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Quercetin: A Versatile Flavonoid

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Associative evidence from observational and intervention studies in human subjects shows that a diet including plant foods (particularly fruit and vegetables rich in antioxidants) conveys health benefits. There is no evidence that any particular nutrient or class of bioactive substances makes a special contribution to these benefits. Flavonoids occur naturally in fruits, vegetables and beverages such as tea and wine. Quercetin is the major flavonoid which belongs to the class called flavonols. Quercetin is found in many common foods including apples, tea, onions, nuts, berries, cauliflower, cabbage and many other foods. Quercetin provides many health promoting benefits, including improvement of cardiovascular health, eye diseases, allergic disorders, arthritis, reducing risk for cancers and many more. The main aim of this review is to obtain a further understanding of the reported beneficial health effects of Quercetin, its pharmacological effects, clinical application and also to evaluate its safety.
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Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
Quercetin: A Versatile Flavonoid
Dr. Parul Lakhanpal*, MD and Dr. Deepak Kumar Rai, MD
*Reader, Department of Pharmacology, SSR Medical College, Mauritius
SMHO, Department of Pediatrics, Ministry of Health & Quality of Life, Mauritius
(Received 04 January 2007 and accepted 29 March 2007)
ABSTRACT: Associative evidence from observational and
intervention studies in human subjects shows that a diet including plant
foods (particularly fruit and vegetables rich in antioxidants) conveys
health benefits. There is no evidence that any particular nutrient or
class of bioactive substances makes a special contribution to these
benefits. Flavonoids occur naturally in fruits, vegetables and beverages
such as tea and wine. Quercetin is the major flavonoid which belongs to
the class called flavonols. Quercetin is found in many common foods
including apples, tea, onions, nuts, berries, cauliflower, cabbage and
many other foods. Quercetin provides many health promoting benefits,
including improvement of cardiovascular health, eye diseases, allergic
disorders, arthritis, reducing risk for cancers and many more.
The main aim of this review is to obtain a further understanding of the
reported beneficial health effects of Quercetin, its pharmacological
effects, clinical application and also to evaluate its safety.
KEY WORDS: Quercetin, Flavonoid, Antioxidant, Health.
INTRODUCTION:
Quercetin is a unique bioflavonoid that has been
extensively studied by researchers over the past
30 years. Bioflavonoids were first discovered by
Nobel Prize laureate Albert Szent Gyorgyi in the
year 1930. Flavonoids belong to a group of
natural substances with variable phenolic
structure and are found in the fruits, vegetables,
grains, bark roots, stem, flowers, tea and wine1.
These natural products were known for their
beneficial effects on health long before
flavonoids were isolated as the effective
compounds. More than 4000 varieties of
flavonoids have been identified, many of which
are responsible for their attractive colors of
flowers, fruits and leaves2.
Flavonoids occur as aglycones, glycosides and
methylated derivatives. The flavonoid aglycone
consists of a benzene ring (A) condensed with a
six membered ring (C), which in the 2-position
carries a phenyl ring (B) as a substituent3. The
Flavonoids can be divided into various classes
on the basis of their molecular structures (Figure
1)4.
Six-member ring condensed with the benzene
ring is either a-pyrone (flavonols and
flavonones) or its dihydroderivative (flavanols
and flavanones). The position of the benzenoid
substituent divides the flavonoid class into
flavonoids (2-position) and isoflavonoids (3-
position). Flavonols differ from flavonones by
hydroxyl group the 3-position and C2-C3 double
bonds5. Flavonoids are often hydroxylated in
position 3, 5, 7, 2’, 3’, 4’, 5’. Methylethers and
acetylesters of the alcohol group are known to
occur in nature. When glycosides are formed, the
glycosidic linkage is normally located in
positions 3 or 7 and the carbohydrate can be L-
rhamnose, D-glucose, glucor-hamnose, galactose
or arabinose6. Flavonoids are mainly divided into
seven major groups (figure-2)7. One of the best
described flavonoids, Quercetin is a member of
this group.
Corresponding Author: Dr. Parul Lakhanpal, Reader, Department of Pharmacology, SSR Medical
College, Belle-Rive, Mauritius, Email: lakhanpalparul@rediffmail.com
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Figure 1: Structures of the major classes of Flavonoid4
Figure 2: Major classes of Flavonoids7
Quercetin is found in abundance in onions,
broccoli, apples and berries. The second group is
flavanones, which are mainly found in citrus
fruits. An example of a Flavonoid in this group is
naringinin. Flavonoids belonging to the catechins
are mainly found in green and black tea and in
red wine, whereas, anthocyanins are found in
strawberries, other berries, grapes, wines and
tea2. Flavonoid contents of different foods are
shown in Table-1.
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Table 1: Main groups of flavonoids, compounds and food sources
Groups Compounds Food sources
Flavonols
Quercetin
Kaempferol
Myricetin
Isorhamnetin
Querctagetin
Yellow onion, Curly kale,
Leek, Cherry tomato,
Broccoli, Apple, Green and
black tea, Black grapes,
Blueberry.
Flavones
Tangeretin
Heptamethoxyflavone
Nobiletin
Sinensetin
Quercetogetin
Chrysin
Apegenin
Luteolin
Disometin
Tricetin
Parsley, Celery, Capsicum
pepper.
Flavanones
Naringenin
Eriodictyol
Hesperetin
Dihydroquercetin
Dihydrofisetin
Dihydrobinetin
Orange juice, Grapefruit
juice, Lemon juice.
Flavanols
Silibinin
Silymarin
Taxifolin
Pinobanksin
Cocoa, Cocoa beverages,
Chocolates.
Catechins
(Proanthocyanidins)
(+) Catechin
Gallocatechin
(-) Epicatechin
Epigallocatechin
Epicatechin 3-gallate
Epigallocatechin 3-gallate
Chocolate, Beans, Apricot,
Cherry, Grapes, Peach, Red
wine, Cider, Green tea, Black
tea, Blackberry.
Isoflavones Daidzein
Genistein
Glycitein
Soy cheese, Soy flour, Soy
bean, Tofu.
Anthocyanins
Cyanidin
Delphinidin
Malvidin
Pelargonidin
Peonidin
Petunidin
Blue berry, Blackcurrant,
Black grapes, Cherry,
Rhubarb, Plum, Strawberry,
Red wine, Red cabbage.
Quercetin, the most abundant of the flavonoids
(the name comes from the Latin –quercetum,
meaning oak forest, quercus oak) consists of 3
rings and 5 hydroxyl groups (Figure-3)8.
Quercetin is a member of the class of flavonoids
called flavonoles and forms the backbone for
many other flavonoids including the citrus
flavonoids like rutin, hesperidins, Naringenin
and tangeritin. It is widely distributed in the
plant kingdom in rinds and barks. Quercetin
itself is an aglycon or aglucone that does not
possess a carbohydrate moiety in its structure.
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Quercetin is typically found in plants as glycone
or carbohydrate conjugates. Quercetin glycone
conjugates include rutin and thujin. Rutin is also
known as Quercetin-3-rutinoside.Thujin is also
known as quercitrin, Quercetin-3-L-rhamnoside
and 3-rhannosyl qurcetin. Onions contain
conjugates of Quercetin and carbohydrate iso
rhamnetin including Quercetin-3-4’-di-o-beta
glucoside, isorhamnetin-4’-o-beta glucoside and
Quercetin-4’-o-beta glucoside.
Figure-2 Molecular structure Quercetin8
MECHANISM OF ACTION:
Anti-oxidative action:
The best described property of Quercetin is its
ability to act as antioxidant. Quercetin seems to
be the most powerful flavonoids for protecting
the body against reactive oxygen species,
produced during the normal oxygen metabolism
or are induced by exogenous damage9,10. One of
the most important mechanisms and the
sequence of events by which free radicals
interfere with the cellular functions seem to be
the lipid peroxidation leading eventually the cell
death. To protect this cellular death to happen
from reactive oxygen species, living organisms
have developed antioxidant line of defense
systems11. These include enzymatic and non-
enzymatic antioxidants that keep in check
ROS/RNS level and repair oxidative cellular
damage. The major enzymes, constituting the
first line of defence, directly involved in the
neutralization of ROS/RNS are: superoxide
dismutase (SOD), catalase (CAT) and
glutathione peroxidase (GPx) The second line of
defence is represented by radical scavenging
antioxidants such as vitamin C, vitamin A and
plant phytochemicals including quercetin that
inhibit the oxidation chain initiation and prevent
chain propagation .This may also include the
termination of a chain by the reaction of two
radicals. The repair and de novo enzymes act as
the third line of defence by repairing damage and
reconstituting membranes. These include lipases,
proteases, DNA repair enzymes and
transferases12.
Direct radical scavenging action:
Free radical production in animal cells can either
be accidental or deliberate. With the increasing
acceptance of free radicals as common place and
important biochemical intermediates, they have
been implicated in a large number of human
diseases13,14. Quercetin acting as free radical
scavengers was shown to exert a protective effect
in reperfusion ischemic tissue damage15,16,17.
Quercetin prevents free radical induced tissue
injury by various ways. One way is the direct
scavenging of free radicals. By scavenging free
radicals, Flavonoid; particularly Quercetin can
inhibit LDL oxidation in vitro18. This action
protects against atherosclerosis.
Inducible nitric oxide syntheses Inhibitory
action:
Quercetin results in a reduction in ischemia –
reperfusion injury by interfering with inducible
nitric oxide synthase activity19. Nitric oxide is
produced by several different types of cells
including endothelial cells and macrophages.
Although the early release of nitric oxide through
the activity of constitutive nitric oxide synthase
is important in maintaining the dilatation of
blood vessels20, the much higher concentration of
nitric oxide produced by inducible nitric oxide
synthase in macrophages can result in oxidative
damage. In these circumstances the activated
macrophages greatly increase their simultaneous
production of both nitric oxide and superoxide
anions. Nitric oxide reacts with free radicals,
thereby producing high damaging peroxynitrite.
Peroxynitrite can directly oxidize LDLs resulting
in irreversible damage to cell membranes.
Quercetin causes scavenging of free radicals;
therefore can no longer react with nitric oxide,
resulting in less damage21. Nitric oxide
interestingly can be viewed as radical itself and
can directly be scavenged by Flavonoids22.
Xanthine oxidase inhibitory action:
The xanthine oxidase pathway has been
implicated as an important route in the oxidative
injury to the tissues especially after ischemia-
reperfusion23. Both xanthine dehydrogenase and
xanthine oxidase are involved in the metabolism
of xanthine to uric acid. Xanthine dehydrogenase
is the form of the enzyme present under
physiological condition but its configuration
changed to xanthine oxidase during oxidative
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stress and ischemic conditions. Quercetin seems
to inhibit xanthine oxidase activity thereby
resulting in decreased oxidative injury19, 24, 25.
Decreasing Leukocyte immobilization:
The immobilization and the firm adhesions of
leukocytes to the endothelial wall is another
major mechanism responsible not only for the
formation of oxygen derived free radicals but
also for the release of cytotoxic oxidants and
inflammatory mediators and further activation of
complement system. Under normal conditions
leukocytes move freely along the endothelial
walls. However during ischemia and
inflammation, various factors mainly endothelial
derived mediators and complement factors may
cause adhesions of the leukocytes to the
endothelial walls, thereby immobilizing them
and stimulating degranulation of neutrophils. As
a result oxidants and inflammatory mediators are
released, resulting in injury to the tissues. Oral
administration of purified micronized flavonoids
fraction was reported to decrease the number of
immobilized leukocytes during reperfusion,
which may be related to its protective
mechanism against inflammatory conditions26.
