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INTRODUCTION Phytochemicals are defined as the 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
[1].
On the basis of C-skelton, polyphenols are classified as: 1. Flavonoids 2. Phenolic acids [2] FLAVONOIDS Flavonoids are low molecular weight polyphenols[9] which play a
[7, 8]
bioactive role in
Phenolics are defined as a class of polyphenols which are important secondary metabolites present in plants
[2]
vital
photosynthesising cells[10]. The original "flavonoid" research apparently began in 1936, when Hungarian scientist Albert Szent-Gyorgi was uncovering a synergy between pure vitamin C and as yet unidentified cofactors from the peels of lemons, which he first called "citrin," and, later, "vitamin P" [11]. Flavonoids are secondary metabolites characterised by flavan nucleus with feature a
[8]
and are also responsible for their antioxidant action are characterised as :
1. Phenolic compounds: Are aromatic organic compounds with at least one hydroxyl group attached directly to a benzene ring. These are hydroxylated derivatives of benzoic acid, present in form of esters and glycosides. 2. Phenolic acids: cinnamic acid derivatives. Often present in esterified form. 3. Glycosidic phenylpropanoid esters [5,6].
Address for correspondence *Bimlesh Kumar (Lecturer) Dept. of Pharmaceutical Sciences, Lovely Professional University, Ludhiana-Jalandhar G.T. Road, Phagwara (Punjab), 144402, India *Mob: +919872260354, +919216260354 E.mail: bimlesh.12474@lpu.co.in, bimlesh1@gmail.com 25
[12, 13].
These are group of structurally related compounds chromane-type of flavonoid is having phenyl substituent in C2-C3 position The basic structural
2-phenyl-benzo--pyrane
nucleus consisting of two benzene rings (A and B) linked through a heterocyclic pyran ring (C) as shown in fig (I) [10].
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Vol 1 Issue 1
4' 5'
1' 2 3
B 6'
Optical activity of flavonoids: The flavonoids are a class of natural product that gains interest due its great variety and the number of its members. The flavonoids are often hydroxylated in positions 3, 5, 7, 3, 4, and 5 as shown in fig (IV) which are frequently methylated, acetylated, or sulphated.
Biosynthesis of Flavonoids:
O S-CoA
3CH3COOH
3' 4'
7 6
5'
HO O
OH
4
O
OH
FLAVAN NUCLEUS Fig (II): Biosynthesis of flavonoids Flavonoids differ in their arrangement of hydroxyl, methoxy and glycosidic side groups and in the conjunction between A and B rings [8]. A variation in C ring provides division of subclasses (fig III) classes [13]:
O O O O H H O O H O OH O
Fig (IV): Numbering of atoms in flavonoid aglycone ] at which substitution may occur [15 The actual number of flavonoids that have been found so far and for which the structure has been completely elucidated is large, but probably does not exceed 1% of the theoretical number of possible variants. This abundance of variants is further augmented by the chirality of the subunits and their connections. Since many stereoisomers do not differ significantly in their electronic or fluorescence spectra so the optical activity of the species is often a useful analytical parameter [16]. Distribution of flavonoids: Flavonoids are widely distributed among the plant
4 B 2' 5 6
[13].
According to
(1) Flavone
(2) Flavonones
(3)Flavonol
(4) Isoflavone
3 2
O+ O H OH H H H OH H OH O O H H
kingdom [10].Flavonoids are found in vegetables, fruits, nuts, seeds, stem, flowers, tea, wine etc. These are an integral part of our daily diet
[15, 17, 18].
The dietary
intake of flavonoids is estimated to be 1-2 g/day [7]. The average intake of flavonols and flavones was found to be 23 mg/day, among which, flavonol quercetin contributed 16 mg/day dietary food sources:
[8].The
Fig (III): Chemical structure of different types of flavonoids [15] In plants, flavonoids are often present as O-glycosides or C-glycosides. The O-glycosides possess sugar substituent bound to OH of aglycone, usually at position 3 or 7, whereas, C-glycosides possess sugar
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26
Functions of Flavonoids in plants: Anthocyanin pigment present in flowers provide colour to it contributing to pollination
[8, 10, 20].
