INTRODUCTION1.1 Definition Flavonoids are low molecular weight (Fernandez et al., 2006) bioactive polyphenols which play a vital role in photosynthesising cells (Tim-Cushnie and Andrew, 2005). They are also referred to as Phytochemicals which are substances found in edible fruits and vegetables that exhibit a potential for modulating human metabolism in a manner beneficial for the prevention of chronic and degenerative diseases (Tripoli et al., 2007).1.2 DescriptionLike other phytochemicals, they are the products of secondary metabolism of plants and currently, it is not possible to determine precisely their number, though over 4000 have been identified. Flavonoids are ubiquitous in photosynthesising cells and are commonly found in fruit, vegetables, nuts, seeds, stems, flowers, tea, wine, propolis and honey (Tim-Cushnie and Andrew, 2005). Flavonoids esterified with sulfate groups have been reported to occur in many plant species, in particular mono- to tetrasulfate esters of flavonols and flavones, and their methylated or glycosylated derivatives (Andersen et al., 2006). The dietary intake of flavonoids is estimated to be 1- 2g/day (Fernandez et al., 2006). They have been found to possess various effects: both beneficial and harmful. Nowadays many pharmaceuticals contain flavonoids as active substance (Marzena and Mateusz, 2012). For example quercetin, the most biologically active and popular dietary flavonoid, is generally used as a dietary supplement (Torreggiani et al., 2005). Flavonoids have free radical scavenging and antioxidation properties, which are useful for their pharmacological activities including their anticancer and anti-ageing properties (Sharma, 2006).

BIOCHEMISTRY OF FLAVONOIDS2.1 Nomenclature and Characterisation of flavonoidsThe basic structure of flavonoids is the flavylium cation (Marzena and Mateusz, 2012) or 2-phenyl-benzo--pyrane (Bimlesh et al., 2011). Two benzene rings A and B linked by a three carbon chain that forms a closed pyran ring (heterocyclic ring containing oxygen, the C ring) with benzenic A ring.

Figure 1: Flavonoid skeleton (Bimlesh et al., 2011)Flavonoids differ in their arrangement of hydroxyl, methoxy and glycosidic side groups and in the conjunction between A and B rings (Heim et al., 2002). A variation in C ring provides division of subclasses (Tsuchiya, 2010). Flavonoids are divided into eight different groups: flavonols, flavanones, flavones, isoflavones, catechins, anthocyanidins, dihydroflavonols and chalcones (Lu et al., 2006).

Table 1: Classification of some flavonoids and their common sources (Mukesh et al., 2005)Chemical ClassExampleMajor Dietary Source

FlavonolQuercetin, Rutin, Myricetin, KaempferolTea, Red wine, Apple, Tomato, Cherry and Onion

FlavanolsCatechin, GallocatechinTea and Apple

FlavonesApigenin, Luteolin, ChrysinThyme and Parsley

IsoflavonesGenistein, Glycitein, Formononetin, DaidzeinSoya bean and other legumes

FlavanonesHesperidin, NarigeninGrape fruit and Orange

FlavanonolsTaxifolinLemon and sour orange

Figure 2: Chemical structure of some representative flavonoids (Tapas et al., 2008)In plants, flavonoids are often present as O-glycosides or C-glycosides (Bimlesh et al., 2011). The O-glycosides possess sugar substituent bound to OH of aglycone, usually at position 3 or 7, whereas, C-glycosides possess sugar groups bound to Carbon of aglycone usually 6-C or 8-C (Rijke et al., 2006).2.2 Bioavailability and Metabolism of FlavonoidsAccording to U.S. Food and Drug Administration (FDA), the definition of bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. Despite the health claim of flavonoids, its bioavailability is generally low and can vary drastically among different flavonoid classes as well as individual compounds in a particular class (Surangi et al., 2013). Relative urinary excretion of anthocyanins and diadzein according to Landete (2012) intake was 0.3% and 43% respectively which explains the variability of bioavailability of flavonoids. When it comes to flavonoids with complex structures and larger molecular weights, bioavailability may be even lower (Landete, 2012).It is quite well established that once eaten, polyphenols enter a complex pathway of bio-transformation so that, the molecular forms reaching the peripheral circulation and tissues to be excreted are usually different from those present in foods (Manach et al., 2004). Flavonoids are substrates for conjugating and hydrolyzing enzymes in the small intestine, liver and colon and all are conjugated to O-glucuronides, sulfate esters and O-methyl esters and hardly any aglycones are present in the plasma (Landete, 2012).

