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Recent Updates on Free Radicals Scavenging Flavonoids: An Overview

Vivek Kumar Gupta, Rachna Kumria, Munish Garg and Monika Gupta
 
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ABSTRACT

Flavonoids are low molecular weight, polyphenolic compounds present in majority of vascular plants, possessing many therapeutic activities vis a vis antioxidant activity. The present review discuss the chemical nature, mechanism of action, current status, pharmacodynamic/pharmacokinetic studies, industrial significance, nutritive value in health system and analysis of flavonoids with the recent technology.
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Vivek Kumar Gupta, Rachna Kumria, Munish Garg and Monika Gupta, 2010. Recent Updates on Free Radicals Scavenging Flavonoids: An Overview. Asian Journal of Plant Sciences, 9: 108-117.

DOI: 10.3923/ajps.2010.108.117

URL: https://scialert.net/abstract/?doi=ajps.2010.108.117
 
Received: January 28, 2010; Accepted: March 17, 2010; Published: June 02, 2010

INTRODUCTION

Reactive Oxygen Species (ROS) including superoxide radicals, hydroxyl radicals, singlet oxygen and hydrogen peroxide are often generated as byproducts of biological reactions or from exogenous factors (Cerutti, 1991). These ROS may be very damaging and attack lipids in cell membranes and also attack DNA, inducing oxidation that causes membrane damage such as membrane lipid peroxidation (Cerutti, 1994; Pietta, 2000; Kumar and Sharma, 2006). Lipid peroxidation has been implicated in the pathogenesis of a number of diseases like arthritis (Naik, 2003), diabetes (Yagi, 1987), cancer (Rekha et al., 2001), atherosclerosis (Tiwari, 2001), neurodegenerative diseases (Thomas and Kalyanaraman, 1997), etc. Definitely, many synthetic antioxidant components have shown toxic and/or mutagenic effects, which have shifted the attention onto the naturally occurring antioxidants (Gupta and Sharma, 2010a,b; Kumar and Sharma, 2006). Flavonoids and their synthetic analogues have been intensely investigated and found the prominent role in the treatment of ovarian, breast, cervical, pancreatic and prostate cancer, in recent years. Their use has mainly centred on prevention and the maintenance of health (Aruoma and Cuppet, 1997). The recognized dietary antioxidants are vitamin C, vitamin E, selenium, carotenoids (beta carotene), etc. However, recent studies have demonstrated that flavonoids found in fruits and vegetables may also act as antioxidants. Like alpha-tocopherol (vitamin E), flavonoids contain chemical structural element that may be responsible for their antioxidant activities (Di Carlo et al., 1999). Flavonoids generally occur in plants as glycosylated derivatives and impart different color shades (blue, scarlet and orange in leaves, flowers and fruits (Brouillard and Cheminat, 1988). Flavonoids are major components of citrus fruits and several other medicinal plants and have been used in traditional medicine around the world (Winston, 1999; Di Carlo et al., 1999; Kadarian et al., 2002; Pascual et al., 2001; Samuelsen, 2000). Many families have been reported to have isoflavonoids in addition to Leguminosae. The spectrum of isoflavonoid producing taxa includes the representatives of four classes of multicellular plants, namely the Bryopsida, the Pinopsida, the Magnoliopsida and the Liliopsida. Isoflavonoids in non-leguminous families provided listing of 164 isoflavonoids altogether reported in 31 non-leguminous angiosperm families (Mackova et al., 2006).

CHEMICAL NATURE OF FLAVONOIDS

Flavonoids are polyphenolic compounds are ubiquitous in nature and categorized into many classes according to their chemical structure. Over 4000 flavonoids have been identified, many of which occur in the fruits, vegetables and beverages (tea, coffee, beer, wine and fruit drinks) (Aruoma and Cuppet, 1997). The flavones apigenin (3b) and luteolin (3a) are common in cereals grains and in aromatic herbs viz., rosemary, thyme, parsley etc. (Pietta et al., 1995). The flavonols quercetin (4b) and kaempferol (4c) are usually present in vegetables and fruits. Flavonoids are formed in the plants from the aromatic amino acids phenylalanine and tyrosine and malonate. Isoflavones are found mostly in legumes (soyabeans, black beans, green beans and chick peas) (Herman, 1976). Flavan oligomers (proanthocyanidins) are found in apples, grapes, berries, barley grains etc. (Franke et al., 1994). Anthocyanidins and their glycosides (anthocyanins) are abundant in berries and red grape (Haslam, 1989). Some major food sources (Hollman and Katan, 1999) are given in Table 1.

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Fig. 1: Chemical structures of the major classes of flavonoids

Table 1: Major food sources of flavonoids
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The basic structural unit of the flavonoid family comprises two benzene rings (A and B) (1) as shown in Fig. 1 linked through a heterocyclic pyran or pyrone ring (C), variation in the C ring and hydroxylation pattern on the A and B rings define the major classes (Cook and Samman, 1996) including Isoflavones (genistein) (2a), Flavones (luteolin) (3a), Flavonols (quercetin) (4b), Flavan-3-ols (epicatechin) (5b), Flavanones (naringenin) (6a), Anthocyanidins (cyanidin) (7). The in vitro anticancer assay with synthetic compounds of structurally related subcategories of flavonoids (viz., flavones, isoflavones, xanthones) indicated the maximum activity with xanthones and least with isoflavones, however, flavones exhibited more significant activity than isoflavones and less significant when compared with xanthones (Wang et al., 2005).