Flavonoids
present in leaves promote physiological survival of plant by protecting it from fungal infections and UV radiations. In addition, flavonoids are involved in photosensitisation, energy transfer, respiration and photosynthesis control, morphogenesis,
[10].
sex-
Indian Plants containing Flavonoids: Table 2: Medicinal plants found in India and rich in flavonoids content
S. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 18. 19. 20. 21. 22. Plant Aloe vera Family Asphodelaceae Luteolin Kaempferol glycosides: mauritianin, clitorin, nicrotiflorin, biorobin in its leaves and flowers Quercetin, kaempferol; Quercetin-3-O- -D-glucoside, myricetin-3-O-rutinoside, quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O--D-glucoside and quercetin-3-O--L-rhamnoside in leaf; isorhamnetin, myricetin, nimbochalcone 5-methoxy-7,8,2,3-tetramethoxyflavone, monohydroxytrimethylflavones, dihydroxy-di-methoxyflavone, skullcaflavone; 5-hydroxy-7,8-dimethoxyflavanone and 5-hydroxy-3,7,8,2-tetramethoxyflavone, as well as the known flavonoid 5-hydroxy-7,8- dimethoxyflavone. Luteolin, luteolin-7-O- -glucopyranoside Quercetrin, myricetin galactoside, kaempferol, myricetin Genistein, prunetine in stem bark Quercetin-3-O-rutinoside, Quercetin quercetin-3-O- -d-galactopyranoside, quercetin-3-O--l-arabinopyranoside, the biflavonoid amentoflavone, (+)-catechin and ()-epicatechin, amentoflavone, in leaves Quercetin, isorhamnetin Orientin, luteolin, luteolin-7-O- -glucopyranoside Seed consists of eriocitrin, hesperidin. Peel consists of neoeriocitrin, naringin, neohesperidin Pectolinarigenin, 7-hydroxyflavone, 7-hydroxyflavonone, 7-O-glucoside Kaempferol-3-O- -glucoside, Quercetin-3-O- -glucoside, myricetin-3-O- -glucoside, isorhamnetin-3-O- glucoside, 3,5,7,4-tetrahydroxy-flavone-3-rhamoglycoside, kaempferol-3-neohesperidoside Liquiritin, isoliquiritin,liquritigenin,isoliquiritigenin, rhamnoliquiritin, liqcoumarin, 2-methylisoflavones Isoquercetin, avicularin, apigenin-7-O- -D-glucoside, cassiaocidentalin B, orientin, isoorientin in aerial parts (2S)-5,7,3,4-tetramethoxyflavone, 5,7,2,5-tetramethoxyflavone, 7-O-methylwogonin, skullcapflavone, 5hydroxy-7,20-dimethoxyflavone present in whole plant. 3,4-methlenedioxyflavone in roots and aerial parts Luteolin-7-O-glycoside,luteolin-7,3-O-diglycoside, apigenin, quercetin-3-O-glycoside, kaempferol-3-Oglycoside; 5,7,4-trihydroxy-6,2,3-trimethoxyflavone Luteolin, kaempferol, quercetin (Agarwal), Chrysin, baicalein, baicalein-7-O-glucoside, Oroxylin B Vitexin, isovitexin, orientin, iso-orientin, 2- -D-glucoside Pongaflavonol , tunicatacatachalcone; Pongamone A-E, 5-hydroxy-40-methoxy-7-[(3-methyl-2-buthenyl) oxy]-isoflavone, ovalichromene-B, pongachin, ponganone III, 5hydroxyfurano[7,6:4,5]flavone , pongaglabol, karanjin, pongapin, lancheolatin B, 50-methoxypongapin, karanjachromene, pongachromene; luteolin; (2S)-3,4-dimethoxy-6,6-dimethylpyrano[2,3:7,8]-flavanone , (2S)-6,3,4-trimethoxy-6,6dimethylpyrano[2,3:7,8]-flavanone, (2S)-7-methoxy-6-O-,-dimethylallyl-3,4-methylenedioxyflavanone, 2-hydroxy-3,4,5-trimethoxy-6,6-dimethylpyrano[2,3:4,3]chalcone, 2,4-dimethoxy-3,4methylenedioxydioxydihydrochalcone, 2,5,-trimethoxy-3,4-methylenedioxy-6,6dimethylpyrano[2,3:4,3]dihydrochalcone, 2,-dimethoxy-3,4-methylenedioxy-furano[2,3:4,3]dihydrochalcone, -hydroxy-2,4,6-trimethoxy-3,4-methylenedioxychalcone and 3-methoxy-furano[2,3:7,6]flavones present in roots Purpurin, pongamol, isolonchocarpin,karanjin, lanceolatin-B, kanjone present in seeds Quercetrin, rutin, hyperoside, tiliroside, astragalin Flavonoid present Reference 20 21 22,23 24, 25 21 26 27 28 29 26 21 1 30 25, 31 26 30 30 32, 33 34 30 26
Acalypha indica Euphorbiaceae Azadirachta indica Andrographis paniculata Bacopa moneirra Betula pendula Butea monospermea Bauhinia monandra Brysonima crassa Calendula officinalis Cannabis sativa Citrus medica Clerodendrum phlomidis Clitoria ternatea Glyccheriza glabra Mimosa pudica Limnophila indica Mentha longifolia Momordica charantia Oroxylum indicum Passiflora incarnate Meliaceae, Zingiberaceae Acanthaceae Scrophulariaceae Betulaceae Fabaceae Fabaceae Malphigaceae Compositae Cannabaceae Rutaceae Verbenaceae Fabaceae Leguminosae Mimosoideae Scrophulariaceae Lamiaceae Curcurbitaceae Bignoniaceaea Passifloraceae
23.
