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Cardiovascular disease is a major cause of death worldwide despite the majority of its risk factors being preventable and treatable. The results of numerous epidemiological studies suggest that a diet rich in fruits and vegetables affords protection against CVD, and this may be attributed, in part, to the flavonoid quercetin. The aims of this review are to summarise the current knowledge on the bioavailability and metabolism of quercetin as well as discuss the current evidence behind the potential mechanisms by which quercetin exerts its cardioprotective effects. This review summarises key human studies administering quercetin that have been published to date. Although interesting results have been seen in animal and cell culture studies, in general, these have not been replicated in human trials. Several studies have, however, shown that quercetin can reduce blood pressure in hypertensive patients. The exact mechanisms are yet to be elucidated. Further studies are required to investigate the use of quercetin as a cardioprotective treatment, in particular long-term and dose–response studies.
The Efficacy of Quercetin in Cardiovascular Health
Nicola P. Bondonno
&Catherine P. Bondonno
&Jonathan M. Hodgson
Natalie C. Ward
&Kevin D. Croft
#Springer Science+Business Media New York 2015
Abstract Cardiovascular disease is a major cause of death
worldwide despite the majority of its risk factors being
preventable and treatable. The results of numerous epide-
miological studies suggest that a diet rich in fruits and
vegetables affords protection against CVD, and this may
be attributed, in part, to the flavonoid quercetin. The aims
of this review are to summarise the current knowledge on
the bioavailability and metabolism of quercetin as well as
discuss the current evidence behind the potential mecha-
nisms by which quercetin exerts its cardioprotective ef-
fects. This review summarises key human studies admin-
istering quercetin that have been published to date. Al-
though interesting results have been seen in animal and
cell culture studies, in general, these have not been repli-
cated in human trials. Several studies have, however,
shown that quercetin can reduce blood pressure in hyper-
tensive patients. The exact mechanisms are yet to be elu-
cidated. Further studies are required to investigate the use
of quercetin as a cardioprotective treatment, in particular
long-term and doseresponse studies.
Keywords Cardiovascular disease .Flavonoids .Quercetin .
Blood pressure .Flow-mediated dilatation .Nitric oxide .
Endothelin-1 .Atherosclerosis .Antioxidant .Oxidative
stress .Lipoproteins .Heme oxygenase-1
Cardiovascular disease (CVD) is a major cause of death
worldwide. There are many risk factors for CVD includ-
ing hypertension, smoking, hypercholesterolemia,
hyperglycaemia, obesity, physical inactivity and an un-
healthy diet [1]. Individuals with one CVD risk factor
are more likely to have other risk factors, and many
cases of CVD can be prevented by identifying a modi-
fiable risk factor and treating it [2]. Although CVD
usually affects older adults, the precursor of CVD, par-
ticularly atherosclerosis, begins early in life. This makes
primary prevention efforts such as healthy eating, exer-
cise and avoidance of smoking necessary from child-
hood [3]. It is well known that a diet rich in fruits
and vegetables is associated with a reduction in CVD
[46]. Recently, it has been suggested that the beneficial
effects of this diet can be attributed, in part, to flavo-
noids [7]. It is the aims of this review to summarise key
(Table 1) and to discuss the current evidence behind
the potential mechanisms by which quercetin is
cardioprotective (summarised in Fig. 1).
This article is part of the Topical Collection on Cardiovascular Disease
*Kevin D. Croft
Nicola P. Bondonno
Catherine P. Bondonno
Jonathan M. Hodgson
Natalie C. Ward
School of Medicine and Pharmacology, The University of Western
Australia, Level 4 Medical Research Foundation Building, Rear 50
Murray Street, Perth, Western Australia 6000, Australia
Curr Nutr Rep
DOI 10.1007/s13668-015-0137-3
Tab l e 1 The cardioprotective effects of quercetin in human interventional studies
Study design Cohort Significant effects observed in
the treated group
Endpoints with no observed effect Year Ref.
Supplement: Q3G 160 mg/day; 4 weeks
Age: 66.4± 7.9 years
Health status: healthy (SBP
125160 mmHg)
in plasma Q after chronic and acute on
chronic ingestion
Change in FMD, SBP, DBP, PWA PWV,
body weight, glucose, insulin, insulin
resistance, NO, ET-1 or any cholesterols
2015 [36]
Supplement: Q aglycone 200 and 400 mg
Age: 25.8± 5.2 years
Health status: healthy
in Q3GA and plasma glutathione at 2 h
in brachial artery diameter at 5 h
in urinary isoprostanes and NOx at 5 h
- change in SBP, DBP, urinary nitrites plus
2014 [38]
Supplement: Q3G 0, 50, 100, 200 and 400 mg
Age: 60.8± 9.3 years
Health status: healthy
Linear doseresponse in plasma Q
metabolites (P<0.001) 1 h post-intervention
Change in BP, FMD, plasma NO production 2014 UP
Supplement: Q aglycone 500 or 1000 mg/day;
12 weeks + vitamin C+niacin
Age:4083 years
Health status: healthy
A shift in plasma 163 metabolites Change in markers of inflammation or
oxidative stress
2012 [86]
Supplement: Q aglycone 1095 mg
N=5 healthy
Age:24±3 years
N=12 stage 1 hypertensive
Age: 41± 12 years
Peak in plasma Q at 10 h
hypertensives only)
Change in plasma ACE activity, ET-1, nitrites
Change in FMD
Change in BP in normotensives
2012 [37]
Supplement: Q dihydrate 2×500 mg/day;
4 weeks
Age:30.1± 1.6 years
Health status: healthy males
in oxLDL
in plasma dendritic cells
Change in NF-κB gene expression, LDL
or HDL
2011 [79]
Supplement: Q dehydrate 150 mg/day;
8 weeks
Age: 59.4± 0.9 years
Health status: healthy with APOE
genotype 3/3, 3/4 or 4/4
in waist circumference
in postprandial SBP and triacylglycerol
HDL, TNF-αand plasma Q
Change in endothelial function, glucose,
insulin, GSH, CRP, oxLDL inflammation or
urinary isoprostanes
2011 [88]
Supplement: Q aglycone 500 or 1000 mg/day;
12 weeks + vitamin C+niacin
Age:1885 years
Health status: varying
in serum creatinine, MAP, HDL and IL-6
in glomerular filtration rate and plasma Q
haematocrit, haemoglobin, TNF-α,
triglycerides and inflammatory markers
2011 [26]
Supplement: 4× 500 mg Q aglycone in 24 h
Age:3169 years
Health status: untreated
sarcoidosis patients
in plasma Q
in markers of oxidative stress (MDA) and
inflammation (TNF-α;IL-10and
IL-8; IL-10)
in plasma oxidative capacity
Change in plasma GSH
Correlations between plasma Q levels and
effects observed
2011 [96]
Supplement: Q aglycone 150 mg/day; 6 weeks
Age: 45.1± 10.5 years
Health status: features of the
metabolic syndrome
in BP in overweight-obese carriers of
the apo 3/3 genotype but not the 4allele
in HDL cholesterol and apoA1
in apo 4 carriers
in oxidised LDL and TNF-αin
apo 3andapo4 groups
Change in CRP or nutritional status (body
weight, waist circumference, fat mass, fat-
free mass)
2010 [41]
Supplement: Q aglycone 500 or 1000 mg/day;
12 weeks + vitamin C+niacin
Age:1885 years
Health status: varying
Dose-dependent increase in plasma
quercetin (peaked in first month)
Change in plasma F
-isoprostanes, oxLDL,
GSH, FRAP or any cholesterols
2009 [85]
Supplement: Q aglycone 150 mg/days;
6 weeks
Age: 45.1± 10.5 years
Health status: features of the
metabolic syndrome
in plasma Q
in SBP
in PP
in serum HDL
Change in body weight, total cholesterol,
2009 [34]
Curr Nutr Rep
Tab l e 1 (continued)
Study design Cohort Significant effects observed in
the treated group
Endpoints with no observed effect Year Ref.
oxidised LDL
Supplement: Q aglycone 200 mg
Age: 43.2± 4.3 years
Health status: healthy males
in plasma S-nitrosothiols.