Target cells and tissuesIngested flavonoids

GlycosidesBlood

LPH hydrolysisAglyconesPhase I & II metabolism Methyl Sulphate Glucoronic acid

Hepatic Portal Vein MetabolitesPhase I & II metabolism Metabolites(sulphates, glucoronidesand/ or methylates)Liver

BileIntestinal re-absorption

Blood

FlavonoidsPhenolic acidsCOLON Excretion via urine

Fecal Elimination

Figure 3: A Schematic of Human Flavonoid Metabolism (Surangi et al., 2013).

ROLES OF FLAVONOIDS IN CHRONIC DISEASESEpidemiological studies have supported the association between better health and long-term consumption of diets rich in foods of plant origin (Jansen et al., 2004). However, this is so because such diets minimize exposure to deleterious substances (e.g., oxidized cholesterol, pyrolysis mutagens, salt, saturated fat, etc.), or maximize intake of certain beneficial nutrients (e.g., isothiocyanates and other sulfur-containing plant constituents, mono-unsaturated fatty acids, and poly-unsaturated fatty acids, PPT, polyacetylenes, selenium, terpenes, etc.) or some combination as advocated in the Polymeal concept, remains unknown (Franco et al., 2004).3.1 Antioxidant Activity of FlavonoidsOxidation is the transfer of electrons from one atom to another (Yaseen et al., 2010). Problems may arise however when the electron flow generates free radicals, such as O2-centred free radicals, known as reactive oxygen species (ROS), and including superoxide (O2), peroxyl (ROO), alkoxyl (RO), hydroxyl (HO) and nitric oxide (NO) radicals (Hamdoon, 2009). This oxidative damage is considered to play a causative role in ageing and several degenerative diseases associated with it, such as heart disease, congestive dysfunction and cancer (Mohammad et al., 2011). To protect the body from such effects; in addition to antioxidant enzymatic system, there are non-enzymatic biomolecules and proteins in living organisms, which act as antioxidant and free radical scavengers (Khan et al., 2012). However, food supplementation containing ascorbates, carotenoids, tocopherols, flavonoids and phenols play a significant role in this matter (Patricia, 2005). Indeed, the phenolic groups of flavonoids serve as a source of a readily available H atoms such that the subsequent radicals produced can be delocalized over the flavonoid structure (Tripoli et al., 2007). Flavonoids inhibit lipid peroxidation in vitro at an early stage by acting as scavengers of superoxide anion and hydroxyl radicals (Bimlesh et al., 2011). They terminate chain radical reaction by donating hydrogen atom to a peroxy radical as in the figure below, thus, forming flavonoids radical, which, further reacts with free radicals thus terminating propagating chain (Ferreira et al., 2010).

Figure 4: Formation of peroxy radical (Bimlesh et al., 2011)3.2 Cardio protective Effect of FlavonoidsCompiled data from several epidemiological studies about cardio protective effect of flavonoids strengthens the inverse association between dietary flavonoid intake and incidence of coronary heart diseases (Maron, 2004). In the context of vascular disease, numerous studies have focused on the ability of phenolic compounds, as pure aglycones and as glycosides, to delay the oxidation of LDL in vitro (Kahkonen and Heinonen, 2005). Reactive Oxygen Species induced oxidative stress, a pathological determinant, is involved in the development and progression of various cardiovascular diseases (Becker, 2004). Previous studies have demonstrated that ROS generated intracellularly causes membrane lipid peroxidation and oxidative damage to nucleic acids, carbohydrates, and proteins, potentially leading to myocardial cell damage and death (Bergamini et al., 2004). As evidenced, free radical scavenging and antioxidant activities of flavonoids may thus be correlated with their cardio protective effects (Mukesh et al., 2005). Flavonoids have been suggested to reduce the risk of cardiovascular disease by modulating various mechanisms (Schroeter et al., 2010). However, the association between cancer risk and dietary flavonoid intake has less supportive evidence from epidemiological studies, and the results have been inconsistent (Woo and Kim, 2013). To date, meta-analyses have focused mainly on dietary flavonoids and cardiovascular disease (Hooper et al., 2008) or tea flavonoids and lung cancer (Sun et al., 2006).Table 2: Proposed positive effect of flavonoids on cardiovascular diseases (Bimlesh et al., 2011)S/NCardiovascular diseasesInfluence of Flavonoids