Pongamia pinnata
Fabaceae
35, 36, 37
24. 25.
Fabaceae Tiliaceae
30 26
27
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PHARMACOLOGY OF FLAVONOIDS: Reported flavonoids: Flavonoids have been reported to exert wide range of biological
11, 15],
Pharmacological
activities
of
O2
e-
.O 2
H+
HO2. HO2. O2
H2O2.
activities. cytotoxic
These antitumour,
includes: treatment
anti[10,
Fig (V): Formation of peroxy radical Naturally, the organism has developed a defence against toxic substances such as peroxynitrite and nitrous acid. An important mechanism is catalyzed by the enzyme superoxide dismutase (SOD), which converts two superoxide anions to H2O2 and O2 [16] as shown in fig (VI). H2O2 + O2 SOD Fig (VI): Mechanism catalysed by SOD Table 3: Reactive oxygen species that can be scavenged or their formation can be inhibited by flavonoids[43]
S. No. 1. 2. Reactive species O2 (Superoxide anion) HO2 H2O2 (Hydrogen peroxide) - Mechanism One-electron reduction product of O2. Produced by phagocytes, formed in autoxidation reaction and generated by oxidases (heme proteins) Protonated form of O2 Two electron reduction product of O2 formed from O2 by - dismutation or directly from O2. Reactivity of O2 and H2O2 is amplified in presence of heme proteins Three electrons reduction products of O2 generated by Fentons reaction, transition metal (iron, copper)catalysed Haber-Weiss reaction; also formed by decomposition of peroxynitrite produced by reaction of O2 with nitric oxide radical. Lipid peroxy radical (LOO ) produced from organic hydroperoxide, ROOH by hydrogen abstraction. Singlet Oxygen
.
of
vasodilatory aggregation,
lipid-peroxidation, permeability
lipoxygenase enzyme activities. They exert these effects as antioxidants, free radical scavengers, chelators of divalent cation
[15, 39, 40].
.O 2
+ .O2-
2H+
reported to inhibit variety of enzymes like hydrolases, hyalouronidase, alkaline phosphatise, arylsulphatase, cAMP phosphodiesterase, lipase, -glucosidase, kinase [41]. 1. Flavonoids as antioxidants:
Mechanism of flavonoids as antioxidants: Flavonoids are powerful antioxidants against free radicals and are described as free-radical scavengers
[42].
donating ability. 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 [1]. Free radical scavenging capacity is primarily attributed to high reactivities of hydroxyl substituents that participate in the reaction [8] as shown in fig (IV): F-OH + R. F-O. + RH Fig (IV): Scavenging capacity of free radical (R.)
3.
4.
OH (Hydroxy radical)
5. 6.
According to kinetic studies of aroxyl radical Flavonoids inhibit lipid peroxidation in vitro at an early stage by acting as scavengers of superoxide anion and hydroxyl radicals. They terminate chain radical reaction by donating hydrogen atom to a peroxy radical as in fig (V), thus, forming flavonoids radical, which, further reacts with free radicals thus terminating propagating chain [15, 6]. formation and decomposition reactions, the antioxidant capacity of a flavonoid is linked to its three structural groups as shown in fig (VII). 1. The ortho-dihydroxy (catechol) structure in the Bring, which confers greater stability which participates in electron dislocation. 2. The 2,3-double bond, in conjugation with a 4-oxo function, responsible for electron dislocation from the B-ring.