Q metabolites and nitrite
in urinary nitrate
in plasma and urinary ET-1
Change in plasma nitrate, urinary
nitrite and F
Adverse side effects
2008 [56]
Supplement: Q dihydrate 50, 100 or
150 mg/day; 2 weeks
Age: 26.2± 3.7 years
Health status: healthy
Dose-dependent increases in plasma Q
Change in serum uric acid, lipids and
lipoproteins, oxLDL, TNF-αand plasma
antioxidative capacity
2008 [87]
Supplement: Q aglycone 1000 mg/day;
3 weeks + vitamin C+niacin (20 mg)
N=18 (quercetin)
Age: 44.2± 2 years
N=21 (placebo)
Age: 46± 2.3 years
Health status: healthy
in plasma Q Difference in plasma antioxidant capacity or
Oxidative damage
Difference in plasma quercetin between the
two groups after a race
2008 [97]
Supplement: Q aglycone 730 mg/day;
28 days
N=19 pre-hypertensive
Age: 47.8± 3.5 years
N=22 stage 1 hypertensive
Age: 49.2± 2.9 years
in SBP, DBP and MAP
(in S1 hypertensives only)
Change in BP in pre-hypertensives
Change markers of oxidative stress,
antioxidant capacity, cholesterols, fasting
glucose and triglycerides
2007 [35]
Supplement: Q 1000 mg/day; 28 days
Age: 53.1 years
Health status: patients with
interstitial cystitis
Improvement in cystitis symptoms Adverse side effects 2001 [123]
Supplement: rutin 500 mg/day; 6 weeks
Age:1848 years
Health status: healthy females
in plasma Q Change in plasma antioxidant capacity,
phenolic content, liver function indicators,
GSH, resistance of lymphocytes to H
damage and markers of oxidative stress
2000 [90]
Supplement:Q30 mg/day;
14 days
Age:3365 years
Health status: healthy males
oxidative resistance of LDL Change in cholesterol, triglycerides, ascorbic
acid and tocopherols
2000 [105]
Supplement: 250 mg Q aglycone +
50 mg rutin 1 g/day; 28 days
Age: 41.5± 2.9 years
Health status: healthy
in plasma Q Change in cholesterol, triglycerides, SBP,
DBP and HR or thrombogenic risk factors
1998 [39]
Aacute, ACE angiotensin-converting enzyme, AM age matched, APOE apolipoprotein E, BP blood pressure, Cchronic, CO crossover, CRP C-reactive protein, DB double blind, DBP diastolic blood
pressure, FRAP ferric-reducing ability of plasma, GSH glutathione, HDL high-density lipoprotein, LDL low-density lipoprotein, NOx nitrogen oxides, oxLDL oxidised low-density lipoprotein, Pparallel,
PC placebo controlled, PWA pulse wave analysis, PWV pulse wave velocity, Qquercetin, Q3G quercetin-3-glucoside, Q3GA quercetin-3-glucuronide, Rrandomised, SB single blind, SBP systolic blood
pressure, TNF-αtumour necrosis factor-α,UP unpublished
Curr Nutr Rep
Polyphenols, compounds that are found in high concentra-
tions in some fruits and vegetables, are produced as secondary
plant metabolites and are usually involved in the defence of
the plant against stress such as UV radiation and invading
pathogens [8]. It has been suggested that molecules used by
plants as a protection against stress may work similarly in
animals that consume these plants as food [9]. The main clas-
ses of polyphenols include phenolic acids, flavonoids, stil-
benes and lignans. Flavonoids are the largest and most
researched subclass of polyphenols. All flavonoids have a
C6-C3-C6 structure made up of two aromatic rings, linked
by a 3-carbon bridge. In the past decade, many studies have
tried to find an association between flavonoid intake and prev-
alence of CVD. However, not all flavonoid-rich foods im-
prove cardiovascular risk factors, and it is likely that certain
flavonoids are more bioactive than others [10].
Quercetin (5,7,3,4-hydroxyflavonol) is the most ubiquitous
of the dietary flavonoids. The richest sources are onions, curly
kale, leeks, broccoli, apples, tea, capers and blueberries, with
onion often being the biggest contributor to total quercetin
intake containing 300 mg/kg fresh onion [11]. Quercetin and
other flavonols are mainly found in the outer and aerial tissue
of the fruit or vegetable, such as the skin and leaves, as their
biosynthesis is stimulated by light [12]. Quercetin in food is
usually in its glycosylated form with the sugar moiety often
being glucose or rhamnose, but other sugars such as galactose,
arabinose and xylose may be involved. Quercetin can be
bought over the counter in capsules that contain between
250 and 1500 mg quercetin, which are purported to be bene-
ficial for a range of ailments including allergies, asthma, bac-
terial infections, arthritis, gout, eye disorders, hypertension
and neurodegenerative disorders [13].
Absorption and Bioavailability of Quercetin
The absorption of quercetin depends on the food matrix in
which it is found and whether it is ingested as an aglycone
or in its glycosylated form. The presence and type of sugar
attached determines the site and extent of absorption, while
the position of the sugar defines the mechanisms of intestinal
uptake [14]. Absorption of glycosides in humans occurs in the
small intestine via diffusion after a crucial deglycosylation
step [15]. Absorption of quercetin aglycone can also occur
in the small intestine via diffusion [16]; however, it is not
absorbed as readily as quercetin glycosides. This may be be-
cause it is chemically unstable in the pH and temperature
conditions of the small intestine, and the intestinal mucus
layer provides a barrier for lipophilic substances such as the
quercetin aglycone. Flavonoid glycosides that are not
absorbed in the small intestine, such as rutin (quercetin-3-O-
rutinoside), pass into the colon where they are acted on by
enterobacterial β-glucosidases and microfloral rhamnosidases
[14]. Although the product that enters the epithelial cells is the
same, absorption is not as efficient due to the smaller ex-
change area and lower density of transporters in the colon.
This explains the lower bioavailability and longer time to peak
for quercetin rhamnoglucosides when compared to quercetin
aglycone or quercetin glucosides. There is higher inter-
Fig. 1 Potential mechanisms by
which quercetin exerts its
cardioprotective effects. ACE
angiotensin-converting enzyme,
AMPK adenosine
monophosphate-activated protein
kinase, eNOS endothelial nitric
oxide synthase, ET-1 endothelin-
1, HMOX-1 heme oxygenase-1,
LDL low-density lipoprotein,
NADPH nicotinamide adenine
dinucleotide phosphate, NO nitric
oxide, Nrf2 nuclear factor
erythroid 2-related factor 2,
PCSK9 proprotein convertase
subtilisin/kexin 9, PON1
paraoxonase 1, ROS reactive ox-
ygen species
Curr Nutr Rep
individual variability after ingestion of rutin, most likely due
to the large diversity of colonic microflora [17].