Modulation of gene expression:
Recent studies indicate that the radical
scavenger property of Quercetin is unlikely to be
the sole explanation for their neuroprotective
capacity and in fact, a wide spectrum of cellular
signaling events may well account for their
biological actions27.
Much recent interest has focused on the potential
of Quercetin to interact with intracellular
signaling pathways such as with the mitogen-
activated protein kinase cascade. The strong
neurotoxic potential of quercetin in primary
cortical neurons may occur via specific and
sensitive interactions within neuronal mitogen-
activated protein kinase and Akt/protein kinase B
(PKB) signaling cascades, both implicated in
neuroal apoptosis. Quercetin induced potent
inhibition of both Akt/PKB and ERK
phosphorylation, resulting in reduced
phosphorylation of BAD and a strong activation
of caspase-327.
Tumor necrosis factor alpha (TNF-α) is one of
the major proinflammatory cytokines involved in
the pathogenesis of chronic inflammatory
diseases and is modulated by oxidative stress28,29.
TNF-α also triggers the cellular release of other
cytokines, chemokines, or inflammatory
mediators and displays antiviral and
antimicrobial effects30,31,32. Quercetin
significantly inhibited TNF-α production and
gene expression in a dose-dependent manner. A
decrease in endogenous TNF-α production in the
presence of quercetin indicates that flavonoids
have the capacity to modulate the immune
response and have potential anti-inflammatory
activity. In addition to its well-known
proinflammatory role, TNF-α has complex
effects on the growth, differentiation, and death
of immune cells. TNF-α inhibition is a validated
approach to treat several inflammatory
diseases28. Quercetin-induced suppression of
TNF-α can result in the stimulation of anti-
inflammatory cytokines via inhibiting the
activation of NF-κβ, and therefore, one can
anticipate that quercetin could be widely used as
an anti-TNF-α therapy. Kaneuchi et al33
showed that quercetin has anti-proliferative
activity and the mechanisms of quercetin action
may be through modulation of cell cycle and cell
growth regulatory genes. Quercetin can suppress
proliferation of Ishikawa cells (endometrial
carcinoma) through down-regulation of EGF and
cyclin D1.
Interaction with other enzyme systems:
Quercetin interacts with calmodulin, a calcium
regulatory protein34. Calmodulin transports
calcium ion across cellular membranes, initiating
numerous cellular process. Quercetin appears to
act as calmodulin antagonist. Through this
mechanism, Quercetin functions at cell
membrane level with a membrane stabilizing
action35. Quercetin inhibits calmodulin
dependent enzyme present at cell membrane
such as ATPases and phospholipases thereby
influencing membrane permeability36. Quercetin
affects other calmodulin dependent enzymes that
control various cellular functions, including the
secretions of histamine from mast cells4. A
number of investigations have demonstrated the
ability of Quercetin, to reduce histamine
secretion from mast cells in various tissues and
also from basophils37-42. The enzyme inhibitory
action of Quercetin extends to phospholipases
which catalyses the release of arachidonic acid
from phospholipids stored in cell membranes.
Arachidonic acid serves as a key substrate for
substances such as thromboxane, inflammatory
prostaglandins and leukotrienes. In addition,
Quercetin also inhibits the enzymes
cyclooxygenase and Lipooxygenase which
catalyses the conversion of arachidonic acid to
its metabolites42,43,44. Reducing levels of these
metabolites as well as histamine levels, is
beneficial in maintaining the normal comfort
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level of body tissue and structures. Quercetin has
also been shown to limit the function of adhesion
molecules on endothelial cells45. Quercetin also
chelates ions of transition metals such as iron
which can initiate the formation of oxygen free
radicals46,47. Direct inhibition of lipid
peroxidation is another protective measures48.
PHARMACOKINETICS:
The metabolism and pharmacokinetics of
flavonoids has been an area of active research in
the last decade. To date, approximately 100
studies have reported the pharmacokinetics of
individual flavonoids in healthy volunteers. The
data indicate considerable differences among the
different types of dietary flavonoids so that the
most abundant flavonoids in the diet do not
necessarily produce the highest concentration of
flavonoids or their metabolites in vivo. Small
intestinal absorption ranges from 0 to 60% of the
dose and elimination half-life (T1/2) range from 2
to 28 h49.
Quercetin is generally believed to be poorly
absorbed. About 25 % of an injected dose of
quercetin is absorbed from small intestine.
Although a recent study by Hollman et al
concludes that humans absorb appreciable
amount of quercetin, contradicts the
assumption50. However, it is found in human
plasma as conjugates with glucuronic acid,
sulfate or methyl groups, with no significant
amounts of free quercetin. Quercetin was found
to reach 0.1-10 µmol/lit (micromole per liter) in
the circulation. The concentration of quercetin
was mainly due to the presence of quercetin
metabolites rather than its aglycon as recently
revised by Murota and Terao51. Regarding the
pharmacokinetics of quercetin glucosides
conjugates; it seems that the main determinant of
absorption of these conjugates is the nature of
the sugar moiety. For example quercetin
glucoside is absorbed from small intestine,
whereas quercetin rutinosides is absorbed from
the colon after the removal of carbohydrate
moiety by bacterial enzymes. In addition to the
chemical form of the flavonol, the fat content of
the diet also influences oral bioavailability of
quercetin. Lesser et al investigated the influence
of dietary fat on oral bioavailability of quercetin.
According to the them, Quercetin bioavailability
from each diet was always higher from the
glucoside than from the aglycon but irrespective
of the chemical form applied, the bioavailability
of quercetin was also found to be higher in the
17% fat diet compared with the 3% fat diet (P <
0.05)52.
Studies have shown that Bromelain, an enzyme
derived from pineapple, enhances the absorption
of quercetin. Bromelain is a complex substance
largely composed of proteolytic enzymes.
Several studies have presented the evidence that
bromelain is a fibrinolytic agent53, 54. Bromelain
is also known to have many of the same
histamine and Leukotriene-inhibitory properties
as quercetin. In this way they enhance each other
properties.
After getting absorbed in small intestine,
quercetin is transported to the liver via portal
circulation, where it undergoes first pass
metabolism. Quercetin and its metabolites are
distributed to various tissues in the body.
Quercetin is strongly bound to the albumin in
plasma. Peak plasma level reaches in 0.7 h to 7.0
hours following its ingestion. The elimination
half life of quercetin is approximately 25 hours55.
The elimination of quercetin was significantly
delayed after its application with fat-enriched
diets (P < 0.05)52.
ADVERSE DRUG REACTION:
Adverse effects reported with oral quercetin
include gastrointestinal effects such as nausea
and rare reports of headache and mild tingling of
the extremities. Oral quercetin is generally well
tolerated. Intravenous quercetin has been
associated with nausea, vomiting, diaphoresis,
flushing, and dyspnoea.
Safety Profile:
There is much controversy regarding the
purported toxic or even mutagenic properties of
quercetin. Formica and Regelson gave an
interesting overview of quercetin in vivo and in
vitro56. The early data on toxic side effects are
mainly derived from in vitro studies. At a
conference of the Federation of American
societies for experimental biology in 1984 on
mutagenic food flavonoids, carcinogenicity was
reported in just one out of 17 feeding studies
conducted in laboratory animals57, 58. Dunnick
and Hailey reported that high doses of quercetin
over several years might result in the formation
of tumors in mice59. However, back in the 1970s,
quercetin was found to have mutagenic activity
as determined by the in vitro Ames test, which
was developed by researcher Bruce Ames to test
if a natural or synthetic substance will cause
DNA mutations in bacteria60. However in other
long term study, no carcinogenicity was found61.
In contrast to earlier studies several more recent
reports indicate that quercetin is antimutagenic in
vivo56, 62, 63. A large clinical study by Knekt et
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al, in which 9959 men and women were
followed for 24 years, showed an inverse
relationship between the intake of quercetin and
lung cancer64. One possible explanation for these
conflicting data is that quercetin is toxic to
cancer cells or immortalized cells but not toxic to
normal cells. In other studies quercetin was also
recognized as genoprotective against mutagenic
agents65, 66. Review of the total body of available
data on quercetin as presented in several
published reviews indicates that quercetin,
although displaying mutagenic activity in vitro is
not carcinogenic in the body. In a number of
studies such as Formica and Regelson56,
Stavric58, Stoewsand67, and recently
Okamoto68, a review of quercetin safety based
on past animal toxicity studies, concluded that
orally administered quercetin is unlikely to cause
any adverse effects although specific dose levels
were not indicated.
CONTRAINDICATIONS AND
PRECAUTIONS:
Contraindication of Quercetin is not known.
Quercetin has been shown to cause chromosomal
mutations in certain bacteria in test tube studies.
However the significance of this finding for
humans is not clear Because of lack of the
availability of long term safety data, quercetin
should be avoided by pregnant women and
nursing mothers.
DRUG INTERACTIONS:
Quercetin shows interaction with following
drugs:
Felodipine:
Quercetin (found in grapefruit juice, tea, onions,
and other foods) has been shown in test tube
studies to inhibit enzymes responsible for
breaking down of Felodipine into inactive forms.
This interaction may result in increased blood
levels of felodipine that could lead to unwanted
side effects69. Until more is known about this
interaction, patients taking felodipine should
avoid supplementing with quercetin. Regular
consumption of grapefruit juice can increase the
quantity of felodipine in the blood by reducing
the breakdown of the drug. The inhibitory effect
of grapefruit juice lasts up to 24 hours after
ingestion and can increase the blood levels
nearly three times the expected amount. In order
to prevent the side effects, individuals taking
felodipine should avoid consuming grapefruits
and its juice70.
Estrogens:
Studies have shown that grapefruit juice
significantly increases estradiol levels in the
blood71,72. One of the flavonoids found in
grapefruit juice is Quercetin. In a test tube study,
quercetin was found to change estrogen
metabolism in human liver cells in a way that it
increases estradiol level and reduces other forms
of estrogens72. However the levels of quercetin
used to alter estrogen metabolism in the test tube
were much higher than the levels found in the
body after supplementing with quercetin.
In a small controlled study of women with
surgically removed ovaries, estradiol levels in
the blood were significantly higher after taking
estradiol with grapefruit juice than when
estradiol was taken alone71. These results have
independently confirmed that women taking oral
estradiol should probably avoid grapefruits
altogether72.
Cyclosporine:
In a randomized study of nine adults with
cyclosporine treated auto-immune diseases,
grapefruit juice causes a significant increase in
cyclosporine blood levels compared with
cyclosporine with water74. In another study by
healthy human volunteers, supplementing
quercetin along with cyclosporine significantly
increased blood level of cyclosporine compared
to when not taken quercetin75.
Quinolones:
Quercetin binds in vitro with DNA gyrase site in
bacteria. Therefore theoretically it can serve as
competitive inhibitor to the Quinolones, which
also bind to the same site76.
Cisplatin:
Because of the theoretical risk of genotoxicity in
normal tissues, in those using cisplatin along
with quercetin, cisplatin users should avoid
quercetin supplements.
Doxorubicin:
Test tube and animal studies suggest that
quercetin may enhance the effect of doxorubicin.
Digoxin:
Treatment with both Digoxin and Quercetin may
result in large amounts of digoxin in blood,
which may cause more side effects of digoxin
than usual. This interaction has been reported in
animals, but how it affects people, is unclear80.