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to aroxyl
Ulcer is a commonly occurring disease in developed countries and its occurrence is emerging with increase in modernisation of living standards. Etiology of gastric ulcer: The stress hormones like epinephrine, norepinephrine, and ACTH, causes a vasoconstriction in the integument and the periphery, whereas, they dilate the vessels of muscles, heart, and brain. But, if the duration of this state gets prolonged, then blood supply to major organs, e.g., stomach, intestine, liver, kidneys, and skin get reduced and thus failing to satisfy demand for oxygen, antibodies and other agents that are required to maintain a healthy condition. As a result, the stress hormones increases the glandular secretion which denatures proteins in plasma membranes and catalyses the hydrolysis of polysaccharide moieties of proteoglycans in the protective mucous coat covering the luminal surface of the stomach and the upper intestine to a perilous extent during prolonged stress. When the walls of the blood vessels supplying oxygen, nutrients, and protective substances to this area gets sufficiently weakened, then slight mechanical insults easily cause ruptures, resulting in leakage of blood into the tissue. Such events start inflammation and repair processes in which eicosanoids, e.g., PGs, participate [16]. Flavonoids in treatment of gastric ulcer: Flavonoids inhibit regulation of protein phosphorylation. Inhibition of P-kinase signalling influence protein phosphatase which reverses the action of protein P-kinase as shown in fig (VIII):
(-) cAMP (-) protein kinase C (-) protein phosphorylation (-) COX
(b)
(c)
HO
HO
HO
OH
OH
b
OH O OH O
OH
Fig VII: Structural groups responsible for antioxidant activity [1] 3,4-catechol structure in B-ring strongly enhances lipid peroxide inhibition and this arrangement is an important characteristic of most potent scavengers of peroxyl, superoxide and peroxynitrite radicals
[8]
and
its absence decreases antioxidant activity. The absence of the hydroxyl group at position 3 in flavanones and flavones decreases their antioxidant ability[1]. Ghasemzadeh et al., reported that high level of total phenolic and flavonoid in Halia Bara variety possessses potent antioxidant activities [44]. Bitis et al., isolated diosmetin, kaempherol, quercetin, kaempherol 3-glucoside (astragalin), quercetin 3rhamnoside (quercitrin), quercetin 3-xyloside and quercetin 3-galactoside (hyperoside) from Rosa agrestis leaves and reported it to possess antioxidant activity [45]. Shariffer et al., reported antioxidant activity of methanolic extract of Teucrium polium and rutin and apigenin were found to be potent inhibitors of lipid peroxidation and oxidation of beta-carotene [46]. Braca et al., isolated several flavonoids from the leaves of Licania licaniaeflora and reported quercetin derivatives to possess strongest antioxidant activity and flavonone 8-hydroxy-naringen and kaempferol 3O--rhamnoside possesses lowest antioxidant activity
[47].
Salucci et al., reported that dietary flavonoids like epicatechin, epigallocatechin, galate, gallic acid, quercetin-3-glucoside activity [48]. Gulati et al., reported that quercetin at a dose of 15 mg/ 100g p.o. produced significant hepatoprotection
[49].
FLAVONOID
possess
strong
antioxidant
Flavonoids are favourable, effective, and usually innocuous substitutes for the classical therapeutic agents. It has also been reported that flavonoids protect against gastric cancer. Similar to aspirin, acylated flavonoids may transfer their acyl group to
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29
the side chain hydroxyl group of serine in the active site of COX
[16].
battle against invasion by microorganisms or their toxins which are recognised by specific antibodies mounted on the surface of the macrophages in a receptor enzymes from the (FcR). i.e. Fc receptor is non-covalently lipase which inositol associated with a second messenger producing phosphatidylinositol membrane. liberates inositol phosphates and diacylglycerol (DAG) plasma Several phosphates activate specific protein phosphokinases
Flavonoids glycosides of Ocimum basilicum decreased ulcer index and thus inhibit gastric acids in aspirininduced ulcers. Quercetin, Kaempferol, rutin when administered intraperitoneally (25-100 mg/kg) inhibited dose-dependent gastric damage produced by ethanol in rats [43]. 3. Effect of flavonoids on inflammation: Etiology: Inflammation is the integrated response of many defence systems of the body to the invasion of a foreign body. Inflammation involves action of the complement system, blood coagulation, humoral and cellular immunity, cytokines, tissue hormones, angiogenesis, and repair processes. It is both a free radical generating and free-radical producing process
[50].
The toxin-antibody
complexes are endocytised, and raise the alarm in the cell, with the result that the latter emits IL-1. This substance induces the expression of the COX gene, which encodes the PG COX that produces the eicosanoids, i.e., signal substances for the pain pathway (fig IX), chemotaxis, and smooth muscle contraction [16].
An important mechanism in inflammation is the recruitment of macrophages to participate in the MEMBRANE PHOSPHOLIPIDS ARACHIDONIC ACID PATHWAY FLAVONOIDS CYCLOOXYGENASE COX-1 COX-2 LIPOOXYGENASE 5-LOX 5-HPETE 12-LOX 12-HETE
PGG2 PGH2
LTA4
PGI2
PGD2
PGE2
PGF2
TXA2
LTE4
LTB4
Fig IX: Arachidonic acid pathway [51] Flavonoids in treatment of inflammation: Flavonoids have been found to be prominent inhibitors of COX or LOX
[42, 45].
catechins) have also been shown to have antiinflammatory activity by inhibiting cycloxygenase-2 (COX2) and inducible nitric oxide synthase [52], which is related to antioxidant activity inhibit neutrophil degranulation inflammation.
[50].
Flavonoids prevent
synthesis of PGs that suppress T-cells. The immune cells communicate with chemical signals called cytokines site. which are also controlled promote by IFN flavonoids. synthesis Flavonoids inhibit the activity of PKC at ATP-binding Flavonoids
[16].Various
Flavonoids also
[40, 53]
and also
head of the bone. These spikes cause tissue lesions, bleeding, inflammation, and pain [16].