Metabolism and Safety of Quercetin
Following absorption, quercetin undergoes three main
types of conjugation: sulphation, methylation and
glucuronidation. This occurs in the enterocyte by the ac-
tion of sulfotransferases, catechol-O-methyl transferases
and UDP-glucuronosyltransferases [8]. This conjugation
process is very efficient and no aglycones or quercetin
glycosides are found in the plasma [18]. The main quer-
cetin metabolites found in the plasma are quercetin-3-sul-
phate, quercetin-3-glucuronide, isorhamnetin-3-glucuro-
nide, quercetin diglucuronide and quercetin glucuronide
sulphate [19]. Ingestion of glycosylated quercetin does
not change circulating metabolites [8].
Metabolites follow two different methods of excretion:
via the urine or as part of biliary secretions back into the
small intestine [8]. Any quercetin not absorbed in the
small intestine, together with that secreted in the bile, is
degraded by colonic microflora with the resultant agly-
cone undergoing ring fission, leading to the production
of phenolic acids and hydroxycinnamates [20]. The elim-
ination of quercetin metabolites is slow with reported
half-livesrangingfrom11to28h[8]. Studies suggest
that lower doses of quercetin are more methylated than
higher doses in humans [21]. Additionally, sulphation is
generally a higher affinity, lower capacity pathway than
glucuronidation; an increase in the amount of quercetin
glucuronidation. A substantial amount of research using
quercetin aglycone in vitro has been questioned due to the
very low concentrations of aglycone found in the plasma.
Furthermore, recent research has shown that the major
metabolites of quercetin found in the plasma show weaker
bioactivity in vitro than the aglycone [22,23]. It has been
hypothesised that quercetin metabolites are deconjugated
in the tissue, by β-glucuronidase, releasing quercetin
aglycone which acts as the final effector, a concept that
has been discussed in greater detail by Perez-Vizcaino
et al. [24].
The safety of quercetin has been extensively reviewed by
Harwood et al. [25]. In brief, quercetin is not classified as
carcinogenic or mutagenic in vivo. Recent studies looking at
both acute and chronic supplementation with high doses of
quercetin up to 1000 mg/day for 12 weeks have not reported
any adverse side effects [26]. It is important to note that quer-
cetin inhibits CYP3A4, an enzyme that breaks down several
commonly prescribed drugs [27]. Quercetin should not be
taken in conjunction with drugs such as alprazolam (Xanax)
and colchicine, which rely on this pathway for metabolism.
The correlation between flavonoid intake and risk of CVD has
been investigated in several epidemiological studies. Most but
not all suggest an inverse association between flavonoid in-
take and CVD. A recent prospective cohort study found that
elderly women with higher total flavonoid consumption were
at a lower risk of all-cause mortality [28]. High total flavo-
noid consumers had a 4050 % reduced risk of CVD com-
pared to those with the lowest intake. In the same cohort,
women in the highest tertile of flavonol intake had a lower
risk of atherosclerotic vascular disease death compared with
women in the lowest tertile [29]. To date, few epidemiological
studies have looked at quercetin intake; in the Finnish Mobile
Clinic Health Examination Survey (n=10,054), it was found
that high quercetin intake was associated with lower mortality
from ischaemic heart disease. In this study, quercetin from the
diet was predominantly from apples and onions. The relative
risk (RR) between the highest and lowest quartiles was 0.79
(95 % CI 0.63, 0.99: Pfor trend=0.02) [7]. Although epide-
miological studies suggest a correlation between increased
flavonoid consumption and lower risk of CVD, these studies
have a number of limitations such as the use of food frequency
questionnaires, confounding and publication bias. Thus, we
must be careful when inferring causality using traditional ep-
idemiological methods. Plasma biomarkers are a promising
new technique for determining flavonoid consumption; how-
ever, the methods need further refinement. Currently, there are
no validated biomarkers of quercetin intake, although it has
been suggested that urinary 4-ethylphenol, benzoic acid and
4-ethylbenzoic acid may be potential markers of quercetin
intake [30]. Problems with this method arise due to large
inter-subject variability, which can result from differences in
gut microflora, as well as the food matrix.
Blood Pressure
Hypertension is a major risk factor for CVD [31] and there is a
strong relationship between arterial pressure and death from
stroke and ischaemic heart disease [32]. A diet high in fruits
and vegetables is known to reduce blood pressure, an effect
also attributed to high flavonoid content. Recent studies have
shown a decrease in systolic BP following quercetin supple-
mentation, ranging from 2.9 to 7 mmHg in hypertensive indi-
viduals [3335] but not in pre-hypertensives or normotensives
[36,37,35,38,40]. Interestingly, in a study by Egert et al.,
6 weeks of 150 mg/day quercetin supplementation led to a
significant decrease in BP (3.4 mmHg, P<0.01) in
overweight-obese carriers of the ApoE3 (Apolipoprotein E3)
gene but not in carriers of the ApoE4 gene [41]. Although the
BP reductions observed in these studies are low, the impact on
CVD for a population would be significant with a 23%
reduction in risk expected for each mmHg reduction in BP
Curr Nutr Rep
[42]. Long-term regular consumption of foods high in specific
flavonoids such as quercetin may be useful dietary lifestyle
changes that could help to decrease the use of pharmaceuti-
cals. The mechanisms behind the beneficial decreases in BP
remain to be elucidated; potential pathways include improve-
ment in endothelial function, increases in nitric oxide bioavail-
ability, decreases in the vasoconstrictor endothelin-1, direct
action on vascular smooth muscle and inhibition of
angiotensin-converting enzyme activity.
Endothelial Function and Dysfunction
The endothelium is a monolayer of cells that lines the lumen
of the heart and blood and lymphatic vessels. It responds to
both physical and chemical stimuli to regulate vascular tone,
inflammation, permeability and growth, as well as blood flu-
idity and coagulation [43]. Interestingly, the endothelium se-
cretes both powerful vasorelaxing (e.g. nitric oxide) and
vasoconstricting substances (e.g. endothelin-1). Endothelial
dysfunction has been defined as an impairment in
endothelium-dependent relaxation, with a tendency towards
a proinflammatory, procoagulatory and prothrombotic state
[44]. Any damage to the endothelium results in a decrease in
the bioavailability of endothelium-derived nitric oxide (NO).
This predisposes the vessel wall to leukocyte and platelet ad-
hesion, vasoconstriction and smooth muscle cell proliferation
[45]. A significant association has been observed between
endothelial dysfunction and increased risk of CVD [46]. In-
deed, endothelial dysfunction is implicated in numerous car-
diovascular pathologies including pre-hypertension, hyperten-
sion, atherosclerosis and stroke [47,48]. Quercetin can poten-
tially improve endothelial health through direct vasorelaxant
activity as well as through the prevention of oxidant-induced
endothelial dysfunction.
Flow-Mediated Dilatation In humans, ultrasonography is a
common method used to assess vascular endothelial function
as NO flow-mediated dilatation (FMD) of the brachial artery
[49]. FMD in the peripheral circulation is primarily mediated
by endothelium-derived NO in response to increased flow and
shear stress and results in smooth muscle relaxation and arte-
rial dilation [50]. The effect of quercetin on endothelial func-
tion has not been widely studied. Two studies have shown that
quercetin has neither an acute (1095 mg quercetin aglycone)
[37] nor chronic (quercetin-3-O-glucoside, 160 mg/day for
4weeks)[36] effect on FMD. Contrastingly, studies using
whole foods (apples) or whole food extracts (onion extract)
rich in quercetin have shown significant improvements in
FMD (acute, 1.1 %) [51] and postprandial FMD (30 days,
1.6 %) [40]. The above studies vary greatly in design and,
as a result, are hard to compare. Further investigations should
be undertaken to determine whether there is a difference be-
tween acute and chronic consumption of quercetin on FMD
and whether different effects are observed in healthy subjects
compared to subjects with risk factors for CVD such as hy-
pertension or obesity.
