quercetin considerations - eg, in neurons... quercetin decreased GSH and led to cell death - essay

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HMGB1 in autism, rheumatic diseases, epilepsy: a role for

quercetin?

Apr 03, 2010

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People thinking of using quercetin are recommended to proceed cautiously,

because quercetin's effects are quite diverse (eg, 13-22).

13. Curcumin, quercetin, and tBHQ modulate

glutathione levels in astrocytes and neurons: importance of the glutamate

cysteine ligase modifier subunit

Lavoie S, Chen Y, Dalton TP, Gysin R, Cuénod M, Steullet

P, Do KQ.

J Neurochem. 2009 Mar;108(6):1410-22. Epub 2009 Jan 22.

http://www3.interscience.wiley.com/cgi-bin/fulltext/121654363/PDFSTART

A decrease in GSH levels, the main redox regulator, can be observed in

neurodegenerative diseases as well as in schizophrenia. In search for

substances able to increase GSH, we evaluated the ability of curcumin

(polyphenol), quercetin (flavonoid), and tert-butylhydroquinone (tBHQ) to

up-regulate GSH-synthesizing enzymes. The gene expression, activity, and

product levels of these enzymes were measured in cultured neurons and

astrocytes. In astrocytes, all substances increased GSH levels and the

activity of the rate-limiting synthesizing enzyme, glutamate cysteine

ligase (GCL). In neurons, curcumin and to a

lesser extent tBHQ increased GCL activity and GSH levels, while quercetin

decreased GSH and led to cell death. In the two cell

types, the gene that showed the greatest increase in its expression was

the one coding for the modifier subunit of GCL (GCLM). The increase in

mRNA levels of GCLM was 3 to 7-fold higher than that of the catalytic

subunit. In astrocytes from GCLM-knock-out mice showing low GSH (-80%)

and low GCL activity (-50%), none of the substances succeeded in

increasing GSH synthesis. Our results indicate that GCLM is essential for

the up-regulation of GCL activity induced by curcumin, quercetin and

tBHQ.

14. Dietary flavonoids modulate PCB-induced

oxidative stress, CYP1A1 induction, and AhR-DNA binding activity in

vascular endothelial cells.

Ramadass P, Meerarani P, Toborek M, on LW, Hennig

B.

Toxicol Sci. 2003 Nov;76(1):212-9. Epub 2003 Sep 11.

http://toxsci.oxfordjournals.org/cgi/reprint/76/1/212

Polychlorinated biphenyls (PCBs), especially the more coplanar PCBs, have

been shown to induce oxidative stress, various transcription factors, and

subsequent inflammatory processes critical to atherosclerosis in vascular

endothelial cells. Dietary flavonoids such as catechins and quercetin

possess antioxidant and anti-inflammatory properties. To test the

hypothesis that flavonoids can modify PCB-mediated endothelial

cytotoxicity, endothelial cells were treated with

epigallocatechin-3-gallate (EGCG; 5 to 50 muM) or quercetin (10 to 100

muM) with or without PCB 77 (3,3',4,4'-tetrachlorobiphenyl, 3.4 muM) for

6 h. EGCG and quercetin strongly, and in a concentration-dependent

manner, inhibited oxidative stress induced by PCB 77 as measured by DCF

fluorescence. The role of cytochrome P450 1A1 (CYP1A1) in the PCB-induced

toxicity was investigated. EGCG at 50 muM and quercetin at 100 muM

concentrations markedly inhibited CYP1A1 mRNA levels and enzyme activity.

Furthermore, EGCG and quercetin downregulated the PCB 77-mediated

increase in aryl hydrocarbon receptor (AhR)-DNA binding activity.

These data suggest that protective effects of

EGCG and quercetin are initiated upstream from CYP1A1 and that these

flavonoids may be of value for inhibiting the toxic effects of PCBs on

vascular endothelial cells.

15. Cytoprotective effect of green tea

extract and quercetin against hydrogen peroxide-induced oxidative

stress

Jeong YM, Choi YG, Kim DS, Park SH, Yoon JA, Kwon SB, Park

ES, Park KC.

Arch Pharm Res. 2005 Nov;28(11):1251-6. {free online}

http://tinyurl.com/c6b4mw

In this study, we evaluated the cytoprotective effects of antioxidative

substances in hydrogen peroxide (H2O2) treated Mel-Ab melanocytes. Tested

substances include selenium, quercetin, green tea (GT) extract, and

several vitamins (ascorbic acid, Trolox, and folic acid). Of these, both

quercetin and GT extract were found to have strong cytoprotective effects

on H2O2-induced cell death. We also examined additive effects, but no

combination of two of any of the above substances was found to act

synergistically against oxidative damage in Mel-Ab cells.