INHIBIT INFLAMMATION
FLAVONOID
Flavonoids
in
treatment
of
Rheumatic
diseases: The beneficial effect of orally consumed flavonoids includes the elimination of the PGs which mediate the pain. An additional effect of the flavonoids may be to activate cytotoxic Tlymphocytes, which kill cells presenting the harmful foreign antigen. Flavonoids do activate cytotoxic Tlymphocytes, but the antigen, against which the lymphocytes are directed, remains unidentified shown in fig (XI).
FLAVONOIDS Activate Cytotoxic T-lymphocytes
[16]
Fig X: Effect of flavonoids on Inflammation Citrus flavonoids, hesperidin is known to possess antiinflammatory and analgesic effects. Apigenin, luteolin, quercetin are known to possess antiinflammatory activity [43]. Guardia et al., reported quercetin and hesperedin given at a daily dose of 80 mg/kg inhibit both acute and chronic phase of inflammation while rutin was found to be effective only in chronic case [54]. Kaempferol, quercetin, myricetin, fisetin are reported to possess COX and LOX inhibitory activities [43]. 4. Effect of flavonoids on rheumatic disease: Etiology of Rheumatic disease: Autoimmunity and inflammation is an important component of rheumatoid arithritis. Since rheumatic disease is associated with painful joints, it is believed that the antigen specificity of the T-cells is directed against an epitope characteristic of the cartilage in a joint, e.g., a part of chondroitin sulphate. IL-1 is produced by macrophages. It acts as a growth hormone on T-lymphocytes, which are induced to proliferate and secrete IL-2, which, in turn, is a mitogen to T and B-lymphocytes, macrophages, granulocytes, and blood vessel endothelial cells. Osteoclasts resembles macrophages because both produce and secrete IL-1 and are phagocytic. If osteoclasts respond to IL-2 secreted from immune cells, then, the enhanced osteoclastic activity leads to the destruction of the heads of the long bones in the joints. In rheumatic arithritis, such a destruction is followed by repair processes, which are uncoordinated with the mechanical requirements defined by the stress gradients. The topological activation pattern of the osteocytes leads to the formation of bony spikes in the
as
Inhibit PGs
Kang
et
al.,
reported
that
apigenin
inhibits
autoantigen-presenting and stimulatory functions of APCs necessary for activation and expansion of autoreactive Th1 and Th17 cells and B cells and reported that it could suppress inflammation in rheumatoid arithritis [53].Guardia et al., reported rutin to be most effective plant flavonoids for the treatment of inflammation in chronic phase [54]. 5. Flavonoids in treatment of thrombosis: Etiology of Thrombosis: 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. Platelet aggregation further contributes to atherosclerosis and acute platelet thrombus formation. Activated platelets adhering to vascular endothelium generate lipid peroxides and oxygen free radicals which inhibit endothelial function of prostacyclin and nitric oxide
[40].
Flavonoids
in
treatment
of
thrombosis:
Flavonoids are used as antithrombotic due to their ability to scavenge free radicals. They inhibit
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cyclooxygenase and lipooxygenase pathway. The main antiaggregatory effect is by the inhibition of thromboxane A2 formation. Flavonoids like quercetin, kaempferol and myricetin are known to possess antiaggregatory properties
[40, 43].
Cancer
cells
manifest
to
varying
degree
of
uncontrolled proliferation, dedifferentiation and loss of function, invasiveness and metastasis that differ it from normal cells [51]. Flavonoids in treatment of Cancer: Flavonoids for a long time have been part of the herbal treatment by lay practitioners, but they were recognised only recently as effector substances. Examples of herbal preparations owing their growing recognition as
(+) cAMP in platelets (-) intracellular Ca++ (-) IP3 formation (-)TxB2 formation (-)TxA2 formation (-) Phospholipase C (-)PIP2 levels (-) Intracellular production of H2O2
and Essiac [16]. 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
Fig (XII): Effect of flavonoids on thrombosis 6. Effect of flavonoids on cancer-related pathways: Etiology of Cancer: Cancer is a growth of diseases caused by disturbance in growth metabolism
[52].
proliferation, differentiation, apoptosis, angiogenesis and metastasis [55] as shown in fig (XIII). Flavonoids have emerged as potential chemopreventive candidates for cancer treatment due to their ability to induce apoptosis[55].
Normal cell
Initiated cell
Prevent further DNA damage Induces apoptosis
Preneoplasts
Prevent further DNA damage, Induces apoptosis cell cycle arrest Inhibit angiogenesis
Metastasis
Tumour
Prevent further DNA damage, Inhibit angiogenesis, Inhibit invasion
Fig XIII: Multistage of carcinogenesis and potential effects of polyphenols on cancer progression [55] Flavonoids have been shown to be highly effective scavengers of most types of oxidizing molecules, including singlet oxygen and various free radicals, which are possibly involved in DNA damage and tumor promotion. Flavonoids may also have a beneficial effect through their impact on the
OH
OH OH OH HO HO O HO O OH OH OH OH O OH O OH O O
OH
bioactivation of carcinogens.
