University of Milan (Italy), for continuous discussion and inspiring collaboration. AGM present address: Radiotherapy Department, Bologna University, Bologna (Italy).
Table S1 Synopsis of the study protocol of the ATHENA trial on anthocyanin supplementation in breast cancer patients undergoing radiotherapy
Supporting info item
Cerletti C., De Curtis A., Bracone F., Digesù C., Morganti A. G., Iacoviello L., de Gaetano G., and Donati M. B. (2017) Dietary anthocyanins and health: data from FLORA and ATHENA EU projects. Br J Clin Pharmacol, 83: 103–106. doi: 10.1111/bcp.12943.