Technologies to Recover Polyphenols from AgroFood By-products and Wastes

Technologies to Recover Polyphenols from AgroFood By-products and Wastes: Applications in Different Fields covers the most used technologies to extract and recover polyphenols from all kinds of by-products and wastes generated by the food industry, restaurant and agricultural sectors. Polyphenols are characterized by different AgroFood by-products and waste sources, hence this book explores the practical applications of these polyphenols in the development of functional foods and pharmaceutical and cosmetic products. Containing definitions, case studies, applications, literature reviews, and coverage of recent developments, this book will be a welcomed resource for food scientists, including those working in sustainability, agriculture and engineering.

• Promotes a circular economy by discussing the valorization of these compounds
• Features case studies that enable the reader to understand the potential of several polyphenols and the possibilities regarding their incorporation into several matrixes
• Presents tools for the development of new lines of research or in support of ongoing investigations with solutions for existing challenges

• Language: English
• Publisher: Academic Press
• Release date: Aug 13, 2022
• ISBN: 9780323852746

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Chapter 1: Importance of polyphenols: Consumption and human health

Glenise Bierhalz Vossa; Ana L.S. Oliveiraa; Elisabete Maria da Cruz Alexandrea,b; Manuela Estevez Pintadoa    a CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal

b LAQV-REQUIMTE, Departamento de Química, Universidade de Aveiro, Aveiro, Portugal

Abstract

Polyphenols are secondary metabolites of plants, and one of the most important phytochemicals found in herb plants, vegetables, and fruits. In recent years, these compounds have attracted increased attention due to the potential health benefits of dietary plant polyphenols as antioxidants. Epidemiological studies have noted the lower risk of chronic diseases, such as cardiovascular diseases, cancer, hypertension, diabetes, and neurodegenerative diseases, with the consumption of diets rich in fruits and vegetables owing to the antioxidant and antiinflammatory properties of phenolic compounds. However, the bioavailability of each phenolic compound differs and there is no relation between the quantity of polyphenols in food and their bioavailability in human organisms. This chapter aimed to show the current evidence relating to polyphenols and health and the potential uses of polyphenols.

Keywords

Polyphenols; Antioxidants; By-products valorisation; Bioaccessibility; Bioavailability; Cancer treatment and prevention; Health benefits

Acknowledgments

Thanks are due to the Universidade Católica Portuguesa for the financial support of the CBQF Associate Laboratory under the FCT project UID/Multi/50016/2020 and to the University of Aveiro and FCT/MCT for the financial support to Laboratório Associado LAQV-REQUIMTE (UIDB/50006/2020) through national funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement. Author Elisabete M.C. Alexandre is also grateful for the financial support of this work funded by national funds (OE), through FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the framework contract foreseen in the numbers 4, 5 and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19.

1: Introduction

Polyphenols have become an emerging field of interest in recent decades gaining more attention from different audiences, namely the scientific community and food, pharmaceutical, and cosmetics industries. This growing attention is mainly due to their implications in human health, which can be explained in part by their antioxidant properties (Faller & Fialho, 2010; Silva et al., 2020). Plants synthesize not only primary metabolites such as carbohydrates, proteins, and fats to maintain basic life functions such as growth and development, respiration, storage, and reproduction but also secondary metabolites such as terpenes, saponins, glycosides, and polyphenols that are used by plants to protect themselves and interact with other plants (Bayir et al., 2019; Pandey & Rizvi, 2009; Rasouli et al., 2017). Most of the secondary metabolites produced are polyphenols, which play a critical role in plants adaptation to the environment and are excellent sources of active pharmaceuticals (Rasouli et al., 2017). The main dietary sources of polyphenols are fruits and vegetables. However, cereals, chocolate, and legumes or beverages such as coffee and tea also contribute to the daily polyphenol intake that should be around 1 g/day (around 10 times more than vitamin C intake). Several fruits such as pear, apple, cherry, and various berries contain up to 200–300 mg of polyphenols per 100 g fresh weight and, for example, a glass of red wine, a cup of tea or coffee also may contain around 100 mg of polyphenols (Faller & Fialho, 2010; Scalbert et al., 2005).

