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Quercetin, a flavonoid with multiple proven health benefits to both man and animals, displays a plethora of biological activities, collectively referred to as pleiotropic. The most studied of these are antioxidant and anti-inflammatory but modulation of signalling pathways is important as well. One of the lesser-known and recently discovered roles of quercetin, is modulation of microRNA (miRNA) expression. miRNAs are important posttranscriptional modulators that play a critical role in health and disease and many of these non-coding oligonucleotides are recognized as oncogenic or tumor suppressor miRNAs. This review is an evaluation of the recent relevant literature on the subject, with focus on the ability of quercetin to modulate miRNA expression. It includes a summary of recent knowledge on miRNAs deregulated by quercetin, an overview of quercetin pharmacokinetics and miRNA biogenesis, for the interested reader.
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Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019 Jun; 163(2):95-106.
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The effect of quercetin on microRNA expression: A critical review
Zdenek Dostala,b, Martin Modrianskya,b
Quercetin, a flavonoid with multiple proven health benefits to both man and animals,displays a plethora ofbiologi-
cal activities, collectively referred to as pleiotropic. The most studied of these are antioxidant and anti-inflammatory
but modulation of signalling pathways is important as well. One of thelesser-known and recently discovered roles of
quercetin, is modulation of microRNA (miRNA) expression. miRNAs are important posttranscriptional modulators that
play a critical role in health and disease and many of these non-coding oligonucleotides are recognized as oncogenic
or tumor suppressor miRNAs. This review is an evaluation of the recent relevant literature on the subject, with focus
on the ability of quercetin to modulate miRNA expression. It includes a summary of recent knowledge on miRNAs
deregulated by quercetin, an overview of quercetin pharmacokinetics and miRNA biogenesis, for the interested reader.
Key words: polyphenols, microRNA, biogenesis, expression
Received: February 27, 2019; Accepted with revision: June 11, 2019; Available online: June 25, 2019
https://doi.org/10.5507/bp.2019.030
aDepartment of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic
bInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic
Corresponding author: Martin Modriansky, e-mail: martin.modriansky@upol.cz
INTRODUCTION
Quercetin, a biologically active compound, is a mem-
ber of an extensive group of natural compounds called
polyphenols. These are ubiquitous in the human diet
and an average person can consume more than 1 g per
day1,2 . The primary role of polyphenols in plants is de-
fense against environmental stress such as UV-irradiation
and predators. They also affect growth (development
regulators), mediate pigmentation and attract pollina-
tors3,4. Polyphenols are classified as flavonoids, lignans,
stilbenes, phenolic acids, coumarins, hydroxycinnamic
acids and others3. They display a number of biological
activities such as radical scavenging, antioxidant and anti-
inflammatory properties as mentioned5. They can also
modulate cell signalling cascades6,7. Some cellular signals
are transmitted and amplified via kinases, some of which
can be inhibited by quercetin and other polyphenols7-9.
Quercetin, whose chemical structure is shown in
Fig. 1, is one of the most abundant flavonoids, belonging
to the flavonol subgroup10. Its protective effects are medi-
ated by multifaceted, pleiotropic action.
Quercetin is found abundantly in various foods such
as fruits (apple and black currant), vegetables (onion and
green beans), beverages (tea) and spices11,12. It exists in
two forms: an aglycone or a glycosylated form. The sugar
moiety, glucose, other monosaccharides or disaccharides
e.g. rhamnose or rutinose, is connected to different car-
bons of the structure via O-glycosidic linkage. The C-3
carbon is the most common position but the glycosylation
may appear on carbons 4’ and 7 (ref.13). 4’-O-glucoside is
considered the major representative of quercetin glyco-
sides in onion14 but C-glycosides have also been described
as well15. From a dietary point of view, mostly quercetin
glycosides are found in food with a negligible portion of
the aglycone16,17 , although some authors have suggested
that the aglycone form may be present in significant quan-
tities in some red wines18. Chemically, quercetin is a bright
yellow crystallic substance with very good solubility either
in DMSO (150 g/L, RT) (ref.19), inferior in 50% ethanol
(4.02 g/L, 37 °C) (ref.20) and practically insoluble in wa-
ter (4.7/10.28 mg/L, 37 °C, based on solubility in PBS)
(ref.20,21).