Nitric Oxide NO is a potent vasodilator that is synthesised in
the endothelium by endothelial NO synthase (eNOS) en-
zymes. It plays a key role in maintaining vascular integrity
through its antithrombotic, antiproliferative and
antiatherogenic properties [52]. Quercetin has been shown to
increase eNOS activity, possibly through phosphorylation of
adenosine monophosphate-activated protein kinase (AMPK),
resulting in an increase in NO production both acute and long
term [53]. Additionally, up-regulation of AMPK can increase
NO bioavailability through inhibition of NADPH oxidase ac-
tivity, reducing superoxide-activated NO depletion [54].
Quercetin increases intracellular Ca
levels in aortic endothe-
lial cells and stimulates eNOS phosphorylation in a dose- and
time-dependent manner, leading to an increase in NO produc-
tion and relaxation of the vessel [55]. In humans, acute quer-
cetin (200 mg) has been shown to significantly increase plas-
ma S-nitrosothiols (metabolites of NO) [56]. Unfortunately,
neither BP nor FMD was measured in this study. Similarly,
quercetin-rich apple has been shown to significantly increase
plasma nitric oxide status (assessed by measuring S-
nitrosothiols + other nitrosylated species (RXNO)) [51]; how-
ever, it would be erroneous to attribute this to quercetin alone.
The results of these studies provide some evidence of one
possible mechanism behind the cardioprotective benefits of
quercetin. Both Larson et al. [37]andPerezetal.[38]report-
ed no changes in plasma nitrite or NOx, despite seeing a de-
crease in BP and a large increase in brachial artery diameter,
respectively. In both studies, nitrite was measured using the
Griess reaction which is not suitable for measurement of
submicromolar levels of nitrate and nitrite due to lack of sen-
sitivity [57]. Correspondingly, Dower et al. found no changes
in NO (measured by chemiluminescence) following 4 weeks
ingestion of 160 mg/day quercetin-3-O-glucoside or after
acute on chronic ingestion (NO measured 2 h after the last
treatment) [36]. It seems that while animal studies suggest
that quercetin can improve endothelial function by increasing
NO bioavailability, these results are not well replicated in
human studies. It is important to note, however, that many
animal studies use supra-physiological doses of pure querce-
tin; thus, care must be taken when interpreting these results.
Interestingly, it has been shown that unlike quercetin agly-
cone, conjugated quercetin metabolites lack a direct
vasorelaxant effect and are unable to modify endothelial func-
tion or NO bioactivity [23].
Nitric Oxide: Endothelin-1 Endothelial dysfunction is asso-
ciated with a diminished bioavailability of the vasodilator NO
resulting in less opposition to vasoconstrictors such as
endothelin-1 (ET-1) [50]. Quercetin has been shown to
Curr Nutr Rep
significantly down-regulate ET-1 gene expression [58], pre-
vent eNOS from endothelin-1-induced uncoupling [54]and
prevent endothelial dysfunction induced by incubation with
ET-1 [23] in isolated rat aortas. These studies support the
hypothesis that quercetin improves vascular function by alter-
ing the balance between NO and ET-1. Loke et al. showed that
urinary ET-1 was significantly lower in people given quercetin
(200 mg) compared to those receiving the placebo [56]. This
was accompanied by an increase in plasma nitrite. In contrast,
no changes in plasma ET-1 were observed in people following
4 weeks ingestion of 160 mg/day quercetin-3-O-glucoside
[36] or after acute administration of 1095 mg quercetin agly-
cone [37]. As results are inconsistent, further clinical interven-
tion studies are needed to determine whether a reduction in
circulating levels of ET-1 is one of the mechanisms behind the
cardioprotective effects of quercetin.
Direct Action on Vascular Smooth Muscle
Up until now, we have been looking at the effects of quercetin
on the endothelium as a way of improving blood vessel reac-
tivity and decreasing BP. There is evidence that quercetin and
its methylated metabolite isorhamnetin can act directly on the
smooth muscle layer, inducing vasorelaxation independent of
the endothelium [5961]. The results of a recent study by Hou
et al. demonstrate that quercetin possesses vasospasmolytic
effects and suggest that depression of Ca
influx through L-
type voltage-gated Ca
channels and augmentation of
voltage-gated K
channel activity in the muscle cells may
underlie coronary relaxation [62]. It is important to note that
the above-mentioned studies use quercetin aglycone. It has not
been confirmed whether this is a representative of in vivo
conditions as pure quercetin is rapidly metabolised upon in-
gestion; however, evidence shows that metabolites are cleaved
by β-glucuronidase in the target tissues, releasing the active
aglycone [24].
Angiotensin-Converting Enzyme
Angiotensin-converting enzyme (ACE) is a crucial element in
the renin-angiotensin-aldosterone system (RAAS) which reg-
ulates BP and fluid loss. The role of ACE is to convert angio-
tensin I into angiotensin II: the peptide responsible for increas-
ing BP [31]. Consequently, chronic over-activation of RAAS
is associated with hypertension [63]. Inhibition of ACE is a
method used for down-regulating RAAS. There is evidence
that plant extracts, rich in flavonoids such as quercetin, can be
effective ACE inhibitors. Evidence is derived from in vitro
models and animal studies [64,65], and several quercetin
metabolites have been shown to be moderate inhibitors of
ACE [6668]. Quercetin has been shown to blunt the increase
in BP observed after administration of angiotensin I in rats,
findings which were further supported by a 31 % decrease in
plasma ACE activity [64]. As well as decreasing BP by
blocking angiotensin II production, resulting in an increase
in urinary volume and sodium output, quercetin has also been
shown to inhibit ACE activity through the down-regulation of
renal angiotensin II receptors [65]. In a study by Larson et al.,
quercetin lowered blood pressure in hypertensive men; how-
ever, they observed no accompanying changes in plasma ACE
activity [37]. A study by Knab et al. found an increase in
urinary output of approximately 30 mL/day after 12 weeks
of quercetin supplementation in humans [26]. Increased urine
output has been proposed as a mechanism behind the decrease
in mean arterial pressure (MAP) that has been reported in
animal models after quercetin supplementation [65]. As evi-
dence of ACE inhibitory effects of quercetin from in vitro and
animal studies has been presented, more studies are required
to investigate this mechanism in humans.
Atherosclerosis, a deposition of lipids in the subendothelial
layer of injured blood vessels, is believed to be the primary
cause of many fatal CVDs [69]. Plaque disruption is initiated
by damage to endothelial cells by inflammatory responses or
reactive oxygen species (ROS) and oxidation of low-density
lipoprotein (LDL). Cardiovascular risk factors, such as hyper-
tension and diabetes, accelerate this process [70]. Primary cell
cultures derived from the damaged endothelium have reduced
expression of eNOS [71] and greater production of oxygen-
derived free radicals (ROS) and have been shown to take up
more LDL and oxidised LDL (oxLDL) [72]. Animal studies
have shown that long-term quercetin consumption leads to a
significant reduction in atherosclerotic lesion formation [73,
74]. Histological and gene expression analyses of aortas treat-
ed with quercetin show that quercetin affects lesional smooth
muscle cell proliferation and inflammatory factors associated
with atherogenesis [73]. Quercetin-3-glucuronide (Q3G) can
accumulate in human atherosclerotic lesions and macrophage-
derived foam cells, but not in healthy aorta cells [75]. Inflam-
matory stimulation of macrophages may initiate lactate secre-
tion, leading to acidification of the surrounds which enhances
the activity of β-glucuronidase [76]. This means that macro-
phages may serve as a potential pool of Q3G which they
deconjugate into the aglycone at the site of pathogenic lesions
[77]. The effect of quercetin on atherosclerotic lesions has not
yet been measured in humans, as the required long-term inter-
ventions are not feasible. However, several studies have in-
vestigated the effects of quercetin on oxidative stress and in-
flammation, which have been implicated in the development
of atherosclerosis [78]. Overall, quercetin has been shown to
have little effect on markers of inflammation such as C-
reactive protein (CRP), cytokines (such as IL-6, IL-1 and
TNF-α) and adhesion molecules (such as ICAM-1, VCAM-
1 and selectins) (refer to Table 1). Interestingly, quercetin
Curr Nutr Rep
(500 mg twice daily for 4 weeks) significantly reduced
plasmacytoid dendritic cells in healthy males [79] which have
been shown to contribute to the initiation of atherosclerosis by
amassing in the lipid plaque [80].
in vitro and has been described as a potent free radical scav-
enger in numerous papers [81]. These properties are primarily
attributed to the presence of a catechol or gallate group in the
B-ring [82]. These claims are supported by studies which
found that quercetin increased total plasma antioxidant capac-
ity 6.24 times more than trolox, a reference antioxidant [83].