1ArtherosclerosisDecrease in LDL oxidation by LOX inhibition and attenuation of oxidative stress, inhibition of leucocyte leucocyte adhesion, myeloperoxidase, decreased expression of iNOS and COX-2.

2ArrhythmiaDecrease in oxidative stress.

3Acute Myocardial infarctionDecrease in ROS burst, inhibition of platelet aggregation

4Heart FailureDecrease in oxidative stress (direct ROS scavenging) inhibition of metalloproteinase

5HypertensionVasodilatory properties, inhibition of NADPH oxidase, recovery of NO due to inhibition of superoxide production

3.3 Anti-Carcinogenic Effect of FlavonoidsStomach and colorectal cancer are common cancers and leading causes of cancer deaths (Ferley et al., 2010). Flavonoids are a large and diverse group of phytochemicals and research into their anti-carcinogenic potential with animal and cellular model systems supports a protective role (Nichenametla et al., 2006). Dietary flavonoids inhibit the proliferation of various cancer cells and tumour growth in animal models (Kanadaswami et al., 2005). Flavonoids are potent bioactive molecules that possess anticarcinogenic effects since they can interfere with the initiation, development and progression of cancer by the modulation of cellular proliferation, differentiation, apoptosis, angiogenesis and metastasis (Ramos, 2007) as shown in the figure below:

Figure 5: Multistage of Carcinogenesis and potential effects of polyphenols on cancer progression (Ramos, 2007)Epidemiologic data suggested that flavonoids consumption may protect against cancer induction in several human tissues (Ewelina et al., 2008). Chemoprevention has the potential to be a major component of colon, lung, prostate and bladder cancer control (Thomasset, 2007). Recently it has been reported that flavonoids sensitized in vitro cancer cells to apoptosis induced by anticancer agents, for example the tumour necrosis factor (TNF) (Nozawa et al., 2004).3.4 Anti-Inflammatory effect of FlavonoidsIn inflammation, bacterial products and proinflammatory cytokines induce the formation of large amounts of nitric oxide (NO) by inducible nitric oxide synthase (iNOS), and compounds that inhibit NO production have anti-inflammatory effects (Mari et al., 2007). A main function of inflammation is to resolve infection and to repair the damage in order to achieve homeostasis equilibrium (Garca-Lafuente et al., 2009). Thus, the ideal inflammatory response is rapid and destructive, yet specific and self-limiting (Barton, 2008). Although steroidal anti-inflammatory drugs and NSAIDs are currently used to treat acute inflammation, these drugs have not been entirely successful in curing chronic inflammatory disorders while such compounds are accompanied by unexpected side effects (Garca-Lafuente et al., 2009). Therefore, there is an urgent need to find safer anti-inflammatory compounds (Yoon and Baek, 2005). It has been reported that flavonoids are able to inhibit expression of isoforms of inducible nitric oxide synthase, cyclooxygenase, and lipooxygenase, which are responsible for the production of a great amount of nitric oxide, prostanoids, leukotrienes, and other mediators of the inflammatory process such as cytokines, chemokines, or adhesion molecules. Apigenin, luteolin, quercetin are known to possess anti-inflammatory activity (Tapas et al., 2008). Kaempferol, quercetin, myricetin, fisetin are reported to possess COX and LOX inhibitory activities (Tapas et al., 2008). Flavonoids also inhibit cytosolic and tyrosine kinase (Kang et al., 2009) and also inhibit neutrophil degranulation.