Polyphenols have a wide range of complex structures but contain at least one aromatic ring and one hydroxyl group, in addition to other components of them. More than 8000 different polyphenols have been identified in foods, which, based on the number of phenolic rings as well as the structural moiety that holds these together, are classified into four categories (Fig. 1.1): flavonoids, lignans, stilbenes, and phenolic acids (Abbas et al., 2017; Bayir et al., 2019; Khurana et al., 2013; Pandey & Rizvi, 2009). Flavonoids comprise the most studied group of polyphenols, with more than 4000 varieties identified to date. All flavonoid compounds are formed as a result of the biosynthesis of shikimic acid and acetate-malonate pathways together and based on the variation in the type of heterocycle involved may be separated into six subclasses: flavonols, flavanols, isoflavones, flavones, flavanones, and anthocyanin (Abbas et al., 2017; Bayir et al., 2019; Fraga et al., 2019; Pandey & Rizvi, 2009). The separation into these subclasses is based on the variation in the number and arrangement of the hydroxyl groups and their extent of alkylation and glycosylation (Pandey & Rizvi, 2009). Some of the most common flavonoids are the flavonols quercetin (abundant in onion, tea, and apple) and catechin (abundant in tea and several fruits); the flavanone hesperetin (abundant in citrus fruits); the anthocyanin cyaniding (abundant in red fruits such as blackcurrant, raspberry, strawberry, etc.); proanthocyanidins (common in many fruits, such as apple, grape, or cocoa); and the isoflavone daidzein (mainly present in soybean) (Scalbert et al., 2005). Phenolic acids also are abundantly found in several food products. These phenolic compounds are separated into two classes: derivatives of benzoic acid (the concentration of hydroxybenzoic acid is usually very small, but can be found in red fruits, onions, and black radishes), and derivatives of cinnamic acid (p-coumaric, caffeic, ferulic, and sinapic acids are some of the most common found in several fruits; hydroxycinnamates—the major phenolic compound in cherries) (Bayir et al., 2019; Pandey & Rizvi, 2009). Stilbenes are formed by two phenyl moieties connected by a two-carbon methylene bridge. Resveratrol is the most common stilbene and is found in grapes, red wine, and some forest fruits. However, the stilbene present in the human diet is very low because they act as antifungal phytoalexins, meaning that they are synthesized only in response to infection or injury (Bayir et al., 2019; Pandey & Rizvi, 2009). Lignans have a 2,3-dibenzylbutane structure formed by the dimerization of two cinnamic acid residues. One of the most common lignan is the phytoestrogen secoisolariciresinol that is found in flax seeds (Bayir et al., 2019; Pandey & Rizvi, 2009).

Fig. 1.1

Fig. 1.1 Different classes of phenolic compounds. No permission required.

Phenolic compounds have been extensively studied, mainly due to their capacity to improve human health (Fig. 1.2). These research studies include a wide variety of clinical and nutritional epidemiological studies, which suggested that the long-term consumption of polyphenols protects against some cancers, cardiovascular diseases, type 2 diabetes, osteoporosis, pancreatitis, gastrointestinal problems, lung damage, and neurodegenerative diseases (Cory et al., 2018; Khurana et al., 2013; Pandey & Rizvi, 2009). Initial studies revealed that the primary mechanism of action of phenolic compounds is related to their direct antioxidant effects. The biochemical scavenger theory states that polyphenolic compounds negate free radicals by forming stabilized chemical complexes preventing further reactions (Cory et al., 2018; Fraga et al., 2019). Additionally, polyphenols may protect against oxidative stress by producing hydrogen peroxide helping to regulate immune response actions, such as cellular growth (Cory et al., 2018). However, it is unclear if these mechanisms are relevant in vivo models or humans since polyphenols do not reach concentrations in most tissues that are high enough to have a significant effect in terms of scavenging free radicals (Fraga et al., 2019). Nevertheless, there is recent evidence elucidating the effect of absorption pharmacokinetics on efficacy of polyphenols as antioxidants and other potentially health-promoting mechanisms, including biochemical and molecular mechanisms, namely multifarious effects within intra- and intercellular signaling pathways, such as regulating nuclear transcription factors and fat metabolism, and modulating the synthesis of inflammatory mediators (Cory et al., 2018; Fraga et al., 2019). Polyphenols can be chemically synthesized, but their extraction from natural resources are preferred due to the tremendous diversity of molecular structure, complexity of synthetic methodologies, and high cost of chemical synthesis technologies (S. Zhao et al., 2014). Moreover, the consumption of fruits and vegetables has been growing due to consumer’s consciousness and consequently, food residues are also a growing problem for food industries, leading to an increase of pollution and economic problems. According to the Food and Agriculture Organization, currently one-third of the food produced for human consumption is lost or wasted, representing 1.3 billion tn/year of food losses and processing wastes (Galanakis, 2012; Papargyropoulou et al., 2014). However, the majority of these residues are rich sources of valuable compounds beneficial to human health, including polyphenols that could have numerous industrial applications. Thus, a more efficient utilization of agricultural residues is needed to ensure food sustainability (Ayala-Zavala et al., 2011). This chapter will revise the main effects and action mechanisms of phenolic compounds in the prevention of several diseases such as obesity and type 2 diabetes, cardiovascular and neurodegenerative diseases, and some cancers.

