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2019 Journal of Research in Pharmacy Practice | Published by Wolters Kluwer - Medknow
Silymarin (SMN) as an ancient plant has various therapeutic usage in many
diseases. Almost all of its properties attributed to antioxidant and anti‑inammatory
properties. Currently, infertility problems impose a heavy burden on many
developing countries. As a result, eective infertility treatment is indicated. The
role of oxidative stress in both male and female infertility has been revealed.
Many studies have shown protective and antioxidative properties of SMN against
adverse eects of chemotherapy medications and environmental toxins in sperms
and oocytes. The antioxidative and clinical role of SMN in infertility has been
reviewed. The use of antioxidants such as SMN can help to improve fertility rate
by scavenging free radicals and inhibiting nuclear factor kappa B transcription
factor. Animal studies in both male and female have indicated a benecial eect
of SMN on fertility recovery. Further clinical studies are needed considering the
phytoestrogenic property of SMN, to determine the right dose and duration of
treatment.
Antioxidants, infertility, Silymarin, therapy
Review for Pharmacy Practitioners
Morvarid Zarif‑Yeganeh1, Mansoor Rastegarpanah1
Address for correspondence:
Dr.Mansoor Rastegarpanah, E‑mail: rastegar@tums.ac.ir
Australia, China, and Central Europe.[5] The main
active polyphenolic components are avonolignans,
silychristin, silydianin, silybin, and isosilybin
(entirely known as silymarin [SMN]).[4]
Due to its protective eects, good pharmacokinetics
prole, and safety, SMN has been used in widespread
area such as Alzheimer’s disease, Parkinson’s disease,
sepsis, burns, osteoporosis, diabetes, ulcerative colitis,
cholestasis, hypercholesterolemia, cancers, neurotoxicity,
nephrotoxicity, cardiotoxicity, Amanita phalloides
poisoning, hepatic and lung disease, depression, prostate
disease, and in vitro fertilization (IVF). Until now,
the hepatoprotective eect of SMN has been shown
clinically.[3,6-16]
SMN does not have signicant adverse eects and
drug interactions. Gastrointestinal upset is the most
common side eect, and infrequent allergic reactions
Review Article
A
great number of factors may aect sperms motility,
numbers, DNA structure, and ultimately fertility.
Last but not least factor is oxidative stress. Destructive
environmental factors, inammation, and infections
trigger reactive oxygen species (ROS) generation by
white blood cells and immature sperm cells in the
semen. ROS dysregulate cell signaling, and it can be
harmful to cellular functions, cells’ proliferation, and
nally increase apoptosis. Enzymatic and nonenzymatic
antioxidant system protect cells against oxidative
stress. Glutathione (GSH), pantothenic acid, coenzyme
Q-10, carnitine, zinc, selenium, copper, and vitamins
(A, E, C, and B complex) are nonenzymatic defense.
Many surveys indicate and recommend that antioxidants
consumption can improve fertility.[1]
Milk thistle,[2] from Asteraceae family and Carduoideae
subfamily, is an old phytotherapic plant which
has several medicinal applications.[3,4] Regarding
geographical distribution, it is native to southern
Europe, Asia Minor, North Africa, and south Russian
Federation; introduced to North and South America,
1Department of Clinical
Pharmacy, Tehran University
of Medical Sciences, Tehran,
Iran
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How to cite this article: Zarif-Yeganeh M, Rastegarpanah M. Clinical role
of silymarin in oxidative stress and infertility: A short review for pharmacy
practitioners. J Res Pharm Pract 2019;8:181-8.
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Zarif-Yeganeh and Rastegarpanah: Role of silymarin in oxidative stress and infertility
182 Journal of Research in Pharmacy Practice ¦ Volume 8 ¦ Issue 4 ¦ October-December 2019
such as pruritus, rash, eczema, and anaphylaxis have
been reported.[17,18] Infertility is a global concern. Based
on the World Health Organization denition, infertility
is dened as “a disease of the reproductive system
dened by the failure to achieve a clinical pregnancy
after 12 months or more of regular unprotected sexual
intercourse.” It is dened as a disability, and in global
ranking for severe disability, female infertility is in the
fth rank.[19] In every four couples, one couple suered
from disability to have a child in developing countries.[20]
Approximately 48.5 million couples (15% of couples) are
aected by infertility worldwide. The highest infertility
rate was observed in Africa and Central/Eastern Europe.