O
The flavonols quercetin (fig XV), kaempferol (fig XIV) and galangin, and the flavones apigenin (fig XVI) have been reported to inhibit cytochrome P450 enzymes of the CYP1A family.
Quercetin (fig XIV) and naringin (fig XVII) have also been shown to inhibit CYP3A4, which is the most abundant P450 enzyme in the liver and beneficial in metabolizing a significant number of carcinogens and medications
[16].
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human diet and it gets extensively metabolized during absorption in the small intestine and in the liver, and thus exerts a dose-dependent inhibitory effect on cell proliferation activity of
[55].
has been speculated that this classical hydrogendonating antioxidant activity cannot account for the bioactivity of flavonoids in the brain as they are present in very low concentrations. Instead, it has been postulated that their effects in the brain is mediated by an ability to protect vulnerable neurons, enhance existing neuronal function, stimulate neuronal regeneration and induce neurogenesis. Indeed, it has become evident that flavonoids are able to exert neuroprotective actions even at low concentration via their interactions with critical neuronal intracellular signalling pathways pivotal in controlling neuronal survival and differentiation, long-term potentiation and memory. Early indications regarding the ability of flavonoids to impact upon brain function were reported in the 1950s, with flavones reported
[14].
studies have shown that tea catechins increase the several enzymes, such as glutathione reductase, glutathione peroxidase, glutathione S-reductase, catalase, and quinone reductase
[16, 55].
In estrogen-dependent
tumor cells or animal models, this anti-proliferative effect has been related to the antiestrogenic properties of certain flavonoids (e.g., isoflavonoids, quercetin). In other in vitro models, flavonoids have also been to affect cell-signaling and cell cycle progression. For example, tea flavonoids inhibit signal transduction pathways mediated by epidermal growth factor and platelet-derived growth factor, favorably affecting downstream events such as angiogenesis. Genistein (fig XVIII) and quercetin inhibit protein tyrosine kinase which is also involved in cell proliferation [16, 55,
56].
to
act
as
novel
brain-stem
stimulants
particular isoflavones such as genistein might be detrimental to memory processes in the brain due to their ability to act as tyrosine kinase inhibitors. Researches revealed that isoflavones results in positive effects on neuro-cognitive functions which is apparent in post-menoupausal women. Activation of
have been shown to cause cell cycle arrest and apoptosis by a p53-dependent mechanism [52].
OH OH O OH HO O HO
both synaptic plasticity and new neural growth may act together to enhance memory and cognition as shown in fig (XX) [57]. It has been found that flavonoids subclasses flavonols, flavanols, flavanones, flavones and anthocyanins do not exert exert oestrogen like effects and thus cannot influence memory and cognition via similar
OH
O OH O
In a nutshell, multiple mechanisms have been identified for the anti-neoplastic effects of flavonoids, including antioxidant, anti-inflammatory and antiproliferative activities, inhibition of bioactivating enzymes, and induction of detoxifying enzymes [52]. Ghasemzadeh et al., studies have shown that some flavonoids components such as quercetin had
mechanism.
SENSORY INFORMATION (EXPERIENCE) AFFERENT NERVE INPUT
Increased Blood flow FLAVONOIDS Angiogenesis Neurogenesis Old neurons Neuronal Maturation Functional integration New Synapses Memory Immature neurons
anticancer activities and were able to inhibit cancer cell growth [46]. 7. Effect of flavonoids on memory: Flavonoids in treatment of memory cognition: Historically, the biological actions of flavonoids to their ability to exert antioxidant actions. However, it
33
Fig XX: Overview of functions of flavonoids on memory system[57] Jan-Mar 2011 Vol 1 Issue 1
Jung et al., showed that quercetin at a dose of 10, 20, 40 mg/kg p.o. impairs cognitive function by suppressing pAkt and pCaMKII thus decreasing pCREB expression in hippocampus [49]. Maher et al., reported fisetin to facilitate memory by activating ERK and inducing cAMP response elementbinding protein phosphorylation [58]. 8. Effect of flavonoids on allergy: Flavonoids in treatment of allergy: Flavonoids inhibit cyclic AMP phosphodiesterase and calciumdependent ATPase which are responsible for histamine release from mast cells and basophils [11].
FLAVONOID
PREVENT ALLERGY
Fig (XXI): Effect of flavonoids on allergy The fig (XXI) depicts the mechanism of flavonoids in allergy. Quercetin prevents immune cells
[59]
and
inhibits both the production and release of histamine and is useful in allergic conditions like asthma, hayfever etc [60]. 9. Effect of flavonoids on depression: Etiology of Depression: Depression is caused by functional deficiency of monoamine transmitters at certain sites in brain [51] as shown in fig (XXII).