Pharmacokinetics of quercetin
The bioavailability of quercetin in a single oral dose is
fairly low (≤ 1% of unchanged compound) (ref.22). In the
high doses used by Gugler et al.22 (4 g), quercetin solubil-
ity is probably the main limitation as more than 50% of
unchanged quercetin was found in the feces. Absorption
of quercetin takes place mainly in the intestine23 but also
in the epithelium of the oral cavity17. Older literature sug-
gested that quercetin glucosides are not absorbed at all
and absorption occurs with aglycone alone24. It has since
been suggested that hydrolysis of the glucosides is medi-
ated by oral and gut microflora17,25. On the other hand,
Fig. 1. Chemical structure of quercetin.
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96
intestinal microflora and chemical reactions can cause
quercetin degradation. In 2001, Walle et al.26 published
data obtained with radiolabeled quercetin and showed
that quercetin is metabolized in the human body with CO2
generation as the end product (mean value 52.1/43.2% of
administrated dose; oral/intravenous application) (ref.26).
This study has the limitation of using only one radiola-
beled carbon that restricts tracking of other products.
Similar results were published with data obtained using a
rat model where CO2 generation was also observed27. The
degradation of flavonoids by intestinal microflora was
found in both in vitro and in vivo and it is usually linked
with ring-fission products25,28.
Other documented possibilities of quercetin glucoside
hydrolysis are enterocyte or liver cytosolic β-glucosidase,
whose activities depend on the sugar moiety and its posi-
tion, and lactase phloridzin hydrolase (LPH) enzymes16,29.
LPH could be important in absorption of quercetin due
to its localization: it resides on the luminal side of the
brush border29. The effect of cytosolic broad specificity
β-glucosidase in enterocytes and hepatocytes is question-
able because the quercetin glucosides would be trans-
ported into the cell before the hydrolytic cleavage occurs
in the intestine. On the other hand, some publications
describe the uptake of a small amount of flavonol gluco-
sides into the circulation30. Hollman et al.31 showed that
quercetin glucosides are better absorbed than the agly-
cone in ileostomy patients but these authors used only
indirect calculation. In fact all samples were subjected
to hydrolysis which means that there is lack of informa-
tion on the aglycone:glucoside ratio in ileostomy fluid or
other tested samples (see Walle et al.32). Also, quercetin
and its glycosides were evaluated for stability during a
two/four/3.25 h long incubation period with gastric fluid/
duodenal fluid/ileostomy effluent, respectively. The re-
sults indicated high stability of tested compounds but it
appears that at least free quercetin tested during the study
exceeded its expected solubility in aqueous solution. The
study also showed only small hydrolysis of rutin and this
corresponds to previously published results16,29.
Quercetin is metabolized by different phase I and II
enzymes after absorption. Products are predominantly
quercetin glucuronides and sulfates that are generated
within hepatocytes and enterocytes3,33,34. Other products
of quercetin metabolism include methylated querce-
tin3,34. While in the intestine, bacterial cleavage of the
hydrophilic moiety can produce aglycone, i.e. cause de-
conjugation, from quercetin metabolites, which could be
re-absorbed3,35. The products of quercetin metabolism are
excreted into urine and feces as well as being exhaled3.
Quercetin is capable of inhibiting some cytochromes
P450 in vitro36, and this may affect the metabolism of
quercetin itself or other drugs. Moreover, a decrease in
CYP1A1 and CYP1B1 mRNA was observed in non-
cancerous colon cells after treatment with flavonol-rich
fraction from yaupon holly containing quercetin-3-rutino-
side37. However, contradictory information is available for
isoquercitrin, a quercetin glucoside. Three selected mem-
bers of the P450 family showed an enhancement of liver
P450 activity after isoquercitrin gastric gavage in rats38.
Increasing the bioavailability of quercetin is another
aim of current research. From results published by Gugler
et al.22, we can conclude that a higher single dose of quer-
cetin does not improve absorption for several reasons,
the most important being solubility in water. It is well-
known that the solubility of quercetin in water is poor
and hence the goal is to improve aqueous solubility (see
below). It is also necessary to facilitate transport across
membranes. An interesting approach is enclosing querce-
tin into special micelles39 or mixing it with various lipids
to create quercetin containing liposomes20. Another idea
is to overcome low bioavailability by using multiple doses
of quercetin repeatedly40. The idea was tested on a human
model and a plasma quercetin concentration of 1.5 µM
was achieved in the test subject when 1 g per day was
applied for 28 days. This study has a limitation due the
pre-analytic sample preparation, which included a hydro-
lysis step that discarded all information about quercetin
metabolites formed by second phase enzymes such as
amount of glucuronides, sulfates etc. (ref.40). The conclu-
sion is that the “long” elimination time is connected with
bioaccumulation of quercetin.