Fig. 1.2

Fig. 1.2 Biological activities of dietary plant polyphenols. No permission required.

2: Phenolic compounds and health

2.1: Therapy of obesity and diabetes

Obesity and diabetes incidence are increasing at a high rate having high social costs. Obesity is a disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, leading to augmented fat mass in the body. Obesity causes the development of metabolic disorders such as diabetes mellitus which is characterized by the destruction of pancreatic β-cells or diminished insulin secretion (Kawser Hossain et al., 2016), increases in oxidative stress and inflammation biomarkers, and potentially, microRNA (miRNA) dysregulation (Corrêa & Rogero, 2019).

The number of publications on the effect of polyphenols on diabetes has increased since 2010 and all groups of phenolics (simple phenols, lignans, stilbenes, and flavonoids) have been reported to have antidiabetic potential (C. Sun et al., 2020).

Investigations suggest that polyphenols can act against diabetes by protecting pancreatic islet β-cell, reducing the cells apoptosis and promotion of their proliferation. Polyphenols can also reduce the oxidative stress, activate insulin signaling, and stimulate the pancreas to secrete insulin. Other mechanisms include inhibition of glucose absorption, inhibition of digestive enzymes, regulation of intestinal microbiota, modification of inflammation response, inhibition of the formation of glycation end products, and microRNA (miRNA) dysregulation (Corrêa & Rogero, 2019; C. Sun et al., 2020).

The majority of published studies on this subject were performed in vitro with cell models and in vivo using diabetic rats (Corrêa & Rogero, 2019).

Among the flavonoids, quercetin has been reported as one of the most widely investigated flavonoid in the literature on antidiabetic effects in animal and cell models (G.J. Shi et al., 2019), followed by kaempferol (Alkhalidy et al., 2018), myricetin (Y. Li et al., 2017), and naringenin (Den Hartogh & Tsiani, 2019).

Isoflavones also lower the risk of diabetes and examples are puerarin (X. Chen, Wang, et al., 2018; X. Chen, Yu, et al., 2018), genistein (Rockwood et al., 2019), biochanin A (Chundi et al., 2016), and formononetin (Oza & Kulkarni, 2018), all of which have antidiabetic effect by different mechanisms that can include the increase of insulin resistance, pancreatic cells protection, antiinflammatory activity, or decrease of oxidative stress.

Catechins can help reduce glycaemia, enhance insulin sensitivity, decrease blood lipids, and reduce white fat depots, but their action is dependent on their chemical structure (C. Sun et al., 2020). The galloylated catechins are one the most studied catechins derivatives and have presented the capacity to inhibit α-glucosidase and α-amylase (Kamiyama et al., 2010). Epigallocatechin 3-gallate (EGCG) has shown to improve glucose homeostasis, lipid metabolism, and endothelial function (X. Li et al., 2018; Mi et al., 2018; Solinas & Becattini, 2017).

Several important hydroxycinnamic acids, such as cinnamic acid (Kasetti et al., 2012), p-coumaric acid (Pei et al., 2016), ferulic acid (Son et al., 2011), caffeic acid (Bezerra et al., 2012), chlorogenic acid (Mei et al., 2018), and rosmarinic acid (Govindaraj & Sorimuthu Pillai, 2015), have shown considerable hypoglycemic activity via in vivo experiments in induced diabetes type 2 animal models.

