**5. Flavonols', anthocyanins', and catechins' health properties**

Flavonoids are known because of their beneficial effect on human health. It has been known for long time and mainly attributed to its antioxidant potential. Compounds able to scavenge free radicals are in general beneficial for health. As all living beings, humans also produce ROS and there is also a system to get rid of these free radicals to prevent damage of the cells (DNA, lipids, and proteins). These damages are called oxidative damages which have been related to carcinogenesis, neurodegeneration, atherosclerosis, diabetes, and aging; however, the precise underlying mechanisms for these health benefits are starting to be unraveled.

Flavonoids have received increasing attention due to their anti-inflammatory, antimicrobial, and anticancer activities. Structural-functional relationship analyses identified luteolin as one of the most potent inhibitors of xanthine oxidase, a key enzyme in ROS production. Reduction of ROS by apigenin prevents endothelial damage during acute inflammation and restores mitochondrial function. Most of the anti-inflammatory and antimicrobial activities attributed to flavones seem to be centered on their ability to regulate the Toll receptor (TLR)/ NFκB axis. This is a central pathway in the host-pathogen interplay in mammals, respon‐ sible for the expression of inflammatory mediators, including tumor necrosis factor (TNFα), interleukin-1 (IL-1β) and cyclooxygenase-2 (COX-2), an enzyme mediating the conversion of arachidonic acid to prostaglandins. Notably, great similarities are found between the mammalian TLR/NFκB and plant pathogen defense pathways, suggesting that flavones may regulate evolutionary conserved targets [55]. It has also been reported that in animal models, apigenin reduces the phosphorylation of the NFκB p65 subunit, required for its transcriptional activity. Inhibition of p65 phosphorylation reduces the expression of inflam‐ matory cytokines, limiting the cell damage characteristic of acute inflammation [56]. Other flavones inhibit COX-2 by halting NFkB nuclear localization [57]. Overall, glycosides show less anti-inflammatory activity than aglycones, probably a consequence of their reduced cel‐ lular absorption [58]. Recent studies identified additional mechanisms responsible of the anti-inflammatory activity of flavones, including the regulation of noncoding RNAs. Large microRNA screenings showed that apigenin reduces microRNA155 (miR155) expression, a main inflammatory regulator miR155 binds to 3′-UTR regions of several inflammatory cyto‐ kines, suggesting an additional mechanism by which flavones can restore homeostasis dur‐ ing acute inflammation, independent of their anti-oxidant activity [1].

*Fusarium* sp. infections than other types of flavonols, and it is believed that is due to the hydroxyl groups [53]. In addition to the antifungal effects reported in plant, some have shown that certain compounds like phenols, phenolic acids, flavonoids, and isoflavonoids inhibit

Flavonoids play a very important role in symbiotic bacteria relations. Bacteria belonging to the family Rhizobiaceae include several genera, each of them specific to a legume species. Rhizobiaceae are capable of fixing nitrogen for the plant; in exchange they obtain photosyn‐ tates. First, they need to establish the symbiotic relationship and form the nodule; in this pro‐ cess, flavonoids are key since these bacteria are attracted by these flavonoids that are specific signals for each rhizobia-legume couple. There are studies of different plants growing in soils with low nitrogen concentration that induces the accumulation of flavonoids [54]. Based on this fact, knowledge of the specific flavonoids that enhance symbiosis establishment could be applied to field production of legumes, in low productivity soils, to enhance nodulation, which in turn, will enhance yield in developing areas. This goal could be achieved at a low cost and easily implemented in local areas therefore contributing to food security, as marked by the FAO. Connecting with this improvement in production and also with their natural physiological role, flavonoids provide color, taste, and fragrance to the fruit and seeds, and also play an important role in pollination, because these characteristics attract insects [45]. Although these characteristics may attract some organisms can also deter some others, in the cases of herbi‐

pathogen proliferation in the rizhosphere, preventing root infections.

vores and some nematodes, avoiding to be eaten by these living beings.

**5. Flavonols', anthocyanins', and catechins' health properties**

Flavonoids are known because of their beneficial effect on human health. It has been known for long time and mainly attributed to its antioxidant potential. Compounds able to scavenge free radicals are in general beneficial for health. As all living beings, humans also produce ROS and there is also a system to get rid of these free radicals to prevent damage of the cells (DNA, lipids, and proteins). These damages are called oxidative damages which have been related to carcinogenesis, neurodegeneration, atherosclerosis, diabetes, and aging; however, the precise underlying mechanisms for these health benefits are starting to be unraveled.