DIETARY AND INDUSTRIAL SIGNIFICANCE OF FLAVONOIDS

The flavonoids exert potential beneficial effects on health (Table 2), extensively employed in the various formulations in the industry and may also be obtained from the diet (dietary flavonoids). In addition to outstanding anti-oxidant activity, flavonoids possess a profound inhibitor action on the formation of lipid peroxides both in vitro (Carini et al., 1992; Villa et al., 1992) as well as in vivo (Chen et al., 1990; Cholbi et al., 1991; Uchida et al., 1988). However, the range of dietary flavonoids varies from low content (<1 mg/100 g) to high content (5-35 mg/100 g) depending upon the biological source (Table 3). Quercetin, kaempferol, myricetin, luteolin, apigenin are some important examples of flavonoids, present in the dietary sources (Hertog et al., 1992, 1993). In addition to these dietary sources, there are a number of plants, which are not the part of diet, used in therapeutics, but having appreciable flavonoidal content like beverages such as wine (red wine), tea, beer etc. (Larson, 1988). Flavonoids are present in a number of drugs/plants, they may occur in any part of the plant but, generally found in more concentration in leaves or flowers (Table 4).

Table 2: Flavonoids showing activities other than antioxidant activity
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Table 3: Dietary sources of flavonoids
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Table 4: Description of some important flavonoidal drugs
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Rutin, a flavonoid, bearing pronounced therapeutic activity, widely used in the industry. It is well documented the plants viz. Saphora japonica L. (Fabaceae), Fagopyrum esculentum Moench. (Polygonaceae), Eucalyptus macrorrhynca F. Muell. (Myrtaceae) are been used at large in industry for extraction of rutin (Bruneton, 1995). Flavonoids, tannins and/or polyphenolic compounds found in some Ficus spp. also showed antoxidant or free radicals scavenging activity (Sharma and Gupta, 2007a, b, 2008).

PHARMACOKINETIC/PHARMACODYNAMIC STUDIES OF FLAVONOIDS

It has been proved that flavonoids from dietary sources exert significant antioxidant effect. It is believed that flavonol, flavone and isoflavone glycosides are initially hydrolyzed to their respective aglycones (Manach et al., 1996; Nielsen et al., 1997).

Table 5: Flavonoidal content of tea
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The glycoside quercetin-3-rutinoside was detected in the blood (after consumption of tomato puree) (Mauri et al., 1999), naringin (4’, 5, 7-trihydroxyflavanone-7-rhamnoglucoside) in urine (after taking naringin orally) (Ishii et al., 2000), epigallocatechin gallate and epicatechin gallate detected in human blood after intake of green tea (green tea has more flavonoidal content as compare to black tea (Anonymous, 1991) (Table 5), decaffeinated green tea extracts and dark chocolates (Michelle et al.,1999; Nakagawa and Miyazawa, 1997; Unno et al., 1996). So, all these facts support that glycosides are absorbable.

Absorption of flavonoids (flavonols, flavones, isoflavones and catechins) in the human body takes place in two ways; first, a small portion of it transformed into their glucouronides and sulfates (King and Brusill, 1998). This small fraction of the absorbed flavonoids is metabolized by the liver enzymes, resulting in more polar conjugates being excreted in the urine or returned to the duodenum via gall bladder. However, the major part of the ingested flavonoids is not absorbed and is largely degraded by the intestinal microflora. The bacterial enzymes catalyze several reactions including hydrolysis, dehydrogenation, cleavage of the heterocyclic oxygen containing ring, decarboxylation etc. In this way several phenolic acids are produced (Pietta et al., 1997). These phenolic acids can be reabsorbed and account a large fraction of the ingested flavonoids (30-60%). Phenolic acids bearing catechol structure possess a radical scavenging ability comparable to that of their intact precursors (Merfort et al., 1996).Further, TEAC values of these metabolites confirm their antioxidant potential (Pietta et al., 2000).

Flavonoids/polyphenolic rich su bstances of natural origin will always exert beneficial therapeutic effects, is not true all times. The most suitable example is tree nuts, a rich source of tocopherols, total phenols, containing wide variety of flavonoids and proanthocyanidins, has not been reported significant antioxidant in vivo (Bolling et al., 2010). Absorption is the other important aspect, which could not be neglected as there are many flavonoids which are poorly absorbed and could not justify their therapeutic potential. So, this area needs to be explored further. However, The clinical applicabilities of polyphenols and other poorly absorbed plant medicines can be improved by phytosome technology which creates intermolecular bonding between individual polyphenol molecules and one or more molecules of the phospholipids, phosphatidylcholine (Kidd, 2009). Research based on strategies to determine phenolic acids and flavonoids in biological fluids, beverages, plant and food exudates may explore the applications in a better way, which is need of the day.

MECHANISM OF ACTION

The free radical scavenging activity of flavonols, flavones and anthocyanins have been reported through various in vitro models (Afanasev et al., 1989; Cui et al., 2002; Dobask et al., 1999; Duthie and Doboson, 1999; Formica and Regelson, 1995; Kerr et al., 1999; Mahesh and Menon, 2004; Pataki et al., 2002; Pietri et al., 1997; Yamashiro et al., 2003). Flavonoids act as antioxidant due to having more number of target sites for free radicals in the oligomeric compounds produced from their semiquinone radicals (Rohdewald, 2002; Bors and Michel, 1999; Bors et al., 2000; Robak and Gryglewski, 1988). Chemically, flavonoids are single electron donors. In in vitro cell culture, flavonoids have good antioxidant potential as they serve as derivative of conjugated ring structures and hydroxyl groups. They act as antioxidant by scavenging superooxide anion (Husain et al., 1987), singlet oxygen (Wang and Goodman, 1999) and lipid peroxyl radicals (Fuchs et al., 1989; Lotito and Frei, 2004).

