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1.  Flavonoids Inhibit the Respiratory Burst of Neutrophils in Mammals 
Neutrophils represent the front-line defence cells in protecting organisms against infection and play an irreplaceable role in the proper performance of the immune system. As early as within the first minutes of stimulation, neutrophilic NADPH oxidase is activated, and cells release large quantities of highly toxic reactive oxygen species (ROS). These oxidants can be highly toxic not only for infectious agents but also for neighboring host tissues. Since flavonoids exhibit antioxidant and anti-inflammatory effects, they are subjects of interest for pharmacological modulation of ROS production. The present paper summarizes contemporary knowledge on the effects of various flavonoids on the respiratory burst of mammalian neutrophils. It can be summarized that the inhibitory effects of flavonoids on the respiratory burst of phagocytes are mediated via inhibition of enzymes involved in cell signaling as well as via modulation of redox status. However, the effects of flavonoids are even more complex, and several sites of action, depending upon the flavonoid structure and way of application, are included.
doi:10.1155/2012/181295
PMCID: PMC3347721  PMID: 22577489
2.  Transport and accumulation of flavonoids in grapevine (Vitis vinifera L.) 
Plant Signaling & Behavior  2008;3(9):626-632.
Flavonoids are a group of secondary metabolites widely distributed in plants that represent a huge portion of the soluble phenolics present in grapevine (Vitis vinifera L.). These compounds play different physiological roles and are often involved in protection against biotic and abiotic stress. Even if the flavonoid biosynthetic pathways have been largely characterized, the mechanisms of their transport and accumulation in cell wall and vacuole are still not completely understood. This review analyses the known mechanisms of flavonoid uptake and accumulation in grapevine, with reference to the transport models and membrane carrier proteins described in other plant species. The effect of different environmental factors on flavonoid biosynthesis and transporters is also discussed.
PMCID: PMC2634543  PMID: 19513253
ABC proteins; active transport; bilitranslocase; biotic and abiotic stress; flavonoid; secondary metabolites
3.  Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying effects on pancreatic β-cell function 
Food & function  2013;4(2):200-212.
Type 2 diabetes is a result of chronic insulin resistance and loss of functional pancreatic β-cell mass. Strategies to preserve β-cell mass and a greater understanding of the mechanisms underlying β-cell turnover are needed to prevent and treat this devastating disease. Genistein, a naturally-occurring soy isoflavone, is reported to have numerous health benefits attributed to multiple biological functions. Over the past 10 years, numerous studies have demonstrated that genistein has anti-diabetic effects, in particular, direct effects on β-cell proliferation, glucose-stimulated insulin secretion and protection against apoptosis, independent of its functions as an estrogen receptor agonist, antioxidant, or tyrosine kinase inhibitor. Effects are structure-specific and not common to all flavonoids. While there are limited data on the effects of genistein consumption in humans with diabetes, there are a plethora of animal and cell-culture studies that demonstrate, at physiologically-relevant concentrations (<10 µM), a direct effect of genistein on β-cells. The effects appear to involve cAMP/PKA signaling and there are some studies that suggest an effect on epigenetic regulation of gene expression. This review focuses on the anti-diabetic effects of genistein in both in-vitro and in-vivo models and potential mechanisms underlying its direct effects on β-cells.
doi:10.1039/c2fo30199g
PMCID: PMC3678366  PMID: 23160185
4.  Synergistic Action of Flavonoids, Baicalein, and Daidzein in Estrogenic and Neuroprotective Effects: A Development of Potential Health Products and Therapeutic Drugs against Alzheimer's Disease 
Despite the classical hormonal effect, estrogen has been reported to mediate neuroprotection in the brain, which leads to the searching of estrogen-like substances for treating neurodegenerative diseases. Flavonoids, a group of natural compounds, are well known to possess estrogenic effects and used to substitute estrogen, that is, phytoestrogen. Flavonoid serves as one of the potential targets for the development of natural supplements and therapeutic drugs against different diseases. The neuroprotection activity of flavonoids was chosen for a possible development of anti-Alzheimer's drugs or food supplements. The estrogenic activity of two flavonoids, baicalein and daidzein, were demonstrated by their strong abilities in stimulating estrogen receptor phosphorylation and transcriptional activation of estrogen responsive element in MCF-7 breast cells. The neuroprotection effects of flavonoids against β-amyloid (Aβ) were revealed by their inhibition effects on in vitro Aβ aggregation and Aβ-induced cytotoxicity in PC12 neuronal cells. More importantly, the estrogenic and neuroprotective activities of individual flavonoid could be further enhanced by the cotreatment in the cultures. Taken together, this synergistic effect of baicalein and daidzein might serve as a method to improve the therapeutic efficacy of different flavonoids against Aβ, which might be crucial in developing those flavonoidsin treating Alzheimer's disease in the future.
