1. Pharmacology. 2003 Oct;69(2):59-67.
Protective Effect of Flavonoids against Aging- and Lipopolysaccharide-Induced
Cognitive Impairment in Mice.
Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK.
Pharmacology Division, University Institute of Pharmaceutical Sciences,
Panjab
University, Chandigarh, India.
Flavonoids, naturally occurring polyphenolic compounds, are known to
inhibit
both lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha and
interleukin 6 release which modulate the proinflammatory molecules that
have
been reported in many progressive neurodegenerative disorders, including
Alzheimer's disease (AD), viral and bacterial meningitis, AIDS dementia
complex,and stroke. The present experiments were performed to study the
possible effects of exogenously administered flavonoids (apigenin-7-glucoside
and quercetin) on the cognitive performance in aged and LPS-treated mice
(an animal model for AD) using passive avoidance and elevated plus-maze
tasks. Aged and LPS-treated mice showed poor retention of memory in step-through
passive avoidance and in plus-maze tasks. Chronic administration of the
flavonoids apigenin-7-glucoside (5-20 mg/kg i.p.) and quercetin (25-100
mg/kg i.p.) dose dependently reversed the age-induced and LPS-induced
retention deficits in both test paradigms. However, flavonoids after chronic
administration in young mice did not show any improvement of memory retention
in both paradigms. Apigenin-7-glucoside showed more efficacy as compared
with quercetin in both models that may be probably due to its greater
efficacy to inhibit cyclooxygenase-2 and inducible nitric oxide synthase.
Chronic treatment with flavonoids did not alter the locomotor activity
in both young and aged mice; however, aged mice showed improvement of
performance on Rota-Rod test. The results showed that chronic treatment
with flavonoids reverses cognitive deficits in aged and LPS-intoxicated
mice which suggests that modulation of cyclooxygenase-2 and inducible
nitric synthase by flavonoids may be important in the prevention of memory
deficits, one of the symptoms related to AD. Copyright 2003 S. Karger
AG, Basel
2. Clin Pharmacokinet. 2003;42(5):437-59.
Clinical pharmacokinetics of antioxidants and their impact on systemic
oxidative
stress.
Schwedhelm E, Maas R, Troost R, Boger RH.
Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology
Unit,
University Hospital of Hamburg-Eppendorf, Hamburg, Germany.
schwedhelm@uke-hamburg.de
Dietary antioxidants play a major role in maintaining the homeostasis
of the
oxidative balance. They are believed to protect humans from disease and
aging.
Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and other
micronutrients such as carotenoids, polyphenols and selenium have been
evaluated as antioxidant constituents in the human diet. This article
addresses data provided from clinical trials, highlighting the clinical
pharmacokinetics of
vitamin C, vitamin E, beta-carotene, lycopene, lutein, quercetin, rutin,
catechins and selenium. The bioavailability of vitamin C is dose-dependent.
Saturation of transport occurs with dosages of 200-400 mg/day. Vitamin
C is not
protein-bound and is eliminated with an elimination half-life (t((1/2)))
of 10
hours. In Western populations plasma vitamin C concentrations range from
54-91
micro mol/L. Serum alpha- and gamma-tocopherol range from 21 micro mol/L
(North America) to 27 micro mol/L (Europe) and from 3.1 micro mol/L to
1.5 micro mol/L, respectively. alpha-Tocopherol is the most abundant tocopherol
in human tissue. The bioavailability of all-rac-alpha-tocopherol is estimated
to be 50% of R,R,R-alpha-tocopherol. The hepatic alpha-tocopherol transfer
protein
(alpha-TTP) together with the tocopherol-associated proteins (TAP) are
responsbile for the endogenous accumulation of natural alpha-tocopherol.
Elimination of alpha-tocopherol takes several days with a t((1/2)) of
81 and 73
hours for R,R,R-alpha-tocopherol and all-rac-alpha-tocopherol, respectively.
The
t((1/2)) of tocotrienols is short, ranging from 3.8-4.4 hours for gamma-
and
alpha-tocotrienol, respectively. gamma-Tocopherol is degraded to 2, 7,
8-trimethyl-2-(beta-carboxyl)-6-hyrdoxychroman by the liver prior to renal
elimination. Blood serum carotenoids in Western populations range from
0.28-0.52 micro mol/L for beta-carotene, from 0.2-0.28 for lutein, and
from 0.29-0.60 for lycopene. All-trans-carotenoids have a better bioavailability
than the
9-cis-forms. Elimination of carotenoids takes several days with a t((1/2))
of
5-7 and 2-3 days for beta-carotene and lycopene, respectively. The bioconversion
of beta-carotene to retinal is dose-dependent, and ranges between 27%
and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites
of carotenoids are known. Flavonols such as quercetin glycosides and rutin
are predominantly absorbed as aglycones, bound to plasma proteins and
subsequently conjugated to glucuronide, sulfate, and methyl moieties.
The t((1/2)) ranges from 12-19 hours. The bioavailabillity of catechins
is low and they are eliminated with a t((1/2)) of 2-4 hours. Catechins
are degraded to several gamma-valerolactone derivatives and phase II conjugates
have also been identified. Only limited clinical pharmacokinetic data
for other polyphenols such as resveratrol have been reported to date.
3. Neurobiol Aging. 2002 Sep-Oct;23(5):891-97.
Natural extracts as possible protective agents of brain aging.
Bastianetto S, Quirion R.
Department of Psychiatry and Pharmacology and Therapeutics, Douglas Hospital
Research Centre, McGill University, 6875 LaSalle Boulevard, Verdun, Que,
Canada H4H 1R3.
A growing number of studies suggest that natural extracts and phytochemicals
have a positive impact on brain aging. We examined the potential of the
Ginkgo
biloba extract EGb 761 and red wine-derived constituents on cell death
produced
by beta-amyloid (Abeta) peptides and oxidative stress, with respect to
their
possible deleterious role in age-related neurological disorders. We found
that
EGb 761, possibly through the antioxidant properties of its flavonoids,
was able
to protect hippocampal cells against toxic effects induced by Abeta peptides.
Moreover, we showed that an exposure of rat hippocampal cells to the nitric
oxide (NO) donor sodium nitroprusside (SNP) resulted in a decrease in
cell
survival and increase in reactive oxygen species (ROS) accumulation. However,
EGb 761 and red wine-derived polyphenols protected against these events,
due to their antioxidant activities, and their ability to block SNP-stimulated
activity
of protein kinase C (PKC). Taken together, these results support the hypothesis
that dietary intake of natural substances may be beneficial in normal
aging of the brain. Copyright 2002 Elsevier Science Inc.
4. Mol Biol Cell. 2002 Jul;13(7):2502-17.
Expression of caveolin-1 induces premature cellular senescence in primary
cultures of murine fibroblasts.
Volonte D, Zhang K, Lisanti MP, Galbiati F.
Department of Pharmacology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15261, USA.
Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1
is the
principal structural component of caveolae in vivo. Several lines of evidence
are consistent with the idea that caveolin-1 functions as a "transformation
suppressor" protein. In fact, caveolin-1 mRNA and protein expression
are lost or
reduced during cell transformation by activated oncogenes. Interestingly,
the
human caveolin-1 gene is localized to a suspected tumor suppressor locus
(7q31.1). We have previously demonstrated that overexpression of caveolin-1
arrests mouse embryonic fibroblasts in the G(0)/G(1) phase of the cell
cycle
through activation of a p53/p21-dependent pathway, indicating a role of
caveolin-1 in mediating growth arrest. However, it remains unknown whether
overexpression of caveolin-1 promotes cellular senescence in vivo. Here,
we
demonstrate that mouse embryonic fibroblasts transgenically overexpressing
caveolin-1 show: 1) a reduced proliferative lifespan; 2) senescence-like
cell
morphology; and 3) a senescence-associated increase in beta-galactosidase
activity. These results indicate for the first time that the expression
of
caveolin-1 in vivo is sufficient to promote and maintain the senescent
phenotype. Subcytotoxic oxidative stress is known to induce premature
senescence in diploid fibroblasts. Interestingly, we show that subcytotoxic
level of
hydrogen peroxide induces premature senescence in NIH 3T3 cells and increases
endogenous caveolin-1 expression. Importantly, quercetin and vitamin E,
two antioxidant agents, successfully prevent the premature senescent phenotype
and the up-regulation of caveolin-1 induced by hydrogen peroxide. Also,
we demonstrate that hydrogen peroxide alone, but not in combination with
quercetin, stimulates the caveolin-1 promoter activity. Interestingly,
premature senescence induced by hydrogen peroxide is greatly reduced in
NIH 3T3 cells harboring antisense caveolin-1. Importantly, induction of
premature senescence is recovered when caveolin-1 levels are restored.
Taken together, these results clearly indicate a central role for caveolin-1
in promoting cellular senescence and they suggest the hypothesis that
premature senescence may represent a tumor suppressor function mediated
by caveolin-1 in vivo.
5. Mech Ageing Dev. 2000 Dec 20;121(1-3):217-30.
Antioxidants may contribute in the fight against ageing: an in vitro model.
Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR.
Molecular Physiology, Unilever Research Laboratory Colworth, Sharnbrook,
Bedford MK44 1LQ, UK.
Elderly humans have altered cellular redox levels and dysregulated immune
responses, both of which are key events underlying the progression of
chronic
degenerative diseases of ageing, such as atherosclerosis and Alzeimer's
disease. Poorly maintained cellular redox levels lead to elevated activation
of nuclear transcription factors such as NFkB and AP-1. These factors
are co-ordinately responsible for a huge range of extracellular signalling
molecules responsible for inflammation, tissue remodelling, oncogenesis
and apoptosis, progessess that orchestrate many of the degenerative processess
associated with ageing. It is now clear that levels of endogenous anti-oxidants
such as GSH decrease with age. This study aimed to investigate the potential
of exogenous anti-oxidants to influence inflammatory responses and the
ageing process itself. We investigated the potential of the dietary antioxidant,
quercetin, to reverse the age related influences of GSH depletion and
oxidative stress using in vitro human umbilical vein endothelial cells
(HUVEC) and human skin fibroblast (HSF) cell models. Oxidative stress-induced
inflammatory responses were investigated in a GSH depletion and a Phorbol
12-myristate 13-acetate (PMA)-induced stress model. As measured with a
sensitive HPLC fluorescence method, GSH in HUVEC was depleted by the addition
of L-buthionine-[S,R]-sulfoxiniine (BSO), a gamma-glutamylcysteine synthetase
inhibitor, to the culture medium at a concentration of 0.25 mM. Time course
studies revealed that the GSH half-life was 4.6 h in HUVEC. GSH depletion
by BSO for 24 h led to a slight increase in intracellular adhesion molecule
– 1 (ICAM1) expression and prostaglandin E2 (PGE2) secretion in
both types of cells. However, GSH depletion markedly enhanced PMA-induced
ICAM and PGE2 production in HUVEC. Responses were progressively elevated
following prolonged BSO treatment. Inhibition studies showed that 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine
(H7), a protein kinase C (PKC) inhibitor, not only abolished most of PMA-induced
ICAM-1 expression and PGE2, production, but also eliminated GSH depletion-enhanced
PMA stimulation. This enhancement was also inhibited by supplementation
with quercetin. The results clearly demonstrate that GSH depletion increased
the susceptibility of vascular endothelial cells and fibroblasts to oxidative
stress associated inflammatory stimuli. This increased in vitro susceptibility
may be extrapolated to the in vivo situation of ageing, providing a useful
model to study the influence of micronutrients on the ageing process.
In conclusion, these data suggest that dietary antioxidants could play
a significant role in the reduction of inflammatory responses.
6. Eur J Clin Nutr. 2000 May;54(5):415-7.
Quercetin intake and the incidence of cerebrovascular disease.
Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Hakkinen S,
Aromaa A, Reunanen A.
National Public Health Institute, Helsinki, Finland. paul.knekt@ktl.fi
OBJECTIVE: To study the relation between intake of the antioxidant flavonoid
quercetin and subsequent incidence of cerebrovascular disease (CVA). DESIGN:
A cohort study carried out among 9208 Finnish men and women 15 y or more
of age and initially free from cardiovascular disease. During a 28 y follow-up
period in 1967-1994, a total of 824 cases with CVA were diagnosed. METHODS:
Food consumption data were collected using a dietary history interview
method covering the total habitual diet during the previous year. RESULTS:
Quercetin intake was not associated with CVA incidence. The relative risk
of CVA adjusted for age, serum cholesterol, body mass index, smoking,
hypertension, diabetes, geographical area, occupation and intake of beta-carotene,
vitamin E, vitamin C, fibre, various fatty acids, and energy between the
highest and lowest quartiles of quercetin intake was 0.99 (95% confidence
interval (CI)=0.71-1.38) for men and 0.85 (CI=0.60-1.21) for women. In
contrast, apples, the major source of quercetin in the study population,
showed a significant inverse associationn both in men and women, mainly
due to an association with thrombotic or embolic stroke. The relative
risks of thrombotic stroke after further adjustment for quercetin intake
were 0.59 (CI=0.35-0.99; P=0.45) and 0.61 (CI=0.33-1.12: P for trend=0.02)
for men and women, respectively. CONCLUSIONS: The results suggest that
the intake of apples is related to a decreased risk of thrombotic stroke.
This association apparently is not due to the presence of the antioxidant
flavonoid quercetin.
7. Free Radic Biol Med. 1997;22(4):669-78.
Quercetin protects cutaneous tissue-associated cell types including sensory
neurons from oxidative stress induced by glutathione depletion: cooperative
effects of ascorbic acid.
Skaper SD, Fabris M, Ferrari V, Dalle Carbonare M, Leon A.