In addition to their free radical scavenging activity, flavonoids enhance intracellular antioxidant defense against free radicals by increasing production of antioxidative enzymes (Bayeta and Lau, 2000; Kandaswami and Middleton, 1994; Lewis, 1993; Wei et al., 1997). Flavonoids inhibit the enzymes responsible for superoxide anion production, such as xanthine oxidase (Hanasaki et al., 1994) and protein kinase C (Ursini et al., 1994). Flavonoids have also been shown to inhibit cyclooxygenase, lipoxygenase, microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase and NADH oxidase, all involved in reactive oxygen species generation (Brown et al., 1998; Korkina and Afanasev, 1997).

Due to their lower redox potentials (Jovanoic et al., 1994) flavonoids (Fl-OH) are thermodynamically able to reduce highly oxidizing free radicals with redox potentials in the range 2.13-1.0 V (Buettner, 1993), such as superoxide, peroxyl, alkoxyl and hydroxyl radicals by hydrogen atom donation:where, R• represents superoxide anion, peroxyl, alkoxyl and hydroxyl radicals (Husain et al., 1987; Robak and Gryglewski, 1988; Terol et al., 1986). The aroxyl radical (Fl-Oÿ) may react with second radical, acquiring a stable quinone structure (Fig. 2).

Fl-OH + R• Fl-O + RH

The aroxyl radicals could interact with oxygen, generating quinines and superoxide anion, rather than terminating chain reactions. The last reaction may take place in the presence of high levels of transient metal ions and is responsible for the undesired prooxidant effect of flavonoids (McCord, 1995). So, it shows the flavonoids to act as antioxidants depends not only on the redox potential of the couple Fl-O•/Fl-OH but also on possible side reactions of the aroxyl radical. Scavenging of superoxide is particularly important, because the radical is ubiquitous in aerobic cells and, despite its mild activity, is a potential precursor of the hydroxyl radical in the Fanton and Haber-Weiss reactions (Cao et al., 1997).

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Fig. 2: Scavenging of ROS (R*) by flavonoids

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Fig. 3: Flavonoids lead to brain development by targeting astrocytes

Flavonoids present in diet are natural antioxidants and possess the potential to stabilize various radicals (oxygen-cenered, carbon-centered, alkoxyl peroxyl, or phenoxyl radicals) and ROS involved in oxidative processes through hydrogenation or complexing with oxidizing species (Nones et al., 2010; Shahidi and Wanasundara, 1992).

Some scientists strongly believe that the physiological benefits of flavonoids is not due to their antioxidant and free radical scavenging effects rather to their capability to target to astrocytes especially in brain development, as astrocytes are pivotal characters in neurodegenerative diseases and brain injury (Fig. 3) (Hackl et al., 2002).

ANALYSIS OF FLAVONOIDS

There are many reports that plant-derived phenolic compounds such as flavonoids have antioxidant properties capable of reducing the risk of developing age related diseases such as atherosclerosis, Alzheimer and osteoarthritis. Many herbal formulation have been prepared and therapeutic effects and flavonoidal content was successfully analyzed through thin-layer chromatography and high performance thin layer chromatography (Pendry et al., 2005).

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Fig. 4: Various techniques involved in analysis of flavonoids

A study was conducted in Taiwan on harvested soybeans to determine major and minors of isoflavones, after subjected to methanol-H(2)O extraction and HPLC analysis with the acetic acid-acetonitrile mobile phase. Among the detected soybeans, daidzin, genistin, malonyldaidzin and malonylgenistin were the majors and glycitin, malonylglycitin, daidzein and genistein were the minors of isoflavones (Tsai et al., 2007). Flavonoids can also be satisfactorily determined by capillary electrophoresis with wall-jet amperometric detection by monitoring the effects of several important factors, such as the running buffer and its corresponding pH and concentration, separation voltage, injection time to acquire the optimum conditions for separation of the flavonoids (Fig. 4) (Xu et al., 2006).

It is well documented that flavonoids (quercetin, rutin, etc.) after absorption produce good therapeutic effect in a number of other ailments also, apart from antioxidant activity (Table 6).

NUTRITIVE VALUE OF FLAVONOIDS

The flavonoids have been used over a period of time in other ailments (Table 2, 6) except as an antioxidant. Tea, the top drink in the world, has flavonoids which act as antioxidants. Apple provides the most concentrated food source of flavonoids, a group of phytochemicals, believed to protect against cancer, heart disease and other serious health problems, lending some truth to the old adage an apple a day keeps the doctor away. Blueberries are another good source of antioxidants, especially good for healthy eyesight. Recent studies have found that chocolate may actually be a healthy food because it provides plenty of flavonoids which are reported to be more effective than tea. Soybean isoflavones are structurally similar to estrogen and exhibit weak estrogenic activity (Ishimi, 2009).

Table 6: Diseases treated with flavonoids
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It was claimed after experimentation on female rats that the administration of a soy extract containing isoflavones prevents oxidative changes in hepatocytes isolated from old ovariectomized female rats, without modifying uterus weight (Castillo et al., 2006). Some epimeric new triterpenoid such as 3alpha-hydroxy-20-oxo-30-norlupane and new flavanone (nubatin; 3) have not been successfully isolated from Salvia species rather these metabolites were found to be moderately bio-active also (Ali et al., 2005).

