**5. Health benefits**

**4. Antioxidant activity**

358 Flavonoids - From Biosynthesis to Human Health

narity [30].

The best described property of almost all groups of flavonoids is their powerful antioxidants, which act as free radical scavengers as they are potential reducing agents and protect from oxidative reactions taking place inside the body [22]. The antioxidant activity of flavonoids is due a combination of their iron chelating and free radical scavenger properties, also the inhi‐ bition of oxidases enzymes such as lipoxygenase, cyclooxygenase, myeloperoxidase, NADPH oxidase and xanthine oxidase; avoiding thereby the formation of reactive oxygen species and organic hydroperoxides [19]. Moreover, flavonoids can inhibit enzymes by indirectly involv‐ ing in the oxidative process, such as phospholipase A2, at the same flavonoids can stimulate

This feature depends of their molecular structure. This free radical scavenging activity is pri‐ marily attributed to the high reactivity of hydroxyl substituents. For example, by scavenging free radicals, the hydroxyl group on the B‐ring donates hydrogen and an electron to hydroxyl, peroxyl and peroxynitrite free radicals, stabilizing them, because of the high reactivity of the hydroxyl group of the flavonoids, radicals are made inactive according to Eq. (1), where R\* is

 F‐OH + R • → F‐O • +RH (1) The significance of other hydroxyl configuration is less clear, but beyond increasing total number of hydroxyl groups, A‐ring substitution correlates little with antioxidant activity. Similarly, the difference in antioxidant activity between polyhydroxylated and polymethox‐ ylated flavonoids is most likely due to differences in both hydrophobicity and molecular pla‐

A lot of studies have realized the antioxidant activity of flavonoids. Majewska et al. [41] evalu‐ ated different flavonoids and compared their antioxidant activity with DPPH radical. The flavonoids such as quercetin, rhamnetin, isorhamnetin, luteolin and apigenin were tested and the results showed that quercetin has the highest antioxidant potential at lower concentration (0.1–5 µg/sample). In other studies, Choi et al. [42] tested the inhibitory activity of xanthine oxidase, linoleic acid peroxidation and scavenging capacity of DPPH with some flavonoids, and obtained the following results at a concentration of 100 µg/ml: for xanthine oxidase, cate‐ chin, morin, naringenin and quercetin showed 100% of inhibition, and rutin only 43%; for lin‐ oleic acid peroxidation, quercetin showed the highest inhibition (82%), followed by catechin (71%), rutin (63%), morin (56%), naringenin (53%); and finally for DPPH catechin, morin and quercetin obtained a high activity (100%) than rutin (95%), naringenin did not show any data. On the other hand, using an aqueous emulsion of linoleic acid/β‐carotene at 50°C, and com‐ pared with synthetic antioxidant BHT, ᴅ,ʟ‐α‐tocopherol and its acetate, Burda and Oleszk [43] examined the antioxidant activity of some flavonoids and observed the highest values were obtained by synthetic ones (88–95%) and slightly lower, but still high antioxidant activity was shown by a group that included fisetin (61%), kaempferol (65%), galangin (64%), quercetin (63%), robinetin (61%), morin (63%) and kaempferide (60%), all of these are flavonols with a

other enzymes with antioxidant activities like catalyse and superoxide dismutase.

a free radical and O\* is the oxygen free radical) [17, 29–31].

free hydroxyl group at the C‐3 position.

Flavonoids are a widely distributed group of polyphenols and comprise the most studied bioactive compounds for about 50 years due their potential health benefits; they have a com‐ plex and unknown biologic function, which are based on their antioxidant activity [9, 39, 44, 45]. Furthermore, because of their remarkable activities and potential health benefits, they are used in the food and cosmetics industries. Their functions can be divided in two (i) general or nonspecific activity (related to the presence of phenolic compounds) and (ii) specific activity (depends on the particular chemical and structural characteristics of the active compound) [46], which are presented in **Table 3**.

