Catherine Rice-Evans’s research while affiliated with Molecular Biology Resources and other places

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Publications (282)


ChemInform Abstract: Structure-Antioxidant Activity Relationship of Flavonoids and Isoflavonoids
  • Article

May 2010

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138 Reads

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132 Citations

ChemInform

C. A. RICE-EVANS

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N. J. MILLER

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.


The Effects of Ascorbic Acid and Iron Co-Supplementation on the Proliferation of 3T3 Fibroblasts

July 2009

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40 Reads

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15 Citations

Clifford S. Collis

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Min Yang

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Susan J. Peach

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[...]

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Catherine Rice-evans

Exposure of 3T3 fibroblasts to Fe reveals a concentration-dependent inhibition of cell proliferation compared to control cells, the apparent threshold for this iron-mediated effect being 5 μM FeII. The inhibition of cell proliferation was accompanied by an enhancement of total malondialdehyde (MDA) levels (as detected directly by hplc) in the cells at higher iron concentrations. The co-supplementation of Fe with varying concentrations of ascorbic acid over the range 5 μM to 240 μM had no significant effect on the threshold for iron toxicity or lipid peroxidation. These results show that there is neither a significant exacerbation of the pro-oxidant effect of FeII nor any protective effect of ascorbate when cultures of 3T3 mouse fibroblasts are exposed to co-supplementation regimes of iron with ascorbic acid.


Figure 1 Click here to download high resolution image  
Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation
  • Article
  • Full-text available

July 2008

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184 Reads

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61 Citations

Neuroscience Letters

Dietary flavonoids, including the citrus flavanone hesperetin, may have stimulatory effects on cytoprotective intracellular signalling pathways. In primary mouse cortical neurone cultures, but not SH-SY5Y human neuroblastoma cells or human primary dermal fibroblasts (Promocells), hesperetin (100-300nM, 15min) caused significant increases in the level of ERK1/2 phosphorylation, but did not increase CREB phosphorylation. Administration of hesperetin for 18h did not alter gene expression driven by the cyclic AMP response element (CRE), assessed using a luciferase reporter system, but 300nM hesperetin partially reversed staurosporine-induced cell death in primary neurones. Our data show that hesperetin is a neuroprotective compound at concentrations where antioxidant effects are unlikely to predominate. The effects of hesperetin are cell-type dependent and, unlike the flavanol (-)epicatechin, neuroprotection in vitro is not associated with enhanced CREB phosphorylation or CRE-mediated gene expression.

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Inhibition of cellular proliferation by the genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone is mediated by DNA damage and activation of the ATR signalling pathway

January 2008

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47 Reads

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34 Citations

Archives of Biochemistry and Biophysics

The cellular actions of genistein, and its in vivo metabolites, are believed to mediate the decreased risk of breast cancer associated with high soy consumption. The genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone (THIF), induced G2-M cell cycle arrest in T47D tumorigenic breast epithelial cells via a mechanism involving the activation of ataxia telangiectasia and Rad3-related kinase (ATR) via its phosphorylation at Ser428. This activation of ATR appeared to result from THIF-induced increases in intracellular oxidative stress, a depletion of cellular GSH and an increase in DNA strand breakage. THIF treatment also led to an inhibition of cdc2, which was accompanied by the phosphorylation of both p53 (Ser15) and Chk1 (Ser296) and the de-activation of cdc25C phosphatase. We suggest the anti-proliferative actions of THIF may be mediated by initial oxidative DNA damage, activation of ATR and downstream regulation of the p53 and Chk1 pathways leading to cell cycle arrest in G2-M. This may represent one mechanism by which genistein exerts its cellular activity in vivo.


Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons

December 2007

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141 Reads

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263 Citations

There is growing interest in the potential beneficial effects of flavonoids in the aging and diseased brain. We have investigated the potential of the flavanone hesperetin and two of its metabolites, hesperetin-7-O-beta-d-glucuronide and 5-nitro-hesperetin, to inhibit oxidative stress-induced neuronal apoptosis. Exposure of cortical neurons to hydrogen peroxide led to the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser963, the phosphorylation of c-jun N-terminal kinase and c-Jun (Ser73) and the activation of caspase 3 and caspase 9. Whilst hesperetin glucuronide failed to exert protection, both hesperetin and 5-nitro-hesperetin were effective at preventing neuronal apoptosis via a mechanism involving the activation/phosphorylation of both Akt/protein kinase B and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Protection against oxidative injury and the activation of Akt and ERK1/2 followed a bell-shaped response and was most apparent at 100 nmol/L concentrations. The activation of ERK1/2 and Akt by flavanones led to the inhibition of the pro-apoptotic proteins, apoptosis signal-regulating kinase 1, by phosphorylation at Ser83 and Bad, by phosphorylation at both Ser136 and Ser112 and to the inhibition of peroxide-induced caspase 9 and caspase 3 activation. Thus, flavanones may protect neurons against oxidative insults via the modulation of neuronal apoptotic machinery.