doi:10.1155/2013/635694
PMCID: PMC3766606  PMID: 24058373
5.  Urinary estrogen metabolites during a randomized soy trial 
Nutrition and Cancer  2012;64(2):307-314.
One of the hypothesized protective mechanisms of soy against breast cancer involves changes in estrogen metabolism to 2-hydroxy (OH) and 16α-OH estrogens. The current analysis examined the effect of soy foods on the 2:16α-OH E1 ratio among premenopausal women during a randomized, crossover intervention study; women were stratified by equol producer status, a characteristic thought to enhance the protective effects of soy isoflavones. The study consisted of a high-soy diet with 2 soy food servings/day and a low-soy diet with <3 servings of soy/week for 6 months each; estrogen metabolites were measured in 3 overnight urines (baseline and at the end of the low- and high-soy diet) using gas chromatography mass spectrometry for the 82 women who completed the study. Urinary isoflavonoids were assessed by liquid chromatography mass spectrometry. When applying mixed models, the 2:16α-OH E1 ratio increased (p=0.05) due to a non-significant decrease in 16α-OH E1 (p=0.21) at the end of high-soy diet. Similar non-significant increases in the 2:16α-OH E1 ratio were observed in equol producers (p=0.13) and non-producers (p=0.23). These findings suggest a beneficial influence of soy foods on estrogen metabolism regardless of equol producer status.
doi:10.1080/01635581.2012.648819
PMCID: PMC3279611  PMID: 22293063
Breast cancer risk; diet and nutrition; estrogen metabolites; isoflavones; soy foods
6.  Structure and function of enzymes involved in the biosynthesis of phenylpropanoids 
As a major component of plant specialized metabolism, phenylpropanoid biosynthetic pathways provide anthocyanins for pigmentation, flavonoids such as flavones for protection against UV photodamage, various flavonoid and isoflavonoid inducers of Rhizobium nodulation genes, polymeric lignin for structural support and assorted antimicrobial phytoalexins. As constituents of plant-rich diets and an assortment of herbal medicinal agents, the phenylpropanoids exhibit measurable cancer chemopreventive, antimitotic, estrogenic, antimalarial, antioxidant and antiasthmatic activities. The health benefits of consuming red wine, which contains significant amounts of 3,4′,5-trihydroxystilbene (resveratrol) and other phenylpropanoids, highlight the increasing awareness in the medical community and the public at large as to the potential dietary importance of these plant derived compounds. As recently as a decade ago, little was known about the three-dimensional structure of the enzymes involved in these highly branched biosynthetic pathways. Ten years ago, we initiated X-ray crystallographic analyses of key enzymes of this pathway, complemented by biochemical and enzyme engineering studies. We first investigated chalcone synthase (CHS), the entry point of the flavonoid pathway, and its close relative stilbene synthase (STS). Work soon followed on the O-methyl transferases (OMTs) involved in modifications of chalcone, isoflavonoids and metabolic precursors of lignin. More recently, our groups and others have extended the range of phenylpropanoid pathway structural investigations to include the upstream enzymes responsible for the initial recruitment of phenylalanine and tyrosine, as well as a number of reductases, acyltransferases and ancillary tailoring enzymes of phenylpropanoid-derived metabolites. These structure–function studies collectively provide a comprehensive view of an important aspect of phenylpropanoid metabolism. More specifically, these atomic resolution insights into the architecture and mechanistic underpinnings of phenylpropanoid metabolizing enzymes contribute to our understanding of the emergence and on-going evolution of specialized phenylpropanoid products, and underscore the molecular basis of metabolic biodiversity at the chemical level. Finally, the detailed knowledge of the structure, function and evolution of these enzymes of specialized metabolism provide a set of experimental templates for the enzyme and metabolic engineering of production platforms for diverse novel compounds with desirable dietary and medicinal properties.
doi:10.1016/j.plaphy.2007.12.009
PMCID: PMC2860624  PMID: 18272377
Phenylpropanoid pathway; Secondary metabolism; Lignin; Flavonoids; Anthocyanins; Plant enzymes; Structure
7.  Mammographic breast density as a biomarker of effects of isoflavones on the female breast 
Breast Cancer Research  2001;4(1):1-4.