CONCLUSION

Vitamin C, E, selenium, carotenoids are well known antioxidants however they do not come under flavonoids but constitute a vital part of our diet. The total daily intake of these dietary antioxidants is quite low, vitamin C (70 mg), vitamin E (7-10 mg) or carotenoids (2-3 mg) as compared to the flavonoids (50-800 mg), which makes a substantial contribution to the antioxidant defense system. There is adequate clinical evidence that flavonoids exert crucial therapeutic effects, many of which have been used in traditional systems of medicine for thousands of years. But, their full potential is yet to be recognized in all aspects. The utility of flavonoids in medicines should be elaborated. More pharmacokinetic and pharmacodynamic studies are required to define the protective role of flavonoids by scavenging free radicals in the mammalians.

REFERENCES
  1. Afanas'ev, I.B., A.I. Dorozhko, A.V. Brodshi, V.A. Kostyak and A.I. Potaporitch, 1989. Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem. Pharmacol., 38: 1763-1769.
    PubMed  |  


  2. Alarcon de la Lastra, C., M.J. Martin, C. La-Casa and V. Motilva, 1994. Antiulcerogenicity of the flavonoid fraction from Bidens aurea: Comparison with ranitidine and omeprazole. J. Ethnopharmacol., 42: 161-168.
    CrossRef  |  PubMed  |  Direct Link  |  


  3. Alcaraz, M.J. and M.L. Ferrandiz, 1987. Modification of arachidonic methabolism by flavonoids. J. Ethnopharmacol., 21: 209-229.
    CrossRef  |  


  4. Ali, M.S., S. Ahmed, S.A. Ibrahim and R.B. Tareen, 2005. Characterization and bioscreening of a new triterpenoid and a flavanone isolated from Salvia nubicola. Chem. Biodivers., 2: 910-916.
    Direct Link  |  


  5. Anonymous, 1991. Coffee, Tea, Mate and Methylxanthines-Methylglyoxyl: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 51, IARC, Lyon, France, pp: 207-271


  6. Aruoma, O.I. and S.L. Cuppett, 1997. Antioxidant Methodology in vivo and in vitro Concepts. AOCS Press, Champaign, Illinois, pp: 41-172


  7. Phyllis, B. and B. James, 2000. Prescription for Nutritional Healing. 3rd Edn., Avery Publishing Group Inc., USA., ISBN-13: 978-1583330777, pp: 784
    Direct Link  |  


  8. Bayeta, E. and B.H.S. Lau, 2000. Pycnogenol inhibits generation of inflammatory mediators in macrophages. Nutr. Res., 20: 249-259.
    Direct Link  |  


  9. Bolling, B.W., D.L. McKay and J.B. Blumberg, 2010. The phytochemical composition and antioxidant actions of tree nuts. Asia Pac. J. Clin. Nutr., 19: 117-123.
    PubMed  |  Direct Link  |  


  10. Bors, W. and C. Michel, 1999. Antioxidant capacity of flavanols and gallate esters: Pulse radiolysis studies. Free Radic. Biol. Med., 27: 1413-1426.
    Direct Link  |  


  11. Bors, W., C. Michel and K. Stettmaier, 2000. Electron paramagnetic resonance studies of radical species of proanthocyanidins and gallate esters. Arch. Biochem. Biophys., 374: 347-355.
    CrossRef  |  Direct Link  |  


  12. Brouillard, R. and A. Cheminat, 1988. Flavonoids and plant color. Prog. Clin. Biol. Res., 280: 93-106.
    Direct Link  |  


  13. Brown, J.E., H. Khodr, R.C. Hider and C. Rice-Evans, 1998. Structural dependence of flavonoids interactions with Cu2+ ions: Implications for their antioxidant properties. Biochem. J., 330: 1173-1178.


  14. Bruneton, J., 1995. Pharmacognosy, Phytochemistry, Medicinal Plants. Lavoisier Publishing, Paris, ISBN-13:9782743000288, Pages: 915


  15. Buettner, G.R., 1993. The pecking order of free radicals and antioxidants: Lipid peroxidation, α-tocopherol and ascorbate. Arch. Biochem. Biophys., 300: 535-543.
    CrossRef  |  PubMed  |  Direct Link  |  


  16. Cao, G., E. Sofic and R.L. Prior, 1997. Antioxidant and prooxidant behavior of flavonoids: Structure-activity relationships. Free Radical Biol. Med., 22: 749-760.
    CrossRef  |  Direct Link  |  


  17. Carini, R., A. Comoglio, E. Albano and G. Poli, 1992. Lipid peroxidation and irreversible damage in the rat hepatocyte model: Protection by the silybin-phospholipid complex IdB 1016. Biochem. Pharmacol., 43: 2111-2115.
    CrossRef  |  


  18. Castillo, C., V. Salazar, C. Ariznavarreta, E. Vara and J.A. Tresguerres, 2006. Effect of isoflavone administration on age-related hepatocyte changes in old ovariectomized femal Wistar rats. Phytomedicine, 13: 468-476.
    PubMed  |  


  19. Cerutti, P., 1994. Oxi-radicals and cancer. Lancet, 344: 862-863.
    Direct Link  |  


  20. Cerutti, P.A., 1991. Oxidant stress and carcinogenesis. Eur. J. Clin. Invest., 21: 1-5.
    CrossRef  |  PubMed  |  Direct Link  |  


  21. Chaumontet, C., M. Suschetet, E. Honikman-Leban, V.A. Krutovskikh and R. Berges et al., 1996. Lack of tumor-promoting effects of flavonoids: Studies on rat liver preneostatic foci and on in vitro gap junctional inter cellular communication. Nutr. Cancer, 26: 251-263.
    Direct Link  |  


  22. Chen, V.T., R.L. Zheng, Z.J. Jia and Y. Ju, 1990. Falvonoids as superoxide scavengers and antioxidants. Free Radic. Biol. Med., 9: 19-21.
    CrossRef  |  