DIETARY SOURCES:
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29
Fruits and vegetables particularly citrus fruits,
apples, onions, parsley, tea, red wine, etc. are the
primary dietary sources of Quercetin. Olive oil,
grapes, dark cherries, and dark berries such as
blueberries and bilberries are also high in
flavonoids including quercetin.
Studies were conducted on the Flavonoids
(Myricetin, Quercetin, Kaempferol, Luteolin and
Apegenin) contents of 62 edible tropical plants.
The highest total flavonoids contents were found
in onion leaves (1497 mg/Kg Quercetin, 391
mg/kg Luteolin and 832 mg/kg Kaempferol)
followed by semambu leaves, bird chillies, black
tea, papaya shoots and guava. Major flavonoids
content in these plant extract is quercetin,
followed by myricetin, and kaempferol. In
vegetables quercetin glycosides predominate but
glycosides of kaempferol, luteolin and apigenin
are also present. Fruits contain almost
exclusively quercetin glycosides, whereas
kaempferol and myricetin glycosides are found
only in trace quantities78. Table-2 shows
contents of Quercetin, Myricetin and Kaempferol
in selected food79.
Table 2: Amount of Quercetin in selected food79
FOOD Quercetin
mg/100g Myricetin
mg/100g Kaempferol
mg/100g
Broccoli, Raw 2.8 0.0 6.3
Carrots, Raw 0.4 0.0 0.0
Celery, Raw 3.5 ---- ----
Cocoa powder, Unsweetened 20.1 ---- ----
Cranberries, Raw 14.0 4.3 0.1
Kale, Raw 5.1 0.0 14.6
Lettuce, Looseleaf, Raw 2.0 0.0 0.0
Lingonberries, Raw 11.3 0.0 0.0
Onions, Raw 22.6 0.0 0.3
Tomatoes, Red ripe, Raw 0.5 0.0 0.1
In another study, content of quercetin was
estimated in 25 edible berries. Sixteen species of
cultivated berries and nine species of wild berries
were collected in Finland in 1997. Quercetin was
found in all the berries such as bog whortleberry
(158 mg/kg fresh weight), lingon berry (74 and
146 mg/kg), cranberry (83 and 121 mg/kg),
chokeberry (89 mg/kg), sweet rowan (85 mg/kg),
rowanberry (63 mg/kg), sea buckthorn berry (62
mg/kg) and crowberry (53 and 56 mg/kg)80.
Onions (Allium cepa L) ranked highest in
quercetin content in a survey of 28 vegetables
and 9 fruits81, 82. Quercetin levels tend to be
highest in red and yellow onions and lowest in
white onions83, 84. Amount of quercetin in onions
vary with bulb color type and variety. Regardless
of onion bulb pigmentation, quercetin
concentration is highest in the outer rings85, 86.
However in another study, more than 60 fresh
fruits, vegetables, and nuts were collected from
four regions across the United States at two
times of the year. Sample collection was
designed and implemented by the Nutrient Data
Laboratory (USDA), using a hydrolysis method
for the anthocyanidins, flavones, and flavonols
and a direct extraction method for the flavan-3-
ols and flavanones. This study showed that the
variation in the flavonoid content of foods, as
purchased by the U.S. consumer, is very large.
The relative standard deviation, averaged for
each flavonoid in each food, was 168%87.
THERAPEUTIC USES:
Quercetin offers a variety of potential therapeutic
uses primarily in the prevention and the
treatment of the conditions listed below.
Quercetin seems to work better when it is used in
conjunction with bromelain, a digestive enzyme
found in pineapple.
Allergies, asthma, hay fever and hives:
Quercetin might be useful in some of the
allergies such as hay fever, hives. It inhibits the
production and release of histamine and other
allergic/inflammatory substances possibly by
stabilizing cell membranes of mast cells86,88.
Mast cells have been proposed as an immune
gate to the brain, as well as sensors of
environmental and emotional stress, and are
likely involved in neuropathologic processes
Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
such as multiple sclerosis. Among mast cell
products, the protease tryptase could be
associated with neurodegenerative processes
through the activation of specific receptors
(PARs) expressed in the brain, while interleukin
(IL)-6 likely causes neurodegeneration and
exacerbates dysfunction induced by other
cytokines; or it could have a protective effect
against demyelinisation. In the year 2006 a study
conducted by Kempuraj et al showed that
quercetin, a natural compound able to act as an
inhibitor of mast cell secretion, causes a decrease
in the release of tryptase and IL-6 and the down-
regulation of histidine decarboxylase (HDC)
mRNA from human mast cell (HMC)-1. As
quercetin dramatically inhibits mast cell tryptase,
IL-6 release and HDC mRNA transcription by
HMC-1 cell line, these results nominate
quercetin as a therapeutical compound in
association with other therapeutical molecules
for neurological diseases mediated by mast cell
degranulation89.
Antibacterial activity:
Quercetin seems to exert antibacterial activity
against almost all the strains of bacteria known
to cause respiratory, gastrointestinal, skin and
urinary disorders90.
Arthritis:
Quercetin inhibits both cyclo-oxygenase and
lipo-oxygenase activities thus diminishing the
formation of inflammatory mediators91,92. In
addition there are reports of people with
rheumatoid arthritis, who experienced an
improvement in their symptoms, when they
switched from a typical western diet to a vegan
diet with lots of uncooked berries, fruits,
vegetables containing amongst other
antioxidants, quercetin93.
Cancers:
Although the etiology of cancer may be
multifactorial (e.g. diet, genetic, environment),
there is wide recognition that reactive oxygen
and nitrogen species (ROS/RNS) play a pivotal
role in the pathophysiological process.
ROS/RON have been shown to be carcinogenic
and may exert their deleterious effects by
causing DNA damage, alter cell signaling
pathways (MAPK, NFkB, AP-1, PLA, ASK-1)
and modulate gene expression (proto-oncogene,
tumour suppressor gene). The evidence from in
vitro and in vivo laboratory studies, clinical trials
and epidemiological investigations show that
plant-based diets have protective effects against
various cancers. Indeed it has been suggested
that about 7-31% of all cancers could be reduced
by diets high in fruits and vegetables94.
In various animal and test tube studies, quercetin
has been shown to inhibit the growth of cancer
cells including those from breast, colon, prostate
and lung cancers63. Quercetin by virtue of its
anti-oxidant property prevents reactive oxygen
species induced DNA damage, leading to
mutational changes. A large clinical study
suggested the presence of an inverse association
between quercetin intake and subsequent
incidence of lung cancers64. In the study done by
Caltagirone et al, quercetin showed the
inhibitory effect on the growth of melanoma and
also influenced the invasive and metastatic
potential in mice95. The bioflavonoid quercetin
may be a potent alternative to reduce cisplatin
induced nephrotoxicity96. Furthermore quercetin
seems to inhibit angiogenesis97. Angiogenesis is
normally a strictly controlled process in the
human body. Pathological, unregulated
angiogenesis occurs in cancers98. Among the
angiogenesis inhibitors quercetin seems to play
an important role99. However the mechanism
behind the anti-angiogenic effect of flavonoids is
unclear. A possible mechanism could be the
inhibition of protein kinase100. As many of the
PTKs are oncogenes, this raised the possibility of
quercetin being an effective anti-cancer
compound. Quercetin was effective in inhibiting
radiation-induced PKC activity. Activation of
PKC is one of the means of conferring
radioresistance on a tumour cell. Suppression of
PKC activity by Quercetin may be one of the
means of preventing the development of
radioresistance following radiotherapy101.
Coronary Heart Diseases:
Anti-oxidant quercetin intake protects against
coronary heart disease (CHD), caused by
oxidized LDL (bad cholesterol). Hertog et al
stated that regular consumption of flavonoids in
the food might reduce the risk of deaths from
CHD in elderly men102,103. Furthermore a
Japanese study reported an inverse correlation
between quercetin intake and total plasma
cholesterol concentration104. Quercetin was also
shown to be effective inhibitor of platelets
aggregation in dogs and monkeys105. The main
antiplatelet aggregating effect is because of the
inhibition of thromboxane A2106. Quercetin
inhibits the proliferation and migration of aortic
smooth muscle cells, and platelet aggregation
along with the inhibition of mitogen–activated
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protein kinase phosphorylation. These findings
provide new insights and a rationale for the
potential use of quercetin in the prevention of
cardiovascular diseases107.
Diabetic complications:
Quercetin has been found to be an inhibitor of
the enzyme aldose reductase, which plays a role
in converting glucose (sugar) to sorbitol (a sugar
alcohol) in the body. People with diabetes
develop secondary problems, such as
neuropathy, retinopathy, diabetic cataracts, and
nephropathy because of sorbitol buildup in the
body. Quercetin may therefore be beneficial in
the nutritional management of diabetes, but
clinical studies need to be conducted to verify
these effects, which have been observed in non-
human experiments108.
Eye disorders:
Free radicals are thought to contribute the
development of certain disorders including
cataracts and macular degeneration. Quercetin
prevents and treats these eye conditions by
neutralizing these free radicals. In a study of
3,072 adults with the symptoms of macular
degeneration, moderate red wine consumption (a
source of quercetin) offered some protection
against the development and the progression of
the disease109. Regular consumption of dark
berries offers benefits for preventing macular
degeneration110.
Gout:
Quercetin by virtue of its xanthine oxidase
inhibitory nature prevents the production of uric
acid, thereby easing the gout symptoms24, 25.
Neurodegenerative disorders:
According to a study conducted by researchers at
Cornell University in New York, a potent
antioxidant (quercetin) in apples and in
vegetables appear to protect brain cells against
oxidative stress, a tissue damaging process
associated with Alzheimer and other
neurodegenerative disorders111. Quercetin seems
to protect the brain functions by inhibiting the
formation if fibrillated amyloid–beta, the senile
plaque found in Alzheimer’s brain106. An
experiment was performed to demonstrate the
possible effects of quercetin on cognitive
performance of young and aged, ethanol
intoxicated mice (animal model), where chronic
quercetin treatment had shown the reversal of
cognitive deficits112. Even though quercetin is
relatively stable during cooking, fresh apples are
always better sources of quercetin than cooked or
processed apples because the compound is
mainly concentrated in the skin of apples. In
general red apples tend have more of antioxidant
than green or yellow ones. Quercetin, through its
COMT and MAO enzymes inhibiting properties,
might potentiate the anticatabolic effect of L-
dopa plus carbidopa treatment. The results of the
present study strongly suggest that quercetin
could serve as an effective adjunct to L-dopa
therapy in Parkinson disease113. Quercetin has
potential for the treatment of neuroleptic-induced
extrapyramidal side effects, such as from
haloperidol114. Quercetin also is a powerful
antioxidant that may protect brain cells from
damage.
Osteoporosis:
In an English study, bone mineral density was
compared between elder women, who consumed
tea and those who did not. Women in the study,
who drank tea (quercetin), had higher bone
mineral density measurements than those who
did not drink tea. Quercetin in the tea might be
responsible for the prevention of osteoporosis115.
Peptic Ulcer:
Quercetin seems to play a very important role in
the prevention and treatment of peptic ulcer. It
acts by promoting mucus secretion, thereby
serves as gastroprotective agent. Apparently,
many peptic ulcers can be caused by infectious
bacteria, known as Helicobacter pylori.
Quercetin has been shown to inhibit the growth
of this bacterium in in-vitro studies116,117.