Isoflavones possess both estrogenic and anti-estrogenic actions, and are hypothesized to protect against breast cancer. However, two intervention studies of markers of proliferation on breast tissue have raised concerns that soy isoflavones may have an estrogenic effect on breast tissue. Increased mammographic breast density is associated with an elevated risk of breast cancer, although the mechanism underlying this relationship has not been explained. Estrogens increase and anti-estrogens decrease breast density. Breast density may therefore serve as a biomarker of estrogenic or anti-estrogenic effects of a treatment on breast tissue. The effect of isoflavones on breast density is under investigation.
doi:10.1186/bcr410
PMCID: PMC138710  PMID: 11879551
breast cancer; diet; hormones; isoflavones; mammographic density
8.  Apigenin Suppresses Cancer Cell Growth through ERβ1 
Neoplasia (New York, N.Y.)  2006;8(11):896-904.
Abstract
Two flavonoids, genistein and apigenin, have been implicated as chemopreventive agents against prostate and breast cancers. However, the mechanisms behind their respective cancer-protective effects may vary significantly. The goal of this study was to determine whether the antiproliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) β is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17β-estradiol, exhibited antiproliferative effects and proapoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERβ transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERβ-selective than genistein, which has equal potency in inducing transactivation through ERα and ERβ. Small interfering RNA-mediated downregulation of ERβ abrogated the antiproliferative effect of apigenin in both cancer cells but did not reverse that of genistein. Our data unveil, for the first time, that the anticancer action of apigenin is mediated, in part, by ERβ. The differential use of ERα and ERβ signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anticancer properties.
PMCID: PMC1716010  PMID: 17132221
Phytoestrogens; genistein; ERα; apoptosis; cancer chemoprevention
9.  Isoflavones and PPAR Signaling: A Critical Target in Cardiovascular, Metastatic, and Metabolic Disease 
PPAR Research  2011;2010:153252.
Isoflavone intake through foods and dietary supplements has both health advocates and critics. The latter come from a concern about the estrogenic effects of isoflavones in certain species. However, careful removal of isoflavones and other estrogens from the diet of rodents leads to the metabolic syndrome. These results suggest that isoflavones have other mechanisms of action, potentially those involving regulation of fatty acid metabolism via the nuclear receptors PPARα and PPARγ. The goal of this paper was to examine the evidence for isoflavone/PPAR signaling and to identify diseases in which such signaling would have an important impact. It is therefore of note that investigators using a chemical structure approach to discover PPAR ligands identified isoflavones as the best structures in the library of compounds that they tested. Future studies will involve careful identification of the underlying mechanisms whereby isoflavones have their action via PPAR signaling.
doi:10.1155/2010/153252
PMCID: PMC3061262  PMID: 21461045
10.  Flavonoid Bioavailability and Attempts for Bioavailability Enhancement 
Nutrients  2013;5(9):3367-3387.
Flavonoids are a group of phytochemicals that have shown numerous health effects and have therefore been studied extensively. Of the six common food flavonoid classes, flavonols are distributed ubiquitously among different plant foods whereas appreciable amounts of isoflavones are found in leguminous plant-based foods. Flavonoids have shown promising health promoting effects in human cell culture, experimental animal and human clinical studies. They have shown antioxidant, hypocholesterolemic, anti-inflammatory effects as well as ability to modulate cell signaling and gene expression related disease development. Low bioavailability of flavonoids has been a concern as it can limit or even hinder their health effects. Therefore, attempts to improve their bioavailability in order to improve the efficacy of flavonoids are being studied. Further investigations on bioavailability are warranted as it is a determining factor for flavonoid biological activity.