Anthocyanidins showed antidiabetic activity mainly via inhibition of oxidative stress, improvement of insulin resistance, and promotion of insulin secretion. The most referenced was cyanidin-glucoside (X. Sun et al., 2018; W. Zhu et al., 2012).

Among the stilbenoids, resveratrol (Sadi et al., 2015) and pterostilbene, a dimethoxyl derivative of resveratrol (X. Zhao, Tao, et al., 2019), have shown antidiabetic activity in animal models and human studies.

Tannins can delay intestinal glucose absorption and the onset of insulin-dependent diabetes mellitus by producing an insulin-like effect on insulin-sensitive tissues, which lowers glucose levels by regulating the antioxidant environment of pancreatic β-cells (Serrano et al., 2009). In animal models, curcumin and extracts rich in curcumin postpone diabetes development, protect β-cell, decrease insulin resistance, regulate lipid metabolism, reduce diabetic cardiomyopathy, attenuate testicular injury and oxidative stress (Jin et al., 2018; Zha et al., 2018) as well as ameliorate diabetic complications, such as liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, and pancreatic disorders (Jin et al., 2018).

Considerable evidence in vivo and in vitro shows that dietary polyphenols might control and prevent type 2 diabetes mellitus; however, clinical trials revealing polyphenols effectiveness remain limited (C. Sun et al., 2020). Table 1.1 summarizes the studies made in the last 5 years in humans proving polyphenols efficacy controlling diabetes mellitus and obesity.

Table 1.1

No permission required.

Daily consumption of curcumin had led to a decrease in blood glucose and weight alleviating complications in diabetes type 2 (Adibian et al., 2019; Hodaei et al., 2019).

Resveratrol has revealed good results as an antidiabetic agent and some clinical trials (Brasnyó et al., 2011; Movahed et al., 2013) have shown that resveratrol consumption improved the glycemic control (Gracia et al., 2016). However, recent and contradictory results showed that a treatment (500 mg/day) for 6 months did not improve metabolic parameters in diabetes (Bo et al., 2016) and did not improve hepatic or peripheral insulin sensitivity (1000 mg/day for 5 weeks) (Timmers et al., 2016).

Anthocyanins can improve glycemic control in type 2 diabetic adults (Soltani et al., 2015) after daily intake of 300 mg of anthocyanins for 6 weeks. Black soybean extract rich in anthocyanins enhanced the hypolipidemic activity of fenofibrate for type 2 diabetic patients (Kusunoki et al., 2015).

Overweight individuals with type 2 diabetes consumed refined olive oil rich in polyphenols (25 mL/day, 577 mg of phenolic compounds/kg) for 4 weeks and presented an increase in circulating inflammatory adipokines (Santangelo et al., 2016).

Studies conducted with human volunteers confirmed the long-held assumption about coffee or extracts rich in caffeoylquinic acids as treatment for diabetes and obesity as recommended by traditional medicine (Xie et al., 2019).

Combining different polyphenols may lead to synergistic and pronounced metabolic effects. Consumption of epigallocatechin-3-gallate (282 mg/day) combined with resveratrol (80 mg/day) for a period of 12 weeks proves to downregulate the expression of genes related to adipogenesis and apoptosis (adipocyte turnover), energy metabolism, oxidative stress, and inflammation in overweight and obese subjects (Most et al., 2018).

Many reports have shown that gut microbiota plays an important role mediating the interaction between consumption of a high-fat diet and obesity. Changes in the composition of gut microbiota may affect the host’s energy homeostasis, systemic inflammation, lipid metabolism, and insulin sensitivity. Polyphenols have demonstrated to be capable of modulating the composition of gut microbiota and reducing the high-fat diet induced obesity (Liu et al., 2020). Polyphenols may stimulate beneficial bacteria such as Lactobacillus spp. and Bifidobacterium spp. in the gut microbiota and hinder the proliferation of pathogenic strains such as Clostridium spp. (Corrêa, Rogero, Hassimotto, & Lajolo, 2019). A study with fecal microbiota from human volunteers fed with grape pomace extracts rich in polyphenols showed an increase in microbial fermentative activity (Gil-Sánchez et al., 2018).