Thus, the role of quercetin in preventing CVD has largely
been associated with its free radical scavenging antioxidant
properties. However, the interpretation of plasma antioxidant
capacity in human blood is difficult, and there is little evidence
to support the antioxidant activity of quercetin in vivo. A
recent review by Forman et al. has presented a new concept
by which antioxidants exert their beneficial effects. Rather
than acting as free radical scavengers in vivo, as was previ-
ously thought, antioxidant compounds generate signals that
induce the transcription of protective enzymes [84]. The
physiological concentration of polyphenols in the plasma is
insufficient to scavenge a significant portion of free radicals,
as is seen in many in vitro studies. Rather, polyphenols will be
oxidised to electrophilic hydroquinones and quinones during
their reaction with free radicals. This step appears to be crucial
to its ability to activate nuclear factor erythroid 2-related factor
2 (Nrf2), which maintains protective oxidoreductases and
their nucleophilic substrates. Quercetin and many other plant
polyphenols have been recommended as antioxidants for
many years, despite little evidence that they decrease oxida-
tive stress in humans [35,56,8587,88,89,90].
Oxidative Stress
Oxidative stress and inflammation are commonly thought to
contribute to the initiation and progression of atherosclerosis
[78]. Oxidative stress is defined as an increase in the produc-
tion of ROS over the ability to degrade them. Many functions
of the endothelium are known to be affected by ROS, includ-
ing endothelial cell apoptosis [91] and adhesion of inflamma-
tory cells [92], initiating and augmenting the progression of
CVD, namely atherosclerosis. As discussed above, quercetin
may decrease oxidative stress by stimulating protective de-
fences and repair systems [84]. F
-isoprostanes are consid-
ered to be the Bgold standard^in vivo biomarker of oxidative
stress [93]. Another commonly used marker of oxidative
stress is malondialdehyde (MDA); however, the methods of
detection are less reliable and MDA itself is not a specific
marker of oxidative stress [94]. The ability of quercetin to
reduce oxidative stress levels has been demonstrated in some
animal studies [95]. To date, only a few studies have shown
this in humans; Boots et al. found a decrease in MDA and
markers of inflammation in the blood of patients with the
inflammatory disease, sarcoidosis [96], and Perez et al. found
a decrease in urinary F
-isoprostanes 5 h after supplementa-
tion of quercetin aglycone (200 and 400 mg). Other studies in
humans have failed to find decreases in oxidative stress after
quercetin consumption [35,56,90,97,98]. Some of these
results may be explained by the fact that the studies were done
in healthy volunteers or volunteers without elevated levels of
oxidative stress; the above results suggest that quercetin may
reduce markers of oxidative stress only when levels are high.
To test this hypothesis, Shanely et al. gave 500 mg or
1000 mg/day doses of quercetin for 12 weeks to a large pop-
ulation of subjects ranging widely in age, BMI and disease
state [85]. They did not find an improvement in antioxidant
capacity or a decrease in oxidative stress in any group. Over-
all, indications that quercetin may reduce or prevent CVD risk
by reducing levels of oxidative stress are much stronger in
animal studies than human studies. This may be because
higher doses of quercetin per kilogram body weight are gen-
erally used in animal studies; the resulting differences in plas-
ma quercetin concentrations may be responsible for the con-
trasting effects of quercetin on oxidative stress. Another ex-
planation may lie within the methods used to quantify oxida-
tive stress.
It has been established that the conversion of LDL to oxidised
LDL is an early event in atherosclerosis [78]. High levels of
oxidised LDL are found in patients with the metabolic syn-
drome and are associated with an increase in the risk of myo-
cardial infarction [99]. Reactive species generated by
myeloperoxidase (MPO) are thought to modify LDL in vivo
[100]. In a recent in vitro study, quercetin and some of its
major metabolites were found to protect LDL from MPO-
mediated modification in vitro [101]. One potential mecha-
nism behind this may be increasing the activity of paraoxo-
nase 1 (PON1), an esterase related to the anti-atherogenic
properties of high-density lipoprotein (HDL) [102]thathas
been shown to inhibit the oxidation of LDL [103]. Quercetin
has been shown to up-regulate PON1 activity and free radical
scavenging and protect against LDL oxidation and lipid per-
oxidation [104]. In a study by Egert et al., 150 mg of quercetin
dehydrate per day for 6 weeks reduced plasma oxidised LDL
concentrations in overweight subjects with a high CVD risk
phenotype [34]. In agreement with these results, Chopra et al.
showed that 30 mg of quercetin per day for 2 weeks signifi-
cantly inhibited LDL oxidation [105]. In contrast to these
results, several other human intervention studies found no
changes in oxidised LDL after chronic quercetin
Curr Nutr Rep
supplementation [85,87,106]. Some animal studies support
improvements in lipid profile following quercetin supplemen-
tation [74,107]. A potential mechanism for this may be in the
reduction of proprotein convertase subtilisin/kexin 9 (PCSK9)
which promotes LDL receptor degradation. Q3G has been
shown to increase LDL receptor expression, stimulate LDL
uptake and reduce PCSK9 secretion [108]. However, results
of human studies measuring lipid profiles after quercetin sup-
plementation are equivocal. Overall, most human studies,
with both acute and chronic quercetin supplementation, have
not reported any changes in the levels of plasma LDL or HDL
cholesterol (refer to Table 1). As hyperlipidemia is an inde-
pendent risk factor for atherosclerosis, it is imperative to in-
vestigate the potential for quercetin to decrease the levels of
LDL and oxidised LDL.
Heme Oxygenase-1
As mentioned previously, quercetin can act as an antioxidant
by signalling the induction of protective enzymes, one of these
being heme oxygenase-1 (HMOX-1) [84]. HMOX-1 is the
inducible form of the enzyme that catalyses the degradation of
heme, producing iron, carbon monoxide and biliverdin, which
is then converted to bilirubin [109]. Several reports have
highlighted the important physiological and beneficial roles
of HMOX-1 in the vasculature, and this has recently been
reviewed by Calay et al. [110]. HMOX-1 exerts an anti-
inflammatory and antioxidant action within the vasculature
and may modulate endogenous cellular ROS generation
[111]. Pharmacological inducers of HMOX-1, such as
probucol, protect against vascular disease in three different
animal models of atherosclerosis [112]. Moreover, this bene-
ficial effect is associated with enhanced protection of arteries
against endothelial dysfunction induced by oxidative stress.
Increasing evidence suggests a central role for HMOX-1 in
cardiovascular protection, and induction of vascular HMOX-1
could be an important therapeutic target [113]. Blood vessels
exposed to the oxidant hypocholorous acid (HOCl), a physi-
ologically relevant oxidant produced by myeloperoxidase, ex-
hibit a defect in endothelium-dependent NO bioavailability as
shown by impaired endothelium-dependent relaxation [114].
