IntechOpen

Home > Books > Flavonoid Metabolism - Recent Advances and Applications in Crop Breeding

Open access peer-reviewed chapter

Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning Pharmacodynamics and Pharmacokinetic Properties

Written By

Asmaa Nabil-Adam, Mohamed E. Elnosary, Mohamed L. Ashour, Nehad M. Abd El-Moneam and Mohamed A. Shreadah

Submitted: 21 September 2022 Reviewed: 17 October 2022 Published: 10 January 2023

DOI: 10.5772/intechopen.108637

Flavonoid Metabolism IntechOpen
Flavonoid Metabolism Recent Advances and Applications in Crop Bree... Edited by Hafiz Muhammad Khalid Abbas

From the Edited Volume

Flavonoid Metabolism - Recent Advances and Applications in Crop Breeding

Edited by Hafiz Muhammad Khalid Abbas and Aqeel Ahmad

Book Details Order Print

Chapter metrics overview

213 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Flavonoids are a major class of secondary metabolites that comprises more than 6000 compounds that have been identified. They are biosynthesized via the phenylpropanoid metabolic pathway that involves groups of enzymes such as isomerases, hydroxylases, and reductases that greatly affect the determination of the flavonoid skeleton. For example, transferase enzymes responsible for the modification of sugar result in changes in the physiological activity of the flavonoids and changes in their physical properties, such as solubility, reactivity, and interaction with cellular target molecules, which affect their pharmacodynamics and pharmacokinetic properties. In addition, flavonoids have diverse biological activities such as antioxidants, anticancer, and antiviral in managing Alzheimer’s disease. However, most marine flavonoids are still incompletely discovered because marine flavonoid biosynthesis is produced and possesses unique substitutions that are not commonly found in terrestrial bioactive compounds. The current chapter will illustrate the importance of flavonoids’ role in metabolism and the main difference between marine and terrestrial flavonoids.

Keywords

  • marine flavonoids
  • biosynthesis
  • pharmacodynamics
  • pharmacokinetics
  • defense mechanism

1. Introduction

Flavonoids with more than 6000 individuals are divided into six main categories: chalcones, flavones, flavonols, flavandiols, anthocyanins, and proanthocyanidins are present in all plants. The aurones group is present in several species [1]. Legumes and a few non-legume plants produce isoflavonoids, but few plants produce 3-deoxyanthocyanins and phlobaphenes. Stabileneds resemble chalcones and are made from grape and peanuts [2]. Flavonoids have several functions, such as protecting plants from UV radiation and phytopathogens, regulating signals, promoting male fertility, transporting auxin, and giving flowers their color to draw pollinators [3]. Flavonoids may increase nutrient recovery during senescence by shielding leaf cells from photooxidative damage. The oldest and most prevalent flavonoids are flavonols, which have potent physiological effects [4]. The phenylpropanoid pathway, which turns phenylalanine into 4-coumaroyl-CoA, produces flavonoids. Chalcone scaffolds are produced by the first flavonoid-specific enzyme, chalcone synthase. Although the principal method for producing flavonoids in plants is consistent, the different flavonoid subclasses are produced depending on the species via isomerases, reductases, hydroxylases, and various Fe2+/2-oxoglutarate-dependent dioxygenases [4]. Transferases alter the solubility, reactivity, and interaction of flavonoid molecules with biological targets by adding sugars, methyl groups, and acyl moieties to the flavonoid backbone [5]. Plants can produce specific organic molecules and prevent metabolic interference thanks to metabolic channeling. P450s-related metabolons have been discovered in several biosynthetic pathways, including phenylpropanoid, flavonoid, cyanogenic glucoside, and others [6]. More proof of intermediate channeling is provided by transgenic tobacco plants that produce two phenylalanine ammonia-lyase isoforms (PAL1 and PAL2) and cinnamate-4-hydroxylase [7]. For example, Yeast-two hybrid assays indicate that rice contains an anthocyanin multienzyme complex [8]. For flavonoids from marine environments, for example, unknown and uncommon marine flavonoids precursors of algal flavonoids are biosynthesized using comparable metabolic mechanisms to those seen in plants. Flavonoids are created by several metabolic pathways [9]. There are a variety of structures in algal flavonoids. Specify flavones, isoflavones, flavanols, flavanones, and favonols. The C6/C3 unit of t-cinnamic acid and the unit of malonyl-C3 CoA make up the backbone. P-coumaric acid is present in Anabaena doliolum, Spongiochloris spongiosa, Porphyra tenera, and Undaria pinnatifida [10]. Phenylalanine Ammonia Lyase is responsible for producing t-cinnamic acid. While p-coumaroyl-CoA may be converted into a chalcone derivative by Claisen condensation, Michael addition, and chalcone synthase-catalyzed enolization, the poly-b-keto ester can be made using the phenylpropanoid pathway. Chalcone is created from the poly-b-keto ester [11] Chalcone is transformed into flavonoid structures via several reductases, isomerases, hydroxylases, acyltransferases, and glycosyltransferases. Within each category, structural heterogeneity is brought on by variations in the number of linked hydroxyl groups, position, degree, type of alkylation, and glycosylation [12].

Further evidence is required for the algal flavonoid synthesis route. For Algal flavonoid composition, the 15-carbon skeleton of flavonoids comprises two phenyl rings (A and B) connected by a 3-carbon unit to form a heterocyclic ring. Their structural categorization is based on where the benzenoid substituent is located [13]: 2-Phenylchromans (flavonoids), which include anthocyanidins, flavanones, flavonols, flavones, and flavan-3-ols. 2. Pterocarpans, isoflavones, and 3-phenylchroman isoflavones. Glycosides represent the majority of flavonoids in marine [14]. Phlorotannins are more often used polyphenols in algae than flavonoids. There is not much literature on these chemicals. Flavanols. The most varied flavonoids found in algae are flavanols. The double bond between carbons 2 and 3 and the carbonyl group in carbon 4 of ring C is absent from flavanols. Occupational and health advantages Polyphenols have a variety of bioactivities in addition to being antioxidants that protect against UV rays and are poisonous to predators [15]. The bioactivity of phlorotannins and flavonoids is regulated by the pattern of -OH group substitutions, double bonds, and the site of their conjugation [16]. Also, Phytoflavonoids bioactivity of the flavonoids found in algae is unclear, but there are several applications for marine flavonoids in medical and cosmetic applications. Acanthophorin A and B, isolated from A. spicifera, shield the rat liver from lipid peroxidation and stop the malondialdehyde generation [17]. Because OH groups combine with H radicals to generate persistent semiquinone radicals, flavonoids have antioxidant properties. Flavonoids scavenge hydroxyl, other functional groups, and unsaturated and conjugated pi bonds [18]. Flavonoids are vital components of the human diet and potent antioxidants that can lower oxidative stress and several diseases in people [19]. Due to their antioxidant, anti-inflammatory, antibacterial, and affinity/inhibitory properties toward inflammatory enzymes, plant extract rich in flavonoids are employed in dermatology and cosmetics. As dietary components, algal flavonoids may protect against several human diseases (Figure 1 and Table 1) [25].

Figure 1.

The metabolic pathways of flavonoids.

Table 1.

The different classes of flavonoids with their activities and examples of each class.

Advertisement

2. Flavonoids as a defense mechanism

Flavonoids are necessary for plant development and plaque resistance. Flavonoids are responsible for many of the hues of angiosperm flowers. They can be found throughout the plant, not just in the blooms [26]. Plant-based foods and drinks like fruits, vegetables, tea, chocolate, and wine are rich in flavonoids. Plants, animals, and even microorganisms contain flavonoids. Flavonoids responsible for The color and aroma of flowers, fruit dispersal, the germination of seeds and spores, and the growth and development of seedlings in plants are all influenced by flavonoids, which are produced in particular locations [27]. In addition to acting as UV filters [28], signal molecules, allopathic chemicals, phytoalexins, detoxifying agents, and antimicrobials, flavonoids shield plants against biotic and abiotic stresses. Plants’ ability to adapt to heat and tolerate freezing may be influenced by flavonoids [29]. Early advances in floral genetics were made possible by mutation techniques that altered flower colors generated from flavonoids, and functional gene silencing in plants was associated with flavonoid synthesis. Today, flavonoids treat illnesses and prevent cancer, and more than 6000 flavonoids color fruits, herbs, vegetables, and medicinal plants. Flavones are a subclass of flavonoids. Positions 2 and 3 of the C ring have double bonds, and position 4 is a ketone [30], Most flavones found in fruits and vegetables have a hydroxyl group at position 5 of the A ring, but other positions—particularly position 7 of the A ring and 3′ and 4′ of the B ring—can vary depending on the taxonomic group. Keto-flavonoids are flavanols. Flavanols can act as antioxidants and reduce the risk of vascular disease [31]. The third hydroxyl group on the C ring of flavonols can be glycosylated. Compared to flavones, flavonols exhibit distinct methylation, hydroxylation, and glycosylation patterns. The most varied group of bioactive polyphenols is flavonoids [32]. A phenyl ring (A ring) joined with heterocyclic benzo-c-pyrone (C ring), which connects to another phenyl ring (B ring) via a carbon-carbon bond, makes up the three rings that make up the diphenyl propane skeleton of flavonoids (C6C3C6). These chemicals contain hydroxyls. The gymnosperms, angiosperms, ferns, and bryophytes contain more than 4000 flavonoids [2]. The first plant to possess flavonoids is green algae [33]. According to Bonfante [34], a symbiotic relationship between algae and a tip-growing fungus is the reason for the plants’ biphyletic origin. When plants transitioned from marine to terrestrial habitats, flavonoids developed primarily to protect against rising UV exposure [35].

Research on plant flavonoid production is an important area of research. The synthesis of flavonoids in algae may differ from higher plants due to algae development. Microalgae contained flavonoids and flavonoid intermediates by Goiris et al. [36]. Phloretin and dihydrochalcone might be intermediates in the production of flavonoids. The findings suggest that flavonoid biosynthesis enzymes may be present in microalgae. Diverse flavonoids compatible with better plant flavonoid synthesis are present in certain algae [36]. Plant-plant interactions may be impacted by flavonoids. Negative relations are mainly based on the inhibition of seedling development and germination. Flavonoids are frequently released into the soil by roots, where they prevent seed germination. They may also be found in leaves and pollen, which prevents the germination of other plants [3, 37]. Barley flavones lessen weed seed germination, while Centaurea maculosa catechins limit Centaurea diffusa and Arabidopsis thaliana germination and growth [38]. The precise allelopathic mechanism of flavonoids is unknown. Allelopathy can be affected by preventing cell division, ATP production, and auxin activity [39]. The Ca2+ signal cascade and root system death are stimulated by flavanols. Due to its ability to inhibit weed development, allelopathy is becoming increasingly important in agriculture [40].

Plants may fight against bacteria and fungi with the assistance of flavonoids. The general antipathogenic properties of flavonoids are largely attributed to their antioxidant properties. They suppress ROS produced by both pathogens and plants [41]. The B ring of flavonoids can intercalate or form hydrogen bonds with nucleic acid bases, limiting bacterial DNA and RNA synthesis and influencing DNA gyrase activity [42]. They can bind to viral nucleic acids or capsid proteins and inhibit viral polymerases [43]. The antipathogenic activity of flavonoids depends on their structure. Flavones and flavanones without substitution have strong antifungal properties. The antifungal activities of these compounds are reduced by hydroxyl and methyl groups, but methylated flavonoids have a greater effect. Isoflavones, flavanes, and flavanones are powerful antibacterial compounds, whereas flavonoids inhibit root infections, particularly fungus (Figure 2) [44, 45].

Figure 2.

The different role of flavonoids and their mechanism of action as a defense mechanism in human Vis plant.

Advertisement

3. Role and function of flavonoids as a protective preventive and curative effect against various diseases

Therapeutic flavonoids are associated negatively with sickness, according to epidemiological research. Conventional flavonoids can interact with key enzyme systems and show polypharmacological action. It follows that the considerable study of chemical structure-activity connections is not surprising. Strong antiviral properties of bioactive flavonoids, including those against the hepatitis C virus, and antimicrobial such as Escherichia coli, have been examined. Chemical processes, including methoxylation, glycosylation, and hydroxylation, have been mostly responsible for these effects. Research on the structure-activity relationship (SAR) covers several elements. C2C3 double bonds are frequently advantageous—hydroxylation substitution style is important [46, 47, 48, 49].

A beneficial role for 5−/7-hydroxyl derivatives in ring A hydroxylation is suggested by six anti-H5N1 influenzas A virus 5, 7-diOH flavonoid candidates, and daidzein’s less potent anti-human fibroblast collagenase catalytic domain (MMP1ca) activities. Better ring B hydroxylation indicates stronger MMP1ca inhibition by 3′-OH and 5′-OH drugs. Catechol is the most common functional group. Innovative drug production has been stimulated by quercetin, more notable than morin inhibition of canine distemper virus [50, 51]. Compared to luteolin, quercetin considerably contributes to ring C. It also affects how many hydroxyl groups there are. More hydroxyl groups lessen the hydrophobicity of flavonoids, preventing membrane partitioning. Hydrophobicity and electronic delocalization impact the intensity of hydroxylation, which causes some hydroxyl-rich flavonoids to act more strongly. Different hydroxyl groups may raise C3 charges while decreasing hydrophobicity, which suggests pharmacological activity. Methylation hurts membrane fluidity and lowers the activity of several viruses and bacteria according to their physiology. Two PMFs performed less well against E. coli than equivalent aglycone. Antiviral activities can be found in flavonoid glycosides [52, 53, 54]. Finding the right screening substances for dietary therapy and medical treatment may result from analyzing the SAR behaviors displayed by certain flavonoids in antiviral/bacterial situations. Apoptosis induction, proteasome inhibition, nuclear factor signaling suppression, differentiation induction, cell cycle arrest induction, receptor contact, and interaction with carcinogenic enzymes are a few of the mechanisms that have highlighted the importance of flavonoids in cancer therapy. Flavonoids have potential as anticancer medications since they can selectively kill cancer cells. The molecular planarity and conjugation between rings C and A/B that the C2C3 double bond produces are necessary to prevent tumor growth. Studies on the C2C3 double bond and its anticancer properties have been conducted using tumor cell lines, such as colon adenocarcinoma cells. Stronger inhibition was obtained by the C2C3 unsaturation and two hydroxyl groups on ring B [55, 56].

