CVD remain the leading cause of death globally. Effective dietary strategies for their reduction are of high priority. Increasing evidence suggests that phytochemicals, particularly dietary flavonoids and nitrates, are key modulators of CVD risk reduction through impact on multiple risk factors. The aim of this review is to explore the evidence for the impact of flavonoid- and nitrate-rich foods and supplements on CVD risk, with specific reference to their importance as mediators of vascular health and platelet function. There is accumulating evidence to support benefits of dietary flavonoids on cardiovascular health. Dose-dependent recovery of endothelial function and lowering of blood pressure have been reported for the flavanol (-)-epicatechin, found in cocoa, apples and tea, through production and availability of endothelial nitric oxide (NO). Furthermore, flavonoids, including quercetin and its metabolites, reduce in vitro and ex vivo platelet function via inhibition of phosphorylation-dependent cellular signalling pathways, although further in vivo studies are required to substantiate these mechanistic effects. Hypotensive effects of dietary nitrates have been consistently reported in healthy subjects in acute and chronic settings, although there is less evidence for these effects in patient groups. Proposed mechanisms of actions include endothelial-independent NO availability, which is dependent on the entro-salivary circulation and microbial conversion of dietary nitrate to nitrite in the mouth. In conclusion, flavonoid- and nitrate-rich foods show promising effects on vascular function, yet further randomly controlled studies are required to confirm these findings and to determine effective doses.

Despite the worldwide research efforts to combat cancer, it remains a leading cause of death. Although various specific kinase inhibitors already have been approved for clinical cancer treatment, occurrence of intrinsic or acquired resistance and intermittent response over longer periods limits long-term success of single kinase-targeted therapies. In this respect, there is a renewed interest in polypharmaceutical natural compounds, which simultaneously target various hyperactivated kinases involved in tumour-inflammation, angiogenesis, cell survival, proliferation, metastasis and angiogenesis. The dietary medicinal phytochemical withaferin A (WA), isolated from Withaferin somnifera (popular Indian name Ashwagandha), holds promise as a novel anti-cancer agent, which targets multiple cell survival kinase pathways, including IκB kinase/NF-κB, PI3 kinase/protein kinase B/mammalian target of rapamycin and mitogen-activated protein kinase/extracellular signal-regulated kinase amongst others. In this review, we propose a novel mechanism of WA-dependent kinase inhibition via electrophilic covalent targeting of cysteine residues in conserved kinase activation domains (kinase cysteinome), which could underlie its pleiotropic therapeutic effects in cancer signalling.

Our current therapeutic drugs for Alzheimer's disease are predominantly derived from the alkaloid class of plant phytochemicals. These drugs, such as galantamine and rivastigmine, attenuate the decline in the cholinergic system but, as the alkaloids occupy the most dangerous end of the phytochemical spectrum (indeed they function as feeding deterrents and poisons to other organisms within the plant itself), they are often associated with unpleasant side effects. In addition, these cholinesterase inhibiting alkaloids target only one system in a disorder, which is typified by multifactorial deficits. The present paper will look at the more benign terpene (such as Ginkgo biloba, Ginseng, Melissa officinalis (lemon balm) and Salvia lavandulaefolia (sage)) and phenolic (such as resveratrol) phytochemicals; arguing that they offer a safer alternative and that, as well as demonstrating efficacy in cholinesterase inhibition, these phytochemicals are able to target other salient systems such as cerebral blood flow, free radical scavenging, anti-inflammation, inhibition of amyloid-β neurotoxicity, glucoregulation and interaction with other neurotransmitters (such as γ-aminobutyric acid) and signalling pathways (e.g. via kinase enzymes).

Many plant tissues contain plant secondary compounds (PSC), which have long been recognised as defensive chemicals that deter herbivory via their toxic effects. However, herbivores may also benefit from including PSC into their diets. Plant-derived phenolics, terpenes and alkaloids have antiparasitic properties and sesquiterpene lactones have antibacterial, antifungal and antiparasitic properties. These actions are in part a consequence of the negative actions that PSC exert across several trophic levels, including the bacteria, parasites and fungi that inhabit herbivores’ bodies. Given the dual action, toxin and medicine, it is possible to hypothesise that self-selection of PSC by herbivores should occur when the benefits outweigh the costs of PSC ingestion. Recent research suggests that sheep and goats self-medicate against parasitic infections. They increase preference for condensed tannin-containing foods when experiencing a parasitic burden. This behaviour improves health; it is triggered by parasitism and weakens when parasitism subsides. However, the causes underlying these responses are not straightforward when viewed under a unidimensional cost–benefit analysis. This is because the intensity of antinutritional/toxic and medicinal effects of PSC is not static or just dependent upon the isolated post-ingestive effects of single PSC. Nutrient–PSC and PSC–PSC interactions, social models, as well as feeding patterns, all influence the perceived net benefit of incorporating medicines into a diet. A better understanding of the net benefit of self-medication in complex feeding environments will allow for the development of innovative managing strategies aimed at providing the food alternatives and conditions for improving the nutrition, health and welfare of grazing animals.