Nevertheless, a multi-combination of GT

extract, quercetin, and folic acid appeared to prevent cellular damage in

a synergistic manner, which suggests that combinations of

antioxidants may be of importance, and that co-treatment with

antioxidants offers a possible means of treating vitiligo, which is known

to be related to melanocyte oxidative stress.

16. Effects of Food Natural Products on the

Biotransformation of PCBs

MO, Sacco JC, Faux LR.

Environ Toxicol Pharmacol. 2008 Mar;25(2):211-217.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2346442/pdf/nihms40361.pdf

Many food products, particularly fruits and vegetables, contain natural

products that affect biotransformation enzymes. These may be expected to

affect the rate of biotransformation of PCBs that are metabolized by the

affected enzymes. The first step in PCB metabolism is cytochrome

P450-dependent monooxygenation. Natural products present in

cruciferous vegetables have

been shown to selectively up-regulate CYP1A1 and CYP1A2 isozymes on

chronic ingestion, and may lead to increased metabolism of those PCB

congeners that are substrates for the induced P450s. On the other hand,

several natural products selectively inhibit monooxygenation, especially

in the intestine, and may lead to increased bioavailability and reduced

metabolism of dietary PCBs. Food natural products are known to affect

phase II pathways important in the detoxication of hydroxylated PCBs,

namely UDP-glucuronosyltransferase and PAPS-sulfotransferase.

Continual dietary exposure to chrysin and

quercetin, found in fruits and vegetables, induces UGT1A1 and may reduce

exposure to hydroxylated PCBs through increased glucuronidation. These

and other natural products are also inhibitors of glucuronidation and

sulfonation, potentially leading to transient decreases in the

elimination of hydroxylated PCBs. In summary, the expected effects of

food natural products on PCB biotransformation are complex and may be

biphasic, with initial inhibition followed by enhanced biotransformation

through monooxygenation and conjugation pathways.

17. Modulation of pro-survival Akt/protein

kinase B and ERK1/2 signaling cascades by quercetin and its in vivo

metabolites underlie their action on neuronal viability

Spencer JP, Rice- C, RJ.

Wolfson Centre for Age-related Diseases, Guy's, King's and St. '

School of Biomedical Sciences, Hodgkin Building, King's College, Guy's

Campus, London, SE1 9RT, United Kingdom.

J Biol Chem. 2003 Sep 12;278(37):34783-93.

http://www.jbc.org/content/278/37/34783.full.pdf+html

Much recent interest has focused on the potential of flavonoids to

interact with intracellular signaling pathways such as with the

mitogen-activated protein kinase cascade. We have investigated whether

the observed strong neurotoxic potential of

quercetin in primary cortical neurons may occur via

specific and sensitive interactions within neuronal mitogen-activated

protein kinase and Akt/protein kinase B (PKB) signaling cascades, both

implicated in neuronal apoptosis. Quercetin induced potent inhibition of

both Akt/PKB and ERK phosphorylation, resulting in reduced

phosphorylation of BAD and a strong activation of caspase-3. High

quercetin concentrations (30 microM) led to sustained loss of Akt

phosphorylation and subsequent Akt cleavage by caspase-3, whereas at

lower concentrations (<10 microM) the inhibition of Akt

phosphorylation was transient and eventually returned to basal levels.

Lower levels of quercetin also induced strong activation of the

pro-survival transcription factor cAMP-responsive element-binding

protein, although this did not prevent neuronal damage. O-Methylated

quercetin metabolites inhibited Akt/PKB to lesser extent and did not

induce such strong activation of caspase-3, which was reflected in the

lower amount of damage they inflicted on neurons. In contrast, neither

quercetin nor its O-methylated metabolites had any measurable effect on

c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was

not toxic and did not evoke any alterations in neuronal signaling,

probably reflecting its inability to enter neurons.

Together these data suggest that quercetin

and to a lesser extent its O-methylated metabolites may induce neuronal

death via a mechanism involving an inhibition of neuronal survival

signaling through the inhibition of both Akt/PKB and ERK

rather than by an activation of the c-Jun N-terminal kinase-mediated

death pathway.

18. Quercetin blocks airway epithelial cell

chemokine expression

Nanua S, Zick SM, Andrade JE, Sajjan US, Burgess JR,

Lukacs NW, Hershenson MB.

University of Michigan, 1150 W. Medical Center Drive, Box 0688, Ann

Arbor, MI 48109-0688, USA.