STRESS
GLUTAMATE
NA
5- HT
BDNF
CRF release
Hypothalamus
NMDA receptor
2 receptor
5HT1A
TrkB receptors
ACTH hormone
transcription response + _
Neural apoptosis
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34
Flavonoids in treatment of depression: Flavonoids have found to be ligands for GABAA receptors in the central nervous system and it led to hypothesis that they act as benzodiazepine-like molecules. Many flavone derivatives were found to be ligands for the GABAA receptors in the CNS; and thus they bind to the benzodiazepine binding site with resulting depressant actions in mice anticonvulsant. Considering the
[7].
propolis. It has been reported to possess inhibitory actions against Aspergillus tamarii, Aspergillus flavus, Cladosporium sphaerospermum, Pencillium digitatum, Penicillium italicum [10]. 5,7,4-trihydroxy-8-methyl-6-(3-methyl-[2-butenyl])2S-flavonone texana isolated from shrub Eysenhardtia and flavonoids 7-hydroxy-3,4-
also found to possess sedative action, tranquilizers, sedative, spontaneous locomotor activity and thiopental-induce sleeping time effects obtained with the flavonoid glycosides, the following decreasing order of action results: 2S-hesperidin>linarin>rutin>diosmin\cong2Sneohesperidin> gossypin2S-naringin.
(methylenedioxy) flavan isolated from Termanalia bellerica possess antifungal activity against Candida albicans. 6,7,4-trihydroxy-3,5-dimethoxyflavone and 5,5-dihydroxy-8,2,4-trimethoxyflavone are effective against Aspergillus flavus [10]. Nobiletin and langeritin isolated from peelings of tangerine orange showed fungistatic action towards Deuterophoma tracheiphila while
[43].
hesperidin
Position of the sugar on the flavonoids nucleus seems relevant as well and position-7 is the most effective but the presence of a double bond between carbons 2 and 3, resulting in flavone derivatives with planar configuration (i.e. linarin) does not appear to be critical for activity. Flavonoid glycosides form the newest group within the growing family of flavonoids with activity on the CNS [7]. Yi et al., reviewed that dietary flavonoids possess multiple neuroprotective actions in Central nervous pathophysiological conditions including depression and it was reported that naringenin possess potent antidepressant-like property via central seotonergic and noradrenergic system. It was further suggested that dietary flavonoids possess a therapeutic potential in disorders especially where monoaminergic system is involve [61]. 10. Effect of flavonoids on antimicrobial activity: Flavonoids have been used extensively since centuries for the treatment of various diseases. Propolis has been used referred even in old testament for its healing properties. The antimicrobial activity of propolis has been attributed to its high flavonoids content. Galangin is a flavonol commonly found in
35
Quercetin, naringenin are reported to be inhibitors of Bacillus subtilis, Candida albicans, Escherichia coli, Staphylococcus nervous, Staphylococcus epidermis, Saccharomyces cerevisiae [62]. Rattanachaikunsopon et al., isolated morin-3-Olyxoside, leaves and morin-3-O-arabinoside, from reported bacteria coli, that these quercetin, guajava possess Bacillus four quercetin-3-O-arabinoside Psidium
bacteriostatic action action against all foodborne pathogenic Escherichia Pseudomonas including Listeria stearothermophilus, Brochothrix thermosphacta, monocytogenes, enteric,
[63].
fluorescens,
Salmonella
Flavonones having sugar moiety showed antimicrobial activity while none of the flavonols and flavonolignans showed inhibitory activity on microorganisms. Quercetin has been reported to completely inhibit growth of Staphylococcus aureus [43].
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1.
Antibacterial activity
2.
Antiviral activity
3.
Antifungal activity
11. Flavonoids in treatment of cardiovascular diseases: Cardiovascular diseases are today the principal cause of death in both developing and developed countries. CVS diseases include atherosclerosis, coronary heart disease, arterial hypertension, and heart failure. The major reason behind CVS diseases is oxidative stress. Oxidative stress is a condition of imbalance between endogenous oxidants and reactive oxygen/nitrogen species (RONS) with predominance of reactive species. Etiology of Cardiovascular Diseases:
transformation of xanthine dehydrogenase into ROS producing xanthine oxidase (XO) play important role
[16].
Common consequences of AMI are heart failure and arrhythmias. Here again, ROS can mediate the cardiac hypertrophy and patients with heart failure have an increased production of ROS. Similarly, ROS, and in particular the superoxide radical, may play an important role in the genesis of some arrhythmias. Patients with arterial hypertension have an increased oxidative stress status [64]. Flavonoids in treatment of CVS: Studies ensure that long-term administration of flavonoids can decrease, or tend to decrease the incidence of cardiovascular diseases and their consequences.