The decrease in consumption of fruits and vegetables has been associated with several diseases. Flavonoids attract attention due to their ability to reduce the incidence of many diseases. Its recommended intake or supplementation of flavonoids with a combination of another antioxidants, vitamins and minerals can reduce incidence of cancer, cardiovascular mortality and ischemic vascular disease [39, 49–53]. According to many studies, in flavo‐ noid‐rich foods the daily intake of these compounds can be range between 50 and 800 mg/ day, mainly with the consumption of fruits and vegetables [6, 54]. However, is also known that flavonoids inhibit proliferation of viruses like herpes simplex, polio and pseudorabies [47]. On the other hand, some results from other different studies have demonstrated that in very high doses, flavonoids can act as pro‐oxidant; so, it is important to consider the recommended daily intake of these compounds to promote their functions on the organism [55].

For many years, plants have been used like traditional Mexican medicine due to their medici‐ nal potential of crude extracts (mainly rich in flavonoids) to the treatment of diarrhoea and stomach diseases [55]. This potential can be attributed for many physiological functions, such as their antioxidant, antibacterial and antigiardial activities to reduce the incidence of this kind of diseases [54].


**Table 3.** Biological functions of flavonoids on humans [46–48].

In recent years, flavonoids have gained interest in health as protective agents against many diseases, which involve radical damage [56]. Likewise, many epidemiological studies have been developed to show the association between consumption of vegetables and fruits and the risk of disease such as cancer, neurological and cardiovascular diseases [57]. Some authors show beneficial results of flavonoids against diseases; studies about the dietary called French paradox revealed that flavonoid‐rich diet is directly correlated with decrease incidence of cardiovascular diseases and increase longevity on Mediterranean population, which is associ‐ ated with consumption of red wine and low‐fat diets [58].

#### **5.1. Anticancer effect of flavonoids**

Cancer is a multifactorial heterogeneous disease, which is the main cause of death in some countries along with cardiovascular diseases, and it is expected to increase about 70% cases in the next 20 years. These have been related to different factors of behavioural and dietary risks, among which are the reduced consumption of vegetables, limited physical activity and consumption of alcohol and tobacco, which may cause negative impact on health [59, 60].

According to some studies, flavonoids have some pharmacological properties that inhibit cell damage [61]. Herrera et al. [51] conducted a study and evaluated the efficiency of supple‐ mentation with correct antioxidant content to reduce cancer incidence; these trials concluded that antioxidant supplementation may inhibit cancer incidence only in healthy subjects. But according with Hollman and Katan [62], bioactive compounds may inhibit various stages in cancer process.

Some studies in animals with some types of chemical carcinogen‐induced or transplanted tumours have been shown good results about the prevention development and growth of various types of cancer. Some mechanisms of biologically active substances, including their antioxidant activity, may act on stages of carcinogenesis such as initiation, promotion and progression. Flavonoids can inactive the carcinogen, inhibit cell proliferation, repair DNA processes and reduce oxidative stress (in initiation and promotion stages); in the progression stage, they may exhibit antioxidant activity, induce apoptosis and develop cytotoxic action against cancer cells [4, 63]. Because inflammation is closely related to tumour promotion, bioactive compounds like flavonoids are expected to exert chemopreventive effects against carcinogenesis, especially in promotion and progression stages, and are estimated to reduce risk of cancer [64].

#### **5.2. Flavonoids on the cardiovascular system**

In the last decade, cardiovascular diseases increased the number of death around the world; this is due to the decrease in consumption of fruits and vegetables, and it is estimated that these diseases will continue affecting the population [65]. Antioxidant properties of flavo‐ noids are interesting due their potential role in prevention of cardiovascular diseases. Other authors suggested that these compounds decrease the risk of coronary diseases, but never‐ theless, their antioxidant and chelating properties are the major mechanisms to inhibit or inactivate reactive oxygen species, which play an important role to affect cardiovascular system [9, 63].

According to some authors, the mechanistic pathways of flavonoids on cardioprotection include some actions, such as improving coronary vasodilatation, decreasing the ability of platelets in the blood to clot, preventing LDLs from oxidizing, inhibition of inflammation propagation, antiapoptotic, antinecrotic, free radical scavenging abilities and its crucial role in the impact on capillary blood vessel [9, 47, 57].

Rice‐Evans et al. [5] studied the correlation with the intake of flavonoids and risk of death from coronary heart disease on a group of Dutch population; these epidemiological study showed that intake natural flavonoids can reduce 2.4 times cardiovascular diseases compared people with lower intake of these bioactive compounds. They established that antioxidant and antithrombotic properties contribute to this protection and may provide a better lifestyle.