20%–30% of infertility is attributed to male factors,
and 50% of them are due to female factors. Although,
the percentage range of male infertility can be varied
from 20‑70% in dierent countries, but overally 20‑30
% of infertility is attributed to male factors, and 50%
of them are due to female factors.[21] The etiology and
pathogenesis of male infertility have not been identied.
Beside anatomical abnormalities and neurological
disorders, some constant and environmental factors may
inuence male fertility. Alcohol abuse, smoking, obesity,
chronic stress, urogenital trauma, reproductive system
inammation, chemicals, heavy metals, pesticides,
heat, and electromagnetic radiation – these factors
by triggering oxidative stress process may impact on
spermatogenesis and induce infertility.[1] There is not
enough evidence for conrming oxidative stress and
its role in female infertility. Endometriosis, polycystic
ovary syndrome (PCOS), unexplained infertility,
spontaneous abortion, recurrent pregnancy loss, and
preeclampsia can be attributed to pro-oxidants and
antioxidants imbalance. Environmental contaminants,
obesity, and some inappropriate habits such as cigarette
smoking, alcohol use, and drug abuse lead to increase in
ROS[22] production and probable infertility.[23,24] Based on
a review, which is written by Sekhon et al. in 2010, over
half of the recurrent pregnancy loss is owing to oxidative
stress.[25] Oxidative stress generates pro-oxidants or
ROS by complicated interactions among cytokines,
hormones, and other factors such as irradiation. These
molecules can damage cell cycle proliferation and
dierentiation. Antioxidants counteract ROS and prevent
cell injuries.[26] Nowadays, infertility problems impose a
heavy burden on many developing countries. As a result,
eective infertility treatment is indicated. The role of
oxidative stress in both male and female infertility has
been revealed. Many studies have shown protective and
antioxidative properties of SMN against adverse eects
of chemotherapy medications and environmental toxins
in sperms and oocytes. Considering the antioxidant
eects of SMN and the potential role of oxidants in the
induction of infertility, this review was conducted to
investigate the antioxidant function of SMN in helping
to improve fertility.
Antioxidant and infertility
Many investigations have suggested that oocyte and
sperm modality might improve using antioxidants,
which result in successful pregnancy increment.[25,26]
A distinct amount of ROS is required for natural cell
operation; the imbalance exists between ROS production
and antioxidants can lead to cell cycle disruption
and apoptosis progression. Endogenous factors such
as mitochondrial respiratory chain and exogenous
factors such as alcohol, cigarette, and environmental
pollutants exposure play a vital role in producing of
ROS.[23,24,27,28] ROS such as oxygen ions, free radicals,
and peroxides which is generated due to oxidative stress
in the male and female reproductive system damage
cells and can cause subfertility and infertility. Most
studies have been done on males, and the mechanisms
of the destructive eects of oxidative stress are almost
more obvious on sperm than oocyte. Two primary
mechanisms were identied for male infertility induced
by oxidative stress: (1) sperm membrane impairment,
sperm motility reduction, and then disturbance in
fusion with the oocyte and (2) DNA damage and
embryo defects.[29,30] In many female complications,
for instance, abortion, pregnancy loss, preeclampsia,
endometriosis, PCOS, and unexplained infertility might
be attributed to an imbalance between antioxidants and
pro-oxidants.[23] Besides, some studies have shown that
in preovulatory follicles, oxidative stress induces cell
apoptosis [Figure 1].[31]
Enzymatic (metal-activated enzymes such as
superoxide dismutase (SOD), GSH peroxidase (GPX),
catalase (CAT), and GSH oxidase) and nonenzymatic
antioxidants consumption (supplements and synthetic
antioxidants such as Vitamin C, Vitamin E, Vitamins
A, and B complex, pantothenic acid, coenzyme
Q10, carnitine, zinc, selenium, copper, GSH, taurine,
hypotaurine, beta-carotene, and carotene) can recline