Figure 1: Epicatechin stimulates cAMP-response element binding protein (CREB) phosphorylation in a concentration-dependent manner. Cortical neurons were exposed to increasing concentrations of (-)epicatechin (30 nmol/L–30 μmol/L) for 15 min and the levels of phosphorylated CREB (Ser133) and total CREB was measured by immunoblotting. (a) Representative immunoblots from a single experiment showing phosphorylated CREB and total CREB in the same cell lysates. (b) Band intensities were determined by densitometric analysis using Bioimage Intelligent Quantifier Software. (-)Epicatechin exhibited bell-shaped concentration response characteristics and stimulated a significant increase in CREB phosphorylation at 100–300 nmol/L (a upper panel and b) compared with the untreated basal, without altering the total levels of CREB (a lower panel). **p < 0.01 one-way anova, followed by Dunnett’s post hoc test, n = 3.
Figure 5: Bioactivity of in vivo metabolites of (-)epicatechin. Cortical neurons were exposed to 100 nmol/L of (-)epicatechin (EC), 3′-O-methyl-(-)epicatechin (Me-EC) or (-)epicatechin-5-O-β-d-glucuronide (Gluc-EC) (structures shown) for 15 min and the levels of dually phosphorylated extracellular signal-regulated kinase 1/2 (ERK) (pTEpY) determined by immunoblotting. Band intensities were determined by densitometric analysis using Bioimage Intelligent Quantifier Software. (-)Epicatechin and Me-EC but not Gluc-EC caused a significant increase in the levels of phosphorylated ERK1/2. **p < 0.01, one-way anova, followed by Dunnett’s post hoc test, n = 3.
Figure 6: Epicatechin stimulates extracellular signal-regulated kinase-dependent CRE activity. (a) Cortical neurons transfected overnight with a CRE-luciferase reporter plasmid and a Renilla luciferase phRL-TK control plasmid were exposed for 15 min to either (-)epicatechin (EC 100 nmol/L) or the in vivo metabolite 3′-O-methyl-(-)epicatechin (Me-EC 100 nmol/L) and luciferase activity measured 18 h later. Data is expressed as firefly luciferase luminescence relative to Renilla luciferase luminescence. (-)Epicatechin and 3′-O-methyl-(-)epicatechin stimulated CRE-luciferase expression relative to vehicle-treated control, *p < 0.05 one-way anova, followed by Dunnett’s post hoc test (n = 6). (b) Transfected neurons (as above) were pre-treated for 5 min with or without the MEK inhibitor U0126 (5 μmol/L) and then exposed for 15 min to (-)epicatechin (EC 100 nmol/L) in the continued presence (black bars) or absence (white bars) of U0126 and luciferase activity measured 18 h later. Exposure to 100 nmol/L (-)epicatechin stimulated a modest increase in luciferase activity only in the absence of U0126. *p < 0.05 paired t-test, n = 5.
(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons

July 2007

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328 Reads

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182 Citations

Emerging evidence suggests that the cellular actions of flavonoids relate not simply to their antioxidant potential but also to the modulation of protein kinase signalling pathways. We investigated in primary cortical neurons, the ability of the flavan-3-ol, (-)epicatechin, and its human metabolites at physiologically relevant concentrations, to stimulate phosphorylation of the transcription factor cAMP-response element binding protein (CREB), a regulator of neuronal viability and synaptic plasticity. (-)Epicatechin at 100-300 nmol/L stimulated a rapid, extracellular signal-regulated kinase (ERK)- and PI3K-dependent, increase in CREB phosphorylation. At micromolar concentrations, stimulation was no longer apparent and at the highest concentration tested (30 mumol/L) (-)epicatechin was inhibitory. (-)Epicatechin also stimulated ERK and Akt phosphorylation with similar bell-shaped concentration-response characteristics. The human metabolite 3'-O-methyl-(-)epicatechin was as effective as (-)epicatechin at stimulating ERK phosphorylation, but (-)epicatechin glucuronide was inactive. (-)Epicatechin and 3'-O-methyl-(-)epicatechin treatments (100 nmol/L) increased CRE-luciferase activity in cortical neurons in a partially ERK-dependent manner, suggesting the potential to increase CREB-mediated gene expression. mRNA levels of the glutamate receptor subunit GluR2 increased by 60%, measured 18 h after a 15 min exposure to (-)epicatechin and this translated into an increase in GluR2 protein. Thus, (-)epicatechin has the potential to increase CREB-regulated gene expression and increase GluR2 levels and thus modulate neurotransmission, plasticity and synaptogenesis.