Numerous studies have demonstrated how hydroxylation affects tumor regulation. Per-methoxylated flavonoids do not have the same anticancer effects as hydroxylated flavonoids. To, 6-OH and 5, 7-diOH contribute, Ring B does not become less active when hydroxyl groups are added [1]. Ring C’s 3-hydroxylation enhances its biological actions. Without 3-OH, flavonoids have less antiproliferative activity. The 3-OH molecule’s affinity for the binding site might be greater [30, 57]. Methylated flavonoids support the enhanced biological action of ringing A polymethoxylation. Among the Organ flavonoids tested in the cell morphology research, two A-ring PMFs exhibit the highest proliferative inhibition, demonstrating the significance of the C-8 position in flavonoids’ antiproliferative impact. The bioactivity of flavonoids against neurodegeneration has traditionally been linked to their antioxidant properties. However, new research has highlighted the significance of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) interactions, mitochondrial dysfunction, key neuronal signaling pathways, and chelation of transition metals in controlling neuronal resistance to neurotoxic oxidants and inflammatory mediators. Ring B hydroxylation may improve learning to avoid cardiovascular disease.

Effects of flavonoids and the eNOS transcription factor the second Krüppel-like component [58, 59]. The C2C3 double bond produces an effective twofold structure in eNOS and ET-1 synthesis, and 4-carbonyl moiety results in about 1.35-fold higher gene expression (quercetin vs. epicatechin/catechin), according to the findings. The “protein-binding” mechanism was highlighted in a SAR examination of 12 flavonoids with paraoxonase1 (rePON1) due, at least in part, to different hydroxylation substitutions, the C2C3 double bond, and the 4-carbonyl group in ring C. Flavones and flavonols have stronger PON1 interactions because of the C2C3 double bond in ring C, which increases molecular planarity and may cause electron delocalization between rings A and B. Coplanarity exists between the 3-hydroxyl group and the 4-carbonyl oxygen atom. Flavonoids’ greatest therapeutic benefits are in managing leukemia, sepsis, asthma, and other inflammatory diseases. SAR research is more important because flavonoids have been extensively investigated and certain mechanisms may not be unified. Double bonds in C2C3 might encourage molecular planarity. For example, Hesperetin’s absence results in a lower volume/surface ratio than diosmetin’s absence [19, 50, 60]. (b) Isoflavones, the ring B catechol moiety, are subject to 3′- and 5′-hydroxylations that promote cell differentiation. (c) Ionizing hydroxyl groups and blocking the NF-kB signaling pathway during methylation boost the anti-inflammatory impact. (d) Because of their decreased hydrophobicity and sterical hindrance, glycosides with lower lipophilicity have fewer anti-inflammatory effects [50, 61]. Moreover, a large replacement has been researched. Anti-inflammatory flavonoids have three taxonomic markers: the C-butyrolactone moiety, the 5-acetic acid/lactone group, and the C7C8 double bond. DM is a sophisticated hyperglycemic condition. The flavonoids that fight diabetes are widely recognized. By hydroxylation and planarity at position 7, several flavonoids can activate PPAR. Methoxylation enhances the antidiabetic efficacy of flavonoids on 3 T3-L1 adipogenesis, but hydroxylation has a detrimental effect [62, 63, 64]. SAR is the substitution of glycosylation, particularly glucosylation at position 3. C-3-Glu/detail. More proof is required on Gly’s mechanism of glucose regulation. Transition metals that promote radical hydroxyl formation in reduced forms through the Fenton reaction can be bound by flavonoids. Due to the resorcinol moiety of ring A, isoflavone has the highest antioxidant activity among studied flavonoids. These numbers indicate the structural elements of antioxidants. SAR is aided by the C2C3 double bond conjugated to a 4-carbonyl group in the flavonoid subclasses ring C. According to some authors, there is no clear connection between these moieties and antioxidant function when other structural conditions are satisfied. Despite cellular ROS inhibition and structural moieties being similar, certain flavonols have strong electron-donating action [32, 65, 66]. A C2C3 double bond conjugated to a 4-carbonyl group improves antioxidant activity when other structural requirements are satisfied. The dissociation constant of phenolic hydroxyl groups and the stability of phenoxy radicals in ring B are both impacted by the 4-carbonyl group’s propensity to create electron shifts through resonance effects. Ring C and A/B can be conjugated thanks to the electron coupling and molecular planarity provided by the unsaturated C2C3 double bond. Likewise, 5-OH creates hydrogen bonds. 4-Carbonyl delocalizes the ring B electron, increasing the antioxidant effect when combined with the C2C3 double bond or other electron-donating groups. The degree and location of hydroxylation affect how anti-oxidative flavonoids are. Stable flavonoid radicals are created when hydroxyl groups on the ring B absorb hydrogen and electrons. Two hydroxyl groups in ring B considerably increase antioxidant activity [67, 68, 69, 70]. The primarily responsible pharmacophore is the 3′, 4′-catechol group, which generates an ortho-semiquinone radical by electron delocalization and confers high activity through intra-molecular hydrogen bonding between catechol hydroxyl groups. Outside of the two hydroxyl groups on ring B, no one substitution makes sense. With 4′-OH, apigenin promotes erythroid differentiation. Higher inhibitory effects were seen from flavonoids with an ortho-dihydroxyl group in ring B than those with a 4′-hydroxylation. In comparison to ring A’s meta-dihydroxylation, ring B’s ortho-dihydroxyl group is more easily oxidized 5, 7-di-OH in ring A inhibits the activity of antioxidants. Strong 5- and 7-OH as 2, 4-substituted resorcinol substructure activities are highlighted by luteolin, quercetin, kaempferol, and apigenin [71, 72, 73]. There is proof that alterations in ring A’s positions 5 and 7 that donate electrons prevent the 3-hydroxylation of ring C. 3-OH inhibits antioxidant activity compared to luteolin and quercetin. When examining overall hydroxylation, both the electron transit within the resonance system and the total hydroxyl groups are considered. The flavonoid nucleus with more hydroxyl groups is held up in the hydrophobic cavity because hydrophilicity rises with the number of hydroxyl groups [18, 74, 75]. The antioxidant activity is decreased by altering the methylation of the free hydroxyl groups on ring B. Methoxyl flavonoid derivatives have higher antioxidant activity due to flavonoid-flavonoid interaction [76, 77]. Ring A’s several methoxylation substitutions should offset the catechol moiety of ring B. Antioxidant activity of flavonoid O- or C-glycosides has been investigated. Chemical tests have shown that c-glycosides are more effective antioxidants than O-glycosides. Compared to O-glycosides, C-glycosyl flavonoids exhibit about 100% higher radical scavenging action [53, 73, 78]. Another experiment shows that the antioxidant activity of c-glycosides is roughly 50%. The aforementioned C-glycoside studies still require in vivo information and in-depth analysis. Flavonoid glycosides develop in food as A- or C-ringed O-glycosides. The author speculates that the sugar moiety in position 3 could exacerbate steric hindrance or polarity. In addition, ring A’s antioxidant capabilities are enhanced by 6-glucosylation but diminished by 8-glucosylation [54, 79].

Advertisement

4. Pharmacokinetics and pharmacodynamics of flavonoids

4.1 Pharmacokinetic characteristics of flavonoids

There are several pharmacological functions for flavonoids. However, problems impede their approval as prescription drugs for usage in clinical settings and, to some extent, future research. Plant yield, bioavailability, and low solubility are problems. For 20 years, researchers have studied the metabolism and absorption of flavonoids. The distribution, metabolism, excretion, toxicity, and absorption of flavonoids are not optimal and differ between classes [80]. Flavonoids’ in vivo concentration is decreased by their low oral absorption. Low solubility, little oral absorption, and significant phase-I and phase-II hepatic enzyme metabolism. Chemical interactions between bacteria and small intestine epithelial cells affect flavonoid absorption due to intestinal metabolism. In small-intestine epithelial cells, flavonoids are glucuronidated, O-methylated, and sulfated, which reduces their bioactivity [81, 82, 83, 84]. In rats, only 20% of oral quercetin was absorbed; the rest was converted to CO2 and excreted in the feces. Within 48 hours, the body excretes absorbed quercetin [85]. The PK profile of flavonoids in plants is influenced by light, temperature, oxygen exposure, pH, and UV radiation. The synthesis of plant flavonoids can be altered by UV light. Flavonoids’ extraction and shelf-life are influenced by temperature. 45 to 60°C are ideal for extracting flavonoids from the tissue of the pericarp of litchi fruit [86, 87].

It is challenging to link a single flavonoid molecule to pharmacological action since flavonoids are available as a plant extract that includes several plant natural components. The PK profile of certain flavonoid changes, such as methylation and glycosylation, can be improved. In the next section, we shall talk about how methylation and glycosylation impact the pharmacokinetics and bioavailability of flavonoids. Derivative of Flavonoids with Better PK Properties [88, 89]. Their chemical structure governs the bioavailability and chemical stability of flavonoids [90, 91, 92].

Absorption, distribution, and metabolism are all impacted by changing the flavonoid skeleton. Methylation, which is the process of adding a methyl group to a substrate, controls cellular energy, epigenetics, and gene expression [93, 94]. Methylated flavonoids, which get a methyl group through the hydroxyl group, and C-methylated flavonoids, in which the methyl group is directly attached to the C atoms of the basic skeleton, are two different types of methylation flavonoids, depending on the location. OMT and CMT catalyze the methylation of O and C, respectively (CMT). SAM provides the methyl group through a biomolecular nuclear substitution (SN2) procedure. The first SAM-dependent methyltransferase to crystallize is catechol-OMT [95, 96]. Methylated flavonoids outperform their non-methylated analogs in terms of stability, potency, and bioavailability. Chemical characteristics, immunogenicity, and PK/PD are all influenced by glycosylation. To increase solubility, stability, and toxicity, flavonoids can be glycosylated to produce O- or C-linked glycosides. Glycosylated flavonoids can either be O-glycosides or C-glycosides, depending on the glycosidic connection to the basic flavonoid skeleton. While the sugar molecule in C-glycosides is connected to the basic flavonoid skeleton by its respective carbon atoms (generally at C-6 and C-8 positions), the sugar moiety in O-glycosides is coupled to the basic skeleton by a hydroxyl bond (commonly at 3-C and 7-C positions) [54, 89, 97]. Glycosylation often occurs in the subclasses of flavones and flavanols. Rutin and hesperidin are two flavonoids that do not dissolve well in water or alcohol. In non-polar solvents, non-glycosylated flavonoids (glycans) dissolve. Glycosylation increases the chemical stability of flavonoids in vitro. The stability of glycosylated flavonoids is increased, making them promising. A few glycosylated flavonoids, including luteolin-4′-O-glucoside and apigenin-7-glucoside, also inhibit BCRP [1, 73, 98]. Glucosylated were mostly used as examples to keep the effects of glycosylation easy to understand.

4.2 Pharmacodynamics of the polyphenolics

The major concern of several studies was the regulatory effects of polyphenolics on the human body to understand the Pharmacodynamics mechanism [99, 100, 101, 102, 103, 104, 105]. The current study investigates the effect of 14 polyphenolic compounds from the sponge, and the pharmacodynamics of the 14 compounds were listed and investigated according to ADME (Adsorption, Distribution, Metabolism, and Excretion). Not all bioavailable compounds are physiologically active. Furthermore, polyphenolic compounds’ pharmacodynamics are not linked to their physiological activity [84]. For that, many studies were established to discover how common polyphenolics’ pharmacodynamics, especially flavonoids, correlate with their inhibitory activities. The polyphenolic bioavailability profiles are classified into subgroups; for example, isoflavones consider the most absorbed type of flavonoids, followed by quercetin. The previous study indicates that the amounts of these compounds in plasma (after intestinal and hepatic metabolism) are very low, indicating their most flavonoids were eliminated rapidly [106]. Quercetin administered significantly inhibited platelet function and signaling in vivo studies. Physiological effects of flavonoids correlate with structural features of these compounds; there is also evidence to show that flavonoid dynamics in vivo are likely to be complex. Also, flavonoids can reduce the pathological effects of atherosclerosis, thrombosis, and CVD risk, while flavonoid bioavailability has been researched extensively [107, 108]. Quercetin is one of the most important plant molecules that has shown many pharmacological activities, such as being anticancer, antiviral, and treating allergic, metabolic, and inflammatory disorders, eye and cardiovascular diseases, and arthritis [109]. It has also shown a wide range of anticancer properties, and several reports indicate its efficacy as a cancer-preventing agent. Quercetin also has psychostimulant properties and has been documented to prevent platelet aggregation, capillary permeability, and lipid peroxidation and enhance mitochondrial biogenesis. Gallic acids mainly involved MAPK and NF-κB signaling pathways. It thus greatly reduced the inflammatory response by decreasing the release of inflammatory cytokines, chemokines, adhesion molecules, and cell infiltration [110, 111]. Thus the main Pharmacological activities and pharmacodynamics mechanism of Gallic acids were associated with anti-inflammatory effect. Pyrogallol is mostly used in pharmaceutical companies for medicinal purposes as a topical antipsoriatic. Pyrogallol showed both prooxidant and antioxidant activities. Additionally, Pyrogallol act as an antimicrobial activity by generating reactive oxygen species and is critical for its [112, 113]. Kaempferol has been confirmed to hurt cancerous cells of different types by triggering apoptosis, cell cycle arrest at the G2/M phase, downregulation of signaling pathways, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT). Kaempferol also induces the activation of cysteine proteases involved in apoptosis initiation, preventing the accumulation of reactive oxygen species (ROS) in cancer development [114]. coumarin has previously reported a wide range of pharmacological activities, such as anticancer, anti-inflammatory, antioxidants, anti-coagulant, and antibacterial [115]. Phenolic acids have two types: hydroxybenzoic acids, such as gallic, and hydroxycinnamic acids, such as ferulic, caffeic, and o-coumaric acid. o-Coumaric acid is a hydroxycinnamic acid with different biological activities, such as anti-lipidemic, antioxidant, and anti-carcinogenic [116]. Furthermore, the therapeutic effect of o-Coumaric acid in a human breast cancer cell line (MCF7) treatment through CYP isozymes mRNA levels was reported by Sen et al. [117], that studied the effect of o-Coumaric acid on drug-metabolizing CYP enzymes at the mRNA and protein expression levels was investigated in a human hepatocarcinoma cell line (HepG2 cells and that also confirmed in the current study as the extract exhibit cytotoxicity against HepG2 with 41.2 ug. Hydroxycinnamic acids (HCAs) (coumaric acid, ferulic acid, caffeic acid, and Chlorogenic acid) in general and Chlorogenic acid acids specifically are of high importance due to their beneficial pharmacological effects [118]. HCAs are mainly recognized as potent antioxidants and have a diverse therapeutic effect against various diseases, for example, cardiovascular and neurodegenerative diseases and cancer Anti-inflammatory and antimicrobial activities. Ferulic acid inhibited the synthesis of TNF-alpha and decreased, Ferulate, their antioxidant mechanism of action through maintaining redox regulation, suppressing NF-κB activation, and modulating the expression of NF-κB-induced, pro-inflammatory such as COX-2 and iNOS [50]. Also, the NF-kB suppression by Ferulate is mediated via suppressing the activation of NIK/IKK and MAPKs. Caffeic acid inhibits the activities of COX-1 and COX-2 enzymes and inhibits prostaglandin synthesis and COX. Caffeic acid also decreased several inflammatory cytokines such as interleukin (IL)-beta, IL-6, and tumor necrosis factor (TNF)-. Chlorogenic acid has an antidiabetic and anti-obesity role and significantly decreases the level of cholesterol and triacylglycerol [119]. The same effect was observed with ferulic acid as the mechanism of action of ferulic involved the suppression and/or down-regulation of lipid metabolism genes [120]. Additionally, chlorogenic acid significantly elevated beta-oxidation and lipase activity in diabetic animals. The catechol has an anti-inflammatory role through inhabiting the NF- κB, and TNF- α [50].

