Structurally Modified &amp;#x2018;Dietary Flavonoids&amp;#x2019;: Are these Viable Drug Candidates for Chemoprevention?

Srinivas, Nuggehally R.

doi:10.2174/157488409787236065

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…In mammals, after absorption from the small intestine, flavonoids undergo extensive metabolism, generating different conjugation forms such as glucuronides and sulfates (19,20). The bioavailability of flavonoids is generally low and can be problematic in pharmacological studies (19,21,22), as these conjugation reactions can enhance the elimination of lipophilic xenobiotics (19,21). It has been shown that glucuronidation of flavonoids can influence the bioavailability of flavonoids in mammals partly by changing their permeability and interactions with their putative transporters such as ATP-binding cassette superfamily transporters (19-21, 23, 24).…”

Section: Discussionmentioning

confidence: 99%

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The silkworm Green b locus encodes a quercetin 5- O -glucosyltransferase that produces green cocoons with UV-shielding properties

Daimon

Hirayama

Kanai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

105

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In the silkworm Bombyx mori, dietary flavonoids are metabolized and accumulate in cocoons, thereby causing green coloration. Classical genetic studies suggest that more than seven independent loci are associated with this trait; however, because of the complex inheritance pattern, none of these loci have been characterized molecularly, and a plausible and comprehensive model for their action has not been proposed. Here, we report the identification of the gene responsible for the Green b (Gb) locus involving the green cocoon trait. In + Gb animals, glucosylation at the 5-O position of dietary quercetin did not occur, and the total amount of flavonoids in tissues and cocoons was dramatically reduced. We performed positional cloning of Gb and found a 38-kb deletion in a UDP-glucosyltransferase (UGT) gene cluster associated with the + Gb allele. RT-PCR and biochemical studies suggested that deletion of Bm-UGT10286 (UGT) is responsible for Gb and Bm-UGT10286 is virtually the sole source of UGT activity toward the 5-O position of quercetin. Our data show that the regiospecific glucosylation of flavonoids by the quercetin 5-O-glucosyltransferase can greatly affect the overall bioavailability of flavonoids in animals. Furthermore, we provide evidence that flavonoids increase the UV-shielding activity of cocoons and thus could confer an increased survival advantage to insects contained in these cocoons. This study will lead to greater understanding of mechanisms for metabolism, uptake, and transport of dietary flavonoids, which have a variety of biological activities in animals and beneficial effects on human health.

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Section: Discussionmentioning

confidence: 99%

“…Flavonoids play various roles in a wide variety of organisms as antioxidants, antibacterial agents, and UV absorbers (19,22,27). We asked whether flavonoids in cocoon shells have functional consequences in silkworm biology.…”

Section: Discussionmentioning

confidence: 99%

The silkworm Green b locus encodes a quercetin 5- O -glucosyltransferase that produces green cocoons with UV-shielding properties

Daimon

Hirayama

Kanai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

105

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“…In general, most of the phytochemicals including flavonoids are shown more effective beneficial pharmacological properties in vitro than in vivo. This could be due to several reasons including low bioavailability, lack of stability, poor membrane penetration, lack of site specific distribution and rapid elimination of these flavonoids [57]. Introducing structural modifications to flavonoids were found to be effective in enhancing some biological functionality of parent flavonoids.…”