miRNA
miRNAs are defined as short non-coding single
strands of RNA with approximately 18–25 bases. The first
mention of these molecules appeared in 1993. Scientists
from Harvard College found a small RNA product of the
lin-4 gene that is able to control the lin-14 protein level in
Caenorhabditis elegans41. These molecules provide a mo-
dality for posttranscriptional modulation of gene expres-
sion in this organism. miRNAs have several valid targets,
sometimes dozens of targets, and some miRNAs can even
share their targets42. As of the writing of this article, 1917
human miRNA precursors have been described in miR-
Base 22 (http://www.mirbase.org/).
miRNA biogenesis
The first step in canonical miRNA biogenesis is RNA
polymerase II catalyzed transcription of their genes from
DNA (ref.43). This reaction generates long primary tran-
scripts typically containing over a thousand nucleotides
(pri-miRNA). The process continues by cropping the pri-
miRNA to the size of up to hundred nucleotides long
products called precursor miRNA (pre-miRNA). The
editing is mediated by a microprocessor complex that
contains two major components Drosha (belongs to the
RNAse III family) and DGCR8 (also called DiGeorge
Syndrome Critical Region 8) (ref.44,45). The next step is
the shuttling of pre-miRNAs to the cytosol. This occurs in
the presence of exportin-5 and RanGTP (ref.46,47). Dicer
(RNAse III enzyme) accesses the pre-miRNAs and di-
gests it to mature, 18 – 25 nucleotide long double stranded
products48,49. Unwinding of miRNA duplexes initiates the
N-domain of argonaute 2 during RISC (RNA inducing
silencing complex) assembly50 while attracting other
important proteins such as Dicer, TRBP (ref.51). Within
the complex formation, a guide strand is incorporated
into the complex (strand with less stable pairing at the
5’end), whereas a passenger strand is degraded52. The ac-
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97
tive RIS complex both reduces stability and cleaves the
target mRNA, which is the case of full complementarity
of miRNA against target mRNA. Partial complementarity
of miRNA blocks mRNA for ribosomal translation but it
does not cleave a target mRNA immediately53. Moreover,
mRNA/RISC complexes are probably stored and also de-
graded in p-bodies. For more detailed information about
p-bodies see a review by Parker et al.54. The canonical
miRNA biogenesis pathway is summarized in Fig. 2.
miRNAs are interesting and important molecules in
cell processes because a single miRNA has the ability
to modulate gene expression of multiple targets, thereby
changing the cell phenotype. There are a number of de-
regulated miRNAs in different types of diseases. They are
therefore being extensively studied especially in relation
to cancer and their level may be associated with specific
types of tumor. Ouzang et al.55 for example identified a
group of up- and down-regulated miRNAs compared to
normal tissue expression. Experiments based on resto-
ration of normal non-pathologic expression of selected
miRNA or even exceeding it showed elevated sensitiv-
ity of tested cancer cells to conventional treatment56.
Modulation of miRNA expression could be used in the
future against a number of diseases.
miRNAs modulated by quercetin
miR-146a
Tao et al.57 found that quercetin increased the ex-
pression of miR-146a in human breast cancer cells57.
Generally, miR-146a is known as a posttranscriptional
modulator of several important genes. For example, its
validated targets are BRCA1, BRCA2 (ref.58) involved
in repairing double strand breaks in DNA or the EGFR
receptor59, a transmembrane tyrosine kinase connected
with pro-survival signalling. Overexpressed EGFR is of-
ten found in tumors and linked to aggressive behavior in
cancer cells. This study found significant upregulation of
miR-146a, approximately four- to five-fold of control for
MCF-7/MDA-MB-231 cells, caused by the highest querce-
tin concentration tested during 48 h treatment. The result
was a reduction in cell survival to below 40%. The ob-
served effect was linked to negatively affected expression
of EGFR, increase in Bax protein level and downstream
activation of caspase-3 during 24 h treatment. In addition,
the authors used miR-146a/anti-miR-146a transfection for
validation of the observed effects. Moreover, a mouse xe-
nograft model was used during the study. These experi-
ments showed decrease in cancer volume and an increase
in expression of miR-146a, almost two-fold higher than
control, after quercetin treatment (10 mg/kg for 8 weeks).
Unfortunately, the authors did not describe the method of
application of quercetin57. The article contains discrepan-
cies between text and images and authors used a non-stan-
dard unit for the concentrations of the tested compound
(see Table 1). The literature suggests conflicting effects of
miR-146a in cancer cell line MCF-7. For example, Gao et
al.60 discusses the impact of the miR-146a-5p overexpres-
sion on enhanced proliferation in this cell line60. Overall,
these results suggest another contribution of quercetin
that cooperates with miR-146a up-regulation.