doi:10.3390/nu5093367
PMCID: PMC3798909  PMID: 23989753
flavonoids; bioavailability; diet; health; disease
11.  In Vitro Phytotoxicity and Antioxidant Activity of Selected Flavonoids 
The knowledge of flavonoids involved in plant-plant interactions and their mechanisms of action are poor and, moreover, the structural characteristics required for these biological activities are scarcely known. The objective of this work was to study the possible in vitro phytotoxic effects of 27 flavonoids on the germination and early radical growth of Raphanus sativus L. and Lepidium sativum L., with the aim to evaluate the possible structure/activity relationship. Moreover, the antioxidant activity of the same compounds was also evaluated. Generally, in response to various tested flavonoids, germination was only slightly affected, whereas significant differences were observed in the activity of the various tested flavonoids against radical elongation. DPPH test confirms the antioxidant activity of luteolin, quercetin, catechol, morin, and catechin. The biological activity recorded is discussed in relation to the structure of compounds and their capability to interact with cell structures and physiology. No correlation was found between phytotoxic and antioxidant activities.
doi:10.3390/ijms13055406
PMCID: PMC3382788  PMID: 22754304
flavonoids; germination; radical elongation; antioxidant activity; structure/activity
12.  Dietary flavonoid intake and non-Hodgkin lymphoma risk 
Background
The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects.
Objective
We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.
Design
During 1998–2000, we identified incident NHL cases aged 20–74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake.
Results
Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes—diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146).
Conclusion
A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.
PMCID: PMC3971470  PMID: 18469269
13.  Post-veraison sunlight exposure induces MYB-mediated transcriptional regulation of anthocyanin and flavonol synthesis in berry skins of Vitis vinifera 
Journal of Experimental Botany  2009;60(3):853-867.
Anthocyanins, flavan-3-ols, and flavonols are the three major classes of flavonoid compounds found in grape berry tissues. Several viticultural practices increase flavonoid content in the fruit, but the underlying genetic mechanisms responsible for these changes have not been completely deciphered. The impact of post-veraison sunlight exposure on anthocyanin and flavonol accumulation in grape berry skin and its relation to the expression of different transcriptional regulators known to be involved in flavonoid synthesis was studied. Treatments consisting of removing or moving aside the basal leaves which shade berry clusters were applied. Shading did not affect sugar accumulation or gene expression of HEXOSE TRANSPORTER 1, although in the leaf removal treatment, these events were retarded during the first weeks of ripening. Flavonols were the most drastically reduced flavonoids following shading and leaf removal treatments, related to the reduced expression of FLAVONOL SYNTHASE 4 and its putative transcriptional regulator MYB12. Anthocyanin accumulation and the expression of CHS2, LDOX, OMT, UFGT, MYBA1, and MYB5a genes were also affected. Other regulatory genes were less affected or not affected at all by these treatments. Non-transcriptional control mechanisms for flavonoid synthesis are also suggested, especially during the initial stages of ripening. Although berries from the leaf removal treatment received more light than shaded fruits, malvidin-3-glucoside and total flavonol content was reduced compared with the treatment without leaf removal. This work reveals that flavonol-related gene expression responds rapidly to field changes in light levels, as shown by the treatment in which shaded fruits were exposed to light in the late stages of ripening. Taken together, this study establishes MYB-specific responsiveness for the effect of sun exposure and sugar transport on flavonoid synthesis.
doi:10.1093/jxb/ern336
PMCID: PMC2652055  PMID: 19129169
bHLH; flavonoids; grape; leaf removal; MYB12; PAR; sugar; source; sink; WDR
14.  Goitrogenic and estrogenic activity of soy isoflavones. 
Environmental Health Perspectives  2002;110(Suppl 3):349-353.
Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate.
PMCID: PMC1241182  PMID: 12060828
15.  Dietary Flavonoids and Flavonoid-Rich Foods Are Not Associated with Risk of Type 2 Diabetes in Postmenopausal Women 
The Journal of nutrition  2006;136(12):3039-3045.