The reaction of flavonoid metabolites with peroxynitrite

January 2007

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156 Reads

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106 Citations

Biochemical and Biophysical Research Communications

There is much interest in the bioactivity of in vivo flavonoid metabolites. We report for the first time the hierarchy of reactivity of flavonoid metabolites with peroxynitrite and characterise novel reaction products. O-Methylation of the B-ring catechol containing flavonoids epicatechin and quercetin, and O-glucuronidation of all flavonoids reduced their reactivity with peroxynitrite. The reaction of the flavanones hesperetin and naringenin and their glucuronides resulted in the formation of multiple mono-nitrated and nitrosated products. In contrast, the catechol-containing flavonoids epicatechin and quercetin yielded oxidation products which when trapped with glutathione led to the production of glutathionyl-conjugates. However, the O-methylated metabolites of epicatechin yielded both mono- and di-nitrated products and nitrosated metabolites. The 3'-O-methyl metabolite of quercetin also yielded a nitrosated species, although its counterpart 4'-O-methyl quercetin yielded only oxidation products. Such products may represent novel metabolic products in vivo and may also express cellular activity.


Suppression of UVA-mediated release of labile iron by epicatechin-A link to lysosomal protection

November 2006

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65 Reads

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33 Citations

Free Radical Biology and Medicine

UVA (320-380 nm) radiation generates an oxidative stress in cells and leads to an immediate release of potentially damaging labile iron pools in human skin cells. Treatment of cultured skin fibroblasts for several hours with physiologically relevant concentrations of either epicatechin (EC), a flavonoid plant constituent present in foods, or methylated epicatechin (3'-O-methyl epicatechin, MeOEC), its major human metabolite, prevents this iron release. The similarity of the effectiveness of EC and MeOEC argues against chelation as the mechanism of iron removal. Evidence based on measurements of lysosomal integrity strongly supports the hypothesis that the catechins protect against lysosomal destruction by UVA. Such damage would normally lead to protease release, which has been previously shown to cause ferritin degradation and release of labile iron.


The intracellular genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone mediates G2-M cell cycle arrest in cancer cells via modulation of the p38 signaling pathway

November 2006

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55 Reads

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37 Citations

Free Radical Biology and Medicine

The cellular actions of genistein are believed to mediate the decreased risk of breast cancer associated with high soy consumption. We have investigated the intracellular metabolism of genistein in T47D tumorigenic and MCF-10A nontumorigenic cells and assessed the cellular actions of resultant metabolites. Genistein selectively induced growth arrest and G2-M phase cell cycle block in T47D but not MCF10A breast epithelial cells. These antiproliferative effects were paralleled by significant differences in the association of genistein to cells and in particular its intracellular metabolism. Genistein was selectively taken up into T47D cells and was subject to metabolism by CYP450 enzymes leading to the formation of both 5,7,3',4'-tetrahydroxyisoflavone (THIF) and two glutathionyl conjugates of THIF. THIF inhibited cdc2 activation via the phosphorylation of p38 MAP kinase, suggesting that this species may mediate genistein's cellular actions. THIF exposure activated p38 and caused subsequent inhibition of cyclin B1 (Ser 147) and cdc2 (Thr 161) phosphorylation, two events critical for the correct functioning of the cdc2-cyclin B1 complex. We suggest that the formation of THIF may mediate the cellular actions of genistein in tumorigenic breast epithelial cells via the activation of signaling through p38.