Prostatitis:
In a prospective double-blind placebo controlled
study, quercetin was found to be helpful in
category III chronic prostatitis (non bacterial
chronic prostatitis and prostodynia). Thirty men
with this disorder received either placebo or 500
mg of quercetin twice daily for one month.
Significant improvement was achieved in treated
group, as measured by the National Institute of
Health Chronic Prostatitis score118. In a follow
up unblind open study, additional men received
the same amount of quercetin for one month, but
this time quercetin was combined with bromelain
and papain, which may enhance its absorption. In
this study 82% achieved a minimum 25%
improvement score.
Viral infections:
The antiviral effect of Flavonoid was shown in a
study conducted by Wang et al119. Some of the
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viruses reported to be affected by Flavonoids are
herpes simplex virus, respiratory syncitial virus
and adenovirus. Quercetin was reported to
exhibit both anti-infective and antireplicative
abilities. By far most of the studies were
performed in vitro and little is known about the
antiviral effect of flavonoids in vivo. There is
some evidence that flavonoids in their glycon
form seem to be more inhibitory effect on
rotavirus infectivity than flavonoids in their
aglycon form120. Because of the worldwide
spread of HIV, since 1980s, the investigations of
the antiviral activity of flavonoids have mainly
focused on HIV. The discovery and the
development of flavonoids as anti-HIV agents
have expanded in the past two decades. Most of
the studies focused on the inhibitory activity of
reverse transcriptase or RNA directed DNA
polymerase but antiintegrase and antiprotease
activities were also reported. Flavonoids have
mainly been studied in vitro experiments;
therefore no clear contribution of flavonoids to
the treatment of HIV infected patients has yet
been shown121, 122.
PREPARATION AND DOSAGES:
The average diet can supply 15 to 40mg of
quercetin per day from fruit and vegetable
consumption. Increasing quercetin intake for
general health reasons can be accomplished by
simply eating more vegetables and fruit.
However, as most people are confronted with the
reality of not being able to maintain an adequate
intake of bioflavonoid from food sources, extra
quercetin can be obtained from dietary
supplements. For therapeutic purposes such as
allergy management, anti-inflammatory
treatment, and disease treatment, higher dosages
of quercetin are usually prescribed. Therapeutic
dosages can range from 250 to 500mg three
times per day. Quercetin is available in the form
of capsules (250 mg, 300 mg, and 500mg) and
tablets (50 mg, 250 mg, and 500mg).
Recommended adult dosages of quercetin vary
depending on the health condition being treated.
For allergic conditions, 250-600 mg per day in
divided doses and for chronic hives, 200-400 mg
thrice daily quercetin is recommended123.
FUTURE IMPLICATIONS:
Various cohort studies indicated an inverse
association between Flavonoids intake
(Quercetin) and coronary heart disease mortality.
These studies are promising and indicate that
flavonoids may be useful food compounds.
Flavonoids have received much attention in the
literature over the past 10 years and a variety of
potential beneficial effects have been elucidated.
However, most of the studies have been
conducted in vitro studies; therefore, it is difficult
to draw definite conclusion about the usefulness
of flavonoids in the diet. Furthermore,
insufficient methods are available to measure
oxidative damage in vivo and the measurement
of objective endpoints remains difficult.
Although recently some studies124,125,126 have
been conducted on absorption and excretion of
flavonols including quercetin but there is a need
to improve analytic techniques to allow
collection of more data in this aspect. Data on
the long-term consequences of chronic quercetin
ingestion are especially scarce. To conclude, in-
vivo studies could be performed to give a hopeful
picture for the future. Currently, the intake of
fruit, vegetables, and beverages (e.g., tea and
moderate amounts of red wine) containing
quercetin is recommended, although it is too
early to make recommendations on daily
quercetin intakes.
REFERENCES:
1. Middleton EJ. Effect of plant flavonoids on
immune and inflammatory cell functions.
Adv Exp Med Biol 1998;439:175-182.
2. De Groot H, Rauen U. Tissue injury by
reactive oxygen species and the protective
effects of flavonoids. Fundam Clin
Pharmacol 1998;12:249-55.
3. Narayana K Raj, Reddy M Sripal, Chaluvadi
MR, Krishna DR. Bioflavonoids
classification, pharmacological, Biochemical
effects and therapeutic potential. Indian
Journal of pharmacology 2001;33:2-16.
4. Molecular structures of major classes of
flavonoids retrieved from
http://www.emolecules.com/cgi-bin/search
5. Havsteen B. Flavonoids: A class of natural
products of high pharmacological potency.
Biochem Pharmacol 1983;32:1141-8.
6. Middleton E. The Flavonoids. Trends
Pharmacol Sci 1984;5:335-8.
7. Murphy Karen J, Chronopoulos Andriana K,
Singh I, el al. Dietary flavanols and
procyanidin oligomers from cocoa
(Theobroma cacao) inhibit platelet function.
American Journal of Clinical Nutrition
2003;77(6):1466-73.
8. Moskuag JO, Carlson H, Myhrstad M, et al.
Molecular Imaging of the biological effects
of Quercetin and Quercetin-rich foods.
Mechanism of Ageing and Development
2004;125:315-24.
32
Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
9. De Groot H. Reactive oxygen species in
tissue injury. Hepatogastroentrology
1994;41:328-32.
10. Grace PA. Ischemia-reperfusion injury. Br J
surg 1994;81:637-47.
11. Halliwell B. How to characterize an
antioxidant: an update. Biochem soc symp
1995;61:73-101.
12. Bahorun T, Soobrattee MA, Luximon-
Ramma V, Aruoma OI. Free Radicals and
Antioxidants in Cardiovascular Health and
Disease. Internet Journal of Medical
Update 2006 Jul-Dec;1(2):
http://www.geocities.com/agnihotrimed/pap
er05_jul-dec2006.htm
13. Wegener T, Fintelmann V. Flavonoids and
Bioactivity. Wein Med Wochem Schr
1999;149:241-7.
14. Ares JJ, Outt PE. Gastroprotective agents for
the prevention of NSAID- induced
gastropathy. Curr Pharm Des 1998;4:7-36.
15. Santos AC, Vyemura SA, Lopes JL, et al.
Effect of naturally occurring flavonoids on
lipid peroxidation and membrane
permeability transition in mitochondria.Free
Radic Biol Med 1998;24:1455-61.
16. Halliwell B. Free radicals, antioxidants and
human disease: curiosity, cause or
constipation? Lancet 1994;344:721-4.
17. Fraga CG, Mactino US, Ferraro GE, et al.
Flavonoids as antioxidants evaluated by in
vitro and insitu liver chemiluminescence.
Biochem Med Metabol BioI 1987;36:717-20.
18. Kerry NL, Abbey M. Red wine and
fractionated phenolic compounds prepared
from red wine inhibits low density
lipoprotein oxidation in vitro.
Atherosclerosis 1997;135:93-102.
19. Shoskes DA. Effect of bioflavonoid
quercetin and curcumin on ischaemic renal
injury: a new class of renoprotective agent.
Transplantation 1998;66:147-52.
20. Huk I, Brovkovych V, Nanobash VJ, et al.
Bioflavonoid quercetin scavenges
superoxide and increase nitric oxide
concentration in ischemia-reperfusion
injury: an experimental study. Br J surg
1998;85:1080-5.
21. Shutenko Z, Henry Y, Pinard E, et al.
Influence of antioxidant quercetin in vivo on
the level of nitric oxide determined by
electron paramagnetic resonance in rat brain
during global ischemia and reperfusion.
Biochem Pharmacol 1990;57:199-208.
22. Van Acker SA, Tromp MN, Haenen GR, et
al. Flavonoids as scavengers of nitric oxide
radical. Biochem Biophys Res Commun
1995;214:755-9.
23. Santrueza J, Valdes J, campos R, et al.
Changes in xanthine
dehydrogenase/xanthine oxidase ratio in the
rat kidney subjected to ischemia-reperfusion
stress: Preventive effect of some flavonoids.
Res commun chem. Pathol pharmacol
1992;78:211-8.
24. Chang WS, Lee YJ, Leu FJ, Chiang HC.
Inhibitory effects of Flavonoids on xanthine
oxidase. Anticancer Res 1993;13:2165-70.
25. Iio M, Ono Y, kai S, Fukumoto M. Effects
of flavonoids on xanthine oxidase as well as
on cytochrome C reduction by milk xanthine
oxidase. J Nutr Sci Vitaminol (Tokyo)
1986;32:635-42.
26. Friesenecker B, Tsai AG, Allegra C,
Intaglietta M. Oral administration of purified
micronized flavonoid fraction suppresses
leukocyte adhesion in ischemia reperfusion
injury: in vivo observation in the hamster
skin fold. Int J microcir clin Exp 1994;
14:50-5.
27. Silvia Mandel, Orly Weinreb, Tamar Amit,
et al. Cell signaling pathways in the
neuroprotective actions of the green tea
polyphenol (-)-epigallocatechin-3-gallate:
implications for neurodegenerative diseases
Journal of Neurochemistry 2004;88:1555-
69.
28. Calamia KT. Current and future use of anti-
TNF agents in the treatment of autoimmune,
inflammatory disorders. Adv. Exp. Med. Biol
2003;528:545-9.
29. Taylor PC, Williams RO, Feldmann M.
Tumour necrosis factor alpha as a
therapeutic target for immune-mediated
inflammatory diseases. Curr. Opin.
Biotechnol. 2004;15:557-63.
30. Aggarwal BB. Tumour necrosis factor
receptor associated signaling molecules and
their role in activation of apoptosis. JNK and
NF-kappa B. Ann. Rheum. Dis. 2000;59:6-
16.
31. Aggarwal BB, Samanta A, Feldmann M.
TNF-α, p. 413. In J. J. Oppenheim, M.
Feldman, S. K. Durum, T. Hirano, J. Vilcek,
and N. A. Nicola (ed.) Cytokine reference,
Vol 1, Academic Press, San Diego, Calif.
2001.
32. Wajant H, Henkler F, Scheurich P. The
TNF-receptor-associated factor family:
scaffold molecules for cytokine receptors,
kinases and their regulators. Cell. Signal.
2001;13:389-400.
33
Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
33. Kaneuchi M, Sasaki M, Tanaka Y, et al.
Quercetin regulates growth of Ishikawa cells
through the suppression of EGF and cyclin
D1. Int J Oncol. 2003 Jan;22(1):159-64.
34. Nishino H, Naitoh E, Iwashima A, et al.
Quercetin interacts with calmodulin, a
calcium regulatory protein. Experientia
1984;40:84-5.
35. Buss WW, Kopp DE, Middleton E.
Flavonoids modulation of human neutrophil
function. Allergy Clin Immunol
1984;73:801-9.
36. Havsteen B. Flavonoids, a class of natural
products of high pharmacological potency.
Biochemical pharmacology 1983;32(7):141-
48.
37. Otsuka H. Histochemical and functional
characteristics of metachromatic cells in the
nasal epithelium in allergic rhinitis. Studies
of nasal scrapings and their dispersed cells. J
Allergy Clin Immunol 1995;96:528-36.
38. Fox CC, Wolf EJ, Kagey-Sobotka A, et al.
Comparison of human lung and intestinal
mast cells. J Allergy Clin Immunol
1988;81:89-94.
39. Pearce FL, Befus AD, Bienenstock J.
Mucosal mast cells III. Effects of quercetin
and other flavonoids on antigen induced
histamine secretion from rat intestinal mast
cells. J Allergy Clin Immunol 1984;73:819-
23.