Researchlife S.c.p.A., Castelfranco Veneto, Italy.
Oxidation reactions are essential biological reactions necessary for
the
formation of high-energy compounds used to fuel metabolic processes, but
can be injurious to cells when produced in excess. Cutaneous tissue is
especially
susceptible to damage mediated by reactive oxygen species and low-density
lipoprotein oxidation, triggered by dysmetabolic diseases, inflammation,
environmental factors, or aging. Here we have examined the ability of
the
flavonoid quercetin to protect cutaneous tissue-associated cell types
from
injury induced by oxidative stress, and possible cooperative effects of
ascorbic
acid. Human skin fibroblasts, keratinocytes, and endothelial cells were
cultured
in the presence of buthionine sulfoximine (BSO), an irreversible inhibitor
of
glutathione (GSH) synthesis. Depletion of intracellular levels of GSH
leads to
an accumulation of cellular peroxides and eventual cell death. Quercetin
concentration-dependently (EC50: 30-40 microM) reduced oxidative injury
of BSO to all cell types, and was also effective when first added after
BSO washout.
BSO caused marked decreases in the intracellular level of GSH, which remained
depressed in quercetin-protected cells. Ascorbic acid, while by itself
not
cytoprotective synergized with quercetin, lowered the quercetin EC50 and
prolonged the window for cytoprotection. The related flavonoids rutin
and
dihydroquercetin also decreased BSO-induced injury to dermal fibroblasts,
albeit
less efficaciously so than quercetin. The cytoprotective effect of rutin,
but
not that of dihydroquercetin, was enhanced in the presence of ascorbic
acid.
Further, quercetin rescued sensory ganglion neurons from death provoked
by GSH depletion. Direct oxidative injury to this last cell type has not
been
previously demonstrated. The results show that flavonoids are broadly
protective for cutaneous tissue-type cell populations subjected to a chronic
intracellular form of oxidative stress. Quercetin in particular, paired
with ascorbic acid, may be of therapeutic benefit in protecting neurovasculature
structures in skin from oxidative damage.
8. Exp Gerontol. 1982;17(3):213-7.
Quercetin, flavonoids and the life-span of mice.
Jones E, Hughes RE.
A dietary supplement of 0.1% quercetin significantly reduced the life
span of
mice. The effect was predominantly on the 'shorter living' males. A blackcurrant
juice extract, containing a mixture of flavonoids in addition to quercetin,
prolonged significantly the life span of the 'older dying' females. The
significance of these results vis-a-vis aging mechanisms and the dietary
intake
of quercetin is discussed.
9. Biochem Pharmacol. 1992 Mar 17;43(6):1167-79.
Effects of flavonoids on immune and inflammatory cell functions.
Middleton E Jr, Kandaswami C.
Department of Medicine, State University of New York, Buffalo 14203.
No doubt can remain that the flavonoids have profound effects on the
function of
immune and inflammatory cells as determined by a large number and variety
of in vitro and some in vivo observations. That these ubiquitous dietary
chemicals may have significant in vivo effects on homeostasis within the
immune system and on the behavior of secondary cell systems comprising
the inflammatory response seems highly likely but more work is required
to strengthen this hypothesis. Ample evidence indicates that selected
flavonoids, depending on structure, can affect (usually inhibit) secretory
processes, mitogenesis, and cell-cell interactions including possible
effects on adhesion molecule expression and function. The possible action
of flavonoids on the function of cytoskeletal elements is suggested by
their effects on secretory processes. Moreover,
evidence indicates that certain flavonoids may affect gene expression
and the elaboration and effects of cytokines and cytokine receptors. How
all of these effects are mediated is not yet clear but one important mechanism
may be the capacity of flavonoids to stimulate or inhibit protein phosphorylation
and thereby regulate cell function. Perhaps the counterbalancing effect
of cellular protein tyrosine phosphatases will also be found to be affected
by flavonoids. Some flavonoid effects can certainly be attributed to their
recognized antioxidant and radical scavenging properties. A potential
mechanism of action that requires scrutiny, particularly in relation to
enzyme inhibition, is the redox activity of appropriately configured flavonoids.
Finally, in a number of
cell systems it seems that resting cells are not affected significantly
by flavonoids but once a cell becomes activated by a physiological stimulus
a flavonoid-sensitive substance is generated and interaction of flavonoids
with that substance dramatically alters the outcome of the activation
process.
10. Thromb Res. 1991 Oct 1;64(1):91-100.
Inhibition of platelet aggregation by some flavonoids.
Tzeng SH, Ko WC, Ko FN, Teng CM.
Department of Pharmacology, Taipei Medical College, Taiwan.
The inhibitory effects of five flavonoids on the aggregation and secretion
of
platelets were studied. These flavonoids inhibited markedly platelet aggregation
and ATP release of rabbit platelets induced by arachidonic acid or collagen,
and
slightly those by platelet-activating factor. ADP-induced platelet aggregation
was also suppressed by myricetin, fisetin and quercetin. The IC50 on arachidonic
acid-induced platelet aggregation was: fisetin, 22 microM; kaempferol,
20
microM; quercetin, 13 microM; morin, 150 microM less than IC50 less than
300
microM. The thromboxane B2 formations were also inhibited by flavonoids
in
platelets challenged with arachidonic acid. Fisetin, kaempferol, morin
and
quercetin antagonized the aggregation of washed platelets induced by U46619,
a
thromboxane A2/prostaglandin endoperoxides mimetic receptor agonist. In
human
platelet-rich plasma, quercetin prevented the secondary aggregation and
blocked
ATP release from platelets induced by epinephrine or ADP. These results
demonstrate that the major antiplatelet effect of flavonoids tested may
be due
to both the inhibition of thromboxane formation and thromboxane receptor
antagonism.
11. Am J Clin Nutr. 2000 Nov;72(5):1150-5.
Erratum in:
Am J Clin Nutr 2001 Feb;73(2):360.
The flavonoids quercetin and catechin synergistically inhibit platelet
function
by antagonizing the intracellular production of hydrogen peroxide.
Pignatelli P, Pulcinelli FM, Celestini A, Lenti L, Ghiselli A, Gazzaniga
PP,
Violi F.