Flavonoids have anti-inflammatory and antioxidative effects and thus may protect against diabetes. Therefore, we hypothesized that consumption of flavonoids and specific food and beverage sources of flavonoids would be associated with reduced risk of incident diabetes. At baseline (1986), diet (by food frequency questionnaire) and health information were collected from 35,816 postmenopausal women free of diabetes. Self-reported incident diabetes was ascertained 5 times during the study (1987, 1989, 1992, 1997, and 2004). Cox proportional hazards regression was used to calculate hazard ratios for incident diabetes according to categories of total flavonoids and anthocyanidins, flavones, flavanones, flavonols, flavan-3-ol monomers, isoflavones, and proanthocyanidins. Hazard ratios according to intake categories of flavonoid-rich foods and beverages were also calculated (apples, pears, berries, broccoli, bran, citrus, tea, and red wine). Flavonoid consumption was not associated with diabetes risk after multivariable adjustment. Although other flavonoid-rich foods and beverages were not associated, red wine was inversely associated with diabetes. Women who reported drinking red wine ≥1 time/wk had a 16% reduced risk of diabetes than those drinking wine <1 time/wk [HR (95% CI): 0.84 (0.71, 0.99)], with parallel findings for white wine, beer, and liquor. In conclusion, these data do not support a diabetes-protective effect of flavonoids. The suggestive evidence of a protective effect of regular red wine consumption is shared with an inverse association between alcohol drinks in general and diabetes risk and may reflect the effects of nonflavonoid constituents that are common to all alcohol drinks.
PMCID: PMC3034085  PMID: 17116717
16.  Apigenin Inhibits Antiestrogen-resistant Breast Cancer Cell Growth through Estrogen Receptor-α-dependent and -independent Mechanisms 
Molecular cancer therapeutics  2008;7(7):2096-2108.
Breast cancer resistance to the antiestrogens tamoxifen and fulvestrant is accompanied by alterations in both estrogen-dependent and -independent signaling pathways. Consequently, effective inhibition of both pathways may be necessary to block proliferation of antiestrogen-resistant breast cancer cells. In this study, we examined the effects of apigenin, a dietary plant flavonoid with potential anticancer properties, on estrogen-responsive, antiestrogen-sensitive MCF7 breast cancer cells and two MCF7 sublines with acquired resistance to either tamoxifen or fulvestrant. We found that apigenin can function as both an estrogen and antiestrogen, in a dose-dependent manner. At low concentrations (1μM), apigenin stimulated MCF7 cell growth but had no effect on the antiestrogen-resistant MCF7 sublines. In contrast, at high concentrations (≥10μM), the drug inhibited growth of MCF7 cells and the antiestrogen-resistant sublines, and the combination of apigenin with either tamoxifen or fulvestrant demonstrated synergistic, growth-inhibitory effects on both antiestrogen-sensitive and -resistant breast cancer cells. To further elucidate the molecular mechanism of apigenin as either an estrogen or antiestrogen, effects of the drug on estrogen receptor-α (ERα) transactivation activity, mobility, stability, and ERα-coactivator interactions were investigated. Low-dose apigenin enhanced receptor transcriptional activity by promoting interaction between ERα and its co-activator AIB1 (amplified in breast cancer-1). However, higher doses (> 10μM) of apigenin inhibited ERα mobility (as determined by FRAP assays), downregulated ERα and AIB1 expression levels, and inhibited multiple protein kinases, including p38, PKA, MAPK and AKT. Collectively, these results show that apigenin can function as both an antiestrogen and protein kinase inhibitor with activity against breast cancer cells with acquired resistance to OHT or fulvestrant. We conclude that apigenin, through its ability to target both ERα-dependent and -independent pathways, holds promise as a new therapeutic agent against antiestrogen-resistant breast cancer.