Advertisement

5. Role of flavonoids against different diseases

5.1 Role of flavonoids as antioxidants

Phenylalanine, tyrosine, and malonate are used by plants to produce flavonoids. The flavan nucleus consists of three rings (C6-C3-C6) with 15 carbon atoms each, referred to as A, B, and C. While individual compounds within a class fluctuate in A- and B-ring substitution, classes of flavonoids vary in the degree of oxidation and pattern of C-ring substitution. Interesting flavonoids include flavones, flavanones, isoflavones, flavonols, flavanonols, flavan-3-ols, and anthocyanidins. Flavonoids include biflavones, chalcones, aurones, and coumarins. Hydrolyzable tannins, proanthocyanidins (oligomers of flavan-3-ol), caffeates, and lignans are all examples of plant phenols. In vitro antioxidant activity. Gutteridge and Halliwell Antioxidants may upregulate or maintain antioxidant defenses, scavenge ROS, and reduce ROS formation by inhibiting enzymes or chelating trace elements involved in free radical creation [121, 122, 123, 124, 125, 126, 127, 128]. The aforementioned procedures are part of flavonoid activity. Some of their effects might result from interactions between enzymes and radical scavenging. The ROS-producing enzymes microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase, and NADH oxidase are all inhibited by flavonoids [129]. The majority of flavonoids are potent antioxidants, which may account for their health advantages. Flavonoids (Fl-OH) can reduce highly oxidizing free radicals with redox potentials of 2.13–1.0 V due to their low redox potentials (0.23 E7 0.75 V) [130]. To do this, they donate a hydrogen atom to the reaction Fl-OH + R• Fl-O• + RH (1), where R• stands for superoxide anion, peroxyl, alkoxyl, and hydroxyl radicals. When combined with another radical, the peroxyl radical (Fl-O•) may create a stable quinone. Free radicals are scavenged by flavonoid antioxidants [131]. Strong free radical scavengers called flavonoids have drawn interest as potential therapies for diseases caused by free radicals and oxidative stress [42]. By forming complexes with them, flavonoids stabilize oxidative free radicals. Studies on the structure of flavonoids and their capacity to absorb free radicals are comprehensive. According to Kumar and Pandey [42], the heterocyclic and B ring structure and substituents affected the radical-scavenging activity. Radical-scavenging ability is determined by the presence of a catechol group in ring B, which has enhanced electron-donating properties and serves as a radical target, and a 2,3-double bond conjugated with the 4-oxo group. The heterocyclic ring’s 3-hydroxyl group aids in radical scavenging, whereas the hydroxyl or methoxyl groups at positions 3,5, and 7 of rings A and C seem to be less important [132]. These structural characteristics increase the antioxidant power of flavonoids or the stability of the peroxyl radical. Both flavonols and flavones containing a catechol group in ring B are very active; flavonols, however, are more potent owing to the presence of the 3-hydroxyl group. Rutin’s capacity to scavenge free radicals is decreased by glycosylation. A hydroxyl group in ring B of myricetin increases its antioxidant capacity (pyrogallol). Ring B’s lone hydroxyl lowers activity [133]. Due to their weak antioxidant properties and 2,3-double bond with the 4-oxo group, flavanonols and flavanones are. The antioxidant effects of flavan monomers and flavanonols are comparable (catechin vs. taxifolin). The antioxidant potential is increased by the allocation of the 3-hydroxyl group or the incorporation of a pyrogallol group in ring B (as in epigallocatechin). If ring B includes catechol, then anthocyanidins and their glycosides (anthocyanins) are comparable to quercetin and catechin gallates (like in cyanidin). Kaempferol’s antioxidant activity is decreased when the 3-hydroxyl group from ring B in pelargonidin is removed (which differs from quercetin because it has a lone hydroxyl group in ring B) [18].

5.2 Role of flavonoids as neuroprotective against different neurodegeneration diseases

There is a long history of using flavonoids in medicine. They are a notable therapeutic class because of their diversity, dispersion, and seclusion. Flavonoids are essential for the development of new drugs since they may be used as natural products and are the basis for many treatments [19]. Medicinal plants, vegetables, fruits, and wines all contain flavonoids. Flavonoids can bind to body proteins, and alter hormones, enzymes, transporters, and DNA. They can also chelate heavy metals and scavenge free radicals [134]. Numerous pharmacological studies demonstrate their efficacy in treating microbiological infections, cancer, cardiovascular diseases, neurological disorders, and diabetic Mellitus (DM) [135]. A recent study suggests that consuming foods high in flavonoids may improve cognitive abilities in humans [136]. In both normal and transgenic preclinical animal models of Alzheimer’s disease (AD), certain flavonoids have been demonstrated to reduce the progression of the disease’s pathology [137]. Foods high in flavonoids, such as chocolate, green tea, and blueberries, have good health effects as a result of their interactions with certain cellular and molecular targets [31]. The expression of neuromodulatory and neuroprotective proteins as well as the quantity and quality of neurons are increased by the interaction of flavonoids with ERK and PI3-kinase/Akt receptors [138]. They may improve cognitive performance by boosting blood flow to the brain and brain neurogenesis thanks to their favorable effects on the cerebrovascular system. Recently, many additional advantages of flavonoids were discovered [139]. Flavonoids lessen symptoms similar to AD and related neurodegenerative diseases [140]. Inhibiting the major enzymes involved in the development of amyloid plaques, oxidative stress, and neuronal death brought on by neuro-inflammation are a few potential treatments [141]. By preserving neuronal number and quality in key areas of the brain, flavonoids guard against diseases that impair cognitive function.

5.3 Effectiveness of flavonoids as therapeutic approach in dementia and Alzheimer’s

In animal models, flavonoids reduce AD and cognitive dysfunctions, demonstrating their therapeutic utility in neurology. By focusing on important enzymes, flavonoids prevent the growth and accumulation of amyloid plaques (A). In an AD mouse model, anthocyanin-rich flavonoids in bilberry and black currant extracts lessen behavioral deficits and alter APP processing [138]. In a transgenic PSAPP animal model of cerebral amyloidosis, chronic therapy with tannic acid may enhance memory and behavior. Nobiletin improves A-mediated memory deficits and reduces A load in the hippocampi of transgenic rats. Grape polyphenols improve memory and lower soluble A oligomers in the brain tissues of Tg2576 rats. Citrus flavonoid luteolin decreases BACE1 activity and A peptide synthesis in APP transgenic neurons [139, 140]. Grape seed extracts rich in polyphenols and curcumin lessen the deposition of A in the brains of AD animals. Through the estrogen receptor, phosphoinositide 3-kinase, and Ak, Epigallocatechin gallate (EGCG) promotes non-amyloidogenic APP processing. Selective estrogen receptor modulators may be a treatment option since post-menopausal estrogen depletion is linked to an increased risk of AD. An alternative to estrogen-based therapy may be EGCG-mediated estrogen receptor modulation [141, 142]. For neuroprotective benefits, EGCG suppresses fibrillogenesis and A-rich amyloid fibrils. Unfolded polypeptides are prevented from converting directly into neurotoxic intermediates by contact with them. Big A fibrils may be split up into smaller proteins by EGCG, avoiding aggregation and negative effects. Cognitive deficits linked to neurodegeneration may benefit from myricetin’s in vitro anti-amyloid activity [143, 144, 145]. These findings imply that flavonoids may inhibit the A-forming enzyme BACE1 and hence prevent the fibrillization process that leads to the generation of A. The neuro-modulating capacity and therapeutic potential of flavonoids need more investigation. With 15 carbon atoms organized into three rings, two of which are aromatic and connected by an oxygenated heterocyclic ring, flavonoids are polyphenolic chemicals that are obtained from plants. They are consumed by people in fruits, nuts, seeds, flowers, tea leaves, herbs, spices, and red wine [30, 146]. Recent research links dietary flavonoids to reduced risk of dementia, relief from neuronal degenerative conditions, and improved memory and learning. Studies reveal that these compounds’ permeability across the blood-brain barrier (BBB) is influenced by their structural configuration, which promotes the investigation of their therapeutic potential. Several flavonoids, including naringenin, quercetin, hispidulin, hesperetin, naringenin, and EGCG, may cross the blood-brain barrier due to their lipophilicity or interactions with BBB efflux transporters, including the P-glycoprotein. Plasma and blood flavonoids provide evidence that they may enter the brain. Following the consumption of meals or beverages high in flavonoids, human plasma contains flavonoids (Figure 3) [147, 148, 149].

Figure 3.

Shows the protective effect of flavonoids against neurodegenerative disorders. Created with BioRender.

5.4 The protective and therapeutic role of flavonoids against diabetes

Anti-diabetic flavonoids include quercetin, naringin, hesperidin, epigallocachetin gallate, apigenin, myricetin, and anthocyanins. They are antioxidants and anti-inflammatory. Flavonoids have impacts on gene regulation. Cells treated with flavonoids reveal an obscure in vivo mechanism. By controlling the activity of the intestinal carbohydrate, flavanols improve glucose homeostasis [114, 150]. Numerous studies demonstrate that the anti-apoptotic properties of flavanols increase cellular replication, insulin secretion, and glucose synthesis. As a result, catechin-rich flavanol increased insulin release prompted by glucose. Increased flavonoid consumption has been linked in human studies to a decreased incidence of diabetes. In human clinical research, flavonoids seem to not affect diabetes Consumption of isoflavones was not linked to modifications in fasting insulin, glucose, or HbA1c. Individual isoflavones seldom ever have an impact on insulin sensitivity and glycemic control [151, 152, 153]. By influencing cell mass and function, Insulin sensitivity, and glucose absorption, anthocyanins may improve glucose homeostasis. Flavonoids and Type 2 Diabetes Flavonoids are plentiful, structurally unique chemicals. Over the last ten years, the anti-oxidant properties of flavonoids have aided diabetic patients in reducing oxidative stress. It has been established that diabetes is caused by oxidative stress. Supplementing with antioxidants has been utilized to lessen oxidative stress caused by diabetes. Flavonoids modulate transcription factors and proinflammatory mediators and have strong in-vitro and in-vivo antioxidant and anti-inflammatory actions. T2DM may be treated by pancreatic islet isolation and transplantation [154, 155, 156]. Pancreatic transplantation and flavonoids may provide new therapeutic insights. A surplus of flavonoid molecules is also necessary. Since most flavonoids impact how complicated carbs are digested and how quickly glucose is absorbed, appropriate doses of pure single flavonoids may improve glycemia. Flavonoids fight against diabetes. As previously mentioned, signaling pathways are potential targets for treatment because they play significant roles in the pathophysiology of oxidative stress-induced diabetes. By limiting the release of cytochrome-c from mitochondria into the cytosol and inhibiting caspase activity, EGCG exhibits anti-inflammatory actions in pancreatic cells. A good target for diabetes treatment is AMPK [69, 157, 158]. As a result of EGCG’s stimulation of the AMPK system, hepatic gluconeogenesis is decreased, fatty acid oxidation is improved, and mitochondrial biogenesis is controlled. In skeletal muscles, AMPK activation causes an increase in GLUT4, which facilitates glucose absorption. Hesperidin and naringin increase WAT GLUT4 while inhibiting liver GLUT2. The IRS-1-PI3-K-PKB/Akt insulin pathway was controlled by flavonoids from Oxytropis falcata Bunge chloroform extract, which decreased inflammatory cytokines by downregulating NF-B expression and increased GLUT4 expression. The flavonoid fisetin is found in foods including strawberries, apples, grapes, cucumbers, and others [159, 160, 161, 162]. Feinstein treatment decreased glycemia, HbA1c, NF-B p65 unit, interleukin-1 beta (IL-1), and serum nitric oxide (NO) due to improved plasma insulin antioxidant status, according to animal studies. By modifying NF-epigenetics, fisetin reduced HG-triggered cytokine levels in monocytes. A diabetic dietary supplement is B’s Fisetin. A flavonoid called morin may be found in wine, fruits, Prunus dulcis, and Psidium guajava [163, 164, 165]. Morin, which has anti-inflammatory properties and is useful in treating inflammatory illnesses, was demonstrated by Heeba et al. [166] to lower the cytokines IL-1, IL-6, and TNF in diabetic mice when administered at a dose of 30 mg/kg body weight. In rat liver and BRL3A cells, morin reduces fructose-induced alterations in hepatic SphK1/S1P signals and hepatic NF-B activation with IL-1b, IL-6, and TNF. The root and fruit of Scutellaria baicalensis Georgi contain a flavonoid called baicalein, which has potent antioxidant properties [166, 167]. Baicalein reduced food intake, body weight, and HbA1c levels in diabetic rats. Baicalein reduced iNOS and TGF-1 expression, inhibited NF-B, and enhanced renal tissue structure. AGEs, TNF, NF-B activation, and histopathological changes are all decreased by baicalein. Adipocytes, skeletal muscle, cardiomyocytes, and other organs all have GLUT-4. It is a glucose transporter that is resistant to insulin. Hormone/metabolic activity and tissue-specific response [168, 169, 170]. Insulin and muscle contraction cause it to move from its natural location in the cytoplasm to the plasma membrane, where it absorbs glucose. Insulin-resistant cells across the plasma membrane have changed intracellular GLUT-4. T2DM is a result of increased insulin resistance, inadequate insulin synthesis, and insulin resistance. According to a study, flavonoids and polyphenols increase GLUT-4 expression and glucose absorption. In adipocytes and skeletal muscle cells, quercetin and procyanidins enhance GLUT-4 mRNA. In mouse embryonic fibroblasts, flavonoids increase the expression of GLUT-4 mRNA. In skeletal muscle cells, epigallocatechin gallate (EGCG) elevates GLUT-4. Adipocyte and skeletal muscle cells treated with hesperidin and naringin had similar outcomes [171, 172, 173]. A flavonoid called Enicostema little increases the expression of the IRS-1, Akt-2, and GLUT-4 genes, which in turn stimulates the IRS-1/PI3K/Akt pathway. Clonal INS-1E cells and pancreatic human islets have shown protective benefits in response to kaempferol flavonoids. In human -cells and islets, 10 M kaempferol enhances viable cell concentration and inhibits apoptosis. By decreasing caspase-3 proteins and glucotoxicity and lipotoxic effects by reducing Akt and Bcl-2 anti-apoptotic activities, activating signaling pathways guards against apoptosis in cells. In chronic hyperglycemia or hyperlipidemia, −cell survival is improved by cAMP-mediated signaling [174, 175]. As previously noted, kaempferol is a special anti-diabetic chemical. Numerous studies have shown the relationship between flavonoids and glucose status. An effective treatment target for T2DM and insulin resistance is provided by flavonoids from banana flowers. Thus, IR/HepG2 cells consume more glucose when exposed to 10 mg/ml of enicostema littoral flavonoid. Hepatic insulin resistance may result from endoplasmic reticulum stress. In those with T2D, ER stress either increases insulin resistance or reduces insulin secretion [176, 177, 178]. Unfolded protein response (UPR) signaling is activated in diabetes by ER stress, which also increases inositol-requiring enzyme 1 (IRE1). Then, by converting dormant XPP-1 s into the active form, XBP1 activates IRE1. The IRE1-XBP1 pathway leads to insulin resistance by phosphorylating IRS-1. This method lowers insulin release from pancreatic islet cells. Insulin secretion is suppressed by pro-insulin mRNA degradation caused by overexpression of IRE1 [179, 180, 181]. The medicinal plant pomegranate has anti-diabetic effects. PGF has been used to treat diabetes for many years. Flavonoids, in particular, are anti-inflammatory and antioxidant polyphenols found in PGF extract. It reduces blood glucose, triglycerides, and insulin resistance, according to animal studies. By activating PPAR- 28, PGF has shown antihyperglycemic effects [182, 183].