  23. Cholbi, M.R., M. Paya and M.J. Alcaraz, 1991. Inhibitory effects of phenolic compounds on CCl4-induced microsomal lipid peroxidation. Cell. Mol. Life Sci., 47: 195-199.
    CrossRef  |  Direct Link  |  


  24. Cook, N.C. and S. Samman, 1996. Flavonoids-chemistry, metabolism, cardioprotective effects, and dietary sources. J. Nutr. Biochem., 7: 66-76.
    CrossRef  |  Direct Link  |  


  25. Craig, W.J., 1999. Health-promoting properties of common herbs. Am. J. Clin. Nutr., 70: 491S-499S.
    PubMed  |  Direct Link  |  


  26. Cui, J., G.A. Cordis, A. Tosaki, N. Maulik and D.K. Das, 2002. Reduction of myocardial ischemia reperfusion injury with regular consumption of grapes. Ann. N. Y. Acad. Sci., 957: 302-307.
    Direct Link  |  


  27. Di Carlo, G., N. Mascolo, A.A. Izzo and F. Capasso, 1999. Flavonoids: Old and new aspects of a class of natural therapeutic drugs. Life Sci., 65: 337-353.
    CrossRef  |  PubMed  |  Direct Link  |  


  28. Dobask, P., C. Courderor-Masuyer, M. Zeller, C. Vergely and A. Laubriet et al., 1999. Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J. Cardiovasc. Pharmacol., 34: 651-659.
    Direct Link  |  


  29. Duthie, S.J. and V.L. Doboson, 1999. Dietary flavonoids protect human colonocyte DNA form oxidative attack in vitro. Eur. J. Nutr., 38: 28-34.
    Direct Link  |  


  30. Felicia, V.S., G. Najla, P.C. Ann, M. Mandeleine and K.C. Keneeth, 1996. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenisis by flavonoids and citrus juices. Nutr. Cancer, 26: 167-181.
    Direct Link  |  


  31. Formica, J.V. and W. Regelson, 1995. Review of the biology of quercetin and related bioflavonoids. Food Chem. Toxicol., 33: 1061-1080.
    CrossRef  |  PubMed  |  


  32. Franke, A.A., L.J. Custer, C.M. Cerna and K.K. Narala, 1994. Quantitation of phytoestrogens in legumes by HPLC. J. Agric. Food Chem., 9: 1905-1913.
    Direct Link  |  


  33. Boege, F., T. Straub, A. Kehr, C. Bosenberg and K. Christiansen et al., 1996. Selected novel flavones inhibit the DNA binding or the DNA relegation step of eukaryotic topoisomerase I. J. Biol. Chem., 271: 2262-2270.
    Direct Link  |  


  34. Fuchs, J., M.E. Huflejit, L.M. Rothfuss, D.S. Wilson, G. Carcama and L. Packer, 1989. Impairment of enzymic and non-enzymic antioxidants in skin by UVB irradiation. J. Invest. Dermatol., 93: 769-773.
    Direct Link  |  


  35. Gupta, V.K. and S.K. Sharma, 2010. Plants as natural antioxidants. Natural Product Radiance, 5: 326-334.


  36. Gupta, V.K. and S.K. Sharma, 2010. In vitro antioxidant activities of aqueous extract of Ficus bangalensis Linn. Root. Int. J. Biol. Chem., 4: 134-140.
    CrossRef  |  Direct Link  |  


  37. Hackl, L.P., G. Cuttle, S.S. Dovichi, M.T. Lima-Landman and M. Nicolau, 2002. Inhibition of angiotensin converting enzyme by quercetin alters the vascular response to brandykinin and angiotensin I. Pharmacology, 65: 182-186.
    Direct Link  |  


  38. Haslam, E., 1989. Plant Polyphenols: Vegetable Tannins Revisited. Cambridge University Press, Cambridge, UK., pp: 230


  39. Herrmann, K., 1976. Flavonols and flavones in food plants: A review. Int. J. Food Sci. Technol., 11: 433-448.
    CrossRef  |  Direct Link  |  


  40. Hertog, M.G.L., P.C.H. Hollman and B. van de Putte, 1993. Content of potentially anticarcinogenic flavonoids of tea infusions, wines and fruit juices. J. Agric. Food Chem., 41: 1242-1246.
    CrossRef  |  Direct Link  |  


  41. Hertog, M.G.L., P.C.H. Hollman and M.B. Katan, 1992. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands. J. Agric. Food Chem., 40: 2379-2383.
    CrossRef  |  Direct Link  |  


  42. Hollman, P.C. and M.B. Katan, 1999. Health effects and bioavailability of dietary flavonols. Free Radic. Res., 31: S75-S80.
    PubMed  |  Direct Link  |  


  43. Huesken, B.C.P., J. Dejong, B. Beekman and R.C.A. Onderwater, 1995. Flavonoids as cardio protective agents. Cancer Chemother. Pharmacol., 37: 55-62.


  44. Igarashi, K. and M. Ohmuna, 1995. Effect of Isoharnneti, Rhamnetin and Quercetin on the concentrations of cholesterol and lipoperoxide in the serum and liver and on the blood and liver antioxidative enzyme activities in rats. Biosci. Biotechnol. Biochem., 59: 595-601.


  45. Ishii, K., T. Furuta and Y. Kasuya, 2000. Mass spectrometric identification and high performance liquid chromatographic determination of a flavonoids glycoside naringen in human urine. J. Agric. Food Chem., 48: 56-59.
    Direct Link  |  


  46. Ishimi, Y., 2009. Nutrition and bone health. Isoflavones in bone health. Clin. Calcium, 19: 1506-1513.
    Direct Link  |  


  47. Izzo, A.A., G. Dicarlo, N. Mascolo, F. Capasso and G. Autore, 1991. Anti-ulcer effects of flavonoids. Role of endogenous PAF. Phytother. Res., 8: 179-181.