Am J Respir Cell Mol Biol. 2006 Nov;35(5):602-10. Epub 2006 Jun 22.

http://ajrcmb.atsjournals.org/cgi/content/full/35/5/602

Quercetin (3,3',4',5,7-pentahydroxyflavone), a dietary flavonoid, is an

inhibitor of phosphatidylinositol (PI) 3-kinase and potent antioxidant.

We hypothesized that quercetin blocks airway epithelial cell chemokine

expression via PI 3-kinase-dependent mechanisms. Pretreatment with

quercetin and the PI 3-kinase inhibitor LY294002 each reduced

TNF-alpha-induced IL-8 and monocyte chemoattractant protein (MCP)-1 (also

called CCL2) expression in cultured human airway epithelial cells.

Quercetin also inhibited TNF-alpha-induced PI 3-kinase activity, Akt

phosphorylation, intracellular H(2)O(2) production, NF-kappaB

transactivation, IL-8 promoter activity, and steady-state mRNA levels,

consistent with the notion that quercetin inhibits chemokine expression

by attenuating NF-kappaB transactivation via a PI 3-kinase/Akt-dependent

pathway. Quercetin also reduced TNF-alpha-induced chemokine secretion in

the presence of the transcriptional inhibitor actinomycin D, while

inducing phosphorylation of eukaryotic translation initiation factor

(eIF)-2alpha, suggesting that quercetin attenuates chemokine expression

by post-transcriptional as well as transcriptional mechanisms. Finally,

we tested the effects of quercetin in cockroach antigen-sensitized and

-challenged mice. These mice show MCP-1-dependent airways

hyperresponsiveness and inflammation. Quercetin significantly reduced

lung MCP-1 and methacholine responsiveness. We conclude that quercetin

blocks airway cell chemokine expression via transcriptional and

post-transcriptional pathways.

19. Dietary flavonols quercetin and

kaempferol are ligands of the aryl hydrocarbon receptor that affect

CYP1A1 transcription differentially

Ciolino HP, Daschner PJ, Yeh GC.

Cellular Defense and Carcinogenesis Section, Basic Research Division of

Basic Sciences, National Cancer Institute-Frederick Cancer Research and

Development Center, National Institutes of Health, Frederick, MD

21702-1201, USA.

Biochem J. 1999 Jun 15;340 ( Pt 3):715-22.

http://www.biochemj.org/bj/340/0715/bj3400715.htm

Transcriptional activation of the human CYP1A1 gene (coding for

cytochrome P450 1A1) is mediated by the aryl hydrocarbon receptor (AhR).

In the present study we have examined the effect of the common dietary

polyphenolic compounds quercetin and kaempferol on the transcription of

CYP1A1 and the function of the AhR in MCF-7 human breast cancer cells.

Quercetin caused a time- and concentration-dependent increase in the

amount of CYP1A1 mRNA and CYP1A1 enzyme activity in MCF-7 cells. The

increase in CYP1A1 mRNA caused by quercetin was prevented by the

transcription inhibitor actinomycin D. Quercetin also caused an increase

in the transcription of a chloramphenicol reporter vector containing the

CYP1A1 promoter. Quercetin failed to induce CYP1A1 enzyme activity in

AhR-deficient MCF-7 cells. Gel retardation studies demonstrated that

quercetin activated the ability of the AhR to bind to an oligonucleotide

containing the xenobiotic-responsive element (XRE) of the CYP1A1

promoter. These results indicate that quercetin's effect is mediated by

the AhR. Kaempferol did not affect CYP1A1 expression by itself but it

inhibited the transcription of CYP1A1 induced by the prototypical AhR

ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), as measured by a

decrease in TCDD-induced CYP1A1 promoter-driven reporter vector activity,

and CYP1A1 mRNA in cells. Kaempferol also abolished TCDD-induced XRE

binding in a gel-shift assay. Both compounds were able to compete with

TCDD for binding to a cytosolic extract of MCF-7 cells. Known ligands of

the AhR are, for the most part, man-made compounds such as halogenated

and polycyclic aromatic hydrocarbons. These results demonstrate that the

dietary flavonols quercetin and kaempferol are natural, dietary ligands

of the AhR that exert different effects on CYP1A1 transcription.

20. The flavonoids, quercetin and

isorhamnetin 3-O-acylglucosides diminish neutrophil oxidative metabolism

and lipid peroxidation

Zieli ska M, Kostrzewa A, Ignatowicz E, Budzianowski

J.

