Chapter 3 - Therapeutic Potentials of the Most Studied Flavonoids: Highlighting Antibacterial and Antidiabetic Functionalities
Introduction
Phytochemical-rich foods, particularly those rich in polyphenols (PPs), have been shown to be effective in the treatment of human diseases such as cancer, DM, age-related disorders, cardiovascular risk, and Alzheimer's disease [1], [2]. Based on data obtained from the Phenol-Explorer database (http://phenol-explorer.eu/), foods from European countries with higher content of each of the major classes of PPs (flavonoids, phenolic acids, lignans, and stilbenes) have been characterized as effective in the treatment of such human diseases [3]. Of the PPs, hot flavonoids [4] are represented by quercetin, rutin, kaempferol, catechin, apigenin, lutelin, and genistein [5]. These compounds are widely distributed in plants, showing a broad range of biological activity such as antioxidant [6], anticarcinogenic, and antimicrobial [7]. Beverages, fruits, and vegetables (e.g., cocoa, tea, soy, black raspberry, apple, peach, apricot, common bean, lowbush blueberry, and capers) are the major sources of flavonoids (bioactive compounds) [4], [8], [9]. Nonetheless, potatoes are also good sources of PPs, with total phenolic content higher than other widespread fruits and vegetables such as carrots, onions, or tomatoes because of their high consumption rates [10]. Studies have shown that flavonoid consumption has been associated with both vascular and cognitive benefits across the lifespan [11] and connected with improvements in a number of different aspects of health through several different biologic and neurologic mechanisms [12]. Owing to the health benefits of flavonoids to the human body, over the past decades these compounds have been considered by the food and pharmaceutical industries as valuable sources of dietary metabolites. Infections caused by multidrug-resistant bacteria are an increasing problem [13] due to the emergence and propagation of microbial-resistant drugs and the lack of development of new antimicrobials. Antibiotics have proven to be powerful drugs in the control of infectious diseases and remain one of the most significant discoveries in modern medicine [14]. Studies have suggested that phytochemicals that produce MIC in the range 100 to 1000 μg mL− 1 in in vitro susceptibility tests can be classified as antimicrobials [15]. In this regard flavonoids show significant antimicrobial activity, and therefore they can be considered for use in a new strategy for the treatment of infectious disease either alone or in combination with commercial antibiotics. In contrast, naturally occurring flavonoids have been considered effective supplements for the management and prevention of DM and its long-term complications based on in vitro and animal models. Diabetes mellitus is the most common endocrine disorder that is characterized by elevated levels of glucose in the bloodstream [16], [17]. Diabetes is classified into two major groups: type 1 and type 2 diabetes. Type 1 DM is directly associated with insufficient secretion of insulin and patients need daily administration of insulin [18]. Type 2 DM, which naturally occurs in adults, results from ineffective use of accessible insulin [19], [20]. It is suggested that a healthy diet, regular exercise, and prevention of weight gain can be useful in the treatment of type 2 diabetes. According to a World Health Organization report in 2016 (http://www.who.int/mediacentre/factsheets/fs312/en/), it is estimated that there are 422 million diabetic individuals in the entire world. It also stated that 1.5 million deaths are directly caused by DM yearly, and it is believed that by the year 2030 DM and its related diseases will be the most important diseases worldwide.
In this chapter the relationship between dietary flavonoids and treatment of DM and infectious diseases is focused on the basis of recent studies. Clearly, the association between flavonoids and human health is crucial to generating interesting results in the future with the aim of improving nutritional policies or designing new functional foods. However, future studies should avoid some of the limitations that beset this issue.
Section snippets
Classification and Chemical Structure of Flavonoids and Other Polyphenols
In recent years the study of natural product chemistry has emerged and many facets of the chemical structures of such products for different goals have been identified and described. As secondary metabolites PPs have been classified into two major groups: flavonoids and nonflavonoids [1], [5], [21] (Fig. 3.1).