2.2: Brain and neurobiology health

Many cognitive impairment and neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases are associated with old age. One of the strategies to minimize or delay the evolution of those neurodegenerative diseases is through nutrition in a preventive way to delay dementia evolution and maintain the cognitive wellness (Bensalem et al., 2016). Foods that could confer higher protection against neurodegenerative disorders are fruits and vegetables since they are rich in polyphenols. Dietary polyphenols have been recognized as promising nutraceuticals to combat brain disorders (Serra et al., 2020).

Polyphenols might modify brain function at three locations: (i) outside the central nervous system (CNS), by improving cerebral blood flow or by altering signaling pathways from peripheral organs to the brain; (ii) at the blood-brain barrier, by altering multidrug-resistant protein-development influx/efflux mechanisms of different biomolecules; and (iii) inside the CNS, by modifying the activity of neurons and glial cells (Schaffer & Halliwell, 2012).

One of the most discussed questions within neurobiology is how and in which form phenolic compounds reach the brain and modulate its function. Upon consumption of food, some phenolic compounds are available in the form of esters, glycosides, or polymers that cannot be absorbed in the intestine. The original molecules are hydrolyzed by microbial enzymes in the colon and transformed via methylation, sulfation, and glucuronidation to derivatives followed by their absorption in the colon and traveling through blood to the brain (Trebatická & Ďuračková, 2015). The blood-brain barrier (BBB) is a dynamic interface that limits and regulates molecular exchanges between the blood and the neuronal tissue. The mechanisms by which polyphenols may permeate the BBB are not fully understood. Studies claims that permeation is by simple diffusion or by specific carrier-mediated transport (Figueira et al., 2017). The permeation of polyphenols could also depend on the degree of lipophilicity where less polar polyphenols or metabolites (i.e., O-methylated derivatives) have greater brain uptake than more polar compounds (i.e., glucuronidated and sulfated derivatives) (Scheepens et al., 2010).

Among isolated polyphenols, curcumin has been reported to display antiamyloidogenic activity, not only by inhibiting the formation of new Aβ aggregates but also by disaggregating existing ones. Encapsulation helped to increase the permeability on the BBB level. Nanoparticles of polylactide-co-glycolic-acid (PLGA) with curcumin showed a significant decrease of Aβ aggregates (Barbara et al., 2017).

Flavonoids, such as epigallocatechin gallate (EGCG), are known for their powerful antioxidant properties and for their ability to attenuate stress and depression (Trebatická & Ďuračková, 2015). Recently, it was demonstrated that significant levels of EGCG could cross a human BBB model and protect cortical cultured neurons from oxidative-stress-induced cell death (Pogačnik et al., 2016). Due to the inflammatory nature of multiple sclerosis (MS), interleukin 6 (IL-6) is high in blood levels, which induces an increase in anxiety related to functional disability. A study where a group of 51 patients with MS received 800 mg EGCG with 80 mL of coconut oil demonstrated a decrease in IL-6, showing an improvement in the state of anxiety and functional capacity (Platero et al., 2020).

Quercetin has been reported as anti-Alzheimer due to improving typical morphology of mitochondria, enhancing the memory impairments, protecting cognitive deficit, and reducing neurodegeneration (Zaplatic et al., 2019).

Apigenin has antiinflammatory properties with the ability to protect neurites and cell viability by promoting a downregulation of cytokine and nitric oxide (NO) release in inflammatory cells of a human model of Alzheimer's disease (Balez et al., 2016). Apigenin has been reported as an antidepressant, to improve long-term memory and exert a neuroprotective role (Nabavi et al., 2018).

Neurodegenerative disorders are characterized by the formation of misfolded protein aggregates inside or outside the neuronal cells. The flavonoid myricetin can eliminate various abnormal proteins from the cellular environment via modulating endogenous levels of Hsp70 chaperone and quality control (QC)-E3 ubiquitin ligase E6-AP (Joshi et al., 2019).

Another well studied compound is resveratrol, which revealed ameliorated cognitive impairment and decreased the prefrontal and hippocampal neuronal activity in a mouse model of chemo brains administered 100 mg of resveratrol/kg (D.D. Shi et al., 2018). Mice fed with a diet supplemented with 100 mg/kg of resveratrol from 2 months of age for 10 months revealed a complete protection against memory loss and brain pathology, inducing simultaneously cognitive enhancement in healthy mice (Corpas et al., 2019).