Department of Experimental Medicine and Pathology, Institute of 1st Clinical
Medicine, University La Sapienza, National Institute for Nutrition, Rome,
Italy.
gazzaniga@uniroma1.it
BACKGROUND: Epidemiologic studies have shown an inverse relation between
moderate consumption of red wine and cardiovascular disease. Studies have
shown
that red wine and its component flavonoids inhibit in vivo platelet activation,
but the underlying mechanism has not yet been identified. OBJECTIVE: Because
we
showed previously that collagen-induced platelet aggregation is associated
with
a burst of hydrogen peroxide, which in turn contributes to stimulating
the
phospholipase C pathway, the aim of this study was to investigate whether
flavonoids synergize in inhibiting platelet function and interfere with
platelet
function by virtue of their antioxidant effect. DESIGN: We tested the
effect of
2 flavonoids, quercetin and catechin, on collagen-induced platelet aggregation
and hydrogen peroxide and on platelet adhesion to collagen. RESULTS: Catechin
(50-100 micromol/L) and quercetin (10-20 micromol/L) inhibited collagen-induced
platelet aggregation and platelet adhesion to collagen. The combination
of 25
micromol catechin/L and 5 micromol quercetin/L, neither of which had any
effect
on platelet function when used alone, significantly inhibited collagen-induced
platelet aggregation and platelet adhesion to collagen. Such a combination
strongly inhibited collagen-induced hydrogen peroxide production, calcium
mobilization, and 1,3,4-inositol triphosphate formation. CONCLUSIONS:
These data
indicate that flavonoids inhibit platelet function by blunting hydrogen
peroxide
production and, in turn, phospholipase C activation and suggest that the
synergism among flavonoids could contribute to an understanding of the
relation
between the moderate consumption of red wine and the decreased risk of
cardiovascular disease.
12. Lancet. 1993 Oct 23;342(8878):1007-11.
Dietary antioxidant flavonoids and risk of coronary heart disease: the
Zutphen
Elderly Study.
Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D.
National Institute of Public Health and Environment Protection, Bilthoven,
Netherlands.
Flavonoids are polyphenolic antioxidants naturally present in vegetables,
fruits, and beverages such as tea and wine. In vitro, flavonoids inhibit
oxidation of low-density lipoprotein and reduce thrombotic tendency, but
their
effects on atherosclerotic complications in human beings are unknown.
We
measured the content in various foods of the flavonoids quercetin, kaempferol,
myricetin, apigenin, and luteolin. We then assessed the flavonoid intake
of 805
men aged 65-84 years in 1985 by a cross-check dietary history; the men
were then
followed up for 5 years. Mean baseline flavonoid intake was 25.9 mg daily.
The
major sources of intake were tea (61%), onions (13%), and apples (10%).
Between
1985 and 1990, 43 men died of coronary heart disease. Fatal or non-fatal
myocardial infarction occurred in 38 of 693 men with no history of myocardial
infarction at baseline. Flavonoid intake (analysed in tertiles) was
significantly inversely associated with mortality from coronary heart
disease (p
for trend = 0.015) and showed an inverse relation with incidence of myocardial
infarction, which was of borderline significance (p for trend = 0.08).
The
relative risk of coronary heart disease mortality in the highest versus
the
lowest tertile of flavonoid intake was 0.42 (95% CI 0.20-0.88). After
adjustment
for age, body-mass index, smoking, serum total and high-density-lipoprotein
cholesterol, blood pressure, physical activity, coffee consumption, and
intake
of energy, vitamin C, vitamin E, beta-carotene, and dietary fibre, the
risk was
still significant (0.32 [0.15-0.71]). Intakes of tea, onions, and apples
were
also inversely related to coronary heart disease mortality, but these
associations were weaker. Flavonoids in regularly consumed foods may reduce
the
risk of death from coronary heart disease in elderly men.
13. Arch Intern Med. 1996 Mar 25;156(6):637-42.
Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the
Zutphen
study.
Keli SO, Hertog MG, Feskens EJ, Kromhout D.
Department of Chronic Disease and Environmental Epidemiology, National
Institute
of Public Health and Environmental Protection, Bilthoven, The Netherlands.
BACKGROUND: Epidemiological studies suggested that consumption of fruit
and
vegetables may protect against stroke. The hypothesis that dietary antioxidant
vitamins and flavonoids account for this observation is investigated in
a
prospective study. METHODS: A cohort of 552 men aged 50 to 69 years was
examined
in 1970 and followed up for 15 years. Mean nutrient and food intake was
calculated from cross-check dietary histories taken in 1960, 1965, and
1970. The
association between antioxidants, selected foods, and stroke incidence
was
assessed by Cox proportional hazards regression analysis. Adjustment was
made
for confounding by age, systolic blood pressure, serum cholesterol, cigarette
smoking, energy intake, and consumption of fish and alcohol. RESULTS:
Forty-two
cases of first fatal or nonfatal stroke were documented. Dietary flavonoids
(mainly quercetin) were inversely associated with stroke incidence after
adjustment for potential confounders, including antioxidant vitamins.
The
relative risk (RR) of the highest vs the lowest quartile of flavonoid
intake ( >
or = 28.6 mg/d vs <18.3 mg/d) was 0.27 (95% confidence interval [CI],
0.11 to
0.70). A lower stroke risk was also observed for the highest quartile
of
beta-carotene intake (RR, 0.54; 95% CI, 0.22 to 1.33). The intake of vitamin
C
and vitamin E was not associated with stroke risk. Black tea contributed
about
70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or
more of
tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84). CONCLUSION:
The habitual intake of flavonoids and their major source (tea) may protect
against stroke.
14. Surgery. 2002 Feb;131(2):198-204.
Quercetin inhibits human vascular smooth muscle cell proliferation and
migration.
Alcocer F, Whitley D, Salazar-Gonzalez JF, Jordan WD, Sellers MT, Eckhoff
DE,
Suzuki K, Macrae C, Bland KI.
Department of Surgery, University of Alabama at Birmingham, 35294-0007,
USA.
BACKGROUND: The French paradox has been associated with regular intake
of red
wine, which is enriched with flavonoids. Quercetin, a flavonoid present
in the
human diet, exerts cardiovascular protection through its antioxidant properties.
We hypothesized that the beneficial effect of quercetin also could be
related to
the inhibition of vascular smooth muscle cell proliferation and migration.
METHODS: Human aortic smooth muscle cells (AoSMC) were grown in culture
in the
presence of serum. Quercetin inhibited the serum-induced proliferation
of AoSMC.
This inhibition was dose-dependent and not attributed to toxicity. Cell
cycle
analysis revealed that quercetin arrested AoSMC in the G(0)/G(1) phase.
The
effect of quercetin on AoSMC migration was examined using explant migration
and
Transwell migration assays. Quercetin significantly decreased migration
in both
assays in a consistent manner. Finally, Western blot analysis of AoSMC
exposed
to quercetin demonstrated a significant reduction in the activation of
mitogen-activated protein kinase, a signaling pathway associated with
the
migration of vascular smooth muscle cells. CONCLUSIONS: Quercetin inhibits
the
proliferation and migration of AoSMC, concomitant with inhibition of
mitogen-activated protein kinase phosphorylation. These findings provide
new
insights and a rationale for the potential use of quercetin in the prophylaxis
of cardiovascular diseases.
15. Mol Pharmacol. 2001 Oct;60(4):656-65.
Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun
N-terminal kinase activation by angiotensin II in cultured rat aortic
smooth
muscle cells.
Yoshizumi M, Tsuchiya K, Kirima K, Kyaw M, Suzaki Y, Tamaki T.