Figure 6: Effect of Flavonoids on inflammation (Bimlesh et al., 2011)

OTHER EFFECTS OF FLAVONOIDS4.1 Gastro-protective Activity of Flavonoid Peptic ulcer is a gastro intestinal disorder due to an imbalance between the aggressive factors like acid, pepsin, Helicobacter pylori and defensive factors like bicarbonate secretion, prostaglandins, gastric mucus, innate resistance of the mucosal cell factors (Dashputre et al., 2011). The mechanism of action responsible for the anti-ulcer activity of flavonoids is their antioxidant properties, seen in garcinol, rutin and quercetin, which involve free radical scavenging, transition metal ions chelation, inhibition of oxidizing enzymes, increase of proteic and nonproteic antioxidants and reduction of lipid peroxidation (Mohamed and Azza, 2011). 4.2 Antimicrobial Activity of Flavonoids4.2.1 Antifungal ActivityHumans and fungi share some of the same molecular processes; therefore, there is always the risk that what is toxic to the fungal cells will be toxic to the host cells (Tasleem et al., 2009). The drugs that were used to treat fungal infections have recoiled because fungi have developed resistance and also some adverse effects. It is then necessary to find alternative means to combat these fungal infections. Amentoflavone from Selaginella tamariscina exhibited potent antifungal activity (IC50 value of 18.3 mg/ml) against several pathogenic fungal strains and has a very low haemolytic effect on human erythrocytes (Jung et al., 2006).An isoflavan, 2-hydroxy maackiain from the root extract of Hildegar diabarteri was observed to have antifungal activity (Meragelman et al., 2005). Flavonoid derivatives, scandenone, tiliroside, quercetin-3,7-O--Ldirhamnoside, and kaempferol-3,7- O--L-dirhamnoside, were reported to have antifungal activities against C. albicans at 1.0mg/ml as potent as ketoconazole (Ozelik et al., 2006).

4.2.2 Antibacterial ActivityA number of flavonoids have displayed antibacterial activities. Rattanachaikunsopon et al., (2010) isolated morin-3-O-lyxoside, morin-3-O-arabinoside, quercetin, quercetin-3-O-arabinoside from Psidium guajava leaves and reported that these four possess bacteriostatic action action against all foodborne pathogenic bacteria including Bacillus stearothermophilus, Brochothrix thermosphacta, Escherichia coli, Listeria monocytogenes, Pseudomonas fluorescens, Salmonella enteric, Staphyloccus aureus, Vibrio cholera. Flavonones having sugar moiety showed antimicrobial activity while none of the flavonols and flavonolignans showed inhibitory activity on microorganisms (Bimlesh et al., 2011). Quercetin has been reported to completely inhibit growth of Staphylococcus aureus (Tapas et al., 2008).4.2.3 Antiviral ActivityThe mechanism of antiviral action of polyphenolic compounds is based on their abilities to act as antioxidants, inhibit enzymes, disrupt cell membranes, prevent viral binding and penetration into cells, and trigger the host cell self-defense mechanisms (Mendel, 2007). A recent area of research that is of particular interest is the apparent inhibitory activity of some flavonoids against human immunodeficiency virus (HIV) (Tim-Cushnie and Andrew, 2005). HIV-1 infection of the host cells proceeds with reverse transcription, viral DNA integration into the host genome, transcription, translation, proteolytic processing of viral proteins and subsequent assembly into nascent viral particles (Greene and Peterlin, 2002). Luteolin, quercetin, myrecetin have been found to have anti-HIV-1 activity (Tewtrakul et al., 2003). In an experiment carried out by Mehla et al., (2011), Luteolin was the most potent and inhibited HIV-1 infection by abrogating Tat-mediated LTR activity.4.3 Hepatoprotective Activity of FlavonoidsDifferent chronic diseases such as diabetes may lead to development of hepatic clinical manifestations. glutamate-cysteine ligase catalytic subunit (Gclc) expression, glutathione, and ROS levels are reported to be decreased in liver of diabetic mice (Shashank and Abhay, 2013). Zhu et al. demonstrated that anthocyanin cyanidin-3-O--glucoside (C3G) increases hepatic Gclc expression by increasing cAMP levels to activate protein kinase A (PKA), which in turn upregulates cAMP response element binding protein (CREB) phosphorylation to promote CREB-DNA binding and increase Gclc transcription. Increased Gclc expression results in a decrease in hepatic ROS levels and proapoptotic signaling (Zhu et al., 2012).Silymarin has been reported to stimulate enzymatic activity of DNA-dependent RNA polymerase 1 and subsequent biosynthesis of RNA and protein, resulting in DNA biosynthesis and cell proliferation leading to liver regeneration only in damaged livers ((Bimlesh et al., 2011). Silymarin has clinical applications in the treatment of cirrhosis, ischemic injury, and toxic hepatitis induced by various toxins such as acetaminophen, and toxic mushroom (Saller et al., 2011).4.4. Anti-thrombotic Activity of Flavonoids Arachidonic acid released by in inflammatory conditions is metabolized by platelets to form prostaglandin, endoperperoxides and thromboxane A2 thus contributing to platelet activation and aggregation (Bimlesh et al., 2011). Platelet aggregation further contributes to atherosclerosis and acute platelet thrombus formation. According to Bimlesh et al., flavonoids are used as antithrombotic due to their ability to scavenge free radicals. The main antiaggregatory effect is by the inhibition of thromboxane A2 formation. Flavonoids like quercetin, kaempferol and myricetin are known to possess antiaggregatory properties (Tapas et al., 2008).