  48. Jager, W., B. Zembsch, P. Wolschann, E. Piettenauer and A.M. Senderovicz et al., 1998. Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases in rat liver. Life Sci., 62: 1861-1873.
    CrossRef  |  


  49. Jovanoic, S.V., S. Steenken, M. Tosic, B. Marjanovic and M.G. Simic, 1994. Flavonoids as antioxidants. J. Am. Chem. Soc., 116: 4846-4851.
    Direct Link  |  


  50. Kadarian, C., A.M. Broussalis, J. Mino, P. Lopez, S. Gorzalczany, G. Ferraro and C. Acevedo, 2002. Hepatoprotective activity of Achyrocline satureioides (Lam.) DC. Pharmacol. Res., 45: 57-61.
    Direct Link  |  


  51. Kandaswami, C. and E. Middleton, Jr., 1994. Free radical scavenging and antioxidant activity of plant flavonoids. Adv. Exp. Med. Biol., 366: 351-376.
    PubMed  |  


  52. Kerr, P.M., S.M. Suleiman and A.P. Halestrap, 1999. Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am. J. Physiol. Heart Circ. Physiol., 276: H496-h502.
    Direct Link  |  


  53. Kidd, P.M., 2009. Bioavailability and activity of phytosome complex from botanical polyphenols: The silymarin, curcumin, green tea and grape seed extracts. Altern. Med. Rev., 14: 226-246.
    Direct Link  |  


  54. King, R.A. and D.B. Brusill, 1998. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am. J. Clin. Nutr., 67: 867-872.
    Direct Link  |  


  55. Kontruck, S.J., T. Radecki, T. Brozozowski, D. Drozdowicz and I. Piastucki et al., 1986. Antiulcer and gastroprotective effects of solon, a synthetic flavonoids detivative of sophorandin. Role of endogenous prostaglandins. Bur. J. Pharmac., 125: 185-192.
    CrossRef  |  


  56. Korkina, L.G. and I.B. Afanas'ev, 1997. Antioxidants in Disease Mechanisms and Therapy. Academic Press, San Diego


  57. Kyo, R., N. Nakalata, I. Sakakifara, M. Kubo and Y. Ohizumi, 1998. Baicalin and baicalein constituents of an important medicinal plant, inhibit intracellular Ca2+ elevation by reducing phospholipase-C activity in C6 rat gliama cells. J. Pharm. Pharmacol., 50: 1179-1182.
    Direct Link  |  


  58. Larson, R.A., 1988. The antioxidant of higher plants. Phytochemistry, 27: 969-978.


  59. Loewenstein, W.R., 1979. Junctional Intercellular communication and the control of growth. Biochem. Biophys. Acta, 560: 1-65.
    Direct Link  |  


  60. Lorenz, W., J. Kusche, H. Barth and C.H. Mathias, 1973. Action of Several Flavonoids on Enzyme of Histidine Metabolism in vitro. In: Histamine, Maslinski, C.Z. (Ed.). Hutchinson and Ross Inc., Pennsylvania, pp: 265-269


  61. Mackova, Z., R. Koblovska and O. Lapcik, 2006. Distribution of isoflavonoids in non-leguminous taxa-an update. Phytochemistry, 67: 849-855.
    CrossRef  |  


  62. Mahesh, T. and V.P. Menon, 2004. Quercetin alleviates oxidative stress in streptozotocin-induced diabetic rats. Phytother. Res., 18: 123-127.
    Direct Link  |  


  63. Manach, C., F. Regerat, O. Texier, G. Agullo, C. Demigne and C. Remesy, 1996. Bioavailability, metabolism and physiological impact of 4-oxo-flavonoids. Nutr. Res., 16: 517-544.
    CrossRef  |  Direct Link  |  


  64. Mauri, P.L., L. Lemoli, C. Gardana, P. Riso, P. Simonetti, M. Porrini and P.G. Pietta, 1999. Liquid chromatography/electrospray ionization mass spectrometric characterization of flavonol glycoside in tomato extracts and human plasma. Rapid Commun. Mass Spectrum., 13: 924-931.
    Direct Link  |  


  65. McCord, J.M., 1995. Superoxide radical: Controversies, contradictions and paradoxes. Proc. Exp. Biol. Med., 209: 112-117.
    Direct Link  |  


  66. Merfort, I., J. Heilmann, M. Weiss, P.G. Pietta and C. Gardana, 1996. Radical scavenging activity of three flavonoids metabolites studied by inhibition of chemiluminescence in human PMNS. Planta Med., 62: 289-292.
    Direct Link  |  


  67. Michelle, M., T. Tavazzi, M. Enslen and E.A. Offord, 1999. Plasma kinetics in man of epicatechin from black chocolate. Eur. J. Clin. Nutr., 53: 22-26.
    Direct Link  |  


  68. Middleton, Jr. E., 1998. Effect of plant flavonoids on immune and inflammatory cell function. Adv. Exp. Med. Biol., 439: 175-182.
    CrossRef  |  PubMed  |  Direct Link  |  


  69. Morino, M., T. Tsuzuki, Y. Ishikawa, T. Shirakami and M. Yoshimura et al., 1997. Specific regulation of HSPS in human tumour cell lines by flavonoids. In Vivo., 11: 265-270.
    Direct Link  |  


  70. Murakami, S., M. Muramatsu and S. Otomo, 1992. Gastric H+/K+ ATPase inhibition by catechins. J. Pharm. Pharmacol., 44: 926-928.
    Direct Link  |  