Department of Pharmacology, The University of Tokushima School of Medicine,
Tokushima, Japan. yoshizu@basic.med.tokushima-u.ac.jp
Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy,
which results in various cardiovascular diseases. Ang II-induced cellular
events
have been implicated, in part, in the activation of mitogen-activated
protein
(MAP) kinases. Although it has been proposed that daily intake of bioflavonoids
belonging to polyphenols reduces the incidence of ischemic heart diseases
(known
as "French paradox"), the precise mechanisms of efficacy have
not been
elucidated. Thus, we hypothesized that bioflavonoids may affect Ang II-induced
MAP kinase activation in cultured rat aortic smooth muscle cells (RASMC).
Our
findings showed that Ang II stimulated rapid and significant activation
of
extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase
(JNK),
and p38 in RASMC. Ang II-induced JNK activation was inhibited by
3,3',4',5,7-pentahydroxyflavone (quercetin), a major bioflavonoid in foods
of
plant origin, whereas ERK1/2 and p38 activation by Ang II were not affected
by
quercetin. Ang II caused a rapid tyrosine phosphorylation of Src homology
and
collagen (Shc), which was inhibited by quercetin. Quercetin also inhibited
Ang
II-induced Shc.p85 association and subsequent activation of phosphatidylinositol
3-kinase (PI3-K)/Akt pathway in RASMC. Furthermore, LY294002, a PI3-K
inhibitor
and a quercetin derivative, inhibited Ang II-induced JNK activation as
well as
Akt phosphorylation. Finally, Ang II-induced [(3)H]leucine incorporation
was
abolished by both quercetin and LY294002. These findings suggest that
the
preventing effect of quercetin on Ang II-induced VSMC hypertrophy are
attributable, in part, to its inhibitory effect on Shc- and PI3-K-dependent
JNK
activation in VSMC. Thus, inhibition of JNK by quercetin may imply its
usefulness for the treatment of cardiovascular diseases relevant to VSMC
growth.
16. Br J Pharmacol. 2001 May;133(1):117-24.
Antihypertensive effects of the flavonoid quercetin in spontaneously
hypertensive rats.
Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo
A,
Tamargo J.
Department of Pharmacology, School of Pharmacy, University of Granada,
18071
Granada, Spain.
1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid
quercetin
for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar
Kyoto
rats (WKY) were analysed. 2. Quercetin induced a significant reduction
in
systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure
and
heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular
weight
index and the kidney weight index in vehicle-treated SHR were significantly
greater than in control WKY and these parameters were significantly reduced
in
quercetin-treated SHR in parallel with the reduction in systolic blood
pressure.
4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside
or to the vasoconstrictor responses to noradrenaline or KCl but enhanced
the
endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%,
P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha)
excretion
and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased
as
compared to WKY rats. However, in quercetin-treated SHR rats both parameters
were similar to those of vehicle-treated WKY. 6. These data demonstrate
that
quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy
and the functional vascular changes in SHR rats without effect on WKY.
These
effects were associated with a reduced oxidant status due to the antioxidant
properties of the drug.
17. Free Radic Biol Med. 2002 Jun 1;32(11):1220-8.
Mitochondrial function in response to cardiac ischemia-reperfusion after
oral
treatment with quercetin.
Brookes PS, Digerness SB, Parks DA, Darley-Usmar V.
Department of Pathology, University of Alabama at Birmingham, Birmingham,
AL
35294-2180, USA. brookes@uab.edu
Polyphenolic compounds present in red wines, such as the flavonol quercetin,
are
thought capable of cardioprotection through mechanisms not yet clearly
defined.
It has been established that mitochondria play a critical role in myocardial
recovery from ischemia-reperfusion (I-R) damage, and in vitro experiments
indicate that quercetin can exert a variety of direct effects on mitochondrial
function. The effects of quercetin at concentrations typically found in
1-2
glasses of red wine on cardiac I-R and mitochondrial function in vivo
are not
known. Quercetin was administered to rats (0.033 mg/kg per day by gavage
for 4
d). Isolated Langendorff perfused hearts were subjected to I-R, and cardiac
functional parameters determined both before and after I-R. Mitochondria
were
isolated from post-I-R hearts and their function assessed. Compared to
an
untreated control group, quercetin treatment significantly decreased the
impairment of cardiac function following I-R. This protective effect was
associated with improved mitochondrial function after I-R. These results
indicate that oral low dose quercetin is cardioprotective, possibly via
a
mechanism involving protection of mitochondrial function during I-R.
18. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9052-7.
The NF-kappa B signal transduction pathway in aortic endothelial cells
is primed
for activation in regions predisposed to atherosclerotic lesion formation.
Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI.
Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto General Research Institute, Toronto, Ontario, M5G 2C4, Canada.
Atherosclerotic lesions form at distinct sites in the arterial tree,
suggesting that hemodynamic forces influence the initiation of atherogenesis.
If NF-kappaB plays a role in atherogenesis, then the activation of this
signal transduction pathway in arterial endothelium should show topographic
variation. The expression of NF-kappaB/IkappaB components and NF-kappaB
activation was evaluated by specific antibody staining, en face confocal
microscopy, and image analysis of endothelium in regions of mouse proximal
aorta with high and low probability (HP and LP) for atherosclerotic lesion
development. In control C57BL/6 mice, expression levels of p65, IkappaBalpha,
and IkappaBbeta were 5- to 18-fold higher in the HP region, yet NF-kappaB
was activated in a minority of endothelial cells. This suggested that
NF-kappaB signal transduction was primed for activation in HP regions
on encountering an activation stimulus. Lipopolysaccharide treatment or
feeding low-density lipoprotein receptor knockout mice an atherogenic
diet resulted in NF-kappaB activation and up-regulated expression of NF-kappaB-inducible
genes predominantly in HP region endothelium. Preferential regional activation
of endothelial NF-kappaB by systemic stimuli, including hypercholesterolemia,
may contribute to the localization of atherosclerotic lesions at sites
with high steady-state expression levels of NF-kappaB/IkappaB components.
19. Clin Exp Allergy. 2000 Apr;30(4):501-8.
Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated
mediator release from human cultured mast cells.
Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H.
Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
BACKGROUND: Flavonoids have a variety of activities including anti-allergic
activities, and are known to inhibit histamine release from human basophils
and murine mast cells. OBJECTIVE: The effects of luteolin, a flavone,
on the immunoglobulin (Ig) E-mediated allergic mediator release from human
cultured mast cells (HCMCs) were investigated and compared with those
of baicalein and quercetin. METHODS: HCMCs were sensitized with IgE, and
then treated with flavonoids before challenge with antihuman IgE. The
amount of released mediators was determined as was mobilization of intracellular
Ca2+ concentration, protein kinase C (PKC) translocation and phosphorylation
of intracellular proteins were detected after anti-IgE stimulation. RESULTS:
Luteolin, baicalein and quercetin inhibited the release of histamine,
leukotrienes (LTs), prostaglandin D2 (PGD2), and granulocyte macrophage-colony
stimulating factor (GM-CSF) from HCMC in a concentration-dependent manner.