ROS and help to provide balance.[1,23] Antioxidants’
consumption and lifestyle modication are convenient
and eective suggested solutions which can help reduce
DNA and RNA damages and improve fertility.[32]
Oxidative stress and the inammatory process can
impact on sperm and oocyte, which is associated
with DNA damage or any disturbance in motility,
fusion, and viability of these cells. All the mentioned
changes might result in infertility, abortion, and fetus
anomaly.[1,23,24,29,32,33]
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Anti‑inammatory eect of silymarin
Studies have shown antioxidant, anti‑inammatory,
anti‑brotic, detoxifying, and regenerative properties
of SMN.[6,34] Beside antioxidant properties of SMN,
dose‑ and time‑dependent immunomodulatory eects
of SMN have been investigated in several studies. Its
anti‑inammatory eects are induced by nuclear factor
kappa B (NF-κB) inhibition and tumor necrosis factor
α (TNF-α) activation. Although low-dose SMN by
inhibiting T lymphocytes showed immunomodulating
activity, superior doses showed stimulatory eects
on inammatory processes. Furthermore, SMN has
dual impacts on growth and death of cells with
diverse nature.[2,9,35] Studies have demonstrated that it
prevents cellular inammation by suppression of the
mammalian target of rapamycin signaling and activation
of activating transcription factor 4 and adenosine
monophosphate protein kinase. Cellular studies show
that more exposure to SMN (24 h) can cause an
increase in anti‑inammatory eects by inhibition of
pro‑inammatory mRNA and signaling pathways such
as NF-κB and forkhead box O.[36]
NF-κB is a regulatory transcription factor which can
lead to interleukins 1 and 6, TNF-α, lymphotoxin,
granulocyte-macrophage colony-stimulating factor, and
interferon production.[37] Inammatory mediators such
as TNF-α, nitrous oxide, interleukin-6, and interleukin-1
receptor antagonist are modulated by SMN.[17]
Silymarin eects on male fertility
Comet assay, a sensitive test for evaluation of DNA
strand breaks in eukaryotic cells, showed that DNA
damage was diminished due to the antigen-toxic
activity of avonoids in human lymphocytes
and sperm cells which were exposed to food
mutagens (3-amino-1-methyl-5H-pyrido (4,3-b)
indole (Trp-P-2), 2-amino-3-methylimidazole-(4,5-f)
quinoline)[32] and avonoids (SMN, myricetin, quercetin,
kaempferol, rutin, and kaempferol-3-rutinoside). SMN,
myricetin, and quercetin had antigenotoxic impacts on
the sperm. Antioxidant eects were ascribed to phenolic
hydroxyl groups, and an incremental pattern of these
eects was observed by the addition of hydroxyl groups
to A and B rings. Antigenotoxic eects in the equivalent
dosage in lymphocytes and sperms showed that this
protective outcome would obtain in either somatic or
germ cell lines.[38]
According to study results, oxidative stress signaling
pathway induction and free radical species production
were imposed on ram sperm by sodium arsenite; cells
which are treated with SMN had better motility. SMN as
an antioxidant by scavenging free radical and promoting
antioxidant enzyme capacity can improve sperm viability,
motility, and mitochondrial membrane potential.[34,39]
In other research which is conducted by Eskandari and
Momeni, plasma membrane and acrosome integrity of
ram epididymal spermatozoa which were exposed to
Figure Role of oxidative stress, reproductive systems, and infertility
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Zarif-Yeganeh and Rastegarpanah: Role of silymarin in oxidative stress and infertility
184 Journal of Research in Pharmacy Practice ¦ Volume 8 ¦ Issue 4 ¦ October-December 2019
arsenite increased signicantly compared to the control
group that was not treated with SMN.[40] These two
studies showed that strong antioxidant properties of
SMN protect ram sperm against the disruptive eects of
arsenite. During sperm storage, lipid peroxidation (LPO)
and ROS production increase and detrimental products
accumulation lead to sperm damage. SMN as ROS
scavenging polyphenols can counteract with this
destructive process. Addition of SMN as a supplement
for ram semen storage showed that sperm quality was