Recently, Chinese researchers administered polyphenol extract PGF to diabetic rat models for 4 weeks at doses of 50 and 100 mg/kg. The results showed that increasing insulin-stimulated phosphorylation of IRS-1, Akt, and GSK-3 improved insulin sensitivity. The ER stress signals IRE1 and XBP-1 splicing are reduced by PGF. IRE1, XBPs, and CHOP were all decreased by PGF. PGF increases insulin resistance, which lowers glucose levels in T2DM rats, and this effect is likely mediated through Akt-GSK3 signaling and a decrease in ER stress. Unfolded protein response, mitochondrial oxidative stress, endoplasmic reticulum, and other signaling pathways all contribute to the development of T2DM. Flavonoids function as enzyme inhibitors, peroxide decomposers, hydrogen and electron donors, quenchers of singlet oxygen, radical scavengers, and metal chelators [184, 185]. These compounds regulate antioxidant enzymes, gene expressions, and protein expressions in oxidative stress-induced in vivo and in vitro models. Concentration, polarity, media, and other antioxidants all affect effectiveness. Diabetes has been associated with ER stress. Interest has grown in small molecules that inhibit ER stress and target UPR proteins [135, 186, 187, 188]. The bioavailability and bioefficacy of flavonoids may be increased by employing nanotechnologies, such as nanoparticulate systems. Flavonoids should not affect physiological processes that involve ROS. Significant antioxidant activity, ROS stability, receptor affinity, low toxicity, and free radical scavenging action are all desirable traits in flavonoids. It is important to think about the detection of ROS/RNS and the linked species and physiological levels (Figure 4).

Figure 4.

Showed the protective effect of flavonoids against diabetics disorders.

5.5 The antiviral role of flavonoids against various types of virus

Viruses have envelopes made of protein, RNA, and DNA. The metabolism and environment of the host are necessary for reproduction and survival. They take advantage of host cells to spread [189]. Flavonoids are phytochemicals that inhibit viruses in a variety of ways. They could prevent DNA replication, protein translation, processing of polypeptides, and viral attachment and entrance into cells. The invasion of healthy cells by viruses may be stopped by them. Flavonoids might bind to viral surface proteins and stop the virus from entering host cells. While other flavonoids obstruct viral assembly, packaging, and release, some of them hinder viral transcription and replication. Flavonoids modify the immune system and reduce viral load [190]. The backbone of flavones is 2-phenyl-1-benzopyran-4-one. Flavones include apigenin, baicalein, chrysin, luteolin, tangeritin, wogonin, and 6-hydroxy flavone. Since the 1990s, when it was shown that apigenin and acyclovir boosted antiviral activity against HSV-1 and HSV-2 in cell culture, flavones have been known to have antiviral properties [191]. Apigenin is effective against HSV-1, poliovirus type 2, HCV adenoviruses and hepatitis [192]. African swine fever virus (ASFV) production is decreased by 3 log due to apigenin’s suppression of viral protein synthesis [193, 194]. According to Shibata et al. [195], apigenin prevents HCV replication by lowering microRNA122 which is unique to the liver. The production of early and late HCMV proteins, as well as DNA, was reduced by baicalein, but not polymerase activity. Baicalein and its analogs may be utilized to treat Tamiflu-resistant viruses, according to novel baicalein analogs with bromine-substituted B-rings that have shown substantial activity against the H1N1 Tamiflu-resistant virus [196, 197]. In early-stage infected cells, baicalin decreased HIV-1 in vitro replication. The antiviral function of baicalin prevents the HIV-1 envelope protein from interacting with immune cells [192, 196, 197]. Against the dengue virus, baicalein and baicalin (DENV). By eliminating extracellular viral particles, they prevented the growth of DENV-2.Baicalein demonstrated a strong affinity for the DENV NS3/NS2B protein (−7.5 kcal/mol) and the NS5 protein (−8.6 kcal/mol), according to in silico studies [198, 199, 200, 201]. Baicalin may prevent CHIKV infection because of its high binding affinity (−9.8 kcal/mol) for the CHIKV nsP3 protein. Lutein prevents HIV-1 reactivation by blocking clade B- and C-Tat-driven LTR transactivation [202, 203, 204, 205] . By reducing the binding of the transcription factor Sp1, luteolin prevented the reactivation of the Epstein-Barr virus (EBV). discovered that luteolin interfered with viral RNA replication. In addition to these antiviral characteristics, luteolin or luteolin-rich fractions showed antiviral efectiveness against rotavirus, CHIKV, JEV, SARS-CoV, and other viruses [192, 206, 207]. The foundation of flavonol is 3-hydroxy-2-phenylchromen-4-one. Kaempferol and quercetin showed potential as antiviral agents. For instance, manager antiviral activity against the respiratory syncytial virus (RSV), HSV-1, and HSV-2 were improved by quercetin in dose-dependent ways in cell cultures [208, 209]. Flavans are defined by 2-phenyl-3,4-dihydro-2H-chromene. Flavan-3,4-diol, flavan-4, and flavan-3,3-ol. Epigallocatechin (EGC), catechin, epicatechin gallate, and epigallocatechin gallate (EGCG) are tea flavan-3-ols that have antiviral properties. Since Rawangkan et al. [210] showed that tea catechins, particularly EGCG, may bind to influenza virus haemagglutinin and prevent its adsorption to Madin-Darby canine kidney cells, the influenza virus has drawn the most attention as a potential target. Recent research demonstrates the antiviral potency of quercetin against several influenza virus strains. By interacting with influenza hemagglutinin, it prevents viral-cell fusion [193]. Quercetin inhibits transcription, protein synthesis, and viral endocytosis. Infected mice with airway cholinergic hyperresponsiveness and rhinovirus multiplication are both decreased by quercetin. HCMV is prevented by kaempferol. Coronavirus 3a channel blockers made of kaempferol derivatives with rhamnose residue are available. The influenza A virus is inhibited in vitro by kaempferol 3-O—L-rhamnopyranoside from Zanthoxylum piperitum. HIV-1 reverse transcriptase is inhibited by kaempferol and kaempferol-7-O-glucoside [106, 211, 212, 213, 214, 215]. The viral envelope may be damaged by EGCG, which prevents influenza virus and cellular membrane hemifusion [216, 217, 218, 219]. Studies have shown that tea catechins are anti- HIV. Due to its ability to combat HIV-1 at all stages of its existence, EGCG is the most potent tea catechin. It inhibits gp120 binding by forming a direct bond with CD4 molecules. CD4’s Trp69, Arg59, and Phe43 may interact with EGCG. Viral gp120 interacts with residues [192, 220]. By inhibiting the MEK/ERK1/2 and PI3-K/Akt signaling pathways, EGCG may shorten the EBV lytic cycle. Additionally, HCV cannot adhere to cells or replicate RNA when EGCG is present. The Zika virus (ZIKV) is inhibited by EGCG, according to a recent study: In vitro, the flavanone naringenin inhibits virus multiplication. The absence of anti-Sindbis virus activity in naringenin’s glycoside form, naringin, demonstrates that rutinose restricts the antiviral action of this compound. Long-term treatment lowers HCV by 1.4 logs and may inhibit intracellular HCV particle assembly [221, 222, 223, 224]. Treatment with naringenin after entrance reduced CHIKV in infected Vero cells. Bovine herpesvirus type 1 and New World arenavirus Pichinde replication are decreased by the isoflavonoid genistein, which inhibits tyrosine kinase. Resting CD4 T cells and macrophages are protected against HIV infection by genistein. Avian leucosis virus subgroup J, HSV-1, and HSV-2 reproduction were all suppressed by genistein (Figure 5) [192, 225].

Figure 5.

Shows the protective effect of flavonoids against viral infection. Created with BioRender.com.

References

  1. 1. Panche AN, Diwan AD, Chandra SR. Flavonoids: An overview. Journal of Nutritional Science. 2016;5:e47. DOI: 10.1017/jns.2016.41
  2. 2. Santos EL, Maia BHLS, Teixeira APFD. Flavonoids: Classification, biosynthesis and chemical ecology. In: Flavonoids - from Biosynthesis to Human Health. London, UK, London, UK: IntechOpen; 2017. DOI: 10.5772/67861
  3. 3. Mierziak J, Kostyn K, Kulma A. Flavonoids as important molecules of plant interactions with the environment. Molecules. 2014;19:16240-16265. DOI: 10.3390/molecules191016240 molecules ISSN 1420-3049. www.mdpi.com/journal/molecules
  4. 4. Nijveldt RJ, Nood EV, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Flavonoids: A review of probable mechanisms of action and potential applications. The American Journal of Clinical Nutrition. 2001;74(4):418-425. DOI: 10.1093/ajcn/74.4.418
  5. 5. Alseekh S, de Souza LP, Benina M, Fernie AR. The style and substance of plant flavonoid decoration; towards defining both structure and function. Phytochemistry. 2020;174:112347
  6. 6. Fujino N, Tenma N, Waki T, Ito K, Komatsuzaki Y, Sugiyama K, et al. Physical interactions among flavonoid enzymes in snapdragon and torenia reveal the diversity in the flavonoid metabolon organization of different plant species. The Plant Journal. 2018;94:372-392
  7. 7. Achnine L, Blancaflor EB, Rasmussen S, Dixon RA. Colocalization of L-phenylalanine ammonia-lyase and cinnamate 4-hydroxylase for metabolic channeling in phenylpropanoid biosynthesis. The Plant Cell. 2004;16(11):3098-3109. DOI: 10.1105/tpc.104.024406. Epub 2004 Oct 7
  8. 8. Nakayama T, Takahashi S, Waki T. Formation of flavonoid metabolons: Functional significance of protein-protein interactions and impact on flavonoid Chemodiversity. Frontiers in Plant Science. 2019;10:821. DOI: 10.3389/fpls.2019.00821
  9. 9. Ferreyra MLF, Rius SP, Casati P. Flavonoids: Biosynthesis, biological functions, and biotechnological applications. Frontiers in Plant Science. 2012;3:222. DOI: 10.3389/fpls.2012.00222
  10. 10. Taboada C, Millan R, Miguez I. Evaluation of marine algae Undaria pinnatifida and Porphyra purpurea as a food supplement: Composition, nutritional value and effect of intake on intestinal, hepatic and renal enzyme activities in rats. Journal of the Science of Food and Agriculture. 2013;93(8):1863-1868. DOI: 10.1002/jsfa.5981. Epub 2013 Apr 16
  11. 11. Kukil K, Lindberg P. Expression of phenylalanine ammonia lyases in Synechocystis sp. PCC 6803 and subsequent improvements of sustainable production of phenylpropanoids. Microbial Cell Factories. 2022;21(1):1-16. DOI: 10.1186/s12934-021-01735-8
  12. 12. Rudrapal M, Khan J, Dukhyil AAB, Alarousy RMII, Attah EI, Sharma T, et al. Chalcone scaffolds, bioprecursors of flavonoids: Chemistry, bioactivities, and pharmacokinetics. Molecules. 2021;26(23):7177. DOI: 10.3390/molecules26237177
  13. 13. Khare S, Dewangan R, Kumar A. Structure-Activity Relationship of Flavonoids. In: Chaurasia PK, Bharati SL, editors. The Chemistry Inside Spices and Herbs: Research and Development. Bentham Science Publisher; 2022. pp. 235-256. DOI: 10.2174/9789815039566122010011.
  14. 14. Dixon RA, Pasinetti GM. Flavonoids and isoflavonoids: From plant biology to agriculture and neuroscience. Plant Physiology. 2010;154(2):453-457. DOI: 10.1104/pp.110.161430
  15. 15. Brglez Mojzer E, Knez Hrnčič M, Škerget M, Knez Ž, Bren U. Polyphenols: Extraction methods, Antioxidative action, bioavailability and Anticarcinogenic effects. Molecules. 2016;21(7):901. DOI: 10.3390/molecules21070901
  16. 16. Shrestha S, Smid S, Zhang W. Phlorotannins: A review on biosynthesis, chemistry and bioactivity. Food Bioscience. 2020;27(14): R713-R715. DOI: 10.1016/j.fbio.2020.100832
  17. 17. Tziveleka LA, Tammam MA, Tzakou O, Roussis V, Ioannou E. Metabolites with antioxidant activity from marine macroalgae. Antioxidants (Basel). 2021;10(9):1431. DOI: 10.3390/antiox10091431
  18. 18. Spiegel M, Sroka Z, Andruniów T. Flavones’ and Flavonols’ antiradical structure–activity relationship—A quantum chemical study. Antioxidants. 2020;9:461. DOI: 10.3390/antiox9060461
  19. 19. Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG, et al. Important flavonoids and their role as a therapeutic agent. Molecules. 2020;25(22):5243. DOI: 10.3390/molecules25225243
  20. 20. Khoo HE, Azlan A, Tang ST, Lim SM. Anthocyanidins and anthocyanins: Colored pigments as food, pharmaceutical ingredients, and the potential health benefits. Food & Nutrition Research. 2017;61(1):1361779. DOI: 10.1080/16546628.2017.1361779
  21. 21. Salehi B, Quispe C, Chamkhi I, El Omari N, Balahbib A, Sharifi-Rad J, et al. Pharmacological properties of Chalcones: A review of preclinical including molecular mechanisms and clinical evidence. Frontiers in Pharmacology. 2021;11:592654. DOI: 10.3389/fphar.2020.592654
  22. 22. Wang L, Yang B, Du X, Yi C. Optimisation of supercritical fluid extraction of flavonoids from Pueraria lobata. Food Chemistry. 2008;108(2):737-741. DOI: 10.1016/j.foodchem.2007.11.031. Epub 2007 Nov 22
  23. 23. Jiang N, Doseff AI, Grotewold E. Flavones: From biosynthesis to health benefits. Plants. 2016;5:27. DOI: 10.3390/plants5020027
  24. 24. Reiter E, Gerster P, Jungbauer A. Red clover and soy isoflavones-an in vitro safety assessment. Gynecological Endocrinology: the Official Journal of the International Society of Gynecological Endocrinology. 2011;27:1037-1042. DOI: 10.3109/09513590.2011.588743
  25. 25. Makhaik MS, Shakya AK, Kale R. Dietary phytochemicals: As a natural source of antioxidants. In: Antioxidants - Benefits, Sources, Mechanisms of Action. London, UK, London, UK: IntechOpen; 2021. DOI: 10.5772/intechopen.99159
  26. 26. Khalid M, Saeed-ur-R QM, Huang D-f. Role of flavonoids in plant interactions with the environment and against human pathogens — A review. Journal of Integrative Agriculture. 2019;18:211-230. DOI: 10.1016/S2095-3119(19)62555-4
  27. 27. Samanta A, Das G, Das S. Roles of flavonoids in plants. International Journal of Pharmaceutical Science and Technology. 2011;6:12-35
  28. 28. Imamovic B, Trebse P, Omeragic E, Becic E, Pecet A, Dedic M. Stability and removal of benzophenone-type UV filters from water matrices by advanced oxidation processes. Molecules. 2022;27:1874. DOI: 10.3390/molecules27061874
  29. 29. Laoué J, Fernandez C, Ormeño E. Plant flavonoids in Mediterranean species: A focus on Flavonols as protective metabolites under climate stress. Plants. 2022;11:172. DOI: 10.3390/plants11020172
  30. 30. Amawi H, Ashby CR, Tiwari AK. Cancer chemoprevention through dietary flavonoids: what’s limiting? Chinese Journal of Cancer. 2017;36:50. DOI: 10.1186/s40880-017-0217-4
  31. 31. Kozłowska A, Szostak-Węgierek D. Flavonoids – Food sources, health benefits, and mechanisms involved. In: Mérillon JM, Ramawat K, editors. Bioactive Molecules in Food. Reference Series in Phytochemistry. Cham: Springer; 2018. DOI: 10.1007/978-3-319-54528-8_54-1
  32. 32. Rodriguez MC, Caleja C, Nuñez-Estevez B, Pereira E, Fraga-Corral M, Reis FS, et al. Flavonoids: A Group of Potential Food Additives with beneficial health effects. In: Lage MÁÁP, Otero P, editors. Natural Food Additives [Working Title]. London, UK, London, UK: IntechOpen; 2021. DOI: 10.5772/intechopen.101466
  33. 33. Alghazeer R, Howell N, El-Naili M, Awayn N. Anticancer and antioxidant activities of some algae from Western Libyan coast. Natural Science. 2018;10:232-246. DOI: 10.4236/ns.2018.107025
  34. 34. Bonfante P. Algae and fungi move from the past to the future. eLife. 2019;8:e49448. DOI: 10.7554/eLife.49448
  35. 35. Nascimento LB, Tattini M. Beyond Photoprotection: The multifarious roles of flavonoids in plant Terrestrialization. International Journal of Molecular Sciences. 2022;23(9):5284. DOI: 10.3390/ijms23095284
  36. 36. Goiris K, Muylaert K, Voorspoels S, Noten B, De Paepe D, Baart G, et al. Detection of flavonoids in microalgae from different evolutionary lineages. Journal of Phycology. 2014;50:483-492. DOI: 10.1111/jpy.12180
  37. 37. Bag S, Mondal A, Mondal SK MA, Banik A. Flavonoid mediated selective cross-talk between plants and beneficial soil microbiome. Phytochemistry Reviews. 2022;1-22. DOI: 10.1007/s11101-022-09806-3
  38. 38. Bais H, Walker T, Kennan A, Stermitz F, Vivanco J. Structure-dependent Phytotoxicity of Catechins and other flavonoids: Flavonoid conversions by cell-free protein extracts of Centaurea maculosa (spotted knapweed) roots. Journal of Agricultural and Food Chemistry. 2003;51:897-901. DOI: 10.1021/jf020978a
  39. 39. Cheng F, Zi C. Research Progress on the use of plant allelopathy in agriculture and the physiological and ecological mechanisms of allelopathy. Frontiers in Plant Science. 2015;6:1020. DOI: 10.3389/fpls.2015.01020
  40. 40. Drew MC, He CJ, Morgan PW. Programmed cell death and aerenchyma formation in roots. Trends in Plant Science. 2000;5(3):123-127. DOI: 10.1016/s1360-1385(00)01570-3
  41. 41. Kim TY, Leem E, Lee JM, Kim SR. Control of reactive oxygen species for the prevention of Parkinson's disease: The possible application of flavonoids. Antioxidants (Basel). 2020;9(7):583. DOI: 10.3390/antiox9070583
  42. 42. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: An overview. Scientific World Journal. 2013;162750. DOI: 10.1155/2013/162750
  43. 43. Cassedy A, Parle-McDermott A, O’Kennedy R. Virus detection: A review of the current and emerging molecular and immunological methods. Frontiers in Molecular Biosciences. 2021;8:637559. DOI: 10.3389/fmolb.2021.637559
  44. 44. Koirala N, Thuan N, Ghimire G, Thang D, Sohng J-K. Methylation of flavonoids: Chemical structures, bioactivities, progress and perspectives for biotechnological production. Enzyme and Microbial Technology. 2016;86:103-116. DOI: 10.1016/j.enzmictec.2016.02.003
  45. 45. Förster C, Handrick V, Ding Y, Nakamura Y, Paetz C, Schneider B, et al. Biosynthesis and antifungal activity of fungus-induced O-methylated flavonoids in maize. Plant Physiology. 2022;188(1):167-190. DOI: 10.1093/plphys/kiab496
  46. 46. Rupasinghe H, Vasantha P. Special issue “flavonoids and their disease prevention and treatment potential”: Recent advances and future perspectives. Molecules. 2020;25:4746. DOI: 10.3390/molecules25204746
  47. 47. Mondal S, Rahaman ST. Flavonoids: A vital resource in healthcare and medicine. Pharmacy & Pharmacology International Journal. 2020;8(2):91-104. DOI: 10.15406/ppij.2020.08.00285
  48. 48. Stan D, Enciu AM, Mateescu AL, Ion AC, Brezeanu AC, Stan D, et al. Natural compounds with antimicrobial and antiviral effect and Nanocarriers used for their transportation. Frontiers in Pharmacology. 2021;12:723233. DOI: 10.3389/fphar.2021.723233
  49. 49. Ninfali P, Antonelli A, Magnani M, Scarpa E. Antiviral properties of flavonoids and delivery strategies. Nutrients. 2020;12:2534. DOI: 10.3390/nu12092534
  50. 50. Wang L, Pan X, Jiang L, Chu Y, Gao S, Jiang X, et al. The biological activity mechanism of Chlorogenic acid and its applications in food industry: A review. Frontiers in Nutrition. 2022;9:943911. DOI: 10.3389/fnut.2022.943911
  51. 51. Conteh E, Okereke M, Turay FU, Bah AS, Muhsinah A. The need for a functional pharmaceutical industry in Sierra Leone: Lessons from the COVID-19 pandemic. Journal of Pharmacy Policy and Practice. 2022;15:46. DOI: 10.1186/s40545-022-00444-w
  52. 52. Ramešová Š, Sokolová R, Degano I, Bulíčková J, Žabka J, Gál M. On the stability of the bioactive flavonoids quercetin and luteolin under oxygen-free conditions. Analytical and Bioanalytical Chemistry. 2011;402:975-982. DOI: 10.1007/s00216-011-5504-3
  53. 53. Veiko AG, Lapshina EA, Zavodnik IB. Comparative analysis of molecular properties and reactions with oxidants for quercetin, catechin, and naringenin. Molecular and Cellular Biochemistry. 2021;476(12):4287-4299. DOI: 10.1007/s11010-021-04243-w
  54. 54. Xie L, Deng Z, Zhang J, Dong H, Wang W, Xing B, et al. Comparison of flavonoid O-glycoside, C-glycoside and their Aglycones on antioxidant capacity and metabolism during In vitro digestion and In vivo. Food. 2022;11(6):882. DOI: 10.3390/foods11060882
  55. 55. Conesa C, Yanez J, Vicente V, Alcaraz M, Benavente-García O, Castillo J, et al. Effects of several polyhydroxylated flavonoids on the growth of B16F10 melanoma and Melan-a melanocyte cell lines: Influence of the sequential oxidation state of the flavonoid skeleton. Melanoma Research. 2003;13:3-9. DOI: 10.1097/01.cmr.0000043160.28051.64
  56. 56. Kopustinskiene DM, Jakstas V, Savickas A, Bernatoniene J. Flavonoids as anticancer agents. Nutrients. 2020;12(2):457. DOI: 10.3390/nu12020457
  57. 57. Naksuriya O, Daowtak K, Tima S, Okonogi S, Mueller M, Toegel S, et al. Hydrolyzed flavonoids from Cyrtosperma johnstonii with superior antioxidant, Antiproliferative, and anti-inflammatory potential for cancer prevention. Molecules. 2022;27(10):3226. DOI: 10.3390/molecules27103226
  58. 58. Katalinić M, Rusak G, Barović J, Sinko G, Jelic D, Kovarik Z. Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase. European Journal of Medicinal Chemistry. 2009;45:186-192. DOI: 10.1016/j.ejmech.2009.09.041
  59. 59. Dabravolski SA, Sukhorukov VN, Kalmykov VA, Grechko AV, Shakhpazyan NK, Orekhov AN. The role of KLF2 in the regulation of atherosclerosis development and potential use of KLF2-targeted therapy. Biomedicine. 2022;10(2):254. DOI: 10.3390/biomedicines10020254
  60. 60. Martínez L, Pons Vila Z, Margalef M, Arola-Arnal A, Muguerza B. Regulation of vascular endothelial genes by dietary flavonoids: Structure-expression relationship studies and the role of the transcription factor KLF-2. The Journal of Nutritional Biochemistry. 2015;26:277-284. DOI: 10.1016/j.jnutbio.2014.11.003
  61. 61. Caporali S, De Stefano A, Calabrese C, Giovannelli A, Pieri M, Savini I, et al. Anti-inflammatory and active biological properties of the plant-derived bioactive compounds Luteolin and Luteolin 7-glucoside. Nutrients. 2022;14(6):1155. DOI: 10.3390/nu14061155
  62. 62. Harmon A, Harp J. Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis. American Journal of Physiology-Cell Physiology. 2001;280:C807-C813. DOI: 10.1152/ajpcell.2001.280.4.C807
  63. 63. Dinda B, Dinda M, Roy A, Dinda S. Dietary plant flavonoids in prevention of obesity and diabetes. Advances in Protein Chemistry and Structural Biology. 2020;120:159-235. DOI: 10.1016/bs.apcsb.2019.08.006
  64. 64. Al-Khayri JM, Sahana GR, Nagella P, Joseph BV, Alessa FM, Al-Mssallem MQ. Flavonoids as potential anti-Inflflammatory molecules: A review. Molecules. 2022;27:2901. DOI: 10.3390/molecules27092901
  65. 65. Górniak I, Bartoszewski R, Króliczewski J. Comprehensive review of antimicrobial activities of plant flavonoids. Phytochemistry Reviews. 2019;18:241-272. DOI: 10.1007/s11101-018-9591-z
  66. 66. Rolt A, Cox LS. Structural basis of the anti-ageing effects of polyphenolics: Mitigation of oxidative stress. BMC Chemistry. 2020;14:50. DOI: 10.1186/s13065-020-00696-0
  67. 67. Pannala A, Chan T, O'Brien P, Rice-Evans C. Flavonoid B-ring chemistry and antioxidant activity: Fast reaction kinetics. Biochemical and Biophysical Research Communications. 2001;282:1161-1168. DOI: 10.1006/bbrc.2001.4705
  68. 68. Musialik M, Kuzmicz R, Pawłowski T, Litwinienko G. Acidity of hydroxyl groups: An overlooked influence on antiradical properties of flavonoids. The Journal of Organic Chemistry. 2009;74:2699-2709. DOI: 10.1021/jo802716v
  69. 69. Al-Mamary MA, Moussa Z. Antioxidant activity: The presence and impact of hydroxyl groups in small molecules of natural and synthetic origin. In: Antioxidants - Benefits, Sources, Mechanisms of Action. London, UK, London, UK: IntechOpen; 2021. DOI: 10.5772/intechopen.95616
  70. 70. Platzer M, Kiese S, Tybussek T, Herfellner T, Schneider F, Schweiggert-Weisz U, et al. Radical scavenging mechanisms of phenolic compounds: A quantitative structure-property relationship (QSPR) study. Frontiers in Nutrition. 2022;9:882458. DOI: 10.3389/fnut.2022.882458
  71. 71. Sánchez-Marzo N, Pérez-Sánchez A, Ruiz-Torres V, Martínez-Tébar A, Castillo J, Herranz Lopez M, et al. Antioxidant and Photoprotective activity of Apigenin and its potassium salt derivative in human keratinocytes and absorption in Caco-2 cell monolayers. International Journal of Molecular Sciences. 2019;20:2148. DOI: 10.3390/ijms20092148
  72. 72. Barreca D, Bisignano C, Ginestra G, Bisignano G, Bellocco E, Leuzzi U, et al. Polymethoxylated, C- and O-glycosyl flavonoids in tangelo (C. reticulata × C. paradisi) juice and their influence on antioxidant properties. Food Chemistry. 2013;141(2):1481-1488. DOI: 10.1016/j.foodchem.2013.03.095
  73. 73. Ekalu A, Habila JD. Flavonoids: Isolation, characterization, and health benefits. Beni-Suef University Journal of Basic and Applied Sciences. 2020;9:45. DOI: 10.1186/s43088-020-00065-9
  74. 74. Xiao J, Chen T, Cao H, Chen L, Yang F. Molecular property-affinity relationship of flavanoids and flavonoids for HSA in vitro. Molecular Nutrition & Food Research. 2011;55:310-317. DOI: 10.1002/mnfr.201000208
  75. 75. Lewandowski W, Lewandowska H, Golonko A, Świderski G, Świsłocka R, Kalinowska M. Correlations between molecular structure and biological activity in “logical series” of dietary chromone derivatives. PLoS One. 2020;15(8):e0229477. DOI: 10.1371/journal.pone.0229477
  76. 76. Sarian MN, Ahmed QU, Mat So'ad SZ, Alhassan AM, Murugesu S, Perumal V, et al. Antioxidant and antidiabetic effects of flavonoids: A structure-activity relationship based study. BioMed Research International. 2017;2017(2017):8386065. DOI: 10.1155/2017/8386065. Epub 2017 Nov 28
  77. 77. Li C, Dai T, Chen J, Chen M, Liang R, Liu C, et al. Modification of flavonoids: Methods and influences on biological activities. Critical Reviews in Food Science and Nutrition. 2022;1-22. DOI: 10.1080/10408398.2022.2083572
  78. 78. Kaurinovic B, Vastag D. Flavonoids and phenolic acids as potential natural antioxidants. In: Antioxidants. London, UK, London, UK: IntechOpen; 2019. DOI: 10.5772/intechopen.83731
  79. 79. Xiao J, Capanoglu E, Jassbi AR, Miron A. Advance on the flavonoid C-glycosides and health benefits. Critical Reviews in Food Science and Nutrition. 2016;56(sup. 1):S29-S45. DOI: 10.1080/10408398.2015.1067595
  80. 80. Manach C, Donovan J. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radical Research. 2004;38:771-785
  81. 81. El-Kattan A, Varma M. Oral absorption, intestinal metabolism and human Oral bioavailability. In: Topics on Drug Metabolism. London, UK, London, UK: IntechOpen; 2012. DOI: 10.5772/31087
  82. 82. Cassidy A, Minihane A-M. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. The American Journal of Clinical Nutrition. 2017;105(1):10-22. DOI: 10.3945/ajcn.116.136051
  83. 83. Murota K, Nakamura Y, Uehara M. Flavonoid metabolism: The interaction of metabolites and gut microbiota. Bioscience, Biotechnology, and Biochemistry. 2018;82:4, 600-610. DOI: 10.1080/09168451.2018.1444467
  84. 84. Hussain MB, Hassan S, Waheed M, Javed A, Farooq MA, Tahir A. Bioavailability and metabolic pathway of phenolic compounds. In: Soto-Hernández M, García-Mateos R, Palma-Tenango M, editors. Plant Physiological Aspects of Phenolic Compounds. London, UK, London, UK: IntechOpen; 2019. DOI: 10.5772/intechopen.84745
  85. 85. Chen X, Yin O, Zuo Z, Chow M. Pharmacokinetics and modeling of quercetin and metabolites. Pharmaceutical Research. 2005;22:892-901. DOI: 10.1007/s11095-005-4584-1
  86. 86. Tiho T, Yao J, Brou Y, Adima A. Drying temperature effect on Total phenols and flavonoids content, and antioxidant activity of Borassus aethiopum Mart ripe fruits’ Pulp. Journal of Food Research. 2017;6:50. DOI: 10.5539/jfr.v6n2p50
  87. 87. Zeng Q, Xu Z, Dai M, Cao X, Xiong X, He S, et al. Effects of simulated digestion on the phenolic composition and antioxidant activity of different cultivars of lychee pericarp. BMC Chemistry. 2019;13:27. DOI: 10.1186/s13065-019-0544-4
  88. 88. Dias MC, Pinto DCGA, Silva AMS. Plant flavonoids: Chemical characteristics and biological activity. Molecules. 2021;26(17):5377. DOI: 10.3390/molecules26175377
  89. 89. Sajid M, Channakesavula CN, Stone SR, Kaur P. Synthetic biology towards improved flavonoid pharmacokinetics. Biomolecules. 2021;11(5):754. DOI: 10.3390/biom11050754
  90. 90. Viskupicova J, Ondrejovič M, Sturdik E. Bioavailability and metabolism of flavonoids. Journal of Food and Nutrition Research. 2008;47:151-162
  91. 91. Shreadah MA, Abdel Monein NM, El-Assar SA, Nabil-Adam A. Phytochemical and pharmacological screening of Sargassium vulgare from Suez Canal, Egypt. Food Science and Biotechnology. 2018a;27(4):963-979
  92. 92. Shreadah MA, Abou Ella HM, Abdel Monein NM, Yakout GA. Isolation, phylogenetic analysis of the microbial community associated with the Red Sea sponge Ircinia Echinata and biological evaluation of their secondary metabolites. Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC. 2018b;12(2):9064-9082
  93. 93. Shreadah MA, Abdel Monein NM, Abou Ella HM. Bacteria from marine sponges: A source of biologically active compounds. Biomedical Journal of Scientific & Technical Research. 2018c;10(5):1-20
  94. 94. Lopes AFC. Mitochondrial metabolism and DNA methylation: A review of the interaction between two genomes. Clinical Epigenetics. 2020;12:182. DOI: 10.1186/s13148-020-00976-5
  95. 95. Zou X, Liu Y-C, Hsu N-S, Huang C-J, Lyu S-Y, Chan H, et al. Structure and mechanism of a nonhaem-iron SAM-dependent C-methyltransferase and its engineering to a hydratase and an O-methyltransferase. Acta Crystallographica. Section D, Biological Crystallography. 2014;70:1549-1560. DOI: 10.1107/S1399004714005239
  96. 96. Lee S, Kang J, Kim J. Structural and biochemical characterization of Rv0187, an O-methyltransferase from mycobacterium tuberculosis. Scientific Reports. 2019;9:8059. DOI: 10.1038/s41598-019-44592-7
  97. 97. Yang B, Liu H, Jiali Y, Gupta V, Jiang Y. New insights on bioactivities and biosynthesis of flavonoid glycosides. Trends in Food Science & Technology. 2018;141(2):1481-1488. DOI: 10.1016/j.tifs.2018.07.006
  98. 98. Slámová K, Kapešová J, Valentová K. “sweet flavonoids”: Glycosidase-catalyzed modifications. International Journal of Molecular Sciences. 2018;19(7):2126. DOI: 10.3390/ijms19072126
  99. 99. Stromsnes K, Lagzdina R, Olaso-Gonzalez G, Gimeno-Mallench L, Gambini J. Pharmacological properties of polyphenols: Bioavailability, mechanisms of action, and biological effects in In vitro studies, animal models, and humans. Biomedicine. 2021;9(8):1074. DOI: 10.3390/biomedicines9081074
  100. 100. Fabbrini M, D’Amico F, Barone M, Conti G, Mengoli M, Brigidi P, et al. Polyphenol and tannin nutraceuticals and their metabolites: How the human gut microbiota influences their properties. Biomolecules. 2022;12(7):875. DOI: 10.3390/biom12070875
  101. 101. Nabil-Adam A, Shreadah MA, Abdel Monein NM, El-Assar SA. Pesudomance sp. bacteria associated with marine sponge as a promising and sustainable source of bioactive molecules. Current Pharmaceutical Biotechnology. 2019;20(11):964-984. DOI: 10.2174/138920102066619061 9092502
  102. 102. Nabil-Adam A, Shreadah MA, Abd El-Moneam NM, El-Assar SA. Various In vitro bioactivities of secondary metabolites isolated from the sponge Hyrtios aff. Erectus from the Red Sea coast of Egypt. Turkish Journal of Pharmaceutical Sciences. 2020a;17(2):127-135. DOI: 10.4274/tjps.galenos.2018.72677
  103. 103. Nabil-Adam A, Shreadah MA, Abd El-Moneam NM, El-Assar SA. Marine algae of the genus Gracilaria as multi products source for different biotechnological and medical applications. Recent Patents on Biotechnology. 2020b;14(3):203-228. DOI: 10.2174/1872208314666200 121144816
  104. 104. Nabil-Adam A, Shreadah MA. Red algae natural products for prevention of lipopolysaccharides (LPS)- induced liver and kidney inflammation and injuries. Bioscience Reports. 2021a;41(1):BSR20202022. DOI: 10.1042/BSR20202022
  105. 105. Nabil-Adam A, Shreadah MA. Ameliorative role of Ulva extract against heavy metal mixture—Induced cardiovascular through oxidative/antioxidant pathways and inflammatory biomarkers. Environmental Science and Pollution Research International. 2021b;28(21):27006-27024. DOI: 10.1007/s11356-020-11994-4. Epub 2021 Jan 26
  106. 106. Nabil-Adam A, Shreadah MA. Anti-inflammatory, antioxidant, lung and liver protective activity of Galaxaura oblongata as antagonistic efficacy against LPS using hematological parameters and immunohistochemistry as biomarkers. Cardiovascular & Hematological Agents in Medicinal Chemistry. 2022;20(2):148-165. DOI: 10.2174/1871525719666210112154800. Epub ahead of print
  107. 107. Ciumărnean L, Milaciu MV, Runcan O, Vesa ȘC, Răchișan AL, Negrean V, et al. The effects of flavonoids in cardiovascular diseases. Molecules. 2020;25(18):4320. DOI: 10.3390/molecules25184320
  108. 108. Grijalva-Guiza RE, Jiménez-Garduño AM, Hernández LR. Potential benefits of flavonoids on the progression of atherosclerosis by their effect on vascular smooth muscle excitability. Molecules. 2021;26(12):3557. DOI: 10.3390/molecules26123557
  109. 109. Mohd Zaid NA, Sekar M, Bonam SR, Gan SH, Lum PT, Begum MY, et al. Promising natural products in new drug design, development, and therapy for skin disorders: An overview of scientific evidence and understanding their mechanism of action. Drug Design, Development and Therapy. 2022;16:23-66. DOI: 10.2147/DDDT.S326332
  110. 110. Batiha GE, Beshbishy AM, Ikram M, Mulla ZS, El-Hack MEA, Taha AE, et al. The pharmacological activity, biochemical properties, and pharmacokinetics of the major natural polyphenolic flavonoid: Quercetin. Food. 2020;9(3):374. DOI: 10.3390/foods9030374
  111. 111. El-Darier SM, Rashed SA, Fayez A, Hassanein SS, Sharaby MR, Tawfik NM, et al. Medicinal plant-derived compounds as potential phytotherapy for COVID-19: Future perspectives. Journal of Pharmacognosy and Phytotherapy. 2021;13(3):68-81
  112. 112. Mendes V, Vilaça R, Freitas V, Ferreira P, Mateus N, Costa V. Effect of Myricetin, Pyrogallol, and Phloroglucinol on yeast resistance to oxidative stress. Oxidative Medicine and Cellular Longevity. 2015;2015:1-10. DOI: 10.1155/2015/782504
  113. 113. Gil JV, Esteban-Muñoz A, Fernández-Espinar MT. Changes in the polyphenolic profile and antioxidant activity of wheat bread after incorporating quinoa flour. Antioxidants. 2022;11:33. DOI: 10.3390/antiox11010033
  114. 114. Imran M, Salehi B, Sharifi-Rad J, Aslam Gondal T, Saeed F, Imran A, et al. Kaempferol: A key emphasis to its anticancer potential. Molecules. 2019;24(12):2277. DOI: 10.3390/molecules24122277
  115. 115. Sharifi-Rad J, Cruz-Martins N, López-Jornet P, Lopez EP, Harun N, Yeskaliyeva B, et al. Natural Coumarins: Exploring the pharmacological complexity and underlying molecular mechanisms. Oxidative Medicine and Cellular Longevity. 2021;2021:6492346. DOI: 10.1155/2021/6492346
  116. 116. Kiokias S, Proestos C, Oreopoulou V. Phenolic acids of plant origin-a review on their antioxidant activity In vitro (O/W emulsion systems) along with their in vivo health biochemical properties. Food. 2020;9(4):534. DOI: 10.3390/foods9040534
  117. 117. Sen A, Atmaca P, Terzioglu G, Arslan S. Anticarcinogenic effect and carcinogenic potential of the dietary phenolic acid: o-coumaric acid. Natural Product Communications. 2013;8(9):1269-1274
  118. 118. Sova M, Saso L. Natural sources, pharmacokinetics, biological activities and health benefits of Hydroxycinnamic acids and their metabolites. Nutrients. 2020;12(8):2190. DOI: 10.3390/nu12082190
  119. 119. Taïlé J, Bringart M, Planesse C, Patché J, Rondeau P, Veeren B, et al. Antioxidant polyphenols of Antirhea borbonica medicinal plant and Caffeic acid reduce cerebrovascular, inflammatory and metabolic disorders aggravated by high-fat diet-induced obesity in a mouse model of stroke. Antioxidants (Basel). 2022;11(5):858. DOI: 10.3390/antiox11050858
  120. 120. Xu T, Song Q, Zhou L, Yang W, Wu X, Qian Q, et al. Ferulic acid alleviates lipotoxicity-induced hepatocellular death through the SIRT1-regulated autophagy pathway and independently of AMPK and Akt in AML-12 hepatocytes. Nutrition & Metabolism (London). 2021;18(1):13. DOI: 10.1186/s12986-021-00540-9
  121. 121. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: Harms and benefits for human health. Oxidative Medicine and Cellular Longevity. 2017;2017:8416763. DOI: 10.1155/2017/8416763. Epub 2017 Jul 27
  122. 122. Aboul-Ela HM, Shreadah MA, Abdel-Monem NM, Yakout GA, Van Soest RWM. Isolation, cytotoxic activity and phylogenetic analysis of bacillus sp. bacteria associated with the red sea sponge Amphimedonochracea. Advances in Bioscience and Biotechnology. 2012;3(7):815-823
  123. 123. Abdel-Monem N, Abdel-Azeem AM, El Ashry ESH, Ghareeb DA, Adam AN. Assessment of secondary metabolites from marine-derived fungi as antioxidant. Journal of Medicinal Chemistry. 2013;3(3):60-73
  124. 124. Abd El Moneam NM, Shreadah MA, Assar SA, Nabil-Adam A. Protective role of antioxidants capacity of Hyrtios aff. Erectus sponge extract against mixture of persistent organic pollutants (POPs)-induced hepatic toxicity in mice liver: Biomarkers and ultrastructural study. Environmental Science and Pollution Research. 2017;24(27):22061-22072
  125. 125. Abd El Moneam NM, Yacout GA, Aboul-Ela HM, Shreadah MA. Hepatoprotective activity of chitosan Nanocarriers loaded with the ethyl acetate extract of Astenotrophomonas sp. bacteria associated with the Red Sea sponge Amphimedon Ochracea In CCl4 induced hepatotoxicity in rats. Advances in Bioscience and Biotechnology (ABB). 2017b;8(1):27-50
  126. 126. Shreadah MA, Abdel Monein NM, El-Assar SA, Nabil-Adam A. The ameliorative role of a marine sponge extract against mixture of persistent organic pollutants induced changes in hematological parameters in mice. Expert Opinion on Environment Biology. 2017;6:2. DOI: 10.4172/2325-9655.1000143
  127. 127. Shreadah MA, Abou Ella M, Abdel Monein NM, Yakout GA. Sponge associated bacteria- isolation, phylogentic Analysiand Biothnological potential. Biomedical Journal of Scientific Research, Biomedical Research Network+, LLC. 2019;15(2):11269-11285. DOI: 10.26717/BJSTR. 2019.15.002692
  128. 128. Shreadah MA, Abd El-Moneam NM, El-Assar SA, Nabil-Adam A. Metabolomics and pharmacological screening of aspergillus versicolor isolated from Hyrtios erectus Red Sea sponge; Egypt. Current Bioactive Compounds. 2020;16(1083):1573407215666191111122711
  129. 129. Tan BL, Norhaizan ME, Liew WP, Sulaiman RH. Antioxidant and oxidative stress: A mutual interplay in age-related diseases. Frontiers in Pharmacology. 2018;9:1162. DOI: 10.3389/fphar.2018.01162
  130. 130. Meng X, Munishkina LA, Fink AL, Uversky VN. Effects of various flavonoids on the α-Synuclein fibrillation process. Parkinsons Disease. 2010;2010:650794. DOI: 10.4061/2010/650794
  131. 131. Lalhminghlui K, Jagetia GC. Evaluation of the free-radical scavenging and antioxidant activities of Chilauni, Schima wallichii Korth in vitro. Future Science OA. 2018;4(2):FSO272. DOI: 10.4155/fsoa-2017-0086
  132. 132. Kurek-Górecka A, Rzepecka-Stojko A, Górecki M, Stojko J, Sosada M, Swierczek-Zieba G. Structure and antioxidant activity of polyphenols derived from propolis. Molecules. 2013;19(1):78-101. DOI: 10.3390/molecules19010078
  133. 133. Chobot V, Hadacek F, Bachmann G, Weckwerth W, Kubicova L. Pro- and antioxidant activity of three selected Flavan type flavonoids: Catechin, Eriodictyol and Taxifolin. International Journal of Molecular Sciences. 2016;17:1986. DOI: 10.3390/ijms17121986
  134. 134. Cherrak SA, Mokhtari-Soulimane N, Berroukeche F, Bensenane B, Cherbonnel A, Merzouk H, et al. In vitro antioxidant versus metal Ion chelating properties of flavonoids: A structure-activity investigation. PLoS One. 2016;11(10):e0165575. DOI: 10.1371/journal.pone.0165575
  135. 135. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. International Journal of Molecular Sciences. 2020;21(17):6275. DOI: 10.3390/ijms21176275
  136. 136. Lamport D. The effects of flavonoid and other polyphenol consumption on cognitive function: A systematic review of human experimental and epidemiological studies. Nutrtion and Aging. 2012;1:5-25. DOI: 10.3233/NUA-2012-0002
  137. 137. Hole KL, Williams RJ. Flavonoids as an intervention for Alzheimer's disease: Progress and hurdles towards defining a mechanism of action. Brain Plasticity. 2021;6(2):167-192. DOI: 10.3233/BPL-200098
  138. 138. Ayaz M, Sadiq A, Junaid M, Ullah F, Ovais M, Ullah I, et al. Flavonoids as prospective Neuroprotectants and their therapeutic propensity in aging associated neurological disorders. Frontiers in Aging Neuroscience. 2019;11:155. DOI: 10.3389/fnagi.2019.00155
  139. 139. Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, et al. Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease. The Journal of Pharmacology and Experimental Therapeutics. 2008;326(3):739-744. DOI: 10.1124/jpet.108.140293. Epub 2008 Jun 10
  140. 140. Uddin MS, Kabir MT, Niaz K, Jeandet P, Clément C, Mathew B, et al. Molecular insight into the therapeutic promise of flavonoids against Alzheimer's disease. Molecules. 2020;25(6):1267. DOI: 10.3390/molecules25061267
  141. 141. Wang Y-J, Thomas P, Zhong J-H, Bi F-F, Kosaraju S, Pollard A, et al. Consumption of grape seed extract prevents amyloid-β deposition and attenuates inflammation in brain of an Alzheimer’s disease mouse. Neurotoxicity Research. 2009;15:3-14. DOI: 10.1007/s12640-009-9000-x
  142. 142. Frandsen J, Narayanasamy P. Flavonoid enhances the glyoxalase pathway in cerebellar neurons to retain cellular functions. Scientific Reports. 2017;7:5126. DOI: 10.1038/s41598-017-05287-z
  143. 143. Fernandes L, Cardim-Pires TR, Foguel D, Palhano FL. Green tea polyphenol epigallocatechin-Gallate in amyloid aggregation and neurodegenerative diseases. Frontiers in Neuroscience. 2021;15:718188. DOI: 10.3389/fnins.2021.718188
  144. 144. Ehrnhoefer D, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nature Structural & Molecular Biology. 2008;15:558-566. DOI: 10.1038/nsmb.1437
  145. 145. Pluta R, Januszewski S, Czuczwar SJ. Myricetin as a promising molecule for the treatment of post-ischemic brain neurodegeneration. Nutrients. 2021;13(2):342. DOI: 10.3390/nu13020342
  146. 146. Chandrasekara A, Shahidi F. Herbal beverages: Bioactive compounds and their role in disease risk reduction-a review. Journal of Traditional and Complementary Medicine. 2018;8(4):451-458. DOI: 10.1016/j.jtcme.2017.08.006
  147. 147. Mozaffarian D, Wu JHY. Flavonoids, dairy foods, and cardiovascular and metabolic health. A review of emerging biologic pathways. Circulation Research. 2018;122:369-384. DOI: 10.1161/CIRCRESAHA.117.309008
  148. 148. Khan A, Ikram M, Hahm JR, Kim M. Antioxidant and anti-inflammatory effects of citrus flavonoid Hesperetin: Special focus on neurological disorders. Antioxidants. 2020;9(7):609. DOI: 10.3390/antiox9070609
  149. 149. Williams-Medina A, Deblock M, Janigro D. In vitro models of the blood–brain barrier: Tools in translational medicine. Frontiers in Medical Technology. 2021;2:623950. DOI: 10.3389/fmedt.2020.623950
  150. 150. Pinent M, Castell-Auví A, Baiges I, Montagut Pino G, Arola L, Ardèvol A. Bioactivity of flavonoids on insulin-secreting cells. Comprehensive Reviews in Food Science and Food Safety. 2008;7:299-308. DOI: 10.1111/j.1541-4337.2008.00048.x
  151. 151. Kuryłowicz A. The role of Isoflavones in type 2 diabetes prevention and treatment-a narrative review. International Journal of Molecular Sciences. 2022;22(1):218. DOI: 10.3390/ijms22010218
  152. 152. Bondonno NP, Dalgaard F, Murray K, Davey RJ, Bondonno CP, Cassidy A, et al. Higher habitual flavonoid intakes are associated with a lower incidence of diabetes. The Journal of Nutrition. 2021;151(11):3533-3542. DOI: 10.1093/jn/nxab269
  153. 153. Barańska A, Błaszczuk A, Polz-Dacewicz M, Kanadys W, Malm M, Janiszewska M, et al. Effects of soy Isoflavones on glycemic control and lipid profile in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Nutrients. 2021;13(6):1886. DOI: 10.3390/nu13061886
  154. 154. Oyenihi O, Nicole L, Oguntibeju O. Oxidative Stress and Diabetic Complications: The Role of Antioxidant Vitamins and Flavonoids. 2014;923-931. DOI: 10.5772/57282
  155. 155. Ribeiro D, Freitas M, Lima J, Fernandes E. Proinflammatory pathways: The modulation by flavonoids. Medicinal research reviews. 2015;35(5):877-936. DOI: 10.1002/med.21347
  156. 156. Pallauf K, Duckstein N, Hasler M, Klotz LO, Rimbach G. Flavonoids as putative inducers of the transcription factors Nrf2, FoxO, and PPARγ. Oxidative Medicine and Cellular Longevity. 2017;2017:4397340. DOI: 10.1155/2017/4397340. Epub 2017 Jul 6
  157. 157. Pournourmohammadi S, Grimaldi M, Stridh M, Lavallard V, Waagepetersen H, Wollheim C, et al. Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state? The International Journal of Biochemistry & Cell Biology. 2017;88:220-225. DOI: 10.1016/j.biocel.2017.01.012
  158. 158. Sok Yen F, Shu Qin C, Tan Shi Xuan S, Jia Ying P, Yi Le H, Darmarajan T, et al. Hypoglycemic effects of plant flavonoids: A review. Evidence-based Complementary and Alternative Medicine. 2021;2021:2057333. DOI: 10.1155/2021/2057333
  159. 159. Viollet B, Guigas B, Leclerc J, Hébrard S, Lantier Goëlzer L, Mounier R, et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives. Acta physiologica (Oxford, England). 2009;196:81-98. DOI: 10.1111/j.1748-1716.2009.01970.x
  160. 160. Yang L, Wang Z, Jiang L, Sun W, Fan Q, Liu T. Total flavonoids extracted from Oxytropis falcata Bunge improve insulin resistance through regulation on the IKKβ/NF-κB inflammatory pathway. Evidence-based Complementary and Alternative Medicine. 2017;2017:2405124. DOI: 10.1155/2017/2405124. Epub 2017 Mar 26
  161. 161. Yang L, Wang Z, Jiang L, Sun W, Fan Q, Liu T. Total flavonoids extracted from Oxytropis falcata Bunge improve insulin resistance through regulation on the IKK ?/NF-? B inflammatory pathway. Evidence-Based Complementary and Alternative Medicine. 2017b;1-6. DOI: 10.1155/2017/2405124
  162. 162. Kerimi A, Gauer JS, Crabbe S, Cheah JW, Lau J, Walsh R, et al. Effect of the flavonoid hesperidin on glucose and fructose transport, sucrase activity and glycaemic response to orange juice in a crossover trial on healthy volunteers. British Journal of Nutrition. 2019;121:782-792
  163. 163. Kapoor R, Kakkar P. Protective role of morin, a flavonoid, against high glucose induced oxidative stress mediated apoptosis in primary rat hepatocytes. PLoS One. 2012;7(8):e41663. DOI: 10.1371/journal.pone.0041663. Epub 2012 Aug 10
  164. 164. Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: A cellular mechanism review. Nutrition & Metabolism (London). 2015;12:60. DOI: 10.1186/s12986-015-0057-7
  165. 165. Reis MB, Elias-Oliveira J, Pastore MR, Ramos SG, Gardinassi LG, Faccioli LH. Interleukin-1 receptor-induced nitric oxide production in the pancreas controls hyperglycemia caused by scorpion envenomation. Toxins (Basel). 2020;12(3):163. DOI: 10.3390/toxins12030163
  166. 166. Heeba GH, Rabie EM, Abuzeid MM, Bekhit AA, Khalifa MM. Morin alleviates fructose-induced metabolic syndrome in rats via ameliorating oxidative stress, inflammatory and fibrotic markers. Korean Journal of Physiology Pharmacology. 2021;25(3):177-187. DOI: 10.4196/kjpp.2021.25.3.177
  167. 167. Lamer-Zarawska E, Leszek J, Parvathaneni K, Yendluri B, Błach-Olszewska Z, Aliev G. Flavones from root of Scutellaria Baicalensis Georgi: Drugs of the future in neurodegeneration? CNS & Neurological Disorders Drug Targets. 2011;10:184-191. DOI: 10.2174/187152711794480384
  168. 168. Wilcox G. Insulin and insulin resistance. Clinical Biochemist Reviews. 2005;26(2):19-39
  169. 169. Vergun O, Svydenko LV, Grygorieva O, Shymanska O, Rakhmetov D, Brindza J, et al. Antioxidant capacity of plant raw material of Scutellaria baicalensis Georgi. Potravinarstvo Slovak Journal of Food Sciences. 2019;13(1)
  170. 170. Kubatka P, Mazurakova A, Samec M, Koklesova L, Zhai K, AL-Ishaq R, et al. Flavonoids against non-physiologic inflammation attributed to cancer initiation, development, and progression—3PM pathways. EPMA Journal. 2021;12:559-587. DOI: 10.1007/s13167-021-00257-y
  171. 171. Casanova E, Salvadó J, Crescenti A, Gibert-Ramos A. Epigallocatechin Gallate modulates muscle homeostasis in type 2 diabetes and obesity by targeting energetic and redox pathways: A narrative review. International Journal of Molecular Sciences. 2019;20(3):532. DOI: 10.3390/ijms20030532
  172. 172. Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Frontiers in Immunology. 2020;11:1582. DOI: 10.3389/fimmu.2020.01582
  173. 173. Casado-Díaz A, Rodríguez-Ramos Á, Torrecillas-Baena B, Dorado G, Quesada-Gómez JM, Gálvez-Moreno MÁ. Flavonoid Phloretin inhibits Adipogenesis and increases OPG expression in adipocytes derived from human bone-marrow mesenchymal stromal-cells. Nutrients. 2021;13(11):4185. DOI: 10.3390/nu13114185
  174. 174. Ansari P, Choudhury ST, Seidel V, Rahman AB, Aziz MA, Richi AE, et al. Therapeutic potential of quercetin in the Management of Type-2 diabetes mellitus. Life (Basel). 2022;12(8):1146. DOI: 10.3390/life12081146
  175. 175. Herat LY, Matthews J, Azzam O, Schlaich MP, Matthews VB. Targeting features of the metabolic syndrome through sympatholytic effects of SGLT2 inhibition. Current Hypertension Reports. 2022;24(3):67-74. DOI: 10.1007/s11906-022-01170-z. Epub 2022 Mar 2
  176. 176. Alkhalidy H, Moore W, Wang Y, Luo J, McMillan RP, Zhen W, et al. The flavonoid Kaempferol ameliorates Streptozotocin-induced diabetes by suppressing hepatic glucose production. Molecules. 2018;23(9):2338. DOI: 10.3390/molecules23092338
  177. 177. Salehi B, Machin L, Monzote L, Sharifi-Rad J, Ezzat SM, Salem MA, et al. Therapeutic potential of quercetin: New insights and perspectives for human health. ACS Omega. 2020;5(20):11849-11872. DOI: 10.1021/acsomega.0c01818
  178. 178. Alaaeldin R, Abdel-Rahman IAM, Hassan HA, Youssef N, Allam AE, Abdelwahab SF, et al. Carpachromene ameliorates insulin resistance in HepG2 cells via modulating IR/IRS1/PI3k/Akt/GSK3/FoxO1 pathway. Molecules. 2021;26(24):7629. DOI: 10.3390/molecules26247629
  179. 179. Lee K, Chan JY, Liang C, Ip CK, Shi YC, Herzog H, et al. XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice. Diabetologia. 2022;65(6):984-996. DOI: 10.1007/s00125-022-05669-7. Epub 2022 Mar 22
  180. 180. Madhavan A, Kok BP, Rius B, Grandjean JMD, Alabi A, Albert V, et al. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nature Communications. 2022;13:608. DOI: 10.1038/s41467-022-28271-2
  181. 181. Huang S, Xing Y, Liu Y. Emerging roles for the ER stress sensor IRE1α in metabolic regulation and disease. The Journal of Biological Chemistry. 2019;294(49):18726-18741. DOI: 10.1074/jbc.REV119.007036. Epub 2019 Oct 30
  182. 182. Olefsky J. Treatment of insulin resistance with peroxisome proliferator-activated receptor ?? Agonists. The Journal of clinical investigation. 2000;106:467-472. DOI: 10.1172/JCI10843
  183. 183. Faddladdeen KA, Ojaimi AA. Protective effect of pomegranate (Punica granatum) extract against diabetic changes in adult male rat liver: Histological study. Journnal of Microscopy Ultrastructure. 2019;7(4):165-170. DOI: 10.4103/JMAU.JMAU_6_19. Epub 2019 Nov 18
  184. 184. Riaz T, Junjappa R, Handigund M, Ferdous J, Kim HR, Chae H-J. Role of endoplasmic reticulum stress sensor IRE1α in cellular physiology, calcium, ROS signaling, and Metaflammation. Cell. 2020;9:1160. DOI: 10.3390/cells9051160
  185. 185. Shah AA, Gupta A. Antioxidants in health and disease with their capability to defend pathogens that attack apple species of Kashmir. In: Ekiert HM, Ramawat KG, Arora J, editors. Plant Antioxidants and Health. Reference Series in Phytochemistry. Cham: Springer; 2021. DOI: 10.1007/978-3-030-45299-5_13-1
  186. 186. Ponnampalam EN, Vahedi V, Giri K, Lewandowski P, Jacobs JL, Dunshea FR. Muscle antioxidant enzymes activity and gene expression are altered by diet-induced increase in muscle essential fatty acid (α-linolenic acid) concentration in sheep used as a model. Nutrients. 2019;11(4):723. DOI: 10.3390/nu11040723
  187. 187. Cao Z-H, Wu Z, Hu C, Zhang M, Wang W-Z, Hu X-B. Endoplasmic reticulum stress and destruction of pancreatic β cells in type 1 diabetes. Chinese Medical Journal. 2020;133(1):68-73. DOI: 10.1097/CM9.0000000000000583
  188. 188. Khanna M, Agrawal N, Chandra R, Dhawan G. Targeting unfolded protein response: A new horizon for disease control. Expert Reviews in Molecular Medicine. 2021;23:E1. DOI: 10.1017/erm.2021.2
  189. 189. Gupta A, Gupta R, Singh RL. Microbes and environment. In: Singh R, editor. Principles and Applications of Environmental Biotechnology for a Sustainable Future. Applied Environmental Science and Engineering for a Sustainable Future. Singapore: Springer; 2017. DOI: 10.1007/978-981-10-1866-4_3
  190. 190. Russo M, Moccia S, Spagnuolo C, Tedesco I, Russo GL. Roles of flavonoids against coronavirus infection. Chemico-Biological Interactions. 2020;328:109211. DOI: 10.1016/j.cbi.2020.109211. Epub 2020 Jul 28
  191. 191. Wang M, Firrman J, Liu L, Yam K. A review on flavonoid Apigenin: Dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. BioMed Research International. 2019;2019:7010467. DOI: 10.1155/2019/7010467
  192. 192. Zakaryan H, Arabyan E, Oo A, Zandi K. Flavonoids: Promising natural compounds against viral infections. Archives of Virology. 2017;162(9):2539-2551. DOI: 10.1007/s00705-017-3417-y. Epub 2017 May 25
  193. 193. Musarra-Pizzo M, Pennisi R, Ben-Amor I, Mandalari G, Sciortino MT. Antiviral activity exerted by natural products against human viruses. Viruses. 2021;13:828. DOI: 10.3390/v13050828
  194. 194. Hong J, Chi X, Yuan X, Wen F, Rai KR, Wu L, et al. I226R protein of African swine fever virus is a suppressor of innate antiviral responses. Viruses. 2022;14(3):575. DOI: 10.3390/v14030575
  195. 195. Shibata C, Ohno M, Otsuka M, Kishikawa T, Goto K, Muroyama R, et al. The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels. Virology. 2014;462–463:42-48. DOI: 10.1016/j.virol.2014.05.024
  196. 196. Evers D, Chao C-F, Wang X, Zhang Z, Huong S-M, Huang E-S. Human cytomegalovirus-inhibitory flavonoids: Studies on antiviral activity and mechanism of action. Antiviral Research. 2006;68:124-134. DOI: 10.1016/j.antiviral.2005.08.002
  197. 197. Geng P, Zhu H, Zhou W, Su C, Chen M, Huang C, et al. Baicalin inhibits influenza a virus infection via promotion of M1 macrophage polarization. Frontiers in Pharmacology. 2020;11:01298. DOI: 10.3389/fphar.2020.01298
  198. 198. Huang L, Peng B, Nayak Y, Wang C, Si F, Liu X, et al. Baicalein and Baicalin promote melanoma apoptosis and senescence via metabolic inhibition. Frontiers in Cell and Development Biology. 2020;8:836. DOI: 10.3389/fcell.2020.00836 Erratum in: Front Cell Dev Biol.;10:876000
  199. 199. Song J, Zhang L, Xu Y, Yang D, Zhang L, Yang S, et al. The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro. Biochemical Pharmacology. 2021;183:114302. DOI: 10.1016/j.bcp.2020.114302. Epub 2020 Oct 27
  200. 200. Low ZX, OuYong BM, Hassandarvish P, Poh CL, Ramanathan B. Antiviral activity of silymarin and baicalein against dengue virus. Scientific Reports. 2021;11(1):21221. DOI: 10.1038/s41598-021-98949-y
  201. 201. Murtuja S, Shilkar D, Sarkar B, Sinha BN, Jayaprakash V. A short survey of dengue protease inhibitor development in the past 6 years (2015-2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases. Bioorganic & Medicinal Chemistry. 2021;49:116415. DOI: 10.1016/j.bmc.2021.116415. Epub 2021 Sep 20
  202. 202. Tambunan BA, Priyanto H, Nugraha J. Soedarsono. CD4+ AND CD8+ T-cells expressing interfer Gama in active pulmonary tuberculosis patients. African Journal of Infectious Diseases. 2018;12(Suppl. 1):49-53. DOI: 10.2101/Ajid.12v1S.6
  203. 203. Oo A, Rausalu K, Merits A, Higgs S, Vanlandingham D, Bakar SA, et al. Deciphering the potential of baicalin as an antiviral agent for chikungunya virus infection. Antiviral Research. 2018;150:101-111. DOI: 10.1016/j.antiviral.2017.12.012. Epub 2017 Dec 19
  204. 204. Jin H, Li D, Lin MH, Li L, Harrich D. Tat-based therapies as an adjuvant for an HIV-1 functional cure. Viruses. 2020;12(4):415. DOI: 10.3390/v12040415
  205. 205. Qin S, Huang X, Qu S. Baicalin induces a potent innate immune response to inhibit respiratory syncytial virus replication via regulating viral non-structural 1 and matrix RNA. Frontiers in Immunology. 2022;13:907047. DOI: 10.3389/fimmu.2022.907047
  206. 206. Wu C-C, Fang C-Y, Cheng Y-J, Hsu H-Y, Chou S-P, Huang S-Y, et al. Inhibition of Epstein-Barr virus reactivation by the flavonoid apigenin. Journal of Biomedical Science. 2017;24(1):1-13. DOI: 10.1186/s12929-016-0313-9
  207. 207. Wang S, Ling Y, Yao Y, et al. Luteolin inhibits respiratory syncytial virus replication by regulating the MiR-155/SOCS1/STAT1 signaling pathway. Virology Journal. 2020;17:187. DOI: 10.1186/s12985-020-01451-6
  208. 208. Silva Dos Santos J, Gonçalves Cirino JP, de Oliveira CP, Ortega MM. The pharmacological action of Kaempferol in central nervous system diseases: A review. Frontiers in Pharmacology. 2021;11:565700. DOI: 10.3389/fphar.2020.565700
  209. 209. Di Petrillo A, Orrù G, Fais A, Fantini MC. Quercetin and its derivates as antiviral potentials: A comprehensive review. Phytotherapy Research. 2021;36(1):266-278. DOI: 10.1002/ptr.7309. Epub 2021 Oct 28
  210. 210. Rawangkan A, Kengkla K, Kanchanasurakit S, Duangjai A, SaoII99kaew S. Anti-influenza with green tea Catechins: A systematic review and meta-analysis. Molecules. 2021;26(13):4014. DOI: 10.3390/molecules 26134014
  211. 211. Farazuddin M, Mishra R, Jing Y, Srivastava V, Comstock AT, Sajjan US. Quercetin prevents rhinovirus-induced progression of lung disease in mice with COPD phenotype. PLoS One. 2018;13(7):e0199612. DOI: 10.1371/journal.pone.0199612
  212. 212. Jung K, Saif LJ, Wang Q. Porcine epidemic diarrhea virus (PEDV): An update on etiology, transmission, pathogenesis, and prevention and control. Virus Research. 2020;2020(286):198045. DOI: 10.1016/j.virusres.;198045. Epub 2020 Jun 2
  213. 213. Anand AV, Balamuralikrishnan B, Kaviya M, Bharathi K, Parithathvi A, Arun M, et al. Medicinal plants, phytochemicals, and herbs to combat viral pathogens including SARS-CoV-2. Molecules. 2021;26:1775. DOI: 10.3390/molecules 26061775
  214. 214. Kim C-H. Anti–SARS-CoV-2 natural products as potentially therapeutic agents. Frontiers in Pharmacology. 2021;12:590509. DOI: 10.3389/fphar.2021.590509
  215. 215. Khazeei Tabari MA, Iranpanah A, Bahramsoltani R, Rahimi R. Flavonoids as promising antiviral agents against SARS-CoV-2 infection: A mechanistic review. Molecules. 2021;26:3900. DOI: 10.3390/molecules26133900
  216. 216. Vanderlinden E, Naesens L. Emerging antiviral strategies to interfere with influenza virus entry. Medicinal Research Reviews. 2014;34(2):301-334. DOI: 10.1002/med.21289
  217. 217. Kaihatsu K, Yamabe M, Ebara Y. Antiviral mechanism of action of Epigallocatechin-3-O-gallate and its fatty acid esters. Molecules. 2018;23(10):2475. DOI: 10.3390/molecules23102475
  218. 218. Song JM. Anti-infective potential of catechins and their derivatives against viral hepatitis. Clinical and Experimental Vaccine Research. 2018;7(1):37-42. DOI: 10.7774/cevr.2018.7.1.37
  219. 219. Nabil-Adam A, Shreadah M. Biogenic silver nanoparticles synthesis from new record aquatic bacteria of Nile tilapia and evaluation of their biological activity. Journal of Pure and Applied Microbiology. 2020;14:2491-2511. DOI: 10.22207/JPAM.14.4.27
  220. 220. Wang YQ, Li QS, Zheng XQ, Lu JL, Liang YR. Antiviral effects of green tea EGCG and its potential application against COVID-19. Molecules. 2021;26(13):3962. DOI: 10.3390/molecules26133962
  221. 221. Khachatoorian R, Arumugaswami V, Raychaudhuri S, Yeh G, Maloney E, Wang J, et al. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle. Virology. 2012;433:346-355. DOI: 10.1016/j.virol.2012.08.029
  222. 222. Liu S, Li H, Tang M, Cao Y. (−)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1. Experimental and Therapeutic Medicine. 2018;15(1):1105-1112. DOI: 10.3892/etm.2017.5495. Epub 2017 Nov 13
  223. 223. Baz M, Boivin G. Antiviral agents in development for Zika virus infections. Pharmaceuticals. 2019;12:101. DOI: 10.3390/ph12030101 www.mdpi.com/journal/pharmaceuticals
  224. 224. Jannat K, Paul AK, Bondhon TA, Hasan A, Nawaz M, Jahan R, et al. Nanotechnology applications of flavonoids for viral diseases. Pharmaceutics. 2021;13(11):1895. DOI: 10.3390/pharmaceutics13111895
  225. 225. Arabyan E, Hakobyan A, Kotsinyan A, Karalyan Z, Arakelov V, Arakelov G, et al. Genistein inhibits African swine fever virus replication in vitro by disrupting viral DNA synthesis. Antiviral Research. 2018;156:128-137. DOI: 10.1016/j.antiviral.2018.06.014. Epub 2018 Jun 22

Written By

Asmaa Nabil-Adam, Mohamed E. Elnosary, Mohamed L. Ashour, Nehad M. Abd El-Moneam and Mohamed A. Shreadah

Submitted: 21 September 2022 Reviewed: 17 October 2022 Published: 10 January 2023

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 4 Purple Corn Cob: Rich Source of Anthocyanins with ...

By Andreea Stănilă, Teodora Daria Pop and Zorița Mari...

106 downloads

Chapter 5 Application of Liquid Chromatography in the Analys...

By Ngoc Van Thi Nguyen

157 downloads

Chapter 6 Recent Advances in Flavonoid Metabolism: An Update...

By Indireddy Theja and Banoth Ramya Kuber

125 downloads