Additionally, the three flavonoids inhibited A23187-induced histamine
release. As concerns Ca2+ signalling, luteolin and quercetin inhibited
Ca2+ influx strongly, although baicalein did slightly. With regard to
PKC signalling, luteolin and quercetin inhibited PKC translocation and
PKC activity strongly, although baicalein did slightly. The suppression
of Ca2+ and PKC signallings might contribute to the inhibition of mediator
release. The activation of extracellular signal-regulated kinases (ERKs)
and c-Jun NH2-terminal kinase (JNK), that were activated just before the
release of LTs and PGD2 and GM-CSF mRNA expression in IgE-mediated signal
transduction events, were clearly suppressed by luteolin and quercetin.
In contrast, the flavonoids did not affect the activation of p38 mitogen-activated
protein kinase (p38 MAPK) pathway. CONCLUSION: These results indicate
that luteolin is a potent inhibitor of human mast cell activation through
the inhibition of Ca2+ influx and PKC activation.
20. Res Commun Chem Pathol Pharmacol. 1992 Nov;78(2):211-8.
Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat
kidney
subjected to ischemia-reperfusion stress: preventive effect of some flavonoids.
Sanhueza J, Valdes J, Campos R, Garrido A, Valenzuela A.
Unidad de Bioquimica Farmacologica y Lipidos, INTA, Universidad de Chile,
Santiago.
The enzyme xanthine oxidase has been implicated in the tissue oxidative
injury
after ischemia-reperfusion. This enzyme, which is a source of oxygen free
radicals, is formed from a dehydrogenase form during ischemia. The ratio
dehydrogenase/oxidase of rat kidney homogenates decreases during the ischemia
and the reperfusion. Two flavonoids, quercetin and silybin, characterized
as
free radical scavengers, exert a protective effect preventing the decrease
in
the dehydrogenase/oxidase ratio observed during ischemia-reperfusion.
The
mechanism of this effect and the role of flavonoids in the ischemia-reperfusion
tissue damage is discussed.
21. Methods Find Exp Clin Pharmacol. 2001 May;23(4):175-81.
Quercetin, a bioflavonoid, protects against oxidative stress-related renal
dysfunction by cyclosporine in rats.
Satyanarayana PS, Singh D, Chopra K.
Pharmacology Division, University Institute of Pharmaceutical Sciences,
Panjab
University, Chandigarh, India.
Nephrotoxicity is the most common and clinically important side effect
of cyclosporine (CsA). Recent evidence suggests that reactive oxygen species
(ROS) play an important role in CsA nephrotoxicity. This study was designed
to demonstrate the role of oxidative stress and its relation to renal
dysfunction and to investigate the effects of quercetin, a bioflavonoid
with antioxidant properties, in CsA-induced nephrotoxicity. Quercetin
(0.5 and 2.0 mg/kg i.p.) was administered 24 h before and concurrently
with CsA (20 mg/kg s.c.) for 21 days. Tissue lipid peroxidation was measured
as thiobarbituric acid reacting
substances (TBARS). Renal function was assessed by estimating plasma creatinine,
blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological
alterations were assessed histopathologically. Pretreatment with CsA (20
mg/kg
s.c.) for 21 days produced elevated levels of TBARS and deteriorated renal
function as assessed by increased plasma creatinine, BUN and decreased
creatinine and urea clearance as compared to vehicle-treated rats. The
kidneys of CsA-treated rats showed severe striped interstitial fibrosis,
arteriopathy, glomerular basement thickening, tubular vacuolization and
hyaline casts. Quercetin (2 mg/kg) markedly reduced elevated levels of
TBARS and significantly attenuated renal dysfunction and morphological
changes in CsA-treated rats. It is likely that quercetin, due to its antioxidant
properties, prevented
CsA-induced ROS and consequently CsA nephrotoxicity. These results clearly
demonstrate the pivotal role of oxidative stress and its relation to renal
dysfunction, and also point to the therapeutic potential of the natural
antioxidant quercetin in CsA-induced nephrotoxicity.
22. Free Radic Biol Med. 2002 Jul 1;33(1):63-70.
Quercetin metabolism in the lens: role in inhibition of hydrogen peroxide
induced cataract.
Cornish KM, Williamson G, Sanderson J.
School of Biological Sciences, University of East Anglia, Norwich, Norfolk,
UK.
Oxidative stress is implicated in the initiation of maturity onset cataract.
Quercetin, a major flavonol in the diet, inhibits lens opacification in
a lens organ culture oxidative model of cataract. The aim of this research
was to investigate the metabolism of quercetin in the lens and show how
its metabolism affects the ability to prevent oxidation-induced opacity.
The LOCH model (Free Radical Biology & Medicine 26:639; 1999) was
employed, using rat lenses to investigate the effects of quercetin and
metabolites on hydrogen peroxide-induced opacification. High-performance
liquid chromatography analysis showed that the intact rat lens is capable
of converting quercetin aglycone to 3'-O-methyl quercetin (isorhamnetin).
Over a 6 h culture period no further metabolism of the 3'-O-methyl quercetin
occurred. Loss of quercetin in the lens was accounted for by the increase
in 3'-O-methyl quercetin. Incubation with
3,5-dinitrocatechol (10 microM), a catechol-O-methyltransferase (COMT)
inhibitor, prevented the conversion of quercetin to 3'-O-methyl quercetin.
The presence of both membrane-bound and soluble COMT was confirmed by
immunoblotting. The results demonstrate that in the rat lens COMT methylates
quercetin and that the product accumulates within the lens. Quercetin
(10 microM) and 3'-O-methyl quercetin (10 microM) both inhibited hydrogen
peroxide- (500 microM) induced sodium and calcium influx and lens opacification.
Incubation of lenses with quercetin in the presence of COMT inhibitor
revealed that the efficacy of quercetin is not dependent on its metabolism
to 3'-O-methyl quercetin. The results indicate dietary quercetin and metabolites
are active in inhibiting oxidative damage in the lens and thus could play
a role in prevention of cataract formation.
23. Free Radic Biol Med. 1999 Sep;27(5-6):683-94.
Structure-activity relationships of quercetin in antagonizing hydrogen
peroxide-induced calcium dysregulation in PC12 cells.
Wang H, Joseph JA.
Jean Mayer United States Department of Agriculture Human Nutrition Research
Center on Aging at Tufts University, Boston, MA 02111, USA.
wang_us@hnrc.tufts.edu
Oxidative stress can induce neurotoxic insults by increasing intracellular
calcium (Ca2+), which has been implicated in various neurodegenerative
diseases
in aging. Previously, we showed that hydrogen peroxide induced calcium
dysregulation in PC12 cells, as evidenced by (i) an increase in calcium
baselines, (ii) a decrease in depolarization-induced calcium influx, and
(iii) a
failure to recover the Ca2+ levels. In the present experiments, we investigated
whether a dietary flavonoid, quercetin, can antagonize the effects of
hydrogen
peroxide in the same cell model. We also investigated the possible
structure-activity relationships of quercetin by comparing the results
with four
other flavonoids, each having a slightly different structure from quercetin.