  71. Naik, S.R., 2003. Antioxidants and their role in biological functions an overview. Indian Drugs, 40: 501-516.
    Direct Link  |  


  72. Nakagawa, K. and T. Miyazawa, 1997. Chemiluminescence high performance liquid chromatographic determination of tea catechin, (-)-epigallocatechin-3-gallate at picomole levels in rat and human plasma. Anal. Biochem., 248: 41-49.
    CrossRef  |  


  73. Nielsen, S.A., M. Kall, U. Justesen, A. Schon and L.O. Dragested, 1997. Human absorption and excretion of flavonoids after broccoli consumption. Cancer Lett., 114: 173-174.
    CrossRef  |  


  74. Nones, J., J. Stipursky, S.L. Costa and F.C. Gomes, 2010. Flavonoids and astrocytes croosstalking: Implications for brain development and pathology. Neurochem. Res.
    CrossRef  |  


  75. Parmar, N.S. and S. Parmar, 1998. Antiulcer potential of flavonoids. Indian J. Physiol. Pharmacol., 42: 343-351.


  76. Pascual, M.E., K. Slowing, E. Carretero, D. Sanchez-Mata and A. Villar, 2001. Lippia: Traditional uses, chemistry and pharmacology: A review. J. Ethnopharmacol., 76: 201-214.
    CrossRef  |  PubMed  |  Direct Link  |  


  77. Pataki, T., I. Bak, P. Lovacs, D. Bagachi, D.K. Das and A. Tosaki, 2002. Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts. Am. J. Clin. Nutr., 75: 894-899.
    Direct Link  |  


  78. Paul, P., J. Ritra, S. Ritva, H. Mackku, T. Lyly, P. Eero and A. Arpo, 1997. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am. J. Epidemiol., 26: 167-181.


  79. Pendry, B., K. Busia and C.M. Bell, 2005. Phytochemical evaluation of selected antioxidant-containing medicinal plants for use in the preparation of a herbal formula-a preliminary study. Chem. Biodivers., 2: 917-922.
    Direct Link  |  


  80. Pietri, S., E. Maurelli, K. Drieu and M. Culcasi, 1997. Cardioprotective and anti-oxidant effects of the terpenoid constituents of Ginkgo biloba extract (EGB 761). J. Mol. Cell Cardiol., 29: 733-742.
    Direct Link  |  


  81. Pietta, P.G., 2000. Flavonoids as antioxidants. J. Nat. Prod., 63: 1035-1042.
    CrossRef  |  PubMed  |  Direct Link  |  


  82. Pietta, P.G., C. Garden and P.L. Mauri, 1997. Assay of soluble guanylate cyclase activity by isocratic high performance liquid chromatography. J Chromatogr. B: Biomed. Sci. Appl., 690: 343-347.
    CrossRef  |  


  83. Pietta, P.G., P. Simonetti, C. Gardana and P.L. Mauri, 2000. Trolox Equivalent Antioxidant Capacity (TEAC) of Ginkgo biloba flavonol and Camellia sinensis catechin metabolites. J. Pharm. Biomed. Anal., 23: 223-226.
    PubMed  |  


  84. Pietta, P.G., P.L. Mauri, P. Simonetti, G. Testolin and J. Fresenius, 1995. Analytical chemistry of fruit bioflavonoids: A review. Anal. Chem., 352: 788-792.


  85. Rekha, P.S., G. Kuttan and R. Kuttan, 2001. Antioxidant activity of brahma rasayana. Indian J. Exp. Biol., 39: 447-452.
    Direct Link  |  


  86. Robak, J. and R.J. Gryglewski, 1988. Flavonoids are scavengers of superoxide anions. Biochem. Pharmacol., 37: 837-841.
    CrossRef  |  Direct Link  |  


  87. Rohdewald, P., 2002. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int. J. Clin. Pharmacol. Ther., 40: 158-168.
    PubMed  |  Direct Link  |  


  88. Samuelsen, A.B., 2000. The traditional uses, chemical constituents and biological activities of Plantago major L. A review. J. Ethnopharmacol., 71: 1-21.
    CrossRef  |  Direct Link  |  


  89. Shahidi, F., P.K. Janitha and P.D. Wanasundara, 1992. Phenolic antioxidants. Crit. Rev. Food Sci. Nutr., 32: 67-103.
    CrossRef  |  Direct Link  |  


  90. Shahidi, F., Z. Yang and Z.O. Saleemi, 1998. Natural flavonoids as stabilizers. J. Food Lipids, 1: 69-75.


  91. Sharma, S.K. and V.K. Gupta, 2007. Free radicals scavenging activity of Ficus racemosa Linn. root. Indian J. Pharma. Educ. Res., 41: 394-396.


  92. Sharma, S.K. and V.K. Gupta, 2007. In vitro antioxidant study of Ficus religiosa Linn. root. Int. J. Chem. Sci., 5: 2365-2371.