pH-dependent nitration of para-hydroxyphenylacetic acid in the stomach

October 2006

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88 Reads

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31 Citations

Free Radical Biology and Medicine

The major urinary metabolite of nitrotyrosine is 3-nitro-4-hydroxyphenylacetic acid (3-Nitro-HPA). However, recent animal studies have shown that the majority of urinary 3-Nitro-HPA is derived from nitration of endogenous para-hydroxyphenylacetic acid (HPA), a metabolite of tyrosine. One potential site for the formation of 3-Nitro-HPA is the stomach, where nitrous acid is formed by the reaction of nitrite in saliva with gastric acid. The aim of this study was to determine whether there is pH-dependent nitration of salivary para-hydroxyphenylacetic acid or tyrosine, and the effects of dietary nitrate. Healthy volunteers (n = 18) ingested either a low or high nitrate diet, with and without the administration of omeprazole, a proton pump inhibitor. Urinary 3-Nitro-HPA excretion increased from 197 +/- 52 to 319 +/- 88 microg/day on switching from a low to a high nitrate diet (P < 0.05), and decreased (166 +/- 53 mug/day, P < 0.05) when gastric pH was increased by omeprazole. To determine whether 3-Nitro-HPA can be formed by nitration of para-hydroxyphenylacetic acid in the stomach, 500 microg of deuterated para-hydroxyphenylacetic acid was ingested with a high nitrate meal. This led to the excretion of both deuterated HPA and 3-Nitro-HPA in the urine, confirming that para-hydroxyphenylacetic acid is absorbed, and nitrated. Since omeprazole decreases the formation of 3-Nitro-HPA, presumably by decreasing the nitration of endogenous para-hydroxyphenylacetic acid present in saliva, and the observation that ingested deuterated para-hydroxyphenylacetic acid is nitrated and excreted, we conclude that endogenous para-hydroxyphenylacetic acid is nitrated in the stomach, absorbed, and excreted as 3-Nitro-HPA.


Citations (88)


... A prominent property of flavonoids is that, through their antioxidant ability, they might provide protection against oxidative stress. The antioxidant activity of flavonoids and other polyphenols is attributed primarily to their ability to scavenge reactive oxygen and nitrogen species [61]. In this study, the rhenium complexes of three flavones and one flavanol were tested as antioxidant agents and inhibitors of lipoxygenase. ...

Reference:

Synthesis, structural characterization and study of antioxidant and anti-PrPSc properties of flavonoids and their rhenium(I)–tricarbonyl complexes
Flavonoids in Health and Disease
  • Citing Book
  • May 2003

... The KEGG pathway enrichment analysis showed that EGFR tyrosine kinase inhibitor resistance, endocrine resistance, pancreatic cancer, prostate cancer, the HIF-1 signaling pathway, and proteoglycans in cancer and other pathways may be potential signaling pathways for the treatment of UTIs with SJT. It has been reported that the HIF-1 signaling pathway is an important mechanism in the treatment of UTIs and that HIF-1α transcriptional regulation plays a key role in the defense of the urinary tract against UPEC infection (Lin et al., 2015), whereas quercetin acts on EGFR (Huang et al., 2009), AKT1 (Spencer et al., 2003), IGF1R (El et al., 2014), and CAMK2B (Wang et al., 2011) targets in the HIF-1 signaling pathway; ellagic acid (C92) acts therapeutically on EGFR, AKT1, IGF1R, and ERBB2 targets in the HIF-1 signaling pathway (Hundsdorfer et al., 2012). These findings indicate that SJT are likely to act on the HIF-1 signaling pathway as well as the above-mentioned targets and exert their effect. ...

Modulation of pro-survival Akt/PKB and ERK1/2 signalling cascades by quercetin and its in vivo metabolites
  • Citing Conference Paper
  • January 2003

Free Radical Biology and Medicine

... In particular, flavan-3-ols are the most structurally complex subclass of flavonoids which have been recognized as antihypertensive agents [3] . They have been also reported to have multiple biological effects, mainly attributed to their antioxidant properties, as they can act as chain breakers or radical scavengers [4] . Moreover, mounting evidence indicates that a higher intake of flavan-3-ols rich foods is closely linked to a reduction in chronicdegenerative diseases such as type 2 diabetes, cardiovascular diseases, and some types of cancer [ 5 , 6 ]. ...

Molecular mechanisms of the antioxidant effects of in vivo metabolites of flavan-3-ols.
  • Citing Article
  • August 2001

ACS National Meeting Book of Abstracts

... In 2011, anthelmintic effect in an extract made with ethanol of each leaves & root of P. Juliflora is being displayed while contrasting it to the conventional treatment Albendazole. The outputs disclosed that the extract of leaf using ethanol is more efficient than the roots extract as anthelmintic action, but it is equally successful in comparison to the synthetic medicine Albendazole [33] .The main sources of anthelmintic effectiveness of extract are condensed tannins, saponins, and alkaloids. Resulting that, these plant-derived compounds might be an optimistic origin for veterinary pharmaceutical development to treat infection with nematodes [34] . ...