doi:10.1158/1535-7163.MCT-07-2350
PMCID: PMC2559959  PMID: 18645020
apigenin; antiestrogen; fulvestrant; tamoxifen; breast cancer
17.  Flavonoids Induce the Synthesis and Secretion of Neurotrophic Factors in Cultured Rat Astrocytes: A Signaling Response Mediated by Estrogen Receptor 
Neurotrophic factors are playing vital roles in survival, growth, and function of neurons. Regulation of neurotrophic factors in the brain has been considered as one of the targets in developing drug or therapy against neuronal disorders. Flavonoids, a family of multifunctional natural compounds, are well known for their neuronal beneficial effects. Here, the effects of flavonoids on regulating neurotrophic factors were analyzed in cultured rat astrocytes. Astrocyte is a major secreting source of neurotrophic factors in the brain. Thirty-three flavonoids were screened in the cultures, and calycosin, isorhamnetin, luteolin, and genistein were identified to be highly active in inducing the synthesis and secretion of neurotrophic factors, including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF). The inductions were in time- and dose-dependent manners. In cultured astrocytes, the phosphorylation of estrogen receptor was triggered by application of flavonoids. The phosphorylation was blocked by an inhibitor of estrogen receptor, which in parallel reduced the flavonoid-induced expression of neurotrophic factors. The results proposed the role of flavonoids in protecting brain diseases, and therefore these flavonoids could be developed for health food supplement for patients suffering from neurodegenerative diseases.
doi:10.1155/2013/127075
PMCID: PMC3708423  PMID: 23878590
18.  Phytochemical Profile and Nutraceutical Value of Old and Modern Common Wheat Cultivars 
PLoS ONE  2012;7(9):e45997.
Among health-promoting phytochemicals in whole grains, phenolic compounds have gained attention as they have strong antioxidant properties and can protect against many degenerative diseases. Aim of this study was to profile grain phenolic extracts of one modern and five old common wheat (Triticum aestivum L.) varieties and to evaluate their potential antiproliferative or cytoprotective effect in different cell culture systems.
Wheat extracts were characterized in terms of antioxidant activity and phenolic composition (HPLC/ESI-TOF-MS profile, polyphenol and flavonoid contents). Results showed that antioxidant activity (FRAP and DPPH) is mostly influenced by flavonoid (both bound and free) content and by the ratio flavonoids/polyphenols. Using a leukemic cell line, HL60, and primary cultures of neonatal rat cardiomyocytes, the potential antiproliferative or cytoprotective effects of different wheat genotypes were evaluated in terms of intracellular reactive oxygen species levels and cell viability. All tested wheat phenolic extracts exerted dose-dependent cytoprotective and antiproliferative effects on cardiomyocytes and HL60 cells, respectively. Due to the peculiar phenolic pattern of each wheat variety, a significant genotype effect was highlighted. On the whole, the most relevant scavenging effect was found for the old variety Verna. No significant differences in terms of anti-proliferative activities among wheat genotypes was observed.
Results reported in this study evidenced a correspondence between the in vitro antioxidant activity and potential healthy properties of different extracts. This suggests that an increased intake of wheat grain derived products could represent an effective strategy to achieve both chemoprevention and protection against oxidative stress related diseases.
doi:10.1371/journal.pone.0045997
PMCID: PMC3458827  PMID: 23049918
19.  Preconditioning and Acute Effects of Flavonoids in Protecting Cardiomyocytes from Oxidative Cell Death 
While flavonoids can reportedly protect against cardiac ischemia-reperfusion injury, the relative effectiveness of different flavonoids and the mechanisms involved are unclear. We compared protection by different flavonoids using rat embryonic ventricular H9c2 cells subjected to simulated ischemia-reperfusion (IR) and to tert-butyl hydroperoxide (t-buOOH). Characterization of the IR model showed the relative contributions of glucose, serum, and oxygen deprivation to cell death. With long-term (2-3 day) pretreatment before IR the best protection was given by catechin, epigallocatechin gallate, proanthocyanidins, and ascorbate, which protected at all doses. Quercetin protected (34%) at 5 μM but was cytotoxic at higher doses. Cyanidin protected mildly (10–15%) at 5 and 20 μM, while delphinidin had no effect at 5 μM and was cytotoxic at higher doses. Comparing long-term and acute protection by catechin, a higher concentration was needed for benefit with acute (1 hr) pretreatment. With a pure oxidative stress (t-buOOH) only quercetin significantly protected with 3-day pretreatment, while with short-term (1 h) pretreatments protection was best with quercetin and epigallocatechin gallate. The results suggest catechins to be especially useful as IR preconditioning agents, while quercetin and epigallocatechin gallate may be the most protective acutely in situations of oxidative stress.
doi:10.1155/2012/782321
PMCID: PMC3399417  PMID: 22829963
20.  Neuroprotective Effect of Kaempferol Glycosides against Brain Injury and Neuroinflammation by Inhibiting the Activation of NF-κB and STAT3 in Transient Focal Stroke 
PLoS ONE  2013;8(2):e55839.