40. Middleton E, Drzewiecki G, Krishnarao D.
Quercetin: an inhibitor of antigen induced
human basophil histamine release. Journal
of Immunology 1981;127 (2):546-50.
41. Bennett JP, Gomperts BD, Wollenweber E.
Inhibitory effects of natural flavonoids on
secretion from mast cell and neutrophils.
Arzneim. Forsch/Drug Res. 1981;31(3):433-
7.
42. Middleton E, Drzewiecki G. Naturally
occurring flavonoids and human basophil
histamine release. Int Arch Allergy Appl
Immun 1985;77:155-7.
43. Yoshimoto T, Furukawa M, Yamamoto S, et
al. Flavonoids: potent inhibitors of
arachidonate 5-lipoxygenase. Biochemical
and biophysical research communications
1983;116(2):612-18.
44. Della Loggia R, Ragazzi E, Tubaro A et al.
Anti-inflammatory activity of Benzopyrones
that are inhibitors of cyclo and
lipoxygenase. Pharmacological research
communications 1988;20 (suppl V):91-94.
45. Middleton E, Suresh A. Quercetin inhibits
lipopolysaccharide induced expression of
endothelial cell intracellular adhesion
molecule-1. Int Arch Allergy Immunol
1995;107:435-6.
46. Afanas’ev IB, Dorozhko AI, Brodskii
A V , e t a l . Chelating and free radical
scavenging mechanisms of inhibitory action
of rutin and quercetin in lipid peroxidation.
Biochemical Pharmacology
1989;38(11):1763-69.
47. Ferrali M, Signorini C, Caciotti B, et al.
Protection against oxidative damage of
erythrocyte membrane by the flavonoid
quercetin and its relation to iron chelating
activity. FEBS Lett 1997;416:123–9.
48. Sorata Y, Takahama U, Kimura M.
Protective effect of quercetin and rutin on
photosensitized lysis of human erythrocytes
in the presence of hematoporphyrin.
Biochim Biophys Acta 1984;799:313–7.
49. Manach C, Donavan J. Pharmacokinetics
and metabolism of Dietary Flavonoids in
humans. Free Radical Research
2004;38:771-785.
50. Hollman PC, de Vries JH, Van Leeuwen
SD, et al. Absorption of dietary quercetin
glycosides and quercetin in healthy
ileostomy volunteers. Am J Clin Nutr
1995;62:1276-1282.
51. Murota K, Terao J. Antioxidative Flavonoid
quercetin: Implication of its intestinal
absorption and metabolism. Arch Biochem
Biophys 2003;417:12-17.
52. Lesser S, Cermak R, Wolffram S.
Bioavailability of quercetin in pigs is
influenced by the dietary fat content. J Nutr.
2004 Jun;134(6):1508-11.
53. Taussig SJ. The mechanism of the
physiological action of bromelain. Medical
Hypothesis 1980;6:99-104.
54. Ako H, Cheung AHS, Matsuura PK.
Isolation of a fibrinolysis activator from
commercial bromelain. Arch. Int.
Pharmacodyn. 1981;284:157-67.
55. Young JF, Nielsen SE, Haraldsdottir J, et al.
Effect of fruit juice intake on urinary
quercetin excretion and biomarkers of
antioxidative status. Am J Clin Nutr
1999;69:87-94.
56. Formica JV, Regelson W. Review of the
biology of quercetin and related
bioflavonoid. Food Chem Toxicol
1995;33:1061–80.
57. Ertrurk E, Hatcher JF, Pamukeu AM.
Bracken fern. Carcinogenesis and quercetin
(abstr). Fed Proc 1984;43:2344.
34
Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
58. Starvic B. Quercetin in our diet: from potent
Mutagen to probable anticarcinogen. Clin
Biochem. 1984;43:2344.
59. Dunnick JK, Hailey JR. Toxicity and
carcinogenicity studies of quercetin, a
natural component of foods. Fundam Appl
Toxicol 1992;19:423–31.
60. Bjeldanes LF, Chang GW. Mutagenic
activity of quercetin and related compounds.
Science 1997:577-8.
61. Zhu BT, Ezell ET, Liehr JG. Catechol-o-
methyl transferase catalysis rapid O-
methylation of mutagenic flavonoids.
Metabolic inactivation as a possible reason
for their lack of carcinogenicity in vivo. J
Biol Chem 2001;269:292–9.
62. Kato K, Mori H, Fujii M, et al. Lack of
promotive effect of quercetin on
methylazoxymethanol acetate
carcinogenesis in rats. J Toxicol Sci
1984;9:319–25.
63. Plakas SM, Lee TC, Wolke RE. Absence of
overt toxicity from feeding the flavonol,
quercetin, to rainbow trout (Salmo
gairdneri). Food Chem Toxicol
1985;23:1077–80.
64. Knekt P, Jarvinen R, Seppanen R, et al.
Dietary flavonoids and the risk of lung
cancer and other malignant neoplasms. Am J
Epidemiol 1997;146:223–30.
65. Beyer G, Melzig MF. Effects of selected
flavonoids and caffeic acid derivatives on
hypoxanthine-xanthine oxidase-induced
toxicity in cultivated human cells. Planta
Med 2003;69:1125-9.
66. Underger U, Aiding S, Basaran AA, Basaran
N. The modulating effects of quercetin and
rutin on the mitomycin C induced DNA
damage. Toxicol Lett 2004;151:143-9.
67. Stoewsand GS, Anderson JL, Boyd JN,
Hrazdina G. Quercetin: a mutagen, not a
carcinogen in Fischer rats. J Toxicol Environ
Health 1984;14:105–14.
68. Okamoto T. Safety of quercetin for clinical
application (Review). Int J Mol Med. 2005
Aug;16(2):275-8.
69. Miniscalco A, Lundahl J, Regardh CG.
Inhibition of dihydropyridine metabolism in
rat and human liver microsomes by
flavonoids found in grapefruit juice. J
Pharmacol Exp Ther 1992;261:1195-9.
70. Bailey DG, Malcolm J, Arnold O, Spence
JD. Grapefruit juice-drug interactions. Br J
Clin Pharmacol 1998;46:101-10.
71. Schubert W, Cullberg G, Edgar B, Hedner
T. Inhibition of 17 beta-estradiol metabolism
by grapefruit juice in ovariectomized
women. Maturitas 1994;20:155-63.
72. Weber A, Jager R, Borner A, et al. Can
grapefruit juice influence ethinylestradiol
bioavailability? Contraception 1996;53:41-
7.
73. Schubert W, Eriksson U, Edgar B, et al.
Flavonoids in grapefruit juice inhibit the in
vitro hepatic metabolism of 17 beta-
estradiol. Eur J Drug Metab Pharmacokinet
1995;3:219-24.
74. Ioannides-Demos LL, Christophidis N, Ryan
P, et al. Dosing implication of a clinical
interaction between grapefruit juice and
cyclosporine and metabolite concentrations
in patients with autoimmune diseases. J
Rheumatol 1997;24:49-54.
75. Choi JS, Choi BS, Choi KE. Effect of
quercetin on the pharmacokinetics of oral
cyclosporine. Am J Health Syst Pharm
2004;61:2406-9.
76. Hilliard JJ, Krause HM, Bersstein JJ, et al. A
comparison of active site binding of 4-
quinolones and novel flavone gyrase
inhibitors to DNA gyrase. Adv Exp Med
Biol.1995;390:59-69.
77. Wang Y-H, Chao P-D L, Hsiu S-L, et al:
Lethal quercetin-digoxin interaction in pigs.
Life Sci 2004;74:1191-7.
78. Miean KH, Mohamed S. Flavonoids
(Myricitin, Quercetin, Kaempferol, Luteolin
and Apigenin) contents of edible tropical
plants. J Agric Food Chem 2001;49
(6):3106-12.
79. Mangels AR, Holden JM, Beecher GR, et al.
Caretenoide contents of fruits and
vegetables: an evaluation of analytical data.
Am Diet. Assoc 1993;93:284-296.
80. Häkkinen S, Kärenlampi S, Heinonen M, et
al. Content of the flavonols quercetin,
myricetin, and kaempferolin 25 edible
berries. J Agric Food Chem. 1999
Jun;47(6):2274-9.
81. Herrmann K. Flavonols and flavones in food
plants: a review. Journal of Food
Technology 1976;11:433-448.
82. Hertog MGL, Hollman PCH. Potential
health effects of the dietary flavonol
quercetin. Euro. J. of Clin. Nutr 1996;50:63-
71.
83. Patil BS, Pike LM, Yoo KS. Variation in the
quercetin content in different colored onions
(Allium cepa L.). Journal of the American
Horticulture Society 1995;120 (6):909-13.
84. Lombard KA, Geoffriau E, Peffley E.
Flavonoid quantification in onion (Allium
35
Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
cepa L.) by spectrophotometric and HPLC
analyses. Hort Science 2002;37(4):682-5.
85. Patil BS, Pike LM. Distribution of quercetin
content in different rings of various colored
onion (Allium cepa L.) cultivars. Journal of
Horticultural Sciences 1995;70(4):643-50.
86. Lombard KA. Investigation of the flavonol
quercetin in onion (Allium cepa L.) by high-
performance liquid chromatography (HPLC)
and spectrophotometric methodology. M.S.
Thesis. Journal of Food Composition and
Analysis 2005;18:635-45.
87. Harnly JM, Doherty RF, Beecher GR, et al.
Flavonoid content of U.S. fruits, vegetables,
and nuts. J Agric Food Chem. 2006 Dec
27;54(26):9966-77.
88. Thornhill SM, Kelly AM. Natural treatment
of perennial allergic rhinitis. Alt Med Rev.
2000;5(5):448-54.
89. Kempuraj D, Castellani ML, Petrarca C, et
al. Inhibitory effect of quercetin on tryptase
and interleukin-6 release, and histidine
decarboxylase mRNA transcription by
human mast cell-1 cell line. Clin Exp Med.
2006 Dec;6(4):150-6.
90. Rigano D, Formisano C, Basile A, et al.
Antibacterial activity of flavonoids and
phenylpropanoids from Marrubium
globosum ssp. libanoticum. Phytother Res.
2006 Dec 21;[Epub ahead of print].
91. Kim HP, Mani I, Iversen L, Ziboh VA.
Effects of naturally-occurring flavonoids
and bioflavonoids on epidermal
cyclooxygenase and lipoxygenase from
guinea-pigs. Prostaglandins Leukot Essent
Fatty Acids 1998;58:17–24.
92. Yoshimoto T, Furukawa M, Yamamoto S, et
al. Flavonoids: potent inhibitors of
arachidonate 5-lipoxygenase. Biochem
Biophys Res Commun 1983;116:612–8.
93. Hanninen, Kaartinen K, Rauma AL, et al.
Antioxidants in vegan diet and rheumatic
disorders. Toxicology. 2000;155(1-3):45-53.
94. Muhammad A, Soobrattee, Bahorun T,
Okezie I Aruoma. Chemopreventive actions
of plyphenolic compounds in cancer.
BioFactors 2006;27:19-35.
95. Caltagirone S, Rossi C, Poggi A, et al.
Flavonoids apigenin and quercetin inhibit
melanoma growth and metastatic potential.
Int J Cancer 2000;87:595–600.