Many studies focused on the use of pure polyphenols as therapeutic agents against neurodegenerative diseases, but an alternative is using natural extracts that could benefit from the synergistic effect of the different biomolecules. In microglia cell cultures, inflammatory response decreased and cell death was inhibited after 24 h exposure to fruit or leaf blueberries extracts (Debnath-Canning et al., 2020). Berry polyphenols have been proved to improve several types of memory and have a global effect on brain plasticity, partly through their antioxidant activity and/or their effect on neuronal signal transduction and neuroinflammation (Bensalem et al., 2016).

Olive leaf polyphenols extracts can have an effective therapeutic action in neurodegenerative diseases. In rats, they have shown a reduction in oxidative stress, upregulated antioxidant enzymes (SOD1, SOD2, and GPX1), SIRT1 (overall and microglial), and antiinflammatory M2 microglia, downregulated proinflammatory M1 type, and preserved myelin integrity (Giacometti & Grubić-Kezele, 2020).

The modulation of the microbiota-gut-brain axis with a view to preventing and treating brain disorders recently became a hot topic for the scientific community (Serra et al., 2020). The central nervous system is closely related to the gastrointestinal tract, playing an important role in regulating gut function and homeostasis. Alteration in the homeostasis of the gut-brain axis has been associated with neurological disorders and neurodegenerative diseases (X. Zhu et al., 2017). Microbiota is able to produce both neurotransmitters and neuropeptide, which can directly influence the brain functions by acting on neuroactive metabolites production (Cryan & Dinan, 2012; Filosa et al., 2018).

Due to the relatively low bioavailability of dietary polyphenols (Pandareesh et al., 2015) on the central nervous system, high and potentially toxic concentrations can only cross the blood brain barrier if the polyphenols are used as either concentrated supplements or therapeutic medicines. Food polyphenols appear to be a promising therapeutic approach to slow down the progression of neurodegenerative diseases acting more as prophylactic rather than therapeutic compounds.

2.3: Cardiac and vascular health and polyphenols

Cardiovascular diseases (CVD) are the leading cause of death in the developing world. The first step for atherosclerosis, a chronic inflammatory disease, is reduced vascular endothelium function. Atherosclerosis is characterized by the accumulation of lipids and fibrous elements in the large arteries, and it is the most important factor in this increase of cardiovascular diseases (Oliveira et al., 2021). Previous epidemiological studies indicated a positive association between the consumption of polyphenols and reduction in the incidence of coronary heart diseases (Pandey & Rizvi, 2009; Vázquez-Fresno et al., 2013).

Ingestion of dietary polyphenols is interesting due to the high antioxidant capacity and antiinflammatory properties, as well the ability to increase the synthesis of nitric oxide and decrease blood pressure, which improves cardiovascular health (Oliveira et al., 2021). Several studies have been carried out to understand the mechanisms of polyphenols on the vascular system. The health-promoting properties of polyphenols include: effects in blood-pressure-lowering (Yoo et al., 2005), the induction of antioxidant defenses (Assefa et al., 2016; Wan et al., 2001), the improvement of endothelial function (Heiss et al., 2005), the inhibition of platelet aggregation (Assefa et al., 2016), low-density lipoprotein (LDL) oxidation (Wan et al., 2001), the modulation of inflammatory response (Simões et al., 2020), and many others. The antioxidant capacity of polyphenols is related to their effectiveness at capturing reactive oxygen species (ROS) and nitrogen species and upregulating other endogenous antioxidant pathways. Another potential mechanism of action of phenolic compounds is the modulation of oxidative stress, especially in the activation of transcription factors involved in antioxidant pathways by the expression of several antioxidant enzymes, such as glutathione-S-transferase, glutathione reductase, superoxide dismutase, and others (Castro-Barquero et al., 2021; Oliveira et al., 2021).

Plenty of scientific evidence shows that the intake of flavonoids is inversely associated with cardiovascular disease. In a previous meta-analysis performed by Wang et al. (2014), the association between the intake of different subclasses of flavonoids and the risk of CVD was investigated, and a significant inverse association between flavonol intake and the risk of cardiovascular disease was found. The authors also evaluated the association between the intake of flavonols and stroke risk, and they showed a significant association between the highest flavonol intake and reduced risk for stroke among men; however, the same was not found for the women group.