Our
results indicated that two structural components, including (i) 3', 4'-hydroxyl
(OH) groups in the B ring and (ii) a 2,3-double bond in conjugation with
a 4-oxo
group in the C ring, along with the polyphenolic structures were crucial
for the
protection. These structural components are found in quercetin, and this
compound was also the most efficacious in reducing both the H2O2-induced
Ca2+
dysregulation in cells and oxidative stress assessed via the dichlorofluorescein
assay. Collectively, these data indicated that the particular polyphenolic
structural components of quercetin provided its strong antioxidant property
of
protecting cells against H2O2-induced oxidative stress and calcium
dysregulation.
24. Zhongguo Yao Li Xue Bao. 1999 May;20(5):426-30.
Quercetin decreased heart rate and cardiomyocyte Ca2+ oscillation frequency
in
rats and prevented cardiac hypertrophy in mice.
Wang Y, Wang HY, Yuan ZK, Zhao XN, Wang JX, Zhang ZX.
School of Medicine, State Key Laboratory of Coordination Chemistry, Nanjing
University, China.
AIM: To study the effects of quercetin (Que) on myocardial excitation-contraction
coupling and cardiac remodeling. METHODS: Left ventricles and femoral
arteries of rats were cannulated for hemodynamic recording. Mouse cardiac
hypertrophy was induced by abdominal aortic coarctation (AAC). Cultured
myocardial cells in neonatal rats were loaded with Fura 2-AM. The intracellular
calcium ([Ca2+]i) and spontaneous [Ca2+]i oscillations ([Ca2+]i-SO) were
tested by AR-CM-MIC cation measurement system. RESULTS: Que 3 or 25 mg.kg-1
i.v. in rats decreased heart rate from (420 +/- 19) to (390 +/- 15) and
(314 +/- 18) beat.min-1, respectively, companied with very modest changes
in both left ventricular pressures (LVP) and its differential dpLV/dtmax.
Que 10, 50, 250 mumol.L-1 concentration-dependently slowed the frequency
of [Ca2+]i-SO in
cultured myocardial cells from (26 +/- 4) to (25 +/- 3), (18 +/- 4), and
(12 +/- 3) time.min-1, respectively, but did not change their resting
[Ca2+]i or amplitudes of [Ca2+]i-SO. Similarly, the increases in frequency
of [Ca2+]i-SO caused by either isoproterenol (Iso) or ouabain (Oua) were
prevented by Que 100 mumol.L-1, while the simultaneous increases in amplitude
of [Ca2+]i-SO remained. Besides, [Ca2+]i rises excited by angiotensin
II (Ang II) but not high [K+]o were prevented by Que 100 mumol.L-1. Daily
administration of Que 120 mg.kg-1 i.g. for 5 d markedly prevented the
cardiac hypertrophy in AAC mice, without effects on the ventricular mass
to body weight ratio (VM/BW) in sham-operated mice. CONCLUSION: Quercetin
decreased myocardial [Ca2+]i-oscillation frequency and prevented cardiac
remodeling, but had no direct effect on cardiac excitation-contraction
coupling.
25. Zhongguo Yao Li Xue Bao. 1995 May;16(3):223-6.
Effects of quercetin on aggregation and intracellular free calcium of
platelets.
Xiao D, Gu ZL, Bai JP, Wang Z.
Department of Pharmacology, Suzhou Medical College, China.
AIM: To study the effects of Que on the intraplatelet free calcium concentration
and the effects of calcium on the inhibition of platelet aggregation by
Que.
METHODS: Using Quin-2 fluorescence technique. RESULTS: Que inhibited the
platelet aggregation and the rise of [Ca2+]i induced by thrombin in platelets.
The values of IC50 and 95% confidence interval were 146.2 (92.4 - 231.3)
and
78.5 (49.5 - 124.4) mumol.L-1, respectively. The inhibitory effects of
Que on
platelet aggregation induced by thrombin were reduced by adding calcium
to the
medium, and Que had no effect on thrombin-induced internal Ca2+ release
from
dense tubular system. CONCLUSION: The inhibitory effects of Que on aggregation
and the rise of [Ca2+]i in platelets was mainly due to an inhibition of
Ca2+
influx.
26. Antiproliferative potency of structurally distinct dietary flavonoids
on human colon cancer cells
Kuo SM.
Nutrition Program, State University of New York at Buffalo, 14214, USA.
smkuo@acsu.buffalo.edu
Cancer Letters (Ireland), 1996, 110/1 2 (41 48)
Dietary flavonoids are known to be antiproliferative and may play an important
role in cancer chemoprevention, especially cancers of the gastrointestinal
tract, because of a direct contact with food. This study was designed
to compare the antiproliferative potency of several structurally distinct
dietary flavonoids in colon cancer cells, Caco 2 and HT 29, and in rat
nontransformed intestinal crypt cells, IEC 6. Flavonoids varied significantly
in their antiproliferative potency depending on the structural features
but the observations were consistent among the three cell lines studied.
Of the two most potent flavonoids, quercetin and genistein, the effect
was found to be dose dependent and chromatin condensation, an indication
of apoptosis, was noticed. Quercetin was found to distribute throughout
the cell with higher amounts in the perinuclear and nucleoli areas. The
lack of specific cell membrane enrichment by quercetin was consistent
with its lack of effect on the transepithelial resistance. While several
flavonoids including quercetin were found to be unstable, the chemical
instability did not correlate with the antiproliferative potency, although
it may contribute to the antiproliferative effect.
27. Preferential requirement for protein tyrosine phosphatase activity
in the 12-O-tetradecanoylphorbol-13-acetate-induced differentiation of
human colon cancer cells.
Kuo ML, Huang TS, Lin JK.
Institute of Toxicology, College of Medicine, National Taiwan University,
Taipei.
Biochem Pharmacol; 50(8):1217-22 1995
Some lines of colon cancer cells are forced to undergo differentiation
by 12-O-tetradecanoylphorbol-13-acetate (TPA). The increases in activities
of both protein tyrosine phosphatase (PTP) and protein tyrosine kinase
(PTK) have been reported to be associated with the TPA-induced differentiation
of HL-60 leukemia cells. In the present study, a 2-fold increase in PTP
activity was observed in SW620 human colon cancer cells after 30 min of
TPA treatment; a maximal level (4- to 5-fold) was reached at 60 min and
continued for more than 6 hr. In addition, two TPA-induced differentiated
characteristics, morphological alteration and release of cellular surface
proteoglycan, were effectively blocked by PTP inhibitors, such as sodium
orthovanadate (50 microM), zinc chloride (100 microM), and iodoacetate
(250 microM), but not by the protein serine/threonine phosphatase inhibitor
okadaic acid (20 nM). On the other hand, although TPA induced a transient
slight increase in PTK activity (1.4-fold) at 60 min, four PTK inhibitors
(genistein, herbimycin A, tyrphostin-23 and quercetin) had different effects
on the TPA-induced release of cell surface proteoglycan. Genistein (60
microM) potentiated this process, but in contrast, quercetin (45 microM)
could partially inhibit the TPA effect. Taken together, these observations
suggest that both PTP and PTK activities were increased in SW620 cells
in response to TPA; however, the activation of PTP seems to be preferentially
required for the TPA-induced differentiation of SW620 human.