improved. Supplementation with caproic acid had a
better impact.[41] In another similar study, the addition
of SMN to sperm maintenance medium showed positive
eects on bull sperm preservation, in both chilled and
frozen condition.[42]
Polyunsaturated fatty acids, which are found abundantly
in the mammalian spermatozoa cell membrane, provide
a vulnerable state that results in ROS production by
LPO and cell’s detriment. Antioxidants neutralize ROS
and defend cells against injury. By assuming antioxidant
activity of SMN, an investigation of the impacts of
silibinin, the most biologically active avonoids of SMN,
on the testicular tissue of mice was conducted. With
a dose‑dependent manner, a signicant improvement
in testosterone level and diameter of spermatid, and
testicular associated factor were observed.[43] In an animal
study, which is conducted by Abedi et al., the eects of
SMN on spermatogenesis, changes of testicular tissue,
and hormones of the hypothalamic–pituitary–gonadal
axis (luteinizing hormone [LH], follicle-stimulating
hormone [FSH], gonadotropin-releasing hormone, and
testosterone) in male rats were evaluated. Compared
to the control group, experimental groups which were
treated with SMN showed a signicant increase in LH,
FSH, gonadotropin-releasing hormone and testosterone
levels, and the number of spermatids and spermatozoa
cells.[44] Male albino rats were treated with testosterone
intramuscularly and SMN orally to evaluate the
protective eects of SMN against testosterone damages
in the reproductive system. In testosterone group,
caspase-3 and P53 overexpression were observed.
Oral SMN had a signicant role in the prevention
of testosterone biochemical and histopathological
adverse reactions.[45] Based on the study results which
is conducted to evaluate the reproductive alteration of
rabbits bucks fed milk thistle seeds and rosemary leaves,
in SMN group (10 g/kg) the sperm concentration,
total sperm output, live sperm, total live sperm, total
motile sperm, testosterone level, and fertility rate were
signicantly improved.[22]
Accordingly, SMN showed an impressive role in the
improvement of sperm-related factors and fertility.
Varicocele with several assumed mechanisms can
lead to induce infertility in men, such as hypoxia
(due to venous stasis), Leydig cell degeneration,
testosterone level decrement, and testicular temperature
increase and androgen receptor impairment.
Furthermore, tissue inammation, leukocyte inltration
and venous stasis-induced hypoxia, inducible nitric
oxide (NO) synthase upregulation, production of
malondialdehyde (MDA), and NO in the varicocele
testis have been observed. Phospholipids’ accumulation
in mammalian spermatozoa cell membrane makes a
susceptible condition which resulted in ROS production
rise. Some studies showed ROS augmentation to
correlate with cell damage in the varicocele. Level of
E2f1 transcription factor as a potent apoptosis inducer
increased in varicocelized animals, which contribute to
hypoxia. Investigations indicated that SMN not only can
regulate E2f1 transcription factor but also has a potential
to decline hypoxia harm. Furthermore, SMN increased
spermatogenesis and ameliorated carbohydrate depletion
in germinal cells.[46]
In another similar study in varicocelized rats which
were exposed to oxidative stress, SMN administration
increased spermatozoa nuclei maturity and viability
signicantly compared to the control group.[47]
Furthermore, SMN increased the serum total antioxidant
capacity and total thiol molecules in varicocelized
rats. Therefore, sperm motility increment and
reduction in DNA damage were observed.[48] Mazhari
et al. evaluated the eect of SMN and celecoxib on
varicocelized rats. Results showed that these two
agents with dierent mechanisms play a decisive role
in decreasing varicocele‑induced injuries. Inammation
downregulation by cyclooxygenase enzymes inhibition
and antioxidant activities enhancement to protect
RNA of germinal cells are proposed mechanisms of
celecoxib and SMN, respectively.[49,50] Consequently,
varicocele-induced oxidative stress can be improved by
SMN due to its antioxidant activities.