Background
Ischemic brain injury is associated with neuroinflammatory response, which essentially involves glial activation and neutrophil infiltration. Transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) contribute to ischemic neuroinflammatory processes and secondary brain injury by releasing proinflammatory mediators. Kaempferol-3-O-rutinoside (KRS) and kaempferol-3-O- glucoside (KGS) are primary flavonoids found in Carthamus tinctorius L. Recent studies demonstrated that KRS protected against ischemic brain injury. However, little is known about the underlying mechanisms. Flavonoids have been reported to have antiinflammatory properties. Herein, we explored the effects of KRS and KGS in a transient focal stroke model.
Methodology/Principal Findings
Rats were subjected to middle cerebral artery occlusion for 2 hours followed by 22 h reperfusion. An equimolar dose of KRS or KGS was administered i.v. at the beginning of reperfusion. The results showed that KRS or KGS significantly attenuated the neurological deficits, brain infarct volume, and neuron and axon injury, reflected by the upregulation of neuronal nuclear antigen-positive neurons and downregulation of amyloid precursor protein immunoreactivity in the ipsilateral ischemic hemisphere. Moreover, KRS and KGS inhibited the expression of OX-42, glial fibrillary acidic protein, phosphorylated STAT3 and NF-κB p65, and the nuclear content of NF-κB p65. Subsequently, these flavonoids inhibited the expression of tumor necrosis factor α, interleukin 1β, intercellular adhesion molecule 1, matrix metallopeptidase 9, inducible nitric oxide synthase, and myeloperoxidase.
Conclusion/Significance
Our findings suggest that postischemic treatment with KRS or KGS prevents ischemic brain injury and neuroinflammation by inhibition of STAT3 and NF-κB activation and has the therapeutic potential for the neuroinflammation-related diseases, such as ischemic stroke.
doi:10.1371/journal.pone.0055839
PMCID: PMC3577792  PMID: 23437066
21.  Estrogen Receptor Signaling and Its Relationship to Cytokines in Systemic Lupus Erythematosus 
Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease, influence cytokine production, the underlying molecular mechanisms remain poorly defined. Recent evidence demonstrates the presence of estrogen receptor in various cell types of the immune system, while divergent effects of estrogens on the cytokine regulation are thought to be implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced modulation of cytokine production in SLE is mediated by the estrogen receptor while simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation and via extranuclear effects are briefly presented. Results regarding the possible correlation between estrogen receptor gene polymorphisms and quantitative changes in the receptor protein to SLE pathology and cytokine production are reviewed.
doi:10.1155/2010/317452
PMCID: PMC2896666  PMID: 20617147
22.  Nongenomic Actions of Low Concentration Estrogens and Xenoestrogens on Multiple Tissues 
Nongenomic estrogenic mechanisms offer an opportunity to explain the conundrum of environmental estrogen and plant estrogen effects on cells and animals at very the low concentrations which are prevalent in our environments and diets. Heretofore the actions of these compounds have not been adequately accounted for by laboratory tests utilizing assays for actions only via the genomic pathway of steroid action and the nuclear forms of estrogen receptor α and β. Membrane versions of these receptors, and the newly described GPR30 (7TMER) receptor protein provide explanations for the more potent actions of xenoestrogens. The effects of estrogens on many tissues demand a comprehensive assessment of the receptors, receptor levels, and mechanisms that might be involved, to determine which of these estrogen mimetic compounds are harmful and which might even be used therapeutically, depending upon the life stage at which we are exposed to them.
doi:10.1016/j.mce.2007.05.011
PMCID: PMC1986712  PMID: 17601655
environmental estrogen; phytoestrogen; membrane estrogen receptors; ERα; ERβ; GPR30; 7TMER
23.  The neuroprotective potential of flavonoids: a multiplicity of effects 
Genes & Nutrition  2008;3(3-4):115-126.