#### **5.3. Flavonoids on the nervous system**

In recent years, flavonoids have gained interest in health as protective agents against many diseases, which involve radical damage [56]. Likewise, many epidemiological studies have been developed to show the association between consumption of vegetables and fruits and the risk of disease such as cancer, neurological and cardiovascular diseases [57]. Some authors show beneficial results of flavonoids against diseases; studies about the dietary called French paradox revealed that flavonoid‐rich diet is directly correlated with decrease incidence of cardiovascular diseases and increase longevity on Mediterranean population, which is associ‐

Cancer is a multifactorial heterogeneous disease, which is the main cause of death in some countries along with cardiovascular diseases, and it is expected to increase about 70% cases in the next 20 years. These have been related to different factors of behavioural and dietary risks, among which are the reduced consumption of vegetables, limited physical activity and consumption of alcohol and tobacco, which may cause negative impact on health [59, 60].

According to some studies, flavonoids have some pharmacological properties that inhibit cell damage [61]. Herrera et al. [51] conducted a study and evaluated the efficiency of supple‐ mentation with correct antioxidant content to reduce cancer incidence; these trials concluded that antioxidant supplementation may inhibit cancer incidence only in healthy subjects. But according with Hollman and Katan [62], bioactive compounds may inhibit various stages in

Some studies in animals with some types of chemical carcinogen‐induced or transplanted tumours have been shown good results about the prevention development and growth of various types of cancer. Some mechanisms of biologically active substances, including their antioxidant activity, may act on stages of carcinogenesis such as initiation, promotion and progression. Flavonoids can inactive the carcinogen, inhibit cell proliferation, repair DNA processes and reduce oxidative stress (in initiation and promotion stages); in the progression stage, they may exhibit antioxidant activity, induce apoptosis and develop cytotoxic action against cancer cells [4, 63]. Because inflammation is closely related to tumour promotion, bioactive compounds like flavonoids are expected to exert chemopreventive effects against carcinogenesis, especially in promotion and progression stages, and are estimated to reduce

In the last decade, cardiovascular diseases increased the number of death around the world; this is due to the decrease in consumption of fruits and vegetables, and it is estimated that these diseases will continue affecting the population [65]. Antioxidant properties of flavo‐ noids are interesting due their potential role in prevention of cardiovascular diseases. Other authors suggested that these compounds decrease the risk of coronary diseases, but never‐ theless, their antioxidant and chelating properties are the major mechanisms to inhibit or inactivate reactive oxygen species, which play an important role to affect cardiovascular

ated with consumption of red wine and low‐fat diets [58].

**5.1. Anticancer effect of flavonoids**

360 Flavonoids - From Biosynthesis to Human Health

cancer process.

risk of cancer [64].

system [9, 63].

**5.2. Flavonoids on the cardiovascular system**

In recent years, experimental and clinical studies have been reported that flavonoids not only have benefits against cancer and cardiovascular diseases. The interest in consump‐ tion of flavonoids has been addressed due their potential neuroprective effects to prevent different diseases related to nervous system such as Alzheimer, Parkinson and slow down cognitive decline, which can generate dementia [45]. Diets rich in these substances (at low concentration) were shown beneficial effects to maintain human cognitive functions to pro‐ mote improvements in memory, protect vulnerable neurons, stimulate neuronal regeneration and prevent oxidative neuronal damages [66].

Reactive oxygen, nitrogen species, inflammatory responses and their mediators are involved in the development in the pathogenesis of various neurodegenerative diseases [61]. Recent works have revealed that flavonoid‐rich food intake (for 8 weeks) provides positive effects on neurocognitive functions due to its antioxidant activity and is effective in reversing age‐related deficits in brain. Previous studies in rats showed that the application of natural extracts rich in polyphenolic compounds represent an important advance to use of these extracts to the gen‐ eration of nutraceuticals products to improve health in humans [44]. According some authors, the neurobiological actions of these compounds may occur in two major ways: the first is regulation of the neuronal signal cellular cascades, which is caused by neurotoxic substances and may damage neurogenesis, neuronal function and brain connectivity. Second, flavonoids seem to improve blood‐flow toward brain and sensory systems and exert beneficial effects on the peripheral and central nervous [4, 63].