  93. Sharma, S.K. and V.K. Gupta, 2008. In vitro antioxidant studies of Ficus racemosa Linn. root. Pharmacognosy, 13: 70-74.
    Direct Link  |  


  94. Spedding, G., A. Ratty and E. Middleton, 1989. Inhibition of reverse transcriptases by flavonoids. Antiviral Res., 12: 99-110.
    Direct Link  |  


  95. Tencate, J.W., N.J. van Haeringen, J. Gerritsen and E. Glasius, 1973. Biological activity of a semisynthetic flavonoid, O-(β-Hydroxyethyl) Rutosine: Light-scattering and metabolic studies of human red cells and platelets. Clin. Chem., 19: 31-35.
    Direct Link  |  


  96. Thomas, C.E. and B. Kalyanaraman, 1997. Oxygen Radicals and the Disease Process. Hardwood Academic Publishers, The Netherlands, Pages: 282


  97. Tiwari, A., 2001. Imbalance in antioxidant defence and human diseases: Multiple approach of natural antioxidants therapy. Curr. Sci., 81: 1179-1187.
    Direct Link  |  


  98. Terol, J., J. Cillard and P. Cillard, 1986. Antioxidant activity of flavonoids and reactivity with peroxy radical. Phytochemistry, 25: 383-385.
    CrossRef  |  Direct Link  |  


  99. Tsai, H.S., L.J. Huang, Y.H. Lai, J.C. Chang, R.S. Lee and R.Y. Chiou, 2007. Solvent effects on extraction and HPLC analysis of soybean isoflavones and variations of isoflavone compositions as affected by crop season. J. Agric. Food Chem., 55: 7712-7715.
    Direct Link  |  


  100. Uchida, S., H. Ohta, R. Edamatsu, M. Hiramatsu and M.M. Akitane et al., 1988. Active oxygen free radicals are scavenged by condensed tannins. Prog. Clin. Biol. Res., 280: 135-138.
    Direct Link  |  


  101. Ursini, F., M. Maiorino, P. Morazzoni, A. Roveri and G. Pifferi, 1994. A novel antioxidant flavonoid (IDB 1031) affecting molecular mechanisms of cellular activation. Free Radic. Biol. Med., 16: 547-553.
    PubMed  |  


  102. Verma, S.D. and J.H. Kinoshita, 1976. Inhibitory effects of plant polyphenols on rat liver glutathione-S-transferase. Biochem. Pharmacol., 25: 2505-2510.


  103. Villa, P., D. Cova, L. De Francesco, A. Gulatini, G. Palladini and R. Perego, 1992. Protective effect of diosmetin on in vitro cell membrane damage and oxidative stress in cultured rat hepatocytes. Toxicology, 73: 179-189.
    Direct Link  |  


  104. Wang, T.C., I.L. Chen, C.M. Lu, D.H. Kuo and C.H. Liao, 2005. Synthesis and cytotoxic and antiplatelet activities of oxime-and methyloxime-containing flavone, isoflavone and xanthone derivatives. Chem. Biodivers., 2: 253-263.
    Direct Link  |  


  105. Wang, W. and M.T. Goodman, 1999. Antioxidant properties of dietary phenolic agents in a human LDL-oxidation ex vivo model: Interaction of protein binding activity. Nutr. Res., 19: 191-202.
    CrossRef  |  


  106. Wei, Z.H., Q.L. Peng and B.H.S. Lau, 1997. Pycnogenol enhances endothelial cell antioxidant defenses. Redox Rep., 3: 219-224.
    Direct Link  |  


  107. Wild, C. and J. Fasel, 1969. Effect of a flavonoid on the capillary resistance of the rectal mucosa in hepatic cirrhosis. Am. J. Proc., 20: 60-62.


  108. Xu, X., H. Ye, W. Wang, L. Yu and G. Chen, 2006. Determination of flavonoids in Houttuynia cordata Thunb. and Saururus chinensis (Lour.) Bail. by capillary electrophoresis with electrochemical detection. Talanta, 68: 759-764.
    CrossRef  |  


  109. Yagi, K., 1987. Lipid peroxides and human diseases. Chem. Physiol. Lipids, 45: 337-351.
    CrossRef  |  Direct Link  |  


  110. Yamashiro, S., K. Noguchi, T. Matsuzaki, K. Miyagi and J. Nakasone et al., 2003. Cardioprotective effects of extracts from Psidium guajava L. and Limonium wrightii, Okinawan medicinal plants against ischemia-reperfusion injury in perfused hearts. Pharmacology, 67: 128-135.
    Direct Link  |  


  111. Zhai, S., R. Dai, F.K. Friedman and R.E. Vestal, 1998. Comparative inhibition of human cytochrome P 450 1A1 and 1A2 by flavonoids. Drug Metabol. Disposit., 26: 989-992.
    Direct Link  |  


  112. Zhai, S., R. Dai, F.K. Friedman and R.E. Vestal, 1998. Inhibition of methoxyresorufin demethylase activity by flavonoids in human liver microsomes. Life Sci., 63: PL119-PL123.
    CrossRef  |  


  113. Hanasaki, Y., S. Ogawa and S. Fukui, 1994. The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radical Biol. Med., 16: 845-850.
    CrossRef  |  PubMed  |  Direct Link  |  


  114. Husain, S.R., J. Cillard and P. Cillard, 1987. Hydroxyl radical scavenging activity of flavonoids. Phytochemistry, 26: 2489-2491.
    CrossRef  |  Direct Link  |  


  115. Kumar, V. and S.K. Sharma, 2006. Antioxidant studies on some plants: A review. Hamdard Med., 49: 25-36.


  116. Unno, T., K. Kondo, H. Itakura and T. Takedo, 1996. Analysis of (-)-epigallocatechin gallate in human serum obtained after ingesting green tea. Biosci. Biotechnol. Biochem., 60: 2066-2068.
    PubMed  |  


  117. Lewis, N.G., 1993. Plant Phenolics. In: Antioxidants in Higher Plants, Alscher, R.G. and J. Hess (Eds.). CRC Press, Boca Raton, Florida, pp: 135-169


  118. Lotito, S.B. and B. Frei, 2004. Relevance of apple polyphenols as antioxidants in human plasma: contrasting in vitro and in vivo effects. Free Radic. Biol. Med., 36: 201-211.
    Direct Link  |  
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