Moreover, in another prospective cohort study of US adults, McCullough et al. (2012) evaluated the correlation between flavonoid intake and CVD mortality among American adults. The results showed that flavonoid consumption was associated with a lower risk of CVD death. Furthermore, it was observed that most inverse associations appeared with intermediate intakes, suggesting that even the intake of relatively small amounts of foods rich in flavonoid compounds may be beneficial to health. Overall, the studies evaluated in this cohort work indicated that intake of diets rich in polyphenols, especially several classes of flavonoids, is associated with a reduction of CVD risk. However, knowledge about the long-term biological effects of these compounds in humans remains limited. In addition, the findings that the benefits of flavonoids consumption were realized at relatively low intake levels requires further examination (McCullough et al., 2012).

2.4: Cancer prevention and treatment

Cancer, also known as neoplasm or malignant tumor, is a multifactorial disease caused by alteration of gene expression and cell signaling pathways (Rajagopal et al., 2018). The development of cancer involves multistage and microevolutionary processes, where a body’s cells can grow uncontrolled, spread to other parts of the body, and can be life-threatening (Pandey & Rizvi, 2009; Understanding cancer, 2021). Cancer is the second leading cause of mortality after cardiovascular diseases (Briguglio et al., 2020). Many factors can directly or indirectly influence the onset of cancer such as metabolic, genetic, occupational, and environmental parameters. Furthermore, evidence suggests that dietary factors are associated with 30%–35% of cancer cases (Briguglio et al., 2020). The consumption of fruits and vegetables containing naturally high levels of polyphenols has been associated with a decreased risk of cancer (Basu & Maier, 2018; Lv et al., 2020; Sajadimajd et al., 2020).

Many epidemiological studies have reported the anticancer potential of polyphenols in different cellular models (Pandey & Rizvi, 2009). However, because the level of antioxidants to neutralize free radicals (endogenous or exogenous) is often insufficient for the defense system of the cell, antioxidants of exogenous origin are necessary. Investigation showed that polyphenols present biological effects in vitro and in vivo, with a protective effect against certain types of cancer (Khan et al., 2020). These compounds present cytotoxic effects on cancer cells, such as stimulation of the activity of different enzymes and apoptosis in cancer cells, therefore reducing the growth of tumors (Bayir et al., 2019).

Several polyphenolic compounds such as curcumin, resveratrol, catechins, isoflavones, lignans, quercetin, flavanones, tea polyphenols, and red wine polyphenols have been tested (Basu & Maier, 2018; Lv et al., 2020; Sarkar & Li, 2003; Zaplatic et al., 2019), and epidemiological studies have observed the effects of many phenolic compounds in different lines of cancer cells, including mouth, stomach, duodenum, colon, liver, breast, and skin (Basu & Maier, 2018; Lv et al., 2020; Poschner et al., 2019; Sarkar & Li, 2003). These studies have found that the protective effects in some models have different mechanisms of action (Pandey & Rizvi, 2009), as can be seen in Table 1.2. However, previous reports of anticancer activities of polyphenols in different cancer cell lines allowed the identification of target signaling pathways or affected gene expressions under controllable conditions. Thus, it was observed that most cancer cells or tissues expressing certain levels of enzymes, such as cytochrome P450, sulfotransferases, UDP-glucuronosyltransferases, and methyltransferases, can transform polyphenols metabolically and generate new products (Murias et al., 2008; Wu et al., 2020). On the other hand, the results obtained from in vitro studies have demonstrated different results than in vivo studies or human clinical trials due to several factors. Additionally, owing to the high metabolism and low bioavailability of the polyphenols, there is controversy about the use of these compounds (Wu et al., 2020).