Atherosclerosis involves modification of LDL particles by oxidative stress with subsequent induction of inflammation which is caused by increased leucocyte adherence [16]. Endothelial dysfunction with increased platelet aggregation facilitates procoagulation, which may induce a thrombosis resulting in an acute myocardial infarction. In the ischemic phase of AMI platelet aggregation, the activation of neutrophils, an increase in cellular free redox active iron, and the
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Flavonoid consumption prevent many cardiovascular diseases including hypertension and atherosclerosis. Quercetin protects LDL against oxidative modifications effect. 7-monohydroxyethylrutoside and 7, 3, 4-trihydroxyethylrutoside are reported to be cardioprotective
[43].
stimulate Ca2+ uptake from isolated islet cells thus suggesting it to be effective even in non-insulin dependent diabetes [43]. Li et al., indicated that flavonoids in Ipmoea batalas leaf possesses antidiabetic activity against alloxaninduced diabetes at a dose of 100 mg/kg [67]. Sriram et al., reported fisetin to be a therapeutic agent for treatment of diabetes mellitus at a dose of 10 mg/kg [68]. 13. Effect of flavonoids in treatment of hepatotoxicity: Role of flavonoids in treatment of hepatotoxicity: Flavonoids bind to subunit of DNAdependent RNA polymerase I, thus activating the enzyme. As a result, protein synthesis gets increased leading to regeneration and production of hepatocytes
[11].
12. Effect of flavonoids on diabetes mellitus: Etiology of diabetes mellitus: Diabetes mellitus is a serious chronic disease. Effective control of the blood glucose level is a key step in preventing or reversing diabetic complications and improving the quality of life in both types 1 and 2 diabetic patients
[65].
Flavonoids in treatment of diabetes mellitus: All flavonoids cannot cure diabetes mellitus because most types of this disease are basically genetic and no single drug can correct an inborn error. However, flavonoids can ameliorate some of the consequences of diabetes mellitus
[66]. [16].
Silymarin,
apigenin,
quercetin,
naringenin
are
reported to be potent therapeutic agents against microcrystin LR-induced hepatotoxicity. Rutin and venoruton are reported to show regeneration and hepatoprotective effects in experimental cirrhosis [43]. Gulati et al., studied hepatoprotective studies on
identified to be good inhibitors of aldose reductase The fig (XXIII) depicts the mechanism of flavonoids in diabetes mellitus.
(-) Aldose reductase, Regenerate pancreatic islets, (+) insulin release, (+) Ca++ uptake PREVENT DIABETES MELLITUS
FLAVONOID
Phyllanthus emblica and quercetin and quercetin and found that if the extract is producing hepatoprotection at a dose of 100 mg/ 100 g p.o., then quercetin is producing hepatoprotection at a dose of 15 mg/ 100 g p.o.; thus concluding that quercetin is a potent hepatoprotective agent [69]. Kim et al., isolated isovitexin, hirustin, trifolin, avicularin and quercetin. It was observed that hirustrin, avicularin, quercetin possess hepatoprotective action against t-BHP in HepG2
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Fig (XXIII): Effect of flavonoids on diabetes mellitus It has been reported by several researchers that quercetin possess antidiabetic activity and it has been found that it brings about regeneration of pancreatic islets and increases insulin release in streptozotocininduced diabetes. Also, it has been reported to
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[10].
Flavonoids
are found to be toxic to cancer or immortalized cells Due to the low solubility of flavonoid aglycones in water, to the short residence time of flavonoids in the intestine, and to the low coefficient of absorption, it is not possible for humans to suffer acute toxic effects from the consumption of flavonoids, with the exception of a rare occurrence of allergy. The margin of safety for the therapeutic use of flavonoids in humans, therefore, is very large and probably not surpassed by any other drug in current use [16]. CONCLUSION Flavonoids constitute a wide array of biological active compounds that are found abundantly in plant kingdom and dietary intake. They are gaining interest due to their wide variants and number of members. These are reported to be effective in pathogenesis of majority of disases. Antioxidant activity is the foundation of many actions which lead to its beneficial effects in majority of the diseases. used in
Oh et al., 2004 reported that among various flavonoids i.e. apigenin, luteolin, kaempherol-3-Oglucoside and quercetin-3-O-glucoside isolated from Equisetum arvense, onitin and luteolin exhibited hepatoprotective activity against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells [57]. Toxicological Profile of flavonoids: Flavonoids are widely distributed in edible plants and beverages toxic and have been previously traditional medicines, so they are believed to be non[10, 15].
possess a diverse range of activities in mammalian cells. So, in-vivo confirmation of their side effects would be necessary for full evaluation of their practical usefulness in the field of modern medicine. Given that the selectivity of flavonoids for eukaryotic enzymes toxicity appears is to vary to from be compound on to compound, a study regarding assessment of its required done these
Reference 41, 43 41 41, 43 54, 53 50, 52 43, 54 43 16 16 16,55, 51 46, 52 16, 55 49 49 58 61 7 43 68, 41 58, 59 41 41 69, 71 71 71 41
4.
Cancer
5. 6. 7. 8. 9. 10. 11.
Thrombosis
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