96. Heloísa D, Coletta Francescato, Terezila M,
et al. Protective effect of quercetin on the
evolution of cisplatin –induced acute tubular
necrosis. Kidney & Blood Pressure
Research 2004;27:148-158
97. Fotsis T, Pepper MS, Aktas E, et al.
Flavonoids, dietary-derived inhibitors of cell
proliferation and in vitro angiogenesis.
Cancer Res 1997;57:2916-21.
98. Fan TP, Jaggar R, Bicknell R. Controlling
the vasculature: angiogenesis, anti-
angiogenesis and vascular targeting of gene
therapy. Trends Pharmacol Sci 1995;16:57-
66.
99. Paper DH. Natural products as angiogenesis
inhibitors. Planta Med 1998;64:686-95.
100. Oikawa T, Shimamura M, Ashino H, et al.
Inhibition of angiogenesis by staurosporine,
a potent protein kinase inhibitor. J Antibiot
(Tokyo) 1992;45:1155-1160.
101. Varadkar P, Dubey P, Krishna M, et al.
Modulation of radiation-induced protein
kinase C activity by phenolics. J. Radiol.
Prot. 2001;21:361-70.
102. Hertog MG, Kromhout D, Aravanis C, et al.
Flavonoid intake and long-term risk of
coronary heart disease and cancer in the
seven countries study. Arch Intern Med
1995;155:381–6.
103. Hertog MG, Feskens EJ, Hollman PC, et al.
Dietary antioxidant flavonoids and risk of
coronary heart disease: the Zutphen Elderly
Study. Lancet 1993;342:1007–11.
104. Arai Y, Watanabe S, Kimira M, et al.
Dietary intakes of flavonols, flavones and
isoflavones by Japanese women and the
inverse correlation between quercetin intake
and plasma LDL cholesterol concentration. J
Nutr 2000;130:2243–50.
105. Osman HE, Maalej N, Shanmuganayagam
D, Folts JD. Grape juice but not orange or
grapefruit juice inhibits platelet activity in
dogs and monkeys. J Nutr 1998;128:2307–
12.
106. Tzeng SH, Ko WC, Ko FN, Teng CM.
Inhibition of platelet aggregation by some
flavonoids. Thromb Res 1991;64:91-100.
107. Hubbard GP, Wolffram S, de Vos R, et al.
Ingestion of onion soup high in quercetin
inhibits platelets aggregation and essential
components of collagen-stimulated platelet
activation pathway in man: A pilot study. Br
J Nutr. 2006 Sep;96(3):428-8.
108. Costantino L, Rastelli G, Gamberini MC, et
al. 1-Benzopyran -4-one antioxidant as
aldose reductase inhibitors. Med Chem
1999;42:1881-93.
109. Cai J, Nelson KC, Wu M, et al. Oxidative
damage and protection of the RPE. Prog
Retin Eye Res. 2000;19(2):205-21.
36
Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge
37
110. Head KA. Natural therapies for ocular
disorders. Part 1: diseases of the retina. Alt
Med Rev. 1999 Oct;5(4):342-59.
111. Heo HJ, Kim DO, Choi SJ, et al. Apple
Phenolics Protect in Vitro Oxidative Stress-
induced Neuronal Cell Death. J Food Sci
2004;69(9):S357-60.
112. Singh A, Naidu PS, Kulkarni SK. Reversal
of aging and chronic ethanol –induced
cognitive dysfunction by quercetin.a
bioflavonoid. Free Radic Res
2003;37(11):1245-52.
113. Singh A, Pattipati S .Quercetin potentiates
L-Dopa Reversal of Drug Induced Catalepsy
in Rats: Possible COMT/MAO inhibition:
Pharmacology 2003;68:81-88.
114. Naidu PS, Kulkarni SK. Quercetin, a
bioflavonoid, reverses haloperidol induced
catalepsy. Methods find Exp Clin
Pharmacol. 2004 Jun;26(5):323-6.
115. Hegarty VM, May HM, Khaw KT. Tea
drinking and bone mineral density in older
women. Am J Clin Nutr 2000;71:1003–7.
116. Martin MJ, La-Casa C, Alarcon-de-La-
Lastra C, et al. Antioxidant mechanism
involved in gastro protective effects of
quercetin. Z Naturforsch [C].1988;53:82-8.
117. Alarcon de La Lastra C, Martin MJ, Motilve
V. Antiulcer and gastroprotective effects of
quercetin: a gross and histological
study.Pharmacol.1994;48:56-62.
118. Shoskes DA, Zeitlin SI, Shahed A, Rajfer J.
Quercetin in men with category III chronic
prostatitis: a preliminary prospective,
double-blind, placebo-controlled trial.
Urology. 1999;54(6):960-3.
119. Wang HK, Xia Y, Yang ZY, et al. Recent
advances in the discovery and development
of flavonoids and their analogues as
antitumor and anti-HIV agents. Adv Exp
Med Biol 1998;439:191–225.
120. Bae EA, Han MJ, Lee M, Kim DH. In vitro
inhibitory effect of some flavonoids on
rotavirus infectivity. Biol Pharm Bull
2000;23:1122–4.
121. Vlietinck AJ, De Bruyne T, et al. Plant-
derived leading compounds for
chemotherapy of human immunodeficiency
virus (HIV) infection. Planta Med
1998;64:97-109.
122. Ng TB, Huang B, Fong WP, Yeung HW.
Anti-human immunodeficiency virus (anti-
HIV) natural products with special emphasis
on HIV reverse transcriptase inhibitors. Life
Sci 1997;61:933–49.
123. Werbach MR. Nutritional Influences on
Illness. 2nd ed. Tarzana, Calif: Third Line
Press. 1993.
124. Mullen W, Edwards CA, Crozier A.
Absorption, excretion and metabolite
profiling of methyl-, glucuronyl-, glucosyl-
and sulpho-conjugates of quercetin in
human plasma and urine after ingestion of
onions. Br J Nutr. 2006 Jul;96(1):107-16.
125. Aziz AA, Edwards CA, Lean ME, Crozier
A. Absorption and excretion of conjugated
flavonols, including quercetin-4’-O-beta-
glucoside and isorhamnetin-4’-O-beta-
glucoside by human volunteers after the
consumption of onions. Free Radic Res.
1998 Sep;29(3):257-69.
126. McAnlis GT, McEneny J, Pearce J.
Absorption and antioxidant effects of
quercetin from onions, in man. Eur J Clin
Nutr. 1999 Feb;53(2):92-6.
Internet Journal of Medical Update
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... Under the activity of the enzyme phenylalanine ammonialyase, a linking enzyme between the primary and secondary plant metabolism, L-phenylalanine is converted into trans-cinnamic acid. The latter is thereafter turned into p-coumaric acid in a reaction catalyzed by the enzyme cinnamate 4-hydroxylase, a cytochrome P450 monooxygenase in plants [22,33,[35][36][37][38]. Through the functional moiety carboxylic acid, the p-coumaric acid is ligated by the p-coumarate:CoA ligase to CoA, forming the intermediary product 4-coumaroyl-CoA. ...
... This reaction yields the essential A-and B-rings of the flavonoid skeleton ( Figure 1) as naringenin chalcone. For the construction of the heterocyclic C-ring, chalcone isomerase acts on naringenin chalcone yielding the flavanone naringenin [6,22,33,36,37]. Naringenin is further hydroxylated through flavanone 3βhydroxylase leading to the synthesis of dihydrokaempferol. ...
... Through a second consecutive hydroxylation reaction, dihydrokaempferol turns into dihydroquercetin with the help of the catalyst flavonol 3 -hydroxylase. Lastly, flavonol synthase acts on dihydroquercetin, yielding the final product in this synthesis, namely, the flavonol quercetin [22,33,36,37]. ...
Article
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Colorectal cancer (CRC) represents the third type of cancer in incidence and second in mortality worldwide, with the newly diagnosed case number on the rise. Among the diagnosed patients, approximately 70% have no hereditary germ-line mutations or family history of pathology, thus being termed sporadic CRC. Diet and environmental factors are to date considered solely responsible for the development of sporadic CRC; therefore; attention should be directed towards the discovery of preventative actions to combat the CRC initiation, promotion, and progression. Quercetin is a polyphenolic flavonoid plant secondary metabolite with a well-characterized antioxidant activity. It has been extensively reported as an anti-carcinogenic agent in the scientific literature, and the modulated targets of quercetin have been also characterized in the context of CRC, mainly in original research publications. In this fairly comprehensive review, we summarize the molecular targets of quercetin reported to date in in vivo and in vitro CRC models, while also giving background information about the signal transduction pathways that it up- and downregulates. Among the most relevant modulated pathways, the Wnt/β-catenin, PI3K/AKT, MAPK/Erk, JNK, or p38, p53, and NF-κB have been described. With this work, we hope to encourage further quests in the elucidation of quercetin anti-carcinogenic activity as single agent, as dietary component, or as pharmaconutrient delivered in the form of plant extracts.
... synthetized lipid-covered polymeric nanoparticles (NPs) and varied water content and rigidity but with the same chemical composition, size, and surface properties59 . They show that nanoparticles with a rigid lipid shell enter cells more easily than flexible ("soft") ones. ...
... The cellular uptake was 198 tested by incubating the vesicles with HELLA cells and human umbilical vein endothelial cells (HUVECs). Also, using MD simulations the authors show that the "soft" NPs are deformed and thus energetically unfavorable for cellular uptake59 . Yu et al. demonstrated, via both moleculardynamics simulations and super resolution microscopy, that liposomes with moderate rigidity displayed enhanced diffusivity through mucus and thus achieved an oral insulin delivery efficacy superior to that of both their soft and hard counterparts60 . ...
Thesis
Dans ce travail, nous avons mesuré la rigidité de liposomes blancs EggPC et de liposomes du même type encapsulant la quercétine. Ceci a été réalisé en mesurant le module d’Young à partir des courbes de forces en mode Force Spectroscopie de la Microscopie à Force Atomique AFM. En parallèle, nous avons calculé le module de flexion k_c des couches phospholipidiques qui imitent la formulation EggPC, tout en utilisant la Dynamique Moléculaire MD. Notre étude a été lancée suite à un large intervalle de valeurs rapportées dans la littérature au module de flexion k_c, calculées par différentes méthodes ou conditions, pour la même composition lipidique. A cet effet, nous avons mesuré la rigidité (module d’Young) des liposomes Egg PC en utilisant quatre types de sondes AFM : deux pointes de forme pyramidale et deux pointes de forme conique, chaque pointe est montée sur un levier ayant une constante de force 0,08 ou 0,32 N/m. Le traitement des courbes de forces obtenues, a été réalisé en utilisant aussi deux modèles mathématiques ; celui de Hertz ou de Shell. Les résultats ont montré que la forme de la pointe AFM, la constante de force du levier ainsi que le modèle mathématique choisi affectent la valeur mesurée de la rigidité en AFM. En Dynamique Moléculaire, nous avons utilisé la méthode de flambement, qui impose une optimisation préliminaire réalisée pour la boîte de simulation dans toutes les dimensions. Nous avons étudié ensuite la variation du module de flexion k_c en fonction de la composition d’une bicouche, contenant les phospholipides les plus courantes. Nous avons exploré la variation de kc en fonction de la composition des mélanges lipidiques : une série de mélanges contenant différentes phosphatidylcholines aussi bien que les phosphatidylcholines et le cholestérol. Nous avons constaté que dans le cas de mélanges homogènes, les valeurs de k_c peuvent être prédites à partir de la pondération moyenne des modules des deux composantes. Alors que dans le cas des mélanges à phases séparées, la rigidité apparente est plus proche de la valeur de la composante la plus molle. La comparaison entre les résultats mesurés par AFM et ceux calculés par la simulation MD pour le module d’élasticité k_c d’une part ainsi que la comparaison avec des mesures AFM de ce paramètre disponibles dans la littérature, nous a mené à des conditions expérimentales optimales de mesure. Dans ces mêmes conditions, nous avons abordé l’effet de la quercétine sur la rigidité d’une membrane. Nos observations AFM ont montré aucun effet de la quercétine sur la morphologie et la structure des liposomes mais les courbes de forces indiquent une diminution de la rigidité des vésicules contenant cette molécule. Des simulations numériques sur des membranes contenant des concentrations de quercétines respectives de 4, 8, 12 et 16% ont montré que les propriétés structurales et dynamiques de la membrane lipidique sont affectées par la présence de quercétine et varient en terme de concentration de quercétine dans la membrane. Quant à la rigidité de cette dernière, les calculs numériques ont montré comme dans le cas des mesures AFM, sa diminution relative au taux de quercétine présent dans la membrane. Dans une étape ultérieure, nous avons étudié par la microscopie AFM la stabilité des liposomes du type EggPC et examiné l’organisation des phospholipides E80 dans quatre solvants eutectiques profonds à base de ChCl (DES) et dans des solutions aqueuses de ces mêmes composants DES. Les observations AFM ont montré que les phospholipides ainsi que les liposomes peuvent être dissous dans les DES et ils peuvent s'auto-assembler conduisant à la formation de vésicules. Nous avons noté que la taille des liposomes réformés a diminué après leur exposition aux DESs. Des résultats similaires ont été obtenus en suivant l'effet de l'incubation de liposomes sphériques dans des solutions aqueuses des composants DESs au fil du temps.