Section: Structurally Modified Flavonoidsmentioning

confidence: 99%

Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of hypertension

Balasuriya

Rupasinghe

2011

FFHD

162

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Background: Angiotensin converting enzyme (ACE) is a key component in the renin angiotensin aldosterone system (RAAS) which regulates blood pressure. As the over expression of RAAS is associated with vascular hypertension, ACE inhibition has become a major target control for hypertension. The research on potential ACE inhibitors is expanding broadly and most are focused on natural product derivatives such as peptides, polyphenolics, and terpenes. Plant polyphenolics are antioxidant molecules with various beneficial pharmacological properties. The current study is focused on investigating and reviewing the ACE inhibitory property of fruit flavonoids. An apple skin extract (ASE) rich in flavonoids, the major constituents of the extract and their selected metabolites were assessed for the ACE inhibitory property in vitro. It is important to investigate the metabolites along with the flavonoids as they are the constituents active inside the human body. Objective: To investigate whether flavonoids, flavonoid rich apple extracts and their metabolites could inhibit ACE in vitro.Method: The samples were incubated with sodium borate buffer (30 µL, pH 8.3), 150 µL of substrate (Hip-His-Liu) and ACE (30 µL) at 37 oC for 1 h. The reaction was stopped by addition of 150 µL of 0.3M NaOH. The enzyme cleaved substrate was detected by making a fluorimetric adduct by adding 100 µL of o-phthaladehyde for 10 min at room temperature. Reaction was stopped by adding 50 µL of 3M HCl. Fluorescence was measured by using a FluoStar Optima plate reader at excitation of 350 nm and emission of 500 nm. Results: The extract and the compounds showed a concentration dependant enzyme inhibition. Increasing concentrations from 0.001 ppm to 100 ppm of ASE showed an increment of 29% to 64% ACE inhibition. The IC50 (concentration of test compound which gives 50% enzyme inhibition) values of ASE, quercetin, quercetin-3-glucoside, quercetin-3-galactoside, cyanidin-3-galactoside were 49 µg/mL, 151 µM, 71 µM, 180 µM, 206 µM, respectively. The major constituents of the ASE that were tested separately showed effective ACE inhibition. From the three metabolites tested, only quercetin-3-glucuronic acid showed concentration dependant ACE inhibition. The ACE inhibition of 0.001 ppm to 100 ppm of quercetin-3-glucuronic was in the range of 43% and 75% and the IC50 value was 27 µM. Conclusion: The results demonstrated that flavonoids have a potential to inhibit ACE in vitro and the inhibitory property varies according to type of sugar moiety attached at C-3 position. The results also revealed that the major contributing compounds of ASE for ACE inhibition belong to flavonoids. Among the tested compounds, the lowest IC50 value is associated with the quercetin-3-glucuronic acid, a major in vivo metabolites of quercetin and its glycosides. The results suggest that certain dietary flavonoids may possess properties of blood pressure regulation.Key words: Hypertension, renin angiotensin system (RAS), angiotensin converting enzyme (ACE), flavonoids, apple

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“…20–22 Flavonoids, which are ubiquitously distributed in many dietary plant materials, have received a great deal of attention because some of them have been shown to exert various beneficial effects on human health. 23 Apigenin (Figure 1) is abundantly present in common fruits and vegetables, and has gained particular interest in recent years as a beneficial and health-promoting agent because of its low intrinsic toxicity. 24 Apigenin has been demonstrated to possess various clinically relevant properties such as anti-inflammatory, anti-oxidant, antiproliferative and pro-apoptotic activities likely through multiple mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo

Chen

Mrazek

Wang

et al. 2014

Bioorganic & Medicinal Chemistry

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Accumulating evidence suggests that activated pancreatic stellate cells (PSC) play an important role in chronic pancreatitis (CP), and inhibition of the activated PSC is considered as a potential strategy for the treatment and prevention of CP. Herein, we disclose our findings that apigenin and its novel analogues suppress the proliferation and induce apoptosis in PSC which reduce the PSC-mediated fibrosis in CP. Chemical modifications of apigenin have been directed to build a focused library of O-alkylamino-tethered apigenin derivatives at 4′-O position of the ring C with the attempt to enhance the potency and drug-like properties including aqueous solubility. A number of compounds such as 14, 16, and 24 exhibited potent antiproliferative effects as well as improved aqueous solubility. Intriguingly, apigenin, new analogues 23 and 24 displayed significant efficacy to reduce pancreatic fibrosis even at a low dose of 0.5 mg/kg in our proof-of-concept study using a preclinical in vivo mouse model of CP.

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Structurally Modified ‘Dietary Flavonoids’: Are these Viable Drug Candidates for Chemoprevention?

Cited by 13 publications

References 29 publications

The silkworm Green b locus encodes a quercetin 5- O -glucosyltransferase that produces green cocoons with UV-shielding properties

The silkworm Green b locus encodes a quercetin 5- O -glucosyltransferase that produces green cocoons with UV-shielding properties

Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of hypertension

Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo

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