Studies have been shown radioprotective eects of
SMN on rat and mice testis tissue.[51,52] Results showed
that in groups of animals treated with SMN 24 h before
gamma radiation exposure, testicular parameters such
as frequency of spermatogonia, primary spermatocyte,
round spermatid, spermatozoa, seminiferous tube and
lumen diameters, the thickness of the epithelium, Leydig
cell nuclear diameter and volume, epithelium height, and
apoptotic cells were improved. Better outcomes were
observed at a dose of 200 mg/kg.[52]
According to results of an investigation which compared
antioxidant eects of SMN and thymoquinone on
male rats’ reproductive functions which tread with
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Journal of Research in Pharmacy Practice ¦ Volume 8 ¦ Issue 4 ¦ October-December 2019
an environmental pollutant (benzo[a] pyrene), SMN
ameliorated the antioxidant enzymes activities including
CAT, GPX, and SOD, as such it regulated antioxidant
status and level of free radicals in testicular tissue.
Thymoquinone not only had no positive eects but
also diminished levels of testosterone, estrogen, and
progesterone.[53]
Methotrexate as a cytotoxic agent leads to testicular
damages, such as decline in diameter of seminiferous
tubules and primary spermatocyte, sperms’ motility
and count reduction, immature and abnormal sperms’
production, germ cells’ apoptosis, and disruption in
spermatogenesis process. In groups of mice which were
exposed to methotrexate and concomitantly were treated
with silibinin (the most bioactive components of SMN),
percent of the dead to live sperm decreased and
interstitial space and diameter of spermatid improved
signicantly. These protective eects can be attributed
to anti‑inammatory and antioxidant and radical
scavenging of SMN.[54,55]
The adverse eects of Doxorubicin, an antineoplastic
anthracycline, on the heart, liver, and testis have been
proven previously. The preventive and protective
role of SMN in male rats, which exposed to
doxorubicin-induced oxidative stress and testis injury,
were indicated. A decrease in MDA production, a LPO
biomarker, and improvement in sperm quality were
observed due to SMN administration.[56] Doxorubicin
and radiation by producing free radicals change the
equivalence of antioxidants and pro‑oxidants and
damage cells. Administration of them altered level
of some factors such as MDA, GSH, GPX, and SOD
(as antioxidants in tissue) in rats.
Addition of SMN to their regimen modied factors
alteration by its antioxidant properties.[57]
In male rabbits, nickle chloride can lead to negative
impacts on sperm count, motility, viability, and fertility
ability of sperm. Furthermore, the reduction in serum
concentration of progesterone, estradiol, and testosterone
was observed. Investigation showed SMN improved
these factors and increased fertility rate.[58]
Silymarin eects on female fertility
In a randomized, double‑blind study, the eects of SMN
on granulosa cell apoptosis and folliculogenesis in forty
healthy women who underwent IVF were evaluated.
Results showed that using SMN and gonadotropin
concomitantly since the 1st day of ovulation induction
can cause a granulosa cell apoptosis decline (P = 0.032),
Although they could not nd any relationship between
SMN consumption and endometrial thickness, oocyte
retrieval, and follicular maturation.[59,60] PCOS is one
the most common causes of infertility in the female.
Considering SMN antioxidant activity and its impacts
on insulin sensitivity, patients who suered from PCOS
were treated with SMN throughout 3 months. The
rst group (n = 20) received SMN (750 mg/day), the
second group received metformin (1500 mg/day), and
the third group received metformin (1500 mg/day) and
SMN (750 mg/day) concurrently. The levels of glucose,
insulin, testosterone, LH, and progesterone were
signicantly improved. The best consequences were
observed in the group which was treated with SMN and
metformin.[61] There are several factors that aect IVF of
bovine embryo; one of the inhibitory factors is oxidative
stress. ROS-mediated oxidative stress was induced in the
bovine oviduct epithelial cell by sodium nitroprusside.
The outcomes showed that SMN via antioxidative
and antiapoptotic gene expression regulation could
ameliorate bovine oviduct epithelial cell livability and
morphology and adverse eects of LPO.