Flavonoids have received increasing attention due to their anti-inflammatory, antimicrobial, and anticancer activities. Structural-functional relationship analyses identified luteolin as one of the most potent inhibitors of xanthine oxidase, a key enzyme in ROS production. Reduction of ROS by apigenin prevents endothelial damage during acute inflammation and restores mitochondrial function. Most of the anti-inflammatory and antimicrobial activities attributed to flavones seem to be centered on their ability to regulate the Toll receptor (TLR)/ NFκB axis. This is a central pathway in the host-pathogen interplay in mammals, respon‐ sible for the expression of inflammatory mediators, including tumor necrosis factor (TNFα), interleukin-1 (IL-1β) and cyclooxygenase-2 (COX-2), an enzyme mediating the conversion

**4.3. Other functions**

140 Flavonoids - From Biosynthesis to Human Health

Consistent with the ability of flavones to regulate inflammation, interventions with the Mediterranean diet, which is rich in flavonoids, showed improved cardiac function, reduced hypertension and obesity [59, 60]. Flavones also affect leukocyte migration, with very spe‐ cific targets, deeply affecting cancer and inflammation [61, 62]. Flavones ability to reduce cell migration has great impact on cancer, suggesting alternative therapeutic approaches to reduce metastasis. The anticarcinogenic effect of flavones is given in part by their ability to induce DNA damage, and is accompanied by cell cycle arrest at G1 or G2, depending on the particular cell type. Interestingly, the ability of apigenin to induce cell death in cancer cells is independent of ROS production [63] supporting a beneficial role of flavones independent of their anti-oxidant activity.

Identification of the direct targets will highly contribute to understand the molecular mech‐ anism related to flavones and health. The use of PD-Seq (phage display high-throughput sequencing), a novel approach for small target identification, identified several targets, sug‐ gesting that dietary compounds, unlike pharmaceuticals, may target several molecules [64]. This statement encourages the use of healthy plant-based foods or extracts, rich in polyphe‐ nols but with a complex mixture of compounds that will contribute to prevent the onset of disease by reaching many small targets simultaneously. Under this rationale, a study of natu‐ rally healthy fruits or plant materials is seriously encouraged to prevent the onset of disease.

As flavonoids, anthocyanins' health-promoting effects have been frequently linked to their high antioxidant activities. However, there is increasing evidence reporting that some of their biological effects may be related to their ability to modulate mammalian cell signaling path‐ ways [65, 66]. Anthocyanins also offer protection against certain age-related degenerative dis‐ eases cancers, cardiovascular disease [9, 55, 67, 68]; anti-inflammatory activity [69], promotion of visual acuity [70], and hindering obesity and diabetes [71, 72] have also been reported as beneficial effects of these compounds.

In addition to the many target-specific effects of each compound detailed above, effects are more complex to evaluate when any of these phenolics are delivered through the diet in a complex food matrix. The variability of effects relays in two points: on the one hand, natural variability in composition and on the other hand, variability in absorption at the individual level. It has been estimated that only 5–10% of the total polyphenol intake is absorbed in the small intestine. Currently, it is estimated that 500–1000 different microbial species inhabit the gastrointestinal tract. However, they do not seem to be ubiquitous but reflect the interpersonal differences in the gut microbial community [73]. Consequently, apart from the interindividual variation in daily intake of polyphenols, interindividual differences in the composition of the gut microbiota may lead to differences in bioavailability and bioefficacy of polyphenols and their metabolites [74, 75].

The other factor that will condition effects on health is intimately associated with the sessile nature of plants. Plants have to overcome environmental changes by changing their chemical composition, synthetizing metabolites that will contribute to a better adaptation to changes in abiotic factors of to fight back biotic challenges. Since environmental conditions are variable along the year, and flavonols and antocyanins play a role in adaptation to UV stress, it may be anticipated that concentration in plant will be higher in spring and summer when light hours and intensity are higher. Hence, fruits produced in winter or in summer will presumably have different concentrations, as has been demonstrated in blackberries [76]. Moreover, given their role in plant defense, their levels may also fluctuate depending on disease prevalence along a given season, and therefore, health benefits will be different, since the dose is differ‐ ent. Consequently, any attempt to modulate the amplitude of these fluctuations will result in enhanced fruit quality, more reliable in terms of health benefits.

In order to achieve this goal, understanding the metabolic pathway and its regulation is a milestone on the way to develop varieties in which the main regulators are overexpressed to ensure a high and constant, or low variability, fruit bioactive contents. This goal may be achieved through crossbreeding or by the means of metabolic engineering in plants [77] or through elicitation of secondary metabolism with external agents such as beneficial bacteria or derived molecules [76, 78] or even other chemical molecules such as salicylic acid.