An article published by Tao et al.57 is not the only
article showing that miR-146a is modulated by quercetin.
Noratto et al.37 examined fractions from yaupon holly leaf
extract. The flavonol-rich fraction turned out to be effec-
tive. Quercetin-3-rutinoside and kaempferol-3-rutinoside
were determined as major flavonol compounds of this
fraction by HPLC/MS (MS2, MS3) and were character-
ized as gallic acid equivalents (GAE). The experiments
were performed with CCD-18Co cells (normal colon
cells), in which LPS treatment down-regulated miR-146a
Fig. 2. Biogenesis of miRNA (basic scheme).
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98
expression. Combined treatment of LPS with the highest
concentration of 40 mg GAE/L resulted in the return
of miR-146a expression to the level of control. Further
experiments yielded interesting data because the relative
expression of miR-146a exceeded the level in control (non-
treated) cells after combination of the extract fraction (20
mg GAE/L) with miR-146a inhibitor as well as combina-
tion of the flavonol rich extract + LPS + miR-146a inhibi-
tor. The authors suggested that miR-146a contributes to
the anti-inflammatory properties of the tested fraction
due to the regulation of its targets IRAK-1 and TRAF-6
(ref.37). IRAK-1 and TRAF-6, a part of the TLR pathway,
were validated as miR-146a targets elsewhere61.
miR-27a
Another example of combined study is Del Follo
Martinez et al.62 who used a quercetin:resveratrol mixture
in a 1:1 ratio. The researchers used the HT-29 cell line
as a model of colon cancer and tested the mixture for its
potential anticancer properties. A decrease in miR-27a
was found. This miRNA is discussed as oncogenic be-
cause it is linked to regulation of ZBTB10, a zinc finger
protein. The main effect of ZBTB10 is probably mediated
via repression of Sp transcription factors. These are a part
of the transcription factor family that regulates several
housekeeping genes related to initiation of cancer and its
progression. miR-27a was downregulated two-fold after
the treatment that resulted in upregulation of ZBTB10.
The impact was partially demonstrated using miR-27a
mimics. On the other hand, modulation of miR-27a by
the mixture did not respond in a dose dependent manner
whereas ZBTB10 mRNA did. The data suggest another
effect of this mixture62.
miR-27a was downregulated in the same way by an-
other combination of polyphenols, namely quercetin and
hyperoside (quercetin-3-O-galactoside), also in a 1:1 ratio.
786-O renal cancer cells were used as the model for these
experiments. It is remarkable that almost all the figures,
results, experimental design and even text bear a strong
resemblance to those presented in Del Follo Martinez et
al.62 with few exceptions. Many results were surprisingly
similar, with IC50 differences smaller than 0.1 µg/mL be-
tween the articles63. It is possible to speculate from the
similarities that quercetin is responsible for the effect and
the other compound plays a spectator role.
miR-21
The same research group published another paper
in 2015 describing the effect of the same combination
quercetin:hyperoside (1:1 ratio) in a different cell model
– prostate cancer cells PC3 cell line. The results show
deregulation of miR-21, a well-known oncogenic miRNA,
caused by quercetin/hyperoside combination. The miR-21
was downregulated compared to control cells by as much
as 4.3-fold at the highest concentration, and the deregu-
lation was accompanied by upregulation of PDCD4, a
tumor suppressor. The influence of miR-21 was validated
via pre-miR-21 transfection64. Because hyperoside is a
quercetin glycoside, its combination with quercetin agly-
con suggests that the synergistic effect may be linked to a
simple increase in free quercetin via deglycosylation. The
same could actually apply to miR-27 as discussed in the
previous paragraph.
Wang and colleagues65 used on a quercetin combina-
tion as well, in this case a mix of quercetin and arctigenin
evaluated in prostate cancer cell models (LAPC-4 and
LNCaP cell lines). They compared miRNA expression of
control cells with those treated with the arctigenin/quer-
cetin combination and uncovered several miRNAs that
were downregulated. Both cell lines showed a decrease of
at least 20% relative to negative control in miR-21, miR-
19b and miR-148a expression. However, LAPC cells were
more sensitive to the treatment (Table 1). Moreover, the
LAPC-4 cell line treated by arctigenin showed almost the
same expression of miR-19b and miR-21 even displayed
a decreasing trend compared to arctigenin/quercetin
samples. However, quercetin monotherapy was usually
weaker and, surprisingly, quercetin displayed an oppo-
site behavior for miR-21 in both cell lines65. MiR-19b and
miR-21 are usually designated as oncogenic66 and their
downregulation is recognized as a positive effect. The last
positive information in the paper is that no type of treat-
ment had any effect on proliferation of normal prostate
epithelial cells (PrEC) (ref.65).