... Besides, dietary polyphenols may strengthen the viscoelastic modulus of the mucus layer via mucin crosslink, thus, mucus layer stabilization (Georgiades et al., 2014;Guri et al., 2015). Further, it was suggested that polyphenols are immune regulators (Lakhanpal and Rai, 2007), but the mechanism by which polyphenol influences the secretion of mucin is not fully understood. There are reports which could indicate the initiation steps towards its secretion and up-regulation. ...
... Extensive in vivo studies have revealed the anti-inflammatory, antiviral, immunoprotective, and antioxidant effects of quercetin (Nair et al., 2002;Robaszkiewicz et al., 2007;Uchide and Toyoda, 2011;Colunga Biancatelli et al., 2020;Salehi et al., 2020). Studies have also shown quercetin as cardioprotective, anticancer, antitumor, antiulcer, antiallergy, antidiabetic, gastroprotective, antihypertensive, and anti-infective/antimicrobial agent (Lakhanpal and Rai, 2007;Salehi et al., 2020;Yang et al., 2020). Quercetin is also a broad-spectrum antiviral and has shown inhibitory activity against many viruses including HIV, herpes simplex virus (type 1 and 2), poliovirus (type 1), parainfluenza (type 3), hepatitis C virus, human respiratory syncytial virus, Sindbis virus, vaccinia virus, SARS-CoV-1, and SARS-CoV-2 (Andersen et al., 1991;Kim et al., 2001;Semple et al., 2001;Yi et al., 2004;Gonzalez et al., 2009;Abian et al., 2020;Lopes et al., 2020;Rizzuti et al., 2021;Bahun et al., 2022). ...
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Background: Curcumin, quercetin, and vitamin D3 (cholecalciferol) are common natural ingredients of human nutrition and reportedly exhibit promising anti-inflammatory, immunomodulatory, broad-spectrum antiviral, and antioxidant activities. Objective: The present study aimed to investigate the possible therapeutic benefits of a single oral formulation containing supplements curcumin, quercetin, and cholecalciferol (combinedly referred to here as CQC) as an adjuvant therapy for early-stage of symptomatic coronavirus disease 2019 (COVID-19) in a pilot open-label, randomized controlled trial conducted at Mayo Hospital, King Edward Medical University, Lahore, Pakistan. Methods: Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed, mild to moderate symptomatic COVID-19 outpatients were randomized to receive either the standard of care (SOC) ( n = 25) (control arm) or a daily oral co-supplementation of 168 mg curcumin, 260 mg quercetin, and 9 µg (360 IU) of cholecalciferol, as two oral soft capsules b.i.d. as an add-on to the SOC ( n = 25) (CQC arm) for 14 days. The SOC includes paracetamol with or without antibiotic (azithromycin). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR test, acute symptoms, and biochemistry including C-reactive protein (CRP), D-dimer, lactate dehydrogenase, ferritin, and complete blood count were evaluated at baseline and follow-up day seven. Results: Patients who received the CQC adjuvant therapy showed expedited negativization of the SARS-CoV-2 RT-PCR test, i.e., 15 (60.0%) vs. five (20.0%) of the control arm, p = 0.009. COVID-19- associated acute symptoms were rapidly resolved in the CQC arm, i.e., 15 (60.0%) vs. 10 (40.0%) of the control arm, p = 0.154. Patients in the CQC arm experienced a greater fall in serum CRP levels, i.e., from (median (IQR) 34.0 (21.0, 45.0) to 11.0 (5.0, 16.0) mg/dl as compared to the control arm, i.e., from 36.0 (28.0, 47.0) to 22.0 (15.0, 25.0) mg/dl, p = 0.006. The adjuvant therapy of co-supplementation of CQC was safe and well-tolerated by all 25 patients and no treatment-emergent effects, complications, side effects, or serious adverse events were reported. Conclusion: The co-supplementation of CQC may possibly have a therapeutic role in the early stage of COVID-19 infection including speedy negativization of the SARS-CoV-2 RT-PCR test, resolution of acute symptoms, and modulation of the hyperinflammatory response. In combination with routine care, the adjuvant co-supplementation of CQC may possibly help in the speedy recovery from early-stage mild to moderate symptoms of COVID-19. Further research is warranted. Clinical Trial Registration: Clinicaltrials.gov , identifier NCT05130671
... QRC is typically found in plants as glycone or conjugates of carbohydrates present in a wide variety of foods; most prominent are red and yellow onion, chili, broccoli, spinach, some flowers and in wine [24]. It may not be found naturally within blue corn, since something related was not found in any bibliography. ...
Article
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Phenolic compounds are secondary metabolites produced by plants, and their study has been increased in recent years due to their ability to improve human health. The aim of this work was the determination of phenolic compounds presents in blue corn flour before and after a fermentation process, where different proportions were used of blue corn (Zea mays L.) flour and Czapek Dox culture medium (90 mL of culture medium with 10 g of blue corn flour, 80 mL of culture medium with 20 g of blue corn flour and 70 mL of culture medium with 30 g of blue corn flour) and were fermented at 3 different times (20, 25 and 30 days) with the Colletotrichum gloeosporioides fungus. A determination of the phenolic compounds was carried out with five standard solutions, which were cyanidin 3-glucoside (CYA), pelargonidin 3-glucoside (PEL), chlorogenic acid (CLA), quercetin (QRC) and cinnamic acid (CA). The obtained results showed the presence of CA and PEL. The most abundant phenolic compound in the fermented samples was CLA over the naturally occurring compounds in blue corn, which are CYA and PEL. QRC was the phenolic compound with the lowest concentration in blue corn flour samples fermented with Colletotrichum gloeosporioides.
... Consequently, the decrease in absorbance observed is an indication of the extent of nitrite radical scavenging potentials [57] and this could be attributed to components such as flavonoids, as reported in previous studies [58,59]. Similarly, the aqueous acetone extracts of H. pandurifolium, H. foetidum H. petiolare, and H. cymocum can act as natural antioxidants with relative activities scavenging free radical species. ...
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Helichrysum Mill. (Asteraceae) is a plant genus comprising distinctively of aromatic plants of about 500–600 species. Since most of these plants have not been previously studied, extensive profiling helps to validate their folkloric uses and determine their potential value as sources of plant-derived drug candidates. This study, therefore, aims to investigate the antioxidant activity (DPPH, NO, FRAP); total antioxidant capacity, total phenolic, total flavonoid, and fatty acid compositions of the aqueous acetone extracts from four Helichrysum plants namely, Helichrysum pandurifolium, Helichrysum foetidum, Helichrysum petiolare, and Helichrysum cymocum. The results obtained showed that the H. cymocum extract had the best DPPH radical scavenging activity (IC50 = 11.85 ± 3.20 µg/mL) and H. petiolare extract had the best nitric oxide scavenging activity (IC50 = 20.81 ± 3.73 µg/mL), while H. pandurifolium Schrank extract (0.636 ± 0.005 µg/mL) demonstrated the best ferrous reducing power, all of which are comparable with results from ascorbic acid used as the standard. The IC50 values of the radical scavenging activity ranged from 11.85–41.13 µg/mL (DPPH), 20.81–36.19 µg/mL (NO), and 0.505–0.636 µg/mL (FRAP), for all the plants studied. The H. petiolare has the highest total antioxidant capacity (48.50 ± 1.55 mg/g), highest total phenolic content (54.69 ± 0.23 mg/g), and highest total flavonoid content (56.19 ± 1.01 mg/g) compared with other species. The fatty acid methyl esters were analysed using gas chromatography-mass spectrometry (GC-MS). The results obtained showed variations in the fatty acid composition of the plant extracts, with H. petiolare having the highest saturated fatty acid (SFA) content (7184 µg/g) and polyunsaturated fatty acid (PUFA) content (7005.5 µg/g). In addition, H. foetidum had the highest monounsaturated fatty acid (MUFA) content (1150.3 µg/g), while H. cymocum had the highest PUFA:SFA ratio of 1.202. In conclusion, the findings from this study revealed that H. pandurifolium Schrank, H. foetidum, H. petiolare, and H. cymocum are repositories of natural bioactive compounds with potential health-promoting benefits that need to be investigated, for both their antioxidant activity in a number of disease conditions and for further exploration in drug discovery and development projects.
... It is one of the most widely used dietary antioxidants and food supplements with potentially beneficial effects on health. It displays a variety of medicinal properties including anti-hypercholesterolemic, antihypertensive, antiinflammatory, vasodilator effects, anticancer, anti-obesity, anti-diabetic, gastroprotective effects, immunomodulatory and anti-infective (Amanzadeh et al., 2019;Anand David et al., 2016;Lakhanpal & Rai, 2007). Quercetin is regarded as a key molecule for brain health. ...
Article
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Among several neurodegenerative diseases, Huntington disease has posed a major threat across the world, particularly in the aged population. The disease is caused due to expansion of cytosine-adenine-guanine repeats which further triggers the formation of a mutant huntingtin protein responsible for neuronal death. Numerous pathophysiologic mechanisms have been implicated in Huntington’s disease. Striatum and cortex represent the most affected parts of the brain. Even though a wide range of medicines are available but they possess serious side effects. Therefore, the emergence of nutraceuticals derived from natural sources has received great attention in the pharmaceutical domain. Nutraceuticals are health-promoting supplements and enhance immunity in human beings. Currently, oxidative stress is the leading factor for chronic diseases that occur due to low intake of antioxidants. Herbal nutraceuticals are said to be enriched with a massive number of antioxidants. Therefore, this article throws light on various herbal nutraceuticals and their noteworthy effects on Huntington’s disease
... Quercetin can be found in basically all kinds of the berries such as whortleberry (158 mg/kg fresh weight) and chokeberry (89 mg/kg), and an average of 5320 mg apigenin glycosides were found per 100 g of dried chamomile flowers. 2,3 Genistein is predominantly present in soy-based foods, with 5.6 to 276 mg/100 g in mature soybeans. 4 Both aglycone and glycoside forms of flavonoids may exist in foods. ...