Furthermore, bovine IVF embryo growth rate
enhancement was observed.[62] The reproductive eect
of extracts of four phytoestrogenic plants: Cucurbita
pepo, Silybummarianum, Linumusitatissmum, and Vitex
agnus-castus was compared with 17 β estradiol on the
ovarian tissue of immature female three spot gourami
sh. Among these extracts, Silybummarianum has the
best impact on fertility improvement.[63] Phytoestrogenic
eects of some plants are due to the existence of
compounds such as lignans, isoavones, coumestans, and
resorcylic acid lactones. Isoavones bind to β estrogen
receptors with low anity while endogenous estradiol
binds to α estrogen receptors with high anity. When
the estradiol level is too low in the body, isoavones
show agonistic eects, and antagonistic properties may
be observed in high levels of estradiol.[63]
Regarding histological and functional changes in
ovariectomized rats, which were treated with SMN, the
estrogenic eects of SMN were indicated.[64] In vitro
receptor gene assays showed that SMN did not activate
aryl hydrocarbon receptor, but some components of
it such as silybin B and taxifolin had partial to full
estrogen receptor agonist activities. Silybin A and
other avonolignans did not have estrogenic features.
Estrogenic eects should be considered as a clinical side
eect, and extract purication based on avonolignans
without estrogenic characteristics is recommended.[65]
Some malformations have been observed in mice fetus
by this plant-based compound.[66] Besides, ingestion
of high dose phytoestrogen for a long time may cause
adverse reproductive eects in animals. Therefore,
histological and hormonal changes in female and
male rats, which exposed to SMN, were assessed.
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186 Journal of Research in Pharmacy Practice ¦ Volume 8 ¦ Issue 4 ¦ October-December 2019
Phytoestrogenic eects of SMN may modify hormonal
levels; SMN with a dose (151.2 mg/kg BW) equivalent
to the human therapeutic dose (420 mg/day) in female
rats increased the FSH, number, and size of follicles,
and endometrial epithelium hypertrophy and prevented
pregnancy on days 1–5 after intercourse. In male rats,
which treated with similar doses of SMN for 1 month,
the increase in testosterone, LH levels, and testis sperm
counts was observed. Based on these results, SMN may
be useful for male fertility.[67] Estrogen has a decisive role
in spermatogenesis and diet with a low level of estrogen
can improve normal sperm production.[68] The agonistic
or antagonistic eect of SMN on estrogen receptors may
be dependent on body estradiol level, dose, and duration
of treatment. Cyclophosphamide, as an oxidative stress
stimulator, induced antral follicle atresia in female rats.
Signicantly in SMN‑treated group, antral follicles’
development and counts were improved.[69] Therefore,
SMN may be used as a protective agent for ovarian
follicles.
SMN intake in one study improved sperm parameters,
reproductive performances, decreased LPO, and
increased antioxidant enzyme activities. The relative
mRNA expression of Bcl-2 was considerably reduced,
and that of Bax, Caspase-3 was increased in the
diabetic rats compared to the control group. SMN
signicantly increased the expression of Bcl‑2 and
decreased the expression of Bax, Caspase-3. Serum
levels of testosterone showed a signicant decreased in
diabetic rats, compared to the control group and serum
testosterone levels revealed an increase in groups that
received SMN.[70]
Due to the psychological and nancial burden of
infertility in the community, application of new
eective, feasible, aordable approaches is necessary.
Investigations showed the distinct role of oxidative stress
in both male and female infertility. Moreover, some
plants extracts are accessible and useful to neutralize
oxidants and protect cells. Therefore, administration of
antioxidants such as SMN can help to improve fertility
rate. Furthermore, many studies showed protective and
anti-oxidative properties of SMN against damages of
chemotherapy medications and environmental toxins in
sperms and oocytes. Its anti‑inammatory eects are
induced by NF-κB inhibition and TNF-α activation.
Antioxidant eects are attributed to the presence of
hydroxyl groups in the chemical structure of these
compounds. Therefore, SMN by scavenging free radicals
and regulating the inammatory cytokines can neutralize
adverse eects of inammation process and oxidative
stress.
Animal studies in both male and female have indicated
a benecial eect of SMN on fertility recovery.
Considering controversies, further studies, particularly in
a human, should be performed while considering some
phytoestrogenic property of SMN, to determine the dose
and duration of treatment.
Morvarid Zarif-Yeganeh and Mansoor Rastegarpanah
performed literature search and acquisition of data,
prepared, edited, reviewed, discussed and contributed to
the nal manuscript. Mansoor Rastegarpanah; devised
the project and the main conceptual ideas, designed,
dened the intellectual content, and was the guarantor.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conicts of interest.
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