The term flavonoids is used to explain compounds that have a C6–C3–C6 structure. These compounds have two benzene rings (A and B) separated by a propane unit derived from a flavone [1],
Biosynthesis of Flavonoids
Thanks to recent advances in metabolomics and analytical chemistry approaches, many aspects of the biosynthetic pathway of PPs and their subclasses have been investigated. A large body of PPs have been biosynthesized from aromatic amino acids, including phenylalanine, tyrosine, and tryptophan. Similar to other PPs, flavonoids can be synthesized via the phenylpropanoid and/or shikimic acid pathway. Aromatic amino acids are primary components in the synthesis of flavonoids. Flavonoids can also be
Storage Sites of Flavonoids
The synthesis of PPs occurs in the chloroplast, in the endoplasmic reticulum membrane, and in the cytoplasm. Roots, rhizomes, wood, peel, bark, seeds, leaves, and flowers are the most favorable places for accumulation of these bioactive compounds. Flavonoids are generally located in the vacuoles of epidermal cells, guard cells, and subepidermal cells of leaves, aerial regions of monocotyledonous and dicotyledonous plants, cortex parenchyma cells, vascular parenchyma cells, flowers, and cell
Most Studied Flavonoids
According to a review of the literature, flavonoids have extensively received more attention from the pharmaceutical and food industries than other metabolites in recent decades. The health benefits of flavonoids have been mentioned in many studies that are accessible in scientific databases [5]. Flavonoids are distributed in nature and consumed as a part of the human diet in considerable amounts. These bioactive compounds are recognized for their antioxidant properties, and their potential
Solubility of Flavonoids
The solubility of flavonoids in many different solvents has been widely investigated in recent years [53], [54]. In an interesting study Chebil et al. [54] evaluated the solubility of flavonoid compounds, including quercetin, isoquercitrin, rutin, chrysin, naringenin, and hesperetin in organic solvents such as acetonitrile, acetone, and tert-amyl alcohol. Their results pointed up just how significantly the nature of solvents and the chemical structure of flavonoids affected the solubility of
Extraction Methods
Extraction is the separation of medicinally active parts of plants using selective solvents by standard procedures [10], [65], [66]. Due to recent advances in chemical approaches a variety of methods currently exist for extraction, purification, quantification, and identification of PPs. There is a correlation between the types of PPs and the strategies used to extract them from natural sources. Basically, five modern methods are used for the extraction of polyphenol families [67], including
Antioxidant Activity
Antioxidant activity is a common feature shared by different classes of flavonoids. The antioxidant properties of many plants are mainly attributed to the presence of flavonoids, but they may also be influenced by other organic and/or inorganic compounds that have partial to moderate antioxidant activity. The term antioxidant describes a set of chemical mechanisms that are responsible for the protection of cells from the dangers of free radicals [76]. Studies have suggested that both flavonoid
Prooxidant Activity
Although a large body of studies have indicated that flavonoids are potent antioxidant compounds, surprisingly these compounds have a prooxidant (oxygen radical generating) behavior in a cellular redox state [83], [87]. In fact, these compounds are “double-edged swords.” They demonstrate a moderate to high prooxidant activity. The prooxidant activity of exogenous antioxidants is correlated with their concentration in the human body after consumption of phytochemical-rich foods. This undesirable
Bioavailability of Flavonoids
The bioavailability of flavonoids is critical to provision of the health benefits of these compounds. Flavonoids are healthy molecules and the food industry aims to preserve these compounds and minimize the loss of these molecules [96]. Studies have shown that the bioavailability of flavonoids and nonflavonoids is dependent on their absorption and metabolism in the human body. Nonetheless, their bioavailability is dependent on their absorption in the digestive system [32], [97]. The
Risks and Safety
Although the beneficial effects of flavonoids on human health are well documented, their consumption in higher doses as food supplements is clearly dangerous. Too much of anything is not good and this certainly holds true for these bioactive compounds. Due to the variable chemical structure of flavonoids their biological activities are wide ranging, and therefore prediction of their toxicity is a sophisticated process. Moreover, the necessary tools for evaluating and monitoring the adverse
Molecular Targets
According to a popular idiom which says you are what you eat, evidence suggests that there is a significant correlation between a healthy diet and body fitness [106]. Many factors, including the modulation/regulation and/or inhibition of cell-signaling pathways, reduction of platelet aggregation, effect on cholesterol synthesis, effect on blood pressure and hormone metabolism, and antioxidant effects confirm the relationship between flavonoid consumption and reduced risk of human diseases [107]
Effect on Diabetes
Annually, billions of dollars are lost due to the treatment of DM and its related disorders. This important issue has attracted the attention of numerous investigators and researchers. Flavonoids are considered a valuable treatment for DM. Due to the relationship between DM and inflammation and the potential for flavonoids to protect the body against free radicals and other oxidative agents, it is assumed that consumption of flavonoid-rich foods may reduce the risk of DM [134].
These natural
Flavonoids as Antibacterial Agents
In recent decades the antibacterial properties of phytochemicals have received more attention due to the multidrug resistance of infectious bacteria against commercial antibiotics. Antibiotics are widely known as miracle drugs [168], [169], [170] since they have been used against various infectious diseases for many years and have saved millions of lives [171]. Due to the recent advances in structural-based drug design approaches, different methods currently exist for the synthesis and
Flavonoids as Vitamins?
Vitamins are essential nutrients for human metabolism and play an important role as coenzymes or enzymes in many vital processes for normal functioning of the body [204]. Dietary intake of bioactive compounds (or dietary metabolites) and/or vitamins is a potentially modifiable factor that may play a role in the prevention of nutritional deficiencies [205]. Due to the biological properties of flavonoids (especially flavones and flavonols) and their health benefits these secondary metabolites are
Therapeutic Perspective for Generating New Drugs
As mentioned earlier, naturally occurring dietary flavonoids have received considerable attention as alternative candidates for clinical therapies as a result of their antioxidative, antiinflammatory, antiamyloidogenic, anticancer, antidiabetic, and antibacterial properties. In an interesting study Baptista et al. [210] considered flavonoids to be therapeutic compounds that could be used to target key proteins in Alzheimer's disease. They concluded that these compounds exert their potential
Conclusion
Flavonoids are bioactive compounds abundantly found in fruit, vegetables, and beverages of plant origin. The dietary intake of flavonoids is suggested to prevent and lower the risk of chronic diseases. In this review we partially discussed the possible mechanisms by which flavonoids play important roles in the management of DM and inhibition of infectious bacteria. Studies have shown that these compounds are good targets for the inhibition of enzymes involved in DM. According to the present
Acknowledgments
We thank the Research Council of Kermanshah University of Medical Sciences (KUMS) for its financial support of this investigation. We specially thank Dr. Sonia González from the Department of Functional Biology, University of Oviedo Spain for her gracious help in reviewing and revising this chapter. The effective, instructive, and invaluable comments provided by the academic editor and reviewers are gratefully acknowledged.
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Dedicated to Prof. Ligia Macedo and Dr. Caio Oliveira who are the best scientists I can imagine.