Quercetin monotherapy modulates miR-21 as pub-
lished by an Iranian group of scientists, who tested the
effects of quercetin on breast cancer cell line MCF-7. The
proliferation of the cell line was strongly affected only at
very high concentrations (50 and 100 µM quercetin) after
24 h treatment. However, the paper presents two conflict-
ing IC50 values: the data from Fig. 1 do not correspond
with the 7.06 µM value presented in the text. Nevertheless,
relative expression of miR-21 was significantly downregu-
lated by quercetin, approximately two-fold at a concentra-
tion of 10 µM. The authors performed RT-PCR analysis of
gene expression of PTEN and Maspin, targets of miR-21
and showed that both mRNA were upregulated67.
Expression of miR-21 responds to the rate of oxidative
stress, e.g. as result of environmental pollutant exposure.
CrVI+ ions, inducers of ROS formation, are designated as
carcinogenic and are connected with lung cancer. The
study evaluated quercetin for its effects on acute CrVI+
response and alleviation of CrVI+ induced malignant trans-
formation. During the study it was discovered that quer-
cetin regulates the transformation through miR-21 and its
target protein PDCD4. Three sets of experiments were
performed (in vitro and in vivo). The first set was done on
BEAS-2B cells, which are lung epithelial cells. miR-21 was
upregulated four-fold by CrVI+ ions, compared to untreated
control (3.4/6.0/18 for chronic exposure – 2/4/6 months,
respectively). The upregulation was reduced by quercetin
approximately three-fold compared to CrVI+ treated cells
in acute CrVI+ exposure and 2.1/2.5/4.3 fold (roughly)
in chronic CrVI+ exposure (2/4/6 months). The chronic
CrVI+ treatment with quercetin resulted in modulation of
colony number. It is promising that the chronic effect of
CrVI+ was reversible by quercetin at a relatively low con-
centration. The second series of experiments included
an athymic nude mouse xenograft model with injected
chromium transformed cells. When the tumor reached
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99
a given volume, the quercetin treatment began and took
30 days (10 mg/kg/day, intraperitoneally). miR-21 was
downregulated in the tumor cells as well, confirming the
positive effect of quercetin in vivo. The third approach
consisted of a mouse xenograft model with application
of pre-treated BEAS-2B cells. The pre-treatment of the
cells was identical to that described in the chronic experi-
ment. Tumor analysis was done 30 days later. Quercetin
pre-treated BEAS-2B produced smaller tumors with lower
expression of miR-21 (ref.68).
Finally, a Chinese research group form Daqingshi No.
4 Hospital published an article describing attenuation of
fibrosis induced by transforming growth factor-β (TGF-β)
in HK-2 cell line (renal tubular epithelial cells) as a result
of quercetin treatment (15 mg/mL) in 2018. The effect
is associated with suppression of miR-21-5p overexpres-
sion caused by TGF-β treatment. The effects of quercetin
are partially reversed by miR-21 mimics. On the other
hand, the doses of quercetin used were extremely high
and unachievable in aqueous medium. It seems that the
concentrations reported correspond to stock solutions,
not the final concentrations in the medium. In addition,
important information is missing in the paper, e.g. dura-
tion of incubation during selected experiments69.
miR-155
Quercetin causes changes in levels of miR-155 (ref.70)
that are induced by the inflammation signalling pathway
but react in the opposite way compared to the effect on
miR-146a. The study assessed modulation of the miRNA
by quercetin and its two important metabolites in murine
RAW264.7 macrophages. Normally, miR-155 is increased
12-fold by LPS treatment, relative to negative control.
However, the presence of quercetin or its metabolite isor-
hamnetin reduced the effect of LPS by approximately
1.8/1.5 fold. The assumed mechanism of miR-155 regula-
tion by quercetin is via direct and indirect modulation
through NFκB. Quercetin-3-glucuronide, that was also
used in the study, had no impact70.
let-7 family
The influence of quercetin on let-7a in pancreatic duc-
tal adenocarcinoma was shown by Appari et al.71. These
authors demonstrated that quercetin treatment for 72 h
increased the amount of let-7a 2.45/1.6/1.45 fold in MIA-
PaCa2/BxPC-3/PacaDD-183 cells compared to control,
3.0/2.3/2.45 fold in MIA-PaCa2/BxPC-3/PacaDD-183
cells in combination treatment with sulforaphane and
3.2/3.1/3.1 fold in MIA-PaCa2/BxPC-3/PacaDD-183
cells with green tea catechins, respectively. let-7a enhance-
ment was accompanied by K-Ras downregulation on both
mRNA and protein levels with the exception of quercetin
only treated cells, in which no changes in K-Ras protein
levels were observed71. The effect of let-7a against Ras
protein correlates with the findings of Johnson et al.72.