Department of Pharmaceutical Biochemistry, Karol Marcinkowski University

of Medical Sciences, Pozna , Poland.

Acta Biochim Pol. 2001;48(1):183-9.

http://www.actabp.pl/pdf/1_2001/183.pdf

Two natural flavonoids, quercetin and isorhamnetin 3-O-acylglucosides,

were examined for their inhibitory influence on the in vitro production

and release of reactive oxygen species in polymorphonuclear neutrophils

(PMNs). The generation of superoxide radical, hydrogen peroxide and

hypochlorous acid were measured by, respectively, cytochrome c reduction,

dichlorofluorescin oxidation and taurine chlorination. Membrane lipid

oxidation was studied by the thiobarbituric acid method in mouse spleen

microsomes. The addition of flavonoids at the concentration range 1-100

microM inhibited PMNs oxidative metabolism and lipid peroxidation in a

dose-dependent manner. The results suggest that these flavonoids suppress

the oxidative burst of PMNs and protect membranes against lipid

peroxidation.

21. The flavonoid quercetin inhibits

proinflammatory cytokine (tumor necrosis factor alpha) gene expression in

normal peripheral blood mononuclear cells via modulation of the NF-kappa

beta system

Nair MP, Mahajan S, Reynolds JL, Aalinkeel R, Nair H,

Schwartz SA, Kandaswami C.

Department of Medicine and Microbiology, Kaleida Health System, Buffalo

General Hospital, State University of New York at Buffalo, Buffalo, NY

14203, USA.

Clin Vaccine Immunol. 2006 Mar;13(3):319-28.

http://cvi.asm.org/cgi/reprint/13/3/319

The flavonoids comprise a large class of low-molecular-weight plant

metabolites ubiquitously distributed in food plants. These dietary

antioxidants exert significant antitumor, antiallergic, and

anti-inflammatory effects. The molecular mechanisms of their biological

effects remain to be clearly understood. We investigated the

anti-inflammatory potentials of a safe, common dietary flavonoid

component, quercetin, for its ability to modulate the production and gene

expression of the proinflammatory cytokine tumor necrosis factor alpha

(TNF-alpha) by human peripheral blood mononuclear cells (PBMC). Our

results showed that quercetin significantly inhibited TNF-alpha

production and gene expression in a dose-dependent manner. Our results

provide direct evidence of the anti-inflammatory effects of quercetin by

PBMC, which are mediated by the inhibition of the proinflammatory

cytokine TNF-alpha via modulation of NF-kappabeta1 and

Ikappabeta.

22. Regulation of IL-1-induced selective IL-6

release from human mast cells and inhibition by quercetin

Kandere-Grzybowska K, Kempuraj D, Cao J, Cetrulo CL,

Theoharides TC.

Department of Biochemistry, Tufts University School of Medicine and Tufts

- New England Medical Center, on avenue, Boston, MA, USA.

Br J Pharmacol. 2006 May;148(2):208-15.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617055/pdf/148-0706695a.pdf

Mast cells are involved in allergic reactions, but also in innate

immunity and inflammation. Crosslinkage of mast cell Fc immunoglobulin E

receptors (FcvarepsilonRI) by multivalent antigen triggers secretion of

granule-stored mediators, as well as de novo synthesis of cytokines,

including interleukin (IL)-6. We showed recently that the proinflammatory

cytokine IL-1 stimulates human leukemic mast cells (HMC-1) and human

umbilical cord blood-derived cultured mast cells (hCBMCs) to release

newly synthesized IL-6 without tryptase in the absence of degranulation.

Here, we investigated several signal-transduction pathways activated by

IL-1 leading to IL-6 production by HMC-1 and hCBMCs. We also investigated

the effect of the flavonol quercetin that was recently shown to strongly

inhibit IL-6 secretion in response to allergic stimulation from

hCBMCs.IL-1 stimulated p38, but did not activate extracellular

signal-regulated kinase (ERK) or c-jun N-terminal kinase (JNK); it also

did not activate protein kinase C (PKC) isozymes alpha, beta, mu and

zeta, except for PKC-theta, which was phosphorylated. The p38 inhibitor

SB203580 and the PKC inhibitors Calphostin C and Gö6976 completely

inhibited IL-1-induced IL-6 production. Quercetin 1-100 microM inhibited

IL-1-induced IL-6 secretion, p38 and PKC-theta phosphorylation in a

dose-dependent manner. These results indicate that IL-1-stimulated IL-6

production from human mast cells is regulated by biochemical pathways

distinct from IgE-induced degranulation and that quercetin can block both

IL-6 secretion and two key signal transduction steps involved.