Epidemiological evidence indicates that high consumption of tomatoes and tomato-based products reduces the risk of chronic diseases such as CVD and cancer. Such potential benefits are often ascribed to high concentrations of lycopene present in tomato products. Mainly from the results of in vitro studies, potential biological mechanisms by which carotenoids could protect against heart disease and cancer have been suggested. These include cholesterol reduction, inhibition of oxidation processes, modulation of inflammatory markers, enhanced intercellular communication, inhibition of tumourigenesis and induction of apoptosis, metabolism to retinoids and antiangiogenic effects. However, with regard to CVD, results from intervention studies gave mixed results. Over fifty human intervention trials with lycopene supplements or tomato-based products have been conducted to date, the majority being underpowered. Many showed some beneficial effects but mostly on non-established cardiovascular risk markers such as lipid peroxidation, DNA oxidative damage, platelet activation and inflammatory markers. Only a few studies showed improvement in lipid profiles, C reactive protein and blood pressure. However, recent findings indicate that lycopene could exert cardiovascular protection by lowering HDL-associated inflammation, as well as by modulating HDL functionality towards an antiatherogenic phenotype. Furthermore, in vitro studies indicate that lycopene could modulate T lymphocyte activity, which would also inhibit atherogenic processes and confer cardiovascular protection. These findings also suggest that HDL functionality deserves further consideration as a potential early marker for CVD risk, modifiable by dietary factors such as lycopene.

A wide range of health benefits have been ascribed to soya intake including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Because it is a hormonally active diet, however, soya can also be endocrine disrupting, suggesting that intake has the potential to cause adverse health effects in certain circumstances, particularly when exposure occurs during development. Consequently, the question of whether or not soya phyto-oestrogens are beneficial or harmful to human health is neither straightforward nor universally applicable to all groups. Possible benefits and risks depend on age, health status, and even the presence or absence of specific gut microflora. As global consumption increases, greater awareness and consideration of the endocrine-disrupting properties of soya by nutrition specialists and other health practitioners is needed. Consumption by infants and small children is of particular concern because their hormone-sensitive organs, including the brain and reproductive system, are still undergoing sexual differentiation and maturation. Thus, their susceptibility to the endocrine-disrupting activities of soya phyto-oestrogens may be especially high. As oestrogen receptor partial agonists with molecular and cellular properties similar to anthropogenic endocrine disruptors such as bisphenol A, the soya phyto-oestrogens provide an interesting model for how attitudes about what is ‘synthetic’ v. what is ‘natural,’ shapes understanding and perception of what it means for a compound to be endocrine disrupting and/or potentially harmful. This review describes the endocrine-disrupting properties of soya phyto-oestrogens with a focus on neuroendocrine development and behaviour.

Epidemiological data on consumption of flavonoid-containing food points to the notion that some of these secondary plant metabolites may favour healthy ageing. The aim of the present paper was to review the literature on lifespan extension by flavonoids in worms, flies and mice. In most studies, worms and flies experienced lifespan extension when supplemented with flavonoids either as extracts or single compounds. Studies with mutant worms and flies give hints as to which gene products may be regulated by flavonoids and consequently enhance longevity. We discuss the data considering putative mechanisms that may underlie flavonoid action such as energy-restriction-like effects, inhibition of insulin-like-growth-factor signalling, induction of antioxidant defence mechanisms, hormesis as well as antimicrobial properties. However, it remains uncertain whether human lifespan could be prolonged by increased flavonoid intake.

Polyphenols are ubiquitous secondary products present in many plant foods. Their intake has been associated with health benefits ranging from reduced incidence of CVD, diabetes and cancers to improved neurodegenerative outcomes. Major dietary sources include beverages such as coffee, teas and foods such as chocolate. Fruits are also major sources and berries in particular are a palatable source of a diverse range of polyphenol components. There are a number of ways that polyphenol uptake could be increased and healthier polyphenol-rich foods could be produced with specific compositions to target-specific health effects. Firstly, we could exploit the genetic diversity of plants (with a focus on berries) to select varieties that have enhanced levels of specific polyphenols implicated in disease mitigation (e.g. anthocyanins, tannins or flavonols). Working with variation induced by environmental and agronomic factors, modern molecular breeding techniques could exploit natural variation and beneficially alter polyphenol content and composition, although this could be relatively long term. Alternatively, we could employ a synthetic biology approach and design new plants that overexpress certain genes or re-deploy more metabolic effort into specific polyphenols. However, such ‘polyphenol-plus’ fruit could prove unpalatable as polyphenols contribute to sensorial properties (e.g. astringency of tannins). However, if the aim was to produce a polyphenol as a pharmaceutical then ‘lifting’ biosynthetic pathways from plants and expressing them in microbial vectors may be a feasible option. Secondly, we could design processing methods to enhance the polyphenolic composition or content of foods. Fermentation of teas, cocoa beans and grapes, or roasting of cocoa and coffee beans has long been used and can massively influence polyphenol composition and potential bioactivity. Simple methods such as milling, heat treatment, pasteurisation or juicing (v. pureeing) can have notable effects on polyphenol profiles and novel extraction methods bring new opportunities. Encapsulation methods can protect specific polyphenols during digestion and increase their delivery in the gastrointestinal tract to target-specific health effects. Lastly we could examine reformulation of products to alter polyphenol content or composition. Enhancing staple apple or citrus juices with berry juices could double polyphenol levels and provide specific polyphenol components. Reformulation of foods with polyphenol-rich factions recovered from ‘wastes’ could increase polyphenol intake, alter product acceptability, improve shelf life and prevent food spoilage. Finally, co-formulation of foods can influence bioavailability and potential bioactivity of certain polyphenols. Within the constraints that certain polyphenols can interfere with drug effectiveness through altered metabolism, this provides another avenue to enhance polyphenol intake and potential effectiveness. In conclusion, these approaches could be developed separately or in combination to produce foods with enhanced levels of phenolic components that are effective against specific disease conditions.