Non-malignant pancreatic ductal cells showed minimal
changes71.
Similar data for let-7 family, 7c isoform in particular,
in pancreatic ductal adenocarcinoma were published by
Nwaeburu et al.73. The miRNA showed approximately
1.8/1.3/1.9 fold higher expression after 50 µM quercetin
treatment in AsPC-1/AsanPACA/PANC-1 cells. A result
of let-7c modulation in AsPC-1 was positive regulation of
Numb protein, inhibitor of Notch, accompanied by a de-
crease in Notch protein level. The authors also confirmed
an additional five miRNAs with response to quercetin via
RT-PCR (miR-200a/200b/103/125b/1202) and published
a heatmap of 24 miRNAs with the highest deregulation
after quercetin treatment73.
miR-200b-3p
A follow-up study by Nwaeburu et al.74 focused on
miR-200b-3p that was significantly modulated (upregu-
lated more than 2.5 times) by quercetin (50 µM) in pan-
creatic ductal adenocarcinoma (AsPC-1). Activity of
miR-200b-3p against Notch 3’ UTR region was demon-
strated. The article describes an unusual combination of
effects. miR-200b caused attenuation of luciferase activity
of reporter gene containing 3’ UTR of Notch1, but there
was no effect on Notch1 mRNA expression. This sug-
gests that miR-200b-3p only blocks translation and does
not cause cleavage of mRNA. The inhibition of Notch
protein is associated with cell fate decision therefore the
quercetin treated cells prefer an asymmetric cell division.
On the other hand, the results of miR-200b-3p transfec-
tion showed activation of Numb transcription74 similar to
let-7c transfection in Nwaeburu et al.73 published in 2016.
It seems that miR-200b-3p associated activation of Numb
is more important than 3’ UTR anti-notch activity. If we
consider both articles published by Nwaeburu et al.73,74, we
can recognize a synergy in the effect of the two miRNAs,
miR-200b-3p and let-7c, on quercetin treated PDA cells.
Both miR-200b-3p, and let-7c, upregulate Numb protein,
the Notch1 inhibitor.
miR-17-3p
Quercetin also affects expression of ferroportin, a
membrane exporter of ferrous iron in the intestine, via
miR-17-3p. The exporter is located in enterocytes, more
precisely on the basolateral membrane75. The main role of
the protein is to transport iron from intracellular to extra-
cellular space. A specific block of enterocyte ferroportin
expression should have an influence on intestinal iron ab-
sorption76. The research group used Caco-2 TC7 cell line
as their cell model for miRNAs experiments. During miR-
NA array analysis, some miRNAs were identified with an
increase in expression of over 1.5 fold after 10 µM querce-
tin treatment, 33 miRNAs in total according to the text,
with another two in the supplementary table. Ferroportin
3’UTR region contains binding site for miR-17-3p. The
PCR data showed that miR-17-3p is upregulated over 90
(a.u.) compared to control. Moreover, quercetin decreases
activity of luciferase plasmid containing the ferroportin 3’
UTR region75. The article also reports that quercetin and
its 4-O-methyl analog increase uptake and decrease efflux
of iron in rat duodenum.
miR-16
Sonoki and colleagues focused on the impact of quer-
cetin treatment in lung adenocarcinoma A549 cells. The
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100
A549 cells were exposed to 50 µM quercetin for 24 h and
observed induction of miR-16 expression, approximately
1.4 fold compared to untreated control. The result was a
decrease in Claudin-2 mRNA and protein level, with the
effect being partially reversed by miR-16 inhibitor77.
miR-217
Zhang et al.78 tested the effect of quercetin on cispla-
tin treatment in an osteosarcoma model. They used the
143B cell line and recognized that miR-217 is partially
responsible for quercetin- mediated sensitivity of cells to
cisplatin. The induced expression of miR-217 caused a
decrease of K-Ras protein and mRNA expression as both
quercetin and cisplatin upregulate miR-217 expression
with a synergic effect if used together. The importance
of miR-217 was shown via miR-217 mimics/anti-miR-217
that partially enhance/reverse cisplatin and/or quercetin
outcome. The paper also includes the information that
K-Ras regulates the PI3K/AKT pathway78. K-Ras is not
the only player in PI3K/AKT regulation in the treatment,
since quercetin is also a known regulator of the pathway.