Pre-treatment of aortic rings from control mice with quercetin
(5 and 10 μmol/L) dose-dependently attenuated endothelial
dysfunction while maintaining eNOS activity [53]. This effect
was not seen in the rings from HMOX-1 heterozygous knock-
out mice suggesting that HMOX-1 is essential for the protec-
tive effects of quercetin. This notion is supported by the in-
creased expression of HMOX-1 protein in arteries isolated
from mice fed a diet supplemented with quercetin which
was also associated with a decrease in atherosclerotic lesions
[95,115]. Several other studies have shown that quercetin
induces the production of HMOX-1 [116,117]. Although
HMOX-1 is not detected in healthy human arteries, high
expression is seen in foam cells and atherosclerotic plaques
[118]. The majority of studies indicate a protective role for
HMOX-1 and its products in atherosclerosis; however, the
exact mechanisms remain to be determined. The potential in-
duction of HMOX-1 by dietary flavonoids, such as quercetin,
is of substantial significance; clinical trials are now required to
determine whether the benefits of quercetin in relation to CVD
are associated with HMOX-1 in humans.
Quercetin in Human Studies
In the past decade, a significant number of human intervention
studies investigating the effect of quercetin on risk factors for
CVD have been conducted. The goal of these studies was to
determine the mechanisms of action by which quercetin may
protect against CVD. Despite these studies, which have
looked at the effects of both pure quercetin (described in
Table 1) and quercetin-rich foods, the precise mechanisms
have not been elucidated. There are a number of limitations
of these studies, but perhaps the most important is the sample
size. Half of the studies presented in Table 1have a sample
size n<20, therefore decreasing the statistical power to detect
changes in the outcome of interest. Thereis a large range in the
doses and form in which quercetin is given; a strength of these
studies is that majority were assessed and showed significant
increases in plasma quercetin levels. Over half of the studies
discussed in Table 1were done in a healthy population; how-
ever, studies looking at the antioxidant effects of quercetin
need to be done on a cohort of people with increased levels
of inflammation and oxidative stress [119]. A healthy and
diverse diet generally supplies sufficient antioxidants to coun-
teract ROS production in healthy individuals, and this may
explain the lack of effect observed in studies with healthy
volunteers [35,56,86]. Additionally, quercetin has only been
shown to decrease BP in a hypertensive population. Table 1
highlights the variety of endpoints measured to demonstrate
the biological effects of quercetin; however, many of these are
not standardised or validated. Unfortunately, this makes it dif-
ficult to compare results and draw conclusions from studies
using a different methodology.
Conclusions and Future Studies
Quercetin is a promising molecule in cardiovascular
health and has been widely researched. Nonetheless, in-
teresting results seen in animal models and cell culture
studies have not been replicated in humans. There are
several possible reasons for this: firstly, many of these
studies use supra-physiological doses of quercetin, which
are not reflective of quercetin content in the human diet.
Secondly, many in vitro studies use quercetin aglycone,
Curr Nutr Rep
which may not accurately represent conditions in vivo.
Thirdly, pathways for quercetin metabolism differ be-
tween humans and rats/mice [120], and the resulting me-
tabolites may function very differently. Another vital fac-
tor to take into consideration when planning future studies
is the metabolism of quercetin by gut microflora [121].
The variability in bacterial species found in the gut be-
tween people and animals, and even between people, may
account for a lot of the variability found in flavonoid
research. Consequently, there is a real need for more hu-
man intervention studies, specifically (i) long-term inter-
vention studies, (ii) doseresponse studies, (iii) studies
administering quercetin glucosides and (iv) studies that
use co-ingestion of quercetin with other flavonoids and
food constituents to improve its bioavailability and bioac-
tivity. Due to reported high inter-subject variability, future
flavonoid studies need to use a cross-over design [120].
Health status and age should play a significant role in the
selection of volunteers as structural damage and arterial
diseases can reduce the potential to improve vascular
function by nutrients alone [34]. As discussed previously,
many studies have reported that quercetin only lowers BP
in hypertensive individuals; it remains to be determined
whether quercetin benefits all forms of hypertension, irre-
spective of pathological cause. One study [34]suggests
that future studies should incorporate 24-h ambulatory
blood pressure measurements, rather than rely on one
blood pressure measurement taken at resting state, in or-
der to gain a better understanding of the effects of quer-
cetin on blood pressure throughout the day and night.
Food databases are potentially powerful tools in epidemi-
ological studies; however, there is a large amount of var-
iation in flavonoid content due to agricultural growth
methods and differing analytical techniques. Spencer
et al. have stressed the importance of establishing quality
biomarkers of flavonoid intake as a means of overcoming
food questionnaire and food database limitations [122].
Although many human studies administering pure querce-
tin yield a negative result, there is certainly evidence that
quercetin contributes to the beneficial effects of a diet rich
in fruits and vegetables.
Acknowledgments NP Bondonno acknowledges the support of an
Australian Postgraduate Award. NC Ward acknowledges the support of
a MRF/UWA Fellowship. JM Hodgson was supported by an NHMRC
Senior Research Fellowship.
Compliance with Ethics Guidelines
Conflict of Interest Nicola P. Bondonno declares that she has no con-
flict of interest.
Catherine P. Bondonno declares that she has no conflict of interest.
Jonathan M. Hodgson has received research support through grants
from the National Health and Medical Research Council of Australia,
Fruit West, Horticulture Australia Limited and Nestlé.
Natalie C. Ward declares that she has no conflict of interest.
Kevin D. Croft has received research support through grants from the
National Health and Medical Research Council of Australia, Fruit West
and the Australian National Apple Breeding Program.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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... Fruits and vegetables, particularly onions, apples, berries, citrus, red grapes, nuts, seeds, and tea, are a good source of quercetin [14]. Several pharmacological studies revealed that, Quercetin supplements are effective in the regulation of redux status [15], reducing inflammation [16], protecting cardiovascular system [17], inhibiting platelet aggregation [18], relaxing vessels smooth muscles [19], and preventing LDL oxidation [20], hypertension [21], cancer development [22,23] and diabetes [24]. It is postulated that hypoglycemic effect of the quercetin is related to insulin signal transduction, such as enhanced protein expression, and tyrosine phosphorylation of insulin receptor (IR), several insulin receptor substrates (IRSs) and glucose transporters (GLUTs) [25]. ...
Polycystic ovary syndrome (PCOS) is a polygenic endocrine disorder and the most common gynecological endocrinopathy among reproductive-aged women. Current remedies are often used only to control its signs and symptoms, while they are not thoroughly able to prevent complications. Quercetin is an herbal bioactive flavonoid commonly used for the treatment of metabolic and inflammatory disorders. Thus, this systematic review was conducted to evaluate the efficacy of quercetin supplementation in subjects with PCOS. Databases until March 2019 were searched. All human clinical trials and animal models evaluating the effects of quercetin on PCOS women were included. Out of 253 articles identified in our search, 8 eligible articles (5 animal studies and 3 clinical trials) were reviewed. The majority of studies supported the beneficial effects of quercetin on the ovarian histomorphology, folliculogenesis, and luteinisation processes. The effects of quercetin on reducing the levels of testosterone, luteinizing hormone (LH), and insulin resistance were also reported. Although quercetin improved dyslipidemia, no significant effect was reported for weight loss. It is suggested that the benefits of quercetin may be more closely related to antioxidant and anti-inflammatory features of quercetin rather than weight-reducing effects. Therefore, this review article provides evidence that quercetin could be considered as a potential agent to attenuate PCOS complications. However, due to the paucity of high-quality clinical trials, further studies are needed.