28. Effect of Quercitrin on acute and chronic experimental colitis in
the rat
De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A.
F.S. De Medina, Department of Pharmacology, School of Pharmacy,
University of Granada, 18071 Granada Spain
Journal of Pharmacology and Experimental Therapeutics (USA) , 1996, 278/2
(771-779)
Quercitrin was tested for acute and chronic anti-inflammatory activity
in
trinitrobenzenesulfonic acid-induced rat colitis. The inflammatory status
was evaluated by myeloperoxidase, alkaline phosphatase and total
glutathione levels, leukotriene B4 synthesis, in vivo colonic fluid
absorption, macroscopical damage and occurrence of diarrhea and adhesions.
Treatment with 1 or 5 mg/kg of quercitrin by the oral route reduced
myeloperoxidase and alkaline phosphatase levels, preserved normal fluid
absorption, counteracted glutathione depletion and ameliorated colonic
damage at 2 days. Increasing or lowering the dose of the flavonoid resulted
in marked loss of effect. The acute anti-inflammatory effect of quercitrin
is unrelated to impairment of neutrophil function or lipoxygenase
inhibition, and it may be caused by mucosal protection or enhancement
of
mucosal repair secondary to increased defense against oxidative insult
and/or preservation of normal colonic absorptive function. When tested
in
chronic colitis (2 and 4 weeks), quercitrin treatment (1 or 5 mg/kg .
day)
decreased colonic damage score and the incidence of diarrhea, and
normalized the colonic fluid transport. All other parameters were
unaffected. The chronic effect of the flavonoid is apparently related
to
its action on colonic absorption, although it can be partly secondary
to
its acute beneficial effect.
29. Inhibition of human breast cancer cell proliferation and delay of
mammary tumorigenesis by flavonoids and citrus juices
So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK.
Department of Pharmacology and Toxicology, University of Western Ontario,
London, Canada.
Nutrition and Cancer (USA) , 1996, 26/2 (167 181)
Two citrus flavonoids, hesperetin and naringenin, found in oranges and
grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin,
genistein, and quercetin, were tested singly and in one to one nd growth
of a human breast carcinoma cell line, MDA MB 435. The concentration at
which cell proliferation was inhibited by 50% (IC50), based on incorporation
of (3H)thymidine, varied from 5.9 to 140 microg/ml for the single flavonoids,
with the most potent being baicalein. IC50 values for the one to one combinations
ranged from 4. 7 microg/ml (quercetin + hespererin, quercetin + naringenin)
to 22.5 microg/ml (naringenin + hespererin). All the flavonoids showed
low cytotoxicity (>500 microg/ml for 50% cell death). Naringenin is
present in grapefruit mainly as its glycosylated form, naringin. These
compounds, as well as grapefruit and orange juice concentrates, were tested
for their ability to inhibit development of mammary tumors induced by
7,12 dimethylbenz(a)anthracene (DMBA) in female Sprague Dawley rats. Two
experiments were conducted in which groups of 21 rats were fed a semipurified
diet containing 5% corn oil and were given a 5 mg dose of DMBA intragastrically
at approximately 50 days of age while in diestrus. One week later, individual
groups were given double strength grapefruit juice or orange juice or
fed naringin or naringenin at levels comparable to that provided by the
grapefruit juice; in the second experiment, the rats were fed a semipurified
diet containing 20% corn oil at that time. As expected, rats fed the high
fat diet developed more tumors than rats fed the low fat diet, but in
both experiments tumor development was delayed in the groups given orange
juice or fed the naringin supplemented diet compared with the other three
groups. Although tumor incidence and tumor burden (grams of tumor/rat)
were somewhat variable in the different groups, rats given orange juice
had a smaller tumor burden than controls, although they grew better than
any of the other groups. These experiments provide evidence of anticancer
properties of orange juice and indicate that citrus flavonoids are effective
inhibitors of human breast cancer cell proliferation in vitro, especially
when paired with quercetin, which is widely distributed in other foods.
30. Quercetin glycosides inhibit lipoxygenase-induced LDL oxidation
Inhibition of mammalian 15-lipoxygenase-dependent lipid peroxidation
in low-density lipoprotein by quercetin and quercetin monoglucosides.
Luiz da Silva E, Tsushida T, Terao J.
National Food Research Institute, Ministry of Agriculture, Forestry, and
Fisheries, Ibaraki, Japan.
Arch Biochem Biophys. 1998 Jan 15;349(2):313-20.
Lipoxygenase is suggested to be involved in the early event of atherosclerosis
by inducing plasma low-density lipoprotein (LDL) oxidation in the subendothelial
space of the arterial wall. Since flavonoids such as quercetin are recognized
as lipoxygenase inhibitors and they occur mainly in the glycoside form,
we assessed the effect of quercetin and its glycosides (quercetin 3-O-beta-glucopyranoside,
Q3G; quercetin 4'-O-beta-glucopyranoside, Q4'G; quercetin 7-O-beta-glucopyranoside,
Q7G) on rabbit reticulocyte 15-lipoxygenase (15-LOX)-induced human LDL
lipid peroxidation and compared it with the inhibition obtained by ascorbic
acid and alpha-tocopherol, the main water-soluble and lipid-soluble antioxidants
in blood plasma, respectively. Quercetin inhibited the formation of cholesteryl
ester hydroperoxides (CE-OOH) and endogenous alpha-tocopherol consumption
effectively throughout the incubation period of 6 h. Ascorbic acid exhibited
an effective inhibition only in the initial stage and LDL preloaded with
fivefold alpha-tocopherol did not affect the formation of CE-OOH compared
with the native LDL. CE-OOH formation was inhibited by both quercetin
and quercetin monoglucosides in a concentration-dependent manner. Quercetin,
Q3G, and Q7G exhibited a higher inhibitory effect than Q4'G (IC50: 0.3-0.5
microM for quercetin, Q3G, and Q7G and 1.2 microM for Q4'G). While endogenous
alpha-tocopherol was completely depleted after 2 h of LDL oxidation, quercetin,
Q7G, and Q3G prevented the consumption of alpha-tocopherol. Quercetin
and its monoglucosides were also exhausted during the LDL oxidation. These
results indicate that quercetin glycosides as well as its aglycone are
capable of inhibiting lipoxygenase-induced LDL oxidation more efficiently
than ascorbic acid and alpha-tocopherol.
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