miR-142-3p
miR-142-3p is another miRNA modulated by querce-
tin. MacKenzie et al.79 discovered that quercetin at 100
µM (as well as triptolide at 100 nM) upregulated the
miRNA in three different types of pancreatic ductal ad-
enocarcinoma cells: over three-fold in MIA PaCa-2 cells,
almost eight-fold in Capan-1 cells and more than three-
fold in S2-013 cells. Most of the experiments however
were performed only with triptolide79.
miR-145
Dose dependent induction of miR-145 was observed
in ovarian cancer cells (SKOV-3 and A2780) as a result
of quercetin treatment (0 – 100 µm/mL). miR-145 was
increased approximately 3/3.5 fold for SKOV-3/A2780 at
the highest concentration after 24 h treatment. Quercetin
(50 µm/mL) was indicated as IC50 for 48 h incubation
and this concentration was used in further experiments.
The miRNA upregulation is linked to growth inhibition
and enhancement of caspase-3 cleavage that can be re-
versed by miRNA-inhibitor. However, the article does not
reveal the molecular mechanism in detail such as which
target protein is modulated by upregulated miR-145. We
assume that the observed caspase effect is a consequence
of miR-145 protein target regulation80. The article provides
concentrations in “µm/mL”, however it is not clear what
this non-standard unit represents (see also in Tao et al.57 ).
In vivo experiments (several miRNAs tested)
In vitro experiments aside, some in vivo studies into
quercetin’s effect on miRNA were performed. An example
is the study by Wien et al.81, in which male Wistar rats
were fed a diet containing approximately 10 mg/kg per
day quercetin for 7 weeks. PCR array analysis of 352 miR-
NA showed 23 deregulated hepatic miRNAs. Nineteen
of them had more than three-fold lower expression than
control group, although the published table in the article
contains only 13 miRNAs. The remaining miRNAs (four
species) showed increased expression by the same value
(see Table 2). The group demonstrated that the most de-
regulated rno-miR-125b-3p (nine fold) presumably induc-
es γ-glutamyl hydrolase expression (measured at mRNA
level by RT-PCR) due to its downregulation81. The authors
used a sample pooled from eight animals for each group
tested, to evaluate miRNA expression via PCR array.
γ-glutamyl hydrolase represents an important enzyme as-
sociated with cancer and its high levels are discussed as
a poor prognosis marker during invasive breast cancer82.
Rats are not the only model used, as there are also at least
five articles using mice as an in vivo model (see Table 2).
Quercetin and 8 other polyphenols were investigated
in apoE deficient mice, a model of deregulated lipid me-
tabolism. The study used microarrays for miRNA (567
species) and mRNA (35,852 probes) expression patterns
(signatures) as a powerful tool of comprehensive analysis.
The experiment was designed as follows - two week’s expo-
sure with 0.006% (w/w) of quercetin in the diet. The dose
corresponds to 30 mg per day for humans. The results
showed 47 miRNAs with different expression for querce-
tin and control group. 22 miRNAs had reduced expres-
sion and 25 miRNAs had induced expression. Moreover,
five miRNAs displayed expression similarities across test-
ed polyphenols. Three species exhibited lower expression
(mmu-miR-30c-1*, mmu-miR-374* and mmu-miR-467b*)
and two remaining miRNAs exhibited higher expression
(mmu-miR-291b-5p and mmu-miR-296-5p) compared to
control. Moreover, the authors discovered an interesting
phenomenon. The ApoE miRNA signature was partially
reversed by polyphenols, including quercetin toward the
wild type signature83.
Another interesting finding is the effect of quercetin,
exercise or their combination on miRNA expression and
their interaction with an atherogenic diet. Authors used
C57BL/6J LDL−/− mice. miRNAs expression was assessed
in aorta and liver tissues. Experiments suggested upregula-
tion of miR-21 in the aorta after exercise and quercetin/
exercise group. Aorta miR-125b was also upregulated in
the quercetin/exercise group. However, miR-451 showed
non-significant changes in the same tissue. In the liver
tissue, expression of miR-21 displayed the same expres-
sion pattern as for the aorta. Moreover, quercetin slightly
potentiated the effect of exercise on liver miR-21 expres-
sion, but quercetin monotherapy was not effective. On
the other hand, exercise decreased expression of miR-451
in the liver and combination with quercetin reduced the
effect of exercise. Quercetin alone caused non-significant
downregulation. miR-125b in the liver samples displayed
almost no effect of quercetin but the same compound
in combination with exercise mildly attenuated (non-sig-
nificant) the exercise induced upregulation of miR-125b.