... Quercetin could be one of the main parts of the medicines for the treatment against protease, skin cancer, as well as tumorigenic cells (Nguyen et al. 2017). Further, oxidation of HDL cholesterol can be highly inhibited via quercetin treatment (Bondonno et al. 2015). Kaempferol is a natural flavonol, a type of flavonoid, found in a variety of plants. ...
Secondary metabolites content as well as petal color changes was quantified in flower extract of Rosa damascena Mill. during four flower development stages [(pre-anthesis; PA), (partially open flower; POF), (full open flower; FOF), and (senescent flower; SF)]. Petal brightness was increased at the last stage of flower opening compare to the PA level. An increase in b* value and decrease in a* value were recorded during damask rose flower development. The result of analysis by HPLC revealed that the main secondary metabolites of Rosa damascena Mill. flowers are phenolic acids [(gallic (GA), caffeic (CA), chlorogenic (CG), and coumaric (CO)] and flavonoids (rutin, quercetin, kaempferol, and apigenin). The content of most phenolic acids were the highest at SF stage, while the flavonoids content was the highest at FOF stage. The apigenin content was the highest at PA stage and then declined. Enzymatic activity of phenylalanine ammonia-lyase (PAL) showed a positive correlation with some flavonoids production. Results indicated that based on the need for specific phenolic compounds in the therapeutic process, flower harvesting at FOF stage or SF stage is suggested.
... The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request. abundant polyphenolic compounds is quercetin, which has antiatherosclerotic effects in human and animals, [14,15] and has been shown to have the ability to fight against inflammation. [16,17] Studies have shown that quercetin could attenuate cell adhesion molecules expression, such as ICAM-1, VCAM-1, and E-selectin. ...
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Background: Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear. Objective: The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation. Methods and results: HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, β-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB. Conclusion: Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.
Lifestyle is an important factor in health, and researchers are trying to see the adverse effect on human health of a change in lifestyle. Many people follow unhealthy lifestyles, which affect human physical and mental health. Millions of people suffer from various problems like cardiovascular disease, overweight, malnutrition, hypertension, stress, violence, etc. There are many medicines that can cure these diseases, but they have side effects. When a man consumes green leaves and vegetables in his diet, his chances of reducing the risk of any disease increase. Every plant has primary and secondary metabolites. Flavonoid is a secondary metabolite found in various plants that plays an important role in the survival of the plant by performing physiological activities and being able to withstand adverse effects from the environment. Quercetin is one such bioflavonoid found in many plants, like onions, citrus fruits, parsley, etc. It comes under the category of flavone, with five hydroxy groups and a chromen-4-one skeletal structure. It has various applications, which include anti-cancer, anti-bacterial, anti-viral, anti-inflammatory, anti-diabetic, etc. However, the use of quercetin is limited due to its poor bioavailability, poor aqueous solubility, lower stability in the gastrointestinal tract, and first-pass effect. To enhance the application of quercetin, various derivatives of quercetin and its metal complex are required that are water soluble, which helps them reach the target site without any first-pass effect and provides them with stability. This review is divided into three main sections: The first section explains about flavonoids and their types; the second section explains about quercetin, its various methods of synthesis, its derivatives, and its metal complex; and the last section represents the complete applications of quercetin, with the drawbacks and how to overcome or deal with the drawbacks.
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The field of nutrigenomics studies the interaction between nutrition and genetics, and how certain dietary patterns can impact gene expression and overall health. The Mediterranean diet (MedDiet), characterized by a high intake of fruits, vegetables, whole grains, and healthy fats, has been linked to better cardiovascular health (CVH) outcomes. This review summarizes the current state of research on the effects of nutrigenomics and MedDiet on cardiovascular health. Results suggest that MedDiet, through its impact on gene expression, can positively influence CVH markers such as blood pressure, lipid profile, and inflammation. However, more research is needed to fully understand the complex interactions between genetics, nutrition, and CVH, and to determine the optimal dietary patterns for individualized care. The aim of this scientific review is to evaluate the current evidence on the effects of nutrigenomics and MedDiet on cardiovascular health. The review summarizes the available studies that have investigated the relationship between nutrition, genetics, and cardiovascular health, and explores the mechanisms by which certain dietary patterns can impact CVH outcomes. The review focuses on the effects of MedDiet, a dietary pattern that is rich in whole foods and healthy fats, and its potential to positively influence CVH through its impact on gene expression. The review highlights the limitations of current research and the need for further studies to fully understand the complex interplay between nutrition, genetics, and cardiovascular health.
Flavonoids are large group of plant-derived aromatic compounds which have diverse functional capabilities. These polyphenolic compounds promote human immune system and protect body against several health ailments. A lot is needed to explore in terms of their bioavailability and their metabolism so as to utilize their broad range potential. Flavonoids are potent substances which are widely used at present because of their antioxidative, anti-inflammatory, antiviral/bacterial, cardioprotective, antidiabetic, antiaging, and anticarcinogenic properties and still have more to be explored and used in the future. This chapter provides view of current and futuristic application of flavonoids.
Background Quercetin, one of the most beneficial flavonoids, has been included in the human diet due to its therapeutic effect on health. Recently, Quercetin is gaining scientific attraction for its multifarious activities, including anti-oxidant, anti-inflammatory, antiviral, anti-diabetic, anti-cancer, anti-arthritic, as well as function to ease some cardiovascular diseases. However, these applications of quercetin in the pharmaceutical field are limited due to its poor aqueous solubility and poor permeability. Objective The present review summarizes various pharmacological activities of quercetin, analyses the barriers like solubility and permeability, which restrict the therapeutic efficiency of quercetin, and also discusses novel approaches to enhance aqueous solubility and permeability of quercetin for its effective clinical use. Methods The current review information sources were peer-reviewed relevant scientific articles of recognized journals from scientific engines and databases (Scopus, Web of Science, PubMed, Science Direct, Google Scholar) using different key words related to quercetin pharmacological effects, mechanism, solubility, permeability, absorption barriers, and formulation approaches. Results Various novel approaches, including solid dispersions, inclusion complex, pro-drugs, nanoemulsion, micelles, liposomes, SNEEDS, and microspheres, have been developed to overcome the solubility and permeability barriers for efficient quercetin delivery. Conclusion This review revealed that the multifaceted pharmacological activities of quercetin for management of various disease are enormously dependent on the development of novel and safe drug delivery systems of quercetin.
Background: Dronedarone HCl is an anti-arrhythmic drug indicated for atrial fibrillation. Dronedarone HCl(DRN) has a low solubility of 2 µg/mL and 4% bioavailability, thus it is formulated as co-amorphous system to enhance its solubility by using Quercetin(QCT) as coformer. Literature lacks a sensitive, accurate and economic method for simultaneous quantification of DRN and QCT in formulation. Objective: To develop a RP-HPLC method for simultaneous estimation of DRN and QCT in DRN-QCT co-amorphous system. Method: Co-amorphous system was prepared using solvent evaporation technique using DRN and QCT in 1:1 molar ratio. The separation was achieved on Purospher® STAR C18 (250 mm × 4.6 mm × 5 μm) column with mobile phase comprising of Acetonitrile and 25 mM phosphate buffer pH 3.6 (60:40, % v/v). Results: DRN and QCT retained at 6.7 and 3.5 min, respectively. For both molecules, method was developed with a wide linearity range of 0.2-500 µg/mL. LOD for DRN was found to be 0.0013 and 0.0026 µg/mL for QCT. Also, LOQ for DRN was found to be 0.0041 and 0.0078 µg/mL for QCT. Conclusion: Method was validated as per ICHQ2R1 guidelines for linearity, precision, accuracy, and robustness. The method was used in simultaneous quantification of DRN and QCT in co-amorphous samples. Highlights: The method developed was used for the analysis of content uniformity and solubility samples of co-amorphous system, where the method was able to successfully quantify DRN and QCT. Low detection and quantification limits contribute to sensitivity of the method and wide linearity range assures the robust and precise quantification of molecules.