Article
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Flavonoids are bioactive phenolic compounds widely present in plant food and used in various nutraceutical, pharmaceutical, and cosmetic products. However, recent studies showed rising concerns of endocrine disruptions and developmental toxicities for many flavonoids. To understand the impacts of flavonoid structure on toxicity, we used a new multitiered platform to investigate the toxicities of four common flavonoids, luteolin, apigenin, quercetin, and genistein, from flavone, flavonol, and isoflavone. Weak estrogenic activity was detected for four flavonoids (genistein, apigenin, quercetin, and luteolin) at 10-12 to 10-7 M by the MCF-7 cell proliferation assay, which agreed with the molecular docking results. Consistent with the simulation results of Toxicity Estimation Software Tool, genistein and luteolin showed high developmental toxicity in the chicken embryonic assay (45-477 μg/kg) with mortality rate up to 50%. Luteolin, quercetin, and apigenin showed signs of mutagenicity at 5 × 10-3 pmol/plate. The findings showed nonmonotonic dose responses for the chemicals.
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Mangifera is one of the most important genus which commercially succesfull in fruit production in the world. Mangifera growth in low rain volume required dry climate for four months to stimulate the inflorensence. The characteristics of Mangifera species in Sumatra were tolerant to high rainfall, capable of fruiting out of season, high production and flowers resist against wet climate. The species with these traits had a germplasm resources potential (Fitmawati et al. 2013). Exploration on Mangifera species has been conducted by Fitmawati et al. (2013), (2015) and (2017) in 8 provinces in Greater Sumatra Island. Twelve of Mangifera species which typical in Sumatra were obtained. Mangifera species in Sumatra were divided into three categories such as: wild species, semi cultivated species and cultivated species (Fitmawati et al. 2015). Due to high frequency of forest and land fires in Sumatra, the specific species of Mangifera Sumatra were threatened in natural habitat, therefore wild germplasm resources must be conserved before became extinct in the wild
Article
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Flavonoids belong to a group of polyphenolic compounds, which are classified as flavonols, flavonones, flavones, flavanols, flavan-3-ols and isoflavones according to the positions of the substitutes present on the parent molecule. Flavonoids of different classes have several pharmacological activities. Flavonoids have also been known to posses biochemical effects, which inhibit a number of enzymes such as aldose reductase, xanthine oxidase, phosphodiesterase, Ca +2 -ATPase, lipoxygenase, cycloxygenase, etc. They also have a regulatory role on different hormones like estrogens, androgens and thyroid hormone. In view of their wide pharmacological and biological actions, they seem to be having a great therapeutic potential. Flavonoids biochemistry pharmacology therapeutic potential SUMMARY
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Quercetin, a naturally occurring flavonol structurally related to the antiallergic drug disodium cromoglycate inhibits anaphylactic histamine release from MMC isolated from the small bowel LP of the rat previously infected with the nematode Nippostrongylus brasiliensis. This contrasts with our previous observation that cromoglycate is inactive in this system. The present effect is immediate and does not decrease on preincubation with the drug. The flavonoids acacetin , apigenin , chrysin , and phloretin also demonstrate significant activity but are less potent than quercetin. Catechin, flavone, morin, and taxifolin are inactive. These results resemble those previously reported for the human basophil. In contrast, all compounds with the possible exception of taxifolin demonstrate significant activity against rat PMC. Acacetin and chrysin are the most effective inhibitors and are more active than quercetin. Rutin (the glycane of quercetin) and phlorezin (the glycane of phloretin) are inactive in both systems. These results are discussed in terms of the functional heterogeneity of mast cells from different sources and identify a group of compounds other than doxantrazole (reported previously), which inhibit histamine secretion by MMC.
Article
Background: Epidemiologic studies suggest that foods rich in flavonoids might reduce the risk of cardiovascular disease. Objective: Our objective was to investigate the effect of intake of flavonoid-containing black currant and apple juice on urinary excretion of quercetin and on markers of oxidative status. Design: This was a crossover study with 3 doses of juice (750, 1000, and 1500 mL) consumed for 1 wk by 4 women and 1 man corresponding to an intake of 4.8, 6.4, and 9.6 mg quercetin/d. Results: Urinary excretion of quercetin increased significantly with dose and with time. The fraction excreted in urine was 0.29–0.47%. Plasma quercetin did not change with juice intervention. Plasma ascorbate increased during intervention because of the ascorbate in the juice. Total plasma malondialdehyde decreased with time during the 1500-mL juice intervention, indicating reduced lipid oxidation in plasma. Plasma 2-amino-adipic semialdehyde residues increased with time and dose, indicating a prooxidant effect of the juice, whereas erythrocyte 2-amino-adipic semialdehyde and γ-glutamyl semialdehyde concentrations, Trolox-equivalent antioxidant capacity, and ferric reducing ability of plasma did not change. Glutathione peroxidase activity increased significantly with juice dose. Conclusions: Urinary excretion of quercetin seemed to be a small but constant function of quercetin intake. Short-term, high intake of black currant and apple juices had a prooxidant effect on plasma proteins and increased glutathione peroxidase activity, whereas lipid oxidation in plasma seemed to decrease. These effects might be related to several components of the juice and cannot be attributed solely to its quercetin content.
Article
Quercetin is the major flavonoid involved in vegetables and fruits. Quercetin is ingested from the daily diet, but in 1970s it was reported as mutagenic. Quercetin possesses a variety of pharmacological activities, and in order for further clinical application, it is important to evaluate its safety. In Ames test, quercetin is regarded as mutagenic. However, recent in vitro studies indicate that quercetin is protective against genotoxicants, and regarded as antimutagenic. Some in vivo studies including National Toxicology Program reported carcinogenic effect of quercetin in F344 rats. However, the method used in the study was unusual and the result was not reproduced. Most of the results of in vivo studies indicate that quercetin is not carcinogenic. Since 1969, the International Agency for Research on Cancer (IARC) has undertaken a program to evaluate the carcinogenic risk of chemicals. In 1999, IARC concluded that quercetin is not classified carcinogenic to humans. In the US and Europe, supplements of quercetin is commercially available, and beneficial effects of quercetin supplements were reported in clinical trials. Overall, quercetin is genotoxic to salmonella, but its safety upon human application is approved.
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The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6′,7′-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
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The aglycone, or free quercetin, and total quercetin content of 75 cultivars and selections was analyzed by reverse-phase high-performance liquid chromatography. Quercetin glycosides were hydrolyzed into aglycones. Total quercetin content in yellow, pink, and red onions varied from 54 to 286 mg·kg ⁻¹ fresh weight in different onion entries grown during 1992. White onions contained trace amounts of total quercetin. Free quercetin content in all the onions was low (< 0.4 mg·kg ⁻¹ ) except in `20272-G' (12.5 mg·kg ⁻¹ fresh weight). Bulbs stored at 5, 24, and 30C and controlled atmosphere (CA) for 0,1,2,3,4, and 5 months showed a most marked change in total quercetin content at 24C compared to other treatments, with a rise in mid-storage followed by a drop. Storage at 5 and 30C also demonstrated a similar change. However, total quercetin content did not vary significantly in bulbs stored at CA for 5 months. We conclude that genetic and storage factors affect quercetin content on onions.
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Accumulating evidence supports the hypothesis that brain iron misregulation and oxidative stress (OS), resulting in reactive oxygen species (ROS) generation from H2O2 and inflammatory processes, trigger a cascade of events leading to apoptotic/necrotic cell death in neurodegenerative disorders, such as Parkinson's (PD), Alzheimer's (AD) and Huntington's diseases, and amyotrophic lateral sclerosis (ALS). Thus, novel therapeutic approaches aimed at neutralization of OS-induced neurotoxicity, support the application of ROS scavengers, transition metals (e.g. iron and copper) chelators and non-vitamin natural antioxidant polyphenols, in monotherapy, or as part of antioxidant cocktail formulation for these diseases. Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols, particularly from green tea and blueberries, improve age-related cognitive decline and are neuroprotective in models of PD, AD and cerebral ischemia/reperfusion injuries. However, recent studies indicate that the radical scavenger property of green tea polyphenols is unlikely to be the sole explanation for their neuroprotective capacity and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this article, the currently established mechanisms involved in the beneficial health action and emerging studies concerning the putative novel molecular neuroprotective activity of green tea and its major polyphenol (-)-epigallocatechin-3-gallate (EGCG), will be reviewed and discussed.
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In an open, randomized, cross-over study the concentrations of 17β-estradiol and estrone in serum were measured over 192 hours in 8 ovariectomized women after a single oral dose intake of 2 mg micronized 17β-estradiol. The subjects were studied with and without grapefruit juice intake containing the three natural flavonoids, naringenin, quercetin and kaempherol, which are found as glycosides in citrus fruit. These flavonoids interact with the metabolism of drugs such as 17β-estradiol and other steroids that are extensively metabolised through the P-450NF (P-450 IIIA4) enzyme or closely related P-450 systems. After administration of grapefruit juice, peak estrone (between 2–6 hours after tablet intake) concentrations increased significantly. The AUC0–48 and AUC0–192 for estrone but not 17β-estradiol, resulting from a single administration of micronized 17β-estradiol, were significantly altered. Combined measured estrogens (i.e. 17β-estradiol and estrone) also increased significantly. The relationship between the ADCs for 17β-estradiol and estrone was not altered by juice intake indicating that a metabolic step after estrone, i.e. further A and/or D ring conversion was inhibited. This study demonstrates that grapefruit juice may alter the metabolic degradation of estrogens, and increase the bioavailable amounts of 17β-estradiol and its metabolite estrone, presumably by affecting the oxidative degradation of estrogens. This food interaction may be one factor behind the interindividual variability in 17β-estradiol, estrone and estriol serum concentrations after exogenous administration of 17β-estradiol to patients.
Article
Representative cultivars of different coloured onions were compared to determine the extent of differences in the distribution of free and total (bound and free) quercetin among different onion rings. The dry skin, outer rings, and inner rings were separated and extracted with ethanol to obtain quercetin glycosides (bound form) that were then hydrolyzed to free quercetin. Free quercetin was used as the standard for quantification by reverse phase high performance liquid chromatography (HPLC). Significant difference (P = 0.05) in total quercetin content was observed between the dry skin and inner rings (edible parts). A decrease in total quercetin content was observed from the dry skin to inner rings. The highest total quercetin concentration was observed in the dry skins of ‘Red Bone’ (30.66 g kg–1 dry weight) while ‘Contessa’ contain the least amount (0.094 g kg–1 dry weight). Total quercetin content in outer rings (1–2) in ‘Kadavan’ was high highest (345.51 mg kg–1 fresh weight); however, trace amounts were observed in ‘Contessa’. Inner rings (5–6 and 7–10) contain less total quercetin in all the cultivars. Outer rings (cataphylls) of all the cultivars except ‘Texas Grano 1015Y’ and ‘Contessa’ contain moderate amounts (2.5–16 mg kg–1 fresh weight) of free quercetin. ‘Red Bone’ skin contain the highest amount of free quercetin (20.64 g kg–1 dry weight). Quercetin distribution based on fresh and dry weight method was also evaluated.