Quite a few of these results were trends84.
Boesch-Saadatmandi and colleagues published a pa-
per in 2012 describing two other miRNAs regulated by
quercetin achieved with in vivo experiment. They used a
female mouse model C57BL/6J with chronic subacute
inflammation induced by a high fat diet. Liver miR-122
and miR-125b were upregulated dose dependently after
six weeks of consumption of the quercetin containing diet.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019 Jun; 163(2):95-106.
101
* Against positive LPS treatment
† Authors determined amount of polyphenols in the fraction via total
reduction capacity and gallic acid was used as standard (20 mg GAE/L
= mg gallic acid equivalents/L)
Proposal = not confirmed directly in the article. For example via anti-
miR experiment
# = not statistically significant
x = compared to CrVI+ treated cells
y = compared to TGF-β treated cells
Table 1. Summary of quercetin mediated miRNAs with modulated targets and treatment characteristics – in vitro. The values for
miRNA expression were usually estimated from article graphs
miRNA
Modulation
of miRNA
[folds of control]
Model
Quercetin treatment
[highest concentration]
Length of treatment
[h]
Involved proteins
Reference
↑ 4.0 MCF-7
↑ 4.5 MDA-MB-231
miR-146a
↑ res tore
to contr ol
level or exceed it
CCD-18Co
undete rmined†
20 - 40 mg GAE /L
(flavonol-rich f rac tion)
Pretreatment
30 min before
st imulat ion w ith LP S
or LP S + an ti-miR
proposa l
(not direc tly confirmed)
IRAK 1 ↓ and TRAF 6 ↓
Nora tto et al., 2011 ( ref.
37
)
miR-27a ↓ 2.0 HT-29
20 µg/ml
(resveratro l/quercet in mixture)
24 ZBTB10 (mRNA level) ↑
Del Follo-Mar tinez et al., 2013 (r ef.
62
)
miR-27a ↓ 2.0
786-O
20 µg/ml
(quercetin/hyperoside mixt ure)
24 ZBTB10 (mRNA level) ↑
Li et al., 2014 (ref.
63
)
miR-21 ↓ 4.3 (77 %) PC3
20 µg/ml
(quercetin/hyperoside mixt ure)
24 PDCD4 ↑
Yang e t al., 2015 (re f.
64
)
miR-19b ↓ 3.4
miR-21 ↓ 1.7
miR-148a ↓ 3.5
miR-19b ↓ 1.2
miR-21 ↓ 1.3
miR-148a ↓ 1.5
miR-19b ↓ 1.45
miR-21 ↑ 1.4
miR-148a ↓ 1.5
miR-19b ↓ 1.75
miR-21 ↑ 1.7
miR-148a ↓ 1.05
miR-21 ↓ 1.8 MCF-7
10 µM 24
PTE N↑ and M aspin ↑
(not direc tly confirmed)
Tofigh et al., 2017 (r ef.
67
)
miR-21
↓ 3.0
x
10 µM (+ 5 µM Cr
VI+
)24 (ac ute) PDCD4 ↑
↓ 2.1
x
2 months PDCD4 ↑
↓ 2.5
x
4 months PDCD4 ↑
↓ 4.3
x
6 months PDCD4 ↑
miR-21-5p
↓ 1.4
y
HK-2 15 mg/ml (50 mM) PTE N ↑ and TIMP3 ↑ Cao e t al., 2018 (re f.
69
)
miR-155 ↓ ~ 1.8* RAW264. 7 10 µM 6
proposa l T NF-α
(not direc tly confirmed)
Boes ch-Saada tmandi et al., 2011 ( ref.
70
)
↑ 2.45 MIA-PaCa2
↑ 1.6 BxPC-3
↑ 1.45 PacaDD-183
↑ 1.35 # CRL1097
↑ 3.0 MIA-Pa Ca2
↑ 2.3 BxPC-3
↑ 2.45 PacaDD-183
↑ 1.5 # CRL1097
↑ 3.2 MIA-Pa Ca2
↑ 3.1 BxPC-3
↑ 3.1 PacaDD-183
↑ 1.6 # CRL1097
↑ 1.8 AsPC-1
Numb ↑
↑ 1.3 ASANPaCa
↑ 1.9 PANC-1
miR-200b ↑ 2.6 Notc h ↓
miR-200a ↑ 2.1
miR-103 ↓ 1.3
miR-125b ↓ 1.4
miR-1202 ↓ 3.3
miR-17-3p
↑ over 1.5