Screening of Phenolics and Flavonoids for Antioxidant Activity
  • Citing Chapter
  • December 1999

... Flavonoids are widely distributed in the plant kingdom and are abundant in flowers, fruits, and leaves of many plants (Du et al., 2010). Based on the different oxygen rings and conformations of the basic molecular structure, flavonoids are generally divided into six categories: flavone, flavonol, isoflavone, flavanone, flavanol, and anthocyanidin (Rice-Evans and Miller, 2010). The starting substrate for plant flavonoid biosynthesis is derived from coumaroyl-CoA of the phenylpropane metabolic pathway and malonyl-CoA from acetyl-coenzymes. ...

ChemInform Abstract: Structure-Antioxidant Activity Relationship of Flavonoids and Isoflavonoids
  • Citing Article
  • May 2010

ChemInform

... Flavonoids are benzo-γ-pyrone derivatives widely distributed in plants kingdom [1][2][3][4]. They have been shown to possess a wide range of biological activities including antiviral, anti-allergic, anti-inflammatory, anti-tumor properties [5,6]. ...

Nutritional Proanthocyanidins, Flavonoids, and Related Phenols
  • Citing Article
  • December 2001

Antioxidants and Redox Signaling

... Notably, the intracellular concentrations of flavonoids required to modulate cellular signaling are significantly lower than those needed to impact cellular antioxidant capacity. Furthermore, even if their antioxidant activity diminishes, flavonoid metabolites may still maintain their ability to interact with cell-signaling proteins [91][92][93]. Numerous in vitro studies suggest that flavonoids may influence chronic diseases by selectively inhibiting kinases [91,94]. Moreover, cell growth and proliferation are regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors on cell membranes. ...

Bioavailability of Flavan3-ols and Procyanidins: Gastrointestinal Tract Influences and Their Relevance to Bioactive Forms In Vivo
  • Citing Article
  • December 2001

Antioxidants and Redox Signaling

... In addition to antioxidative, anti-inflammatory, anti-viral, anti-tumor, and heart-protective properties, NRG can also exert neuroprotective effects 14 . Besides, it has been proven that NRG can penetrate the blood-brain barrier, suggesting the significant potential of NRG in the treatment of neurodegenerative diseases 15,16 . ...

Corrigendum to Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic. Biol. Med. 36: 592–604; 2004
  • Citing Article
  • May 2004

Free Radical Biology and Medicine

... Antioxidants reduce the prevalence of ASCVD by capturing and deactivating free radicals, which can result in tissue damage. Antioxidants can slow down or prevent plaque formation by inhibiting low-density lipoprotein oxidation, regulating platelet activity, reducing thrombogenicity, and regulating vascular reactivity [27][28][29][30][31][32][33]. Several observational studies have also found that antioxidant intake is associated with a lower risk of major cardiovascular events [34][35][36]. ...

Moderate supplementation with natural α-tocopherol decreases platelet aggregation and low-density lipoprotein oxidation
  • Citing Article
  • November 1999

Atherosclerosis

... Our studies also attempted to address issues of bioefficacy and biotargeting of resveratrol, in the context of its limited bioavailability and enzymatic conversion to metabolites with largely unknown activities. Since resveratrol has been shown to convert to its glucuronidated and sulfated metabolites in isolated rat intestine studies sections or in human feeding experiments [50,[70][71][72][73][74], and because resveratrol is found in red wine or grape juice mostly as piceid (resveratrol glycosides) [75], we tested effects of piceid, 3-O-and 4'-O-glucuronidated resveratrol and piceatannol on the induction of HPAEC eotaxin-1 by combined IL-13/TNF-α. Only a small reduction in eotaxin-1 mRNA levels by the resveratrol metabolites was observed (Figure 5), a notable exception was found in piceatannol Figure 7 A proposed mechanistic scheme illustrating induction of eotaxin-1 gene transcription by IL-13 and TNF-α and modulation by resveratrol. ...

Absorption and metabolism of resveratrol in the small intestine. Implications for resveratrol in vivo
  • Citing Article
  • January 2000