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Quercetin, a naturally occurring dietary flavonoid, is well known to ameliorate chronic diseases and aging processes in humans, and its antiviral properties have been investigated in numerous studies. In silico and in vitro studies demonstrated that quercetin can interfere with various stages of the coronavirus entry and replication cycle such as PLpro, 3CLpro, and NTPase/helicase. Due to its pleiotropic activities and lack of systemic toxicity, quercetin and its derivatives may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections. There is evidence that quercetin in combination with, for example, vitamins C and D, may exert a synergistic antiviral action that may provide either an alternative or additional therapeutic/preventive option due to overlapping antiviral and immunomodulatory properties. This review summarizes the antiviral significance of quercetin and proposes a possible strategy for the effective utilization of natural polyphenols in our daily diet for the prevention of viral infection.
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Angiotensin-converting enzyme 2 (ACE2) is a host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Inhibiting the interaction between the envelope spike glycoproteins (S-proteins) of SARS-CoV-2 and ACE2 is a potential antiviral therapeutic approach, but little is known about how dietary compounds interact with ACE2. The objective of this study was to determine if flavonoids and other polyphenols with B-ring 3′,4′-hydroxylation inhibit recombinant human (rh)ACE2 activity. rhACE2 activity was assessed with the fluorogenic substrate Mca-APK(Dnp). Polyphenols reduced rhACE2 activity by 15−66% at 10 μM. Rutin, quercetin-3-O-glucoside, tamarixetin, and 3,4-dihydroxyphenylacetic acid inhibited rhACE2 activity by 42−48%. Quercetin was the most potent rhACE2 inhibitor among the polyphenols tested, with an IC50 of 4.48 μM. Thus, quercetin, its metabolites, and polyphenols with 3′,4′-hydroxylation inhibited rhACE2 activity at physiologically relevant concentrations in vitro.
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The main dietary sources of polyphenols are reviewed, and the daily intake is calculated for a given diet containing some common fruits, vegetables and beverages. Phenolic acids account for about one third of the total intake and flavonoids account for the remaining two thirds. The most abundant flavonoids in the diet are flavanols (catechins plus proanthocyanidins), anthocyanins and their oxidation products. The main polyphenol dietary sources are fruit and beverages (fruit juice, wine, tea, coffee, chocolate and beer) and, to a lesser extent vegetables, dry legumes and cereals. The total intake is ∼1 g/d. Large uncertainties remain due to the lack of comprehensive data on the content of some of the main polyphenol classes in food. Bioavailability studies in humans are discussed. The maximum concentration in plasma rarely exceeds 1 μM after the consumption of 10–100 mg of a single phenolic compound. However, the total plasma phenol concentration is probably higher due to the presence of metabolites formed in the body's tissues or by the colonic microflora. These metabolites are still largely unknown and not accounted for. Both chemical and biochemical factors that affect the absorption and metabolism of polyphenols are reviewed, with particular emphasis on flavonoid glycosides. A better understanding of these factors is essential to explain the large variations in bioavailability observed among polyphenols and among individuals.
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Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea). We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health. Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function. Epicatechin supplementation did not change flow-mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (Δ insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (Δ homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors. Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at as NCT01691404. © 2015 American Society for Nutrition.
Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue1 and for the inhibition of platelet aggregation2 and platelet adhesion3 attributed to endothelium-derived relaxing factor4. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay5, chemiluminescence1 or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-receptor blockers [ARBs], and diuretics or β blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death.
The flavonoid quercetin is metabolized into isorhamnetin, tamarixetin, and kaempferol, the vascular effects of which are unknown. In the present study, the effects of quercetin and its metabolites were analyzed on isometric tension in isolated rat thoracic and abdominal aorta, in isolated intact and β-escin-permeabilized iliac arteries, and on perfusion pressure in the isolated mesenteric resistance vascular bed. In noradrenaline-precontracted vessels, the four flavonoids produced a vasodilator effect, which was inversely correlated with the diameter of the vessel studied; i.e., quercetin, isorhamnetin, tamarixetin, and kaempferol were 5-, 25-, 4-, and 6-fold, respectively, more potent in the resistance mesenteric bed (−log IC50 = 5.35 ± 0.15, 5.89 ± 0.11, 5.34 ± 0.10, and 5.66 ± 0.06, respectively) than in the thoracic aorta (−log IC50 = 4.68 ± 0.08, 4.61 ± 0.08, 4.73 ± 0.11, and 4.81 ± 0.13, respectively; n = 4–6). The vasodilator responses of quercetin and isorhamnetin were not significantly modified after removal of the endothelium in the thoracic aorta or in the mesenteric bed. Furthermore, the guanylate cyclase inhibitor ODQ (1 H -[1,2,4]oxadiazolo[4,3- a ]quinoxalin-1-one; 10−6 M), the adenylate cyclase inhibitor SQ22536 [9-(tetrahydro-2-furanyl)-9 H -purin-6-amine; 10−6 M], KCl (40 mM), or ouabain (10−3 M) had no effect on isorhamnetin-induced vasodilation in the mesenteric bed. In permeabilized iliac arteries stimulated with Ca2+(pCa of 5.9), isorhamnetin was also significantly more potent (−log IC50 = 5.27 ± 0.15) than quercetin (−log IC50 = 4.56 ± 0.15). In conclusion, quercetin and its metabolites showed vasodilator effects with selectivity toward the resistance vessels. These effects are not due to or modulated by endothelial factors and are unrelated to changes in cytosolic Ca2+.
Flavonoids are bioactive compounds found in foods such as tea, chocolate, red wine, fruit, and vegetables. Higher intakes of specific flavonoids and flavonoid-rich foods have been linked to reduced mortality from specific vascular diseases and cancers. However, the importance of flavonoids in preventing all-cause mortality remains uncertain. The objective was to explore the association between flavonoid intake and risk of 5-y mortality from all causes by using 2 comprehensive food composition databases to assess flavonoid intake. The study population included 1063 randomly selected women aged >75 y. All-cause, cancer, and cardiovascular mortalities were assessed over 5 y of follow-up through the Western Australia Data Linkage System. Two estimates of flavonoid intake (total flavonoidUSDA and total flavonoidPE) were determined by using food composition data from the USDA and the Phenol-Explorer (PE) databases. During the 5-y follow-up period, 129 (12%) deaths were documented. Participants with high total flavonoid intake were at lower risk [multivariate-adjusted HR (95% CI)] of 5-y all-cause mortality than those with low levels of total flavonoid consumption [total flavonoidUSDA: 0.37 (0.22, 0.58); total flavonoidPE: 0.36 (0.22, 0.60)]. Similar beneficial relationships were observed for both cardiovascular disease mortality [total flavonoidUSDA: 0.34 (0.17, 0.69); flavonoidPE: 0.32 (0.16, 0.61)] and cancer mortality [total flavonoidUSDA: 0.25 (0.10, 0.62); flavonoidPE: 0.26 (0.11, 0.62)]. Using the most comprehensive flavonoid databases, we provide evidence that high consumption of flavonoids is associated with reduced risk of mortality in older women. The benefits of flavonoids may extend to the etiology of cancer and cardiovascular disease. © 2015 American Society for Nutrition.