Flavonoids exert a multiplicity of neuroprotective actions within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. These effects appear to be underpinned by two common processes. Firstly, they interact with critical protein and lipid kinase signalling cascades in the brain leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and synaptic plasticity. Secondly, they induce beneficial effects on the vascular system leading to changes in cerebrovascular blood flow capable of causing angiogenesis, neurogenesis and changes in neuronal morphology. Through these mechanisms, the consumption of flavonoid-rich foods throughout life holds the potential to limit neurodegeneration and to prevent or reverse age-dependent loses in cognitive performance. The intense interest in the development of drugs capable of enhancing brain function means that flavonoids may represent important precursor molecules in the quest to develop of a new generation of brain enhancing drugs.
doi:10.1007/s12263-008-0091-4
PMCID: PMC2593006  PMID: 18937002
Flavonoid; Brain; Neuroprotection; Neuroinflammation; Memory; Cognitive function
24.  SULT1A3-Mediated Regiospecific 7-O-Sulfation of Flavonoids in Caco-2 Cells Can Be Explained by the Relevant Molecular Docking Studies 
Molecular Pharmaceutics  2012;9(4):862-873.
Flavonoids are the polyphenolic compounds with various claimed health benefits, but the extensive metabolism by uridine-5'-diphospho-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) in liver and intestine led to poor oral bioavailabilities. The effects of structural changes on the sulfonation of flavonoids have not been systemically determined, although relevant effects of structural changes on the glucuronidation of flavonoids had. We performed the regiospecific sulfonation of sixteen flavonoids from five different subclasses of flavonoids, which are represented by apigenin (flavone), genistein (isoflavone), naringenin (flavanone), kaempherol (flavonol), and phloretin (chalcone). Additional studies were performed using 4 mono-hydroxyl flavonoids with –OH group at 3, 4’, 5 or 7 position, followed by 5 di-hydroxyl-flavonoids, and 2 tri-hydroxyl flavonoids by using expressed human SULT1A3 and Caco-2 cell lysates. We found that these compounds were exclusively sulfated at the 7-OH position by SULT1A3 and primarily sulfated at 7-OH position in Caco-2 cell lysates with minor amounts of 4’-O-sulfates formed as well. Sulfonation rates measured using SULT1A3 and Caco-2 cell lysates were highly correlated at substrate concentrations of 2.5 and 10 µM. Molecular docking studies provided structural explanations as to why sulfonation only occurred at the 7-OH position of flavones, flavonols and flavanones. In conclusion, molecular docking studies explain why SULT1A3 exclusively mediates sulfonation at the 7-OH position of flavones/flavonols, and correlation studies indicate that SULT1A3 is the main isoform responsible for flavonoid sulfonation in the Caco-2 cells.
doi:10.1021/mp200400s
PMCID: PMC3404749  PMID: 22352375
Flavonoids; Sulfonation; Sulfation; SULT; SULT1A3; Caco-2; Molecular Docking
25.  Structure pre-requisites for isoflavones as effective antibacterial agents 
Pharmacognosy Reviews  2011;5(9):13-18.
Recent reports reveal that there is increasing incidence of infections of multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Flavonoids and related compounds have been shown to possess potent antimicrobial activities. Most of the flavonoids are considered as constitutive antimicrobial substances recently termed as “Phytoanticipins,” especially those belonging to prenylated flavonoids and isoflavones. The current review highlights the structure prerequisites for isoflavones as antibacterial agents. Structure–activity relationship (SAR) conclusions have been drawn by comparing the reported minimum inhibitory concentration values for the various isoflavones against S. aureus and MRSA. There exists a significant co-relationship between the presence of certain functional groups (prenyl group, phenolic hydroxyl) at particular positions and antibacterial activity of the compounds. These trends have been postulated with a view of assisting better drug designing of future next-generation antiinfectives, particularly against the bothersome multidrug-resistant microbes. The SAR of these isoflavones has also proved to be a basis to explore the mechanism of antibacterial action. Thus, the study would prove extremely useful to synthesize antibacterial isoflavones in future, which would eventually be beneficial for optimizing the lead molecule for the antibacterial action
doi:10.4103/0973-7847.79095
PMCID: PMC3210004  PMID: 22096314
Antibacterial activity; Isoflavones; SAR of isoflavones

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