Table 1.2

2.5: Skin cancer

Skin cancer is a result of several mutations in cancer-related genes, including protooncogenes and tumor suppressors in skin cells. Furthermore, skin cancer is considered to be the most common type of cancer worldwide, and presents a growth rate and mortality comparable to other diseases (Sajadimajd et al., 2020). The main classes of skin cancer are cutaneous melanoma and nonmelanoma. Nonmelanoma skin cancer (NMSC) includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as the major subtypes (Gordon, 2013). Most NMSC cases are highly curable, particularly if diagnosed in the early stages. The BCC is the most common type of skin cancer. However, it presents the lowest mortality rate due to its low potential to metastasize. On the other hand, although malignant melanoma skin cancer represents only 4% of total skin cancer cases, it is responsible for 65% of all skin cancer deaths (Cummins et al., 2006; Gordon, 2013; Sajadimajd et al., 2020). Phytochemicals are promising for the development of innovative strategies for the prevention/treatment of melanoma (Pal et al., 2015). Natural agents such as polyphenols have been demonstrated as cancer preventive with therapeutic potential in several preclinical, clinical, and epidemiologic studies (Pandey & Rizvi, 2009; Wootton-Beard & Ryan, 2011). The anticancer mechanisms of the polyphenols studies have shown that several phenolic and polyphenolic compounds isolated from various plants have the potential to inhibit cellular proliferation, invasion, and metastasis in melanoma models (Caltagirone et al., 2000; Pal et al., 2015; Sajadimajd et al., 2020; H. Shi et al., 2015).

An in vitro and in vivo study performed in melanoma cells using fisetin, a flavonoid found in several fruits and vegetables, demonstrated that the fisetin treatment inhibited the PI3K signaling pathway in melanoma cells. Therefore, they investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis, and tumor growth. This study showed that lower doses of combined treatment (fisetin and sorafenib) than the individual treatment was required to reduce the growth of BRAF-mutated human melanoma cells. Additionally, the combined treatment improved (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K (Pal et al., 2015).

The treatment of melanoma continues to be a challenge due to its aggressive metastatic ability and resistance to current therapeutic approaches. However, epidemiological evidence indicates that polyphenols bring a significant advantage in defeating carcinogenesis and metastasis of skin cells due to their antioxidant, antiinflammatory, antiproliferative, and chemoprotective properties. Nonetheless, the antimelanoma mechanisms of some compounds are not fully understood (Briguglio et al., 2020; Cao et al., 2014; Pal et al., 2015; Sajadimajd et al., 2020).

2.6: Breast cancer

Breast cancer is the most common type of tumor in women and the second most frequent type of cancer worldwide (Basu & Maier, 2018). In addition, breast cancer accounts for approximately 25% of all diagnosed tumors, being the leading cause of cancer death in women (Briguglio et al., 2020; Poschner et al., 2019; Shaikh et al., 2019). Therefore, the combination of chemoprevention and anticancer treatment is crucial for reducing the incidence of disease and mortality. Many factors can be attributed to the high incidence of breast cancer, including nonmodifiable factors such as increasing age and genotype, as well as modifiable factors such as nutrition, smoking, alcohol consumption, and physical activity (Briguglio et al., 2020; Shaikh et al., 2019). Previous studies suggested that natural constituents present in the diet can act as chemopreventive agents to inhibit mammary carcinogenesis (Basu & Maier, 2018; Lv et al., 2020; Poschner et al., 2019; Shaikh et al., 2019; T.T. Zhao, Jin, et al., 2019). In addition, considering that the incidence of breast cancer is higher in Western countries than in Asia and the several experiments about the role of soy foods in mammary tumorigenesis and their protective effects against breast cancer, researchers have associated the consumption of high levels of isoflavones from soy and soy-based products with a lower incidence of breast cancer in Asian populations (T.T. Zhao, Jin, et al., 2019). Isoflavones are the most relevant group of phenolic compounds found, occurring exclusively in members of the Fabaceae family; soybeans and soy-based products are good examples of sources with high contents of isoflavones (mainly daidzein, genistein, and their conjugates) (Křížová et al., 2019; Veiga et al., 2019). Investigations have suggested that isoflavone levels are associated with the level of estrogen (steroidal hormones) (Hua et al., 2018; T.T. Zhao, Jin, et al., 2019). Considering that approximately 80% of all breast cancer cases diagnosed in postmenopausal women are affected by the presence of estrogens, the regulation of estrogen activity is an important factor for the prevention or treatment of breast cancer (Poschner et al., 2019).

T.T. Zhao, Jin, et al. (2019) performed a meta-analysis to study the relationship between isoflavone intake and breast cancer risks, and the results of this meta-analysis indicate that a high intake of soy foods presented a beneficial role in reducing the risk of breast cancer. Another meta-analysis performed by M. Chen et al. (2014) evaluated the soy isoflavones and the risk of breast cancer for women according to menopausal status (pre and postmenopausal). This study showed that soy isoflavone intake presents a protective effect of breast cancer risk for Asian premenopausal and postmenopausal women, but no significant association was found in Western