FLAVONOID TOXICITY PROFILEIt has been suggested that because flavonoids are widely distributed in edible plants and beverages and have previously been used in traditional medicine, they are likely to have minimal toxicity (Tim-Cushnie and Andrew, 2005). Given that the selectivity of flavonoids for eukaryotic enzymes appears to vary from compound to compound, a study regarding assessment of its toxicity is required to be done on these phytochemicals on an individual basis (Tim-Cushnie and Andrew, 2005). High doses do not appear to cause serious side effects, even for amounts as high as 100 grams a day. Excess intake is simply excreted in urine. As for green tea, highly concentrated doses of it might contain too much caffeine for cancer and hepatitis patients, and for those people sensitive to caffeine (HSNG, 2008).

CONCLUSION/RECOMMENDATIONSeveral diseases have found their way to exist among humans. These diseases are caused by microorganisms, most of which have made the internal environment of human (Host) their abode. Many drugs are used to combat these diseases, but because of the various side effects and even the ability of these organisms to develop resistance, the efficacy of these drugs has decreased over the years. Researchers have therefore resorted to the ancient means of treating diseases i.e. the use of natural medicinal plants. Dietary flavonoids found in vegetables, fruits, chocolates e.t.c. are hereby recommended to be part of our daily diet since studies have demonstrated positive effects in the prevention and treatment of many diseases. However, further research is needed to affirm the dosage limits of these bioactive compounds and also discover more.

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APPENDIXAppendix 1Table 3: Diseases treated with flavonoidsS/NDISEASESFLAVONOIDSTARGETREFERENCES

1UlcerKaempferol,Sofalcone, QuercetinPAFPG Synthesis(Tapas et al, 2008)

2Rheumatoid ArthritisApigenin, rutinSuppress inflammation by acting on COX(Kang et al, 2009)

3InflammationHesperidin, luteolin,Fisetin, Quercetin

COX, iNOSPG Synthesis(Tapas et al, 2008)

4CancerGenistein, QuercetinApigenin, luteolinCatechinsTyrosine kinaseP53 dependentGlutathione reductase, quinine reductase, catalase(Ramos, 2007)(Sharififar et al, 2009)(Ramos, 2007)

5Memory dysfunctionGenistein,Quercetin,FisetinTyrosine kinasepAKt and pCREBERK and cAMP response element(Jung et al, 2010)(Maher et al, 2006)

6DepressionNaringenin,2S-hesperidin, Linarin(Yi et al, 2010)(Fernandez, 2006)

7Cardiovascular diseasesQuercetin,7-monohydroxyethylrutoside,7',3',4'-trihydroxyrutoside

LDL(Bimlesh et al, 2011)(Tapas et al, 2011)(Bimlesh et al, 2011)

8Diabetes mellitusFisetin(Sriram et al, 2011)

9AntiallergicQuercetinMast cells(Maher et al, 2006)

10HepatoprotectiveQuercetin,Avicularin, hirustrin,Onitin, luteolin

(Oh et al, 2004)(Oh et al, 2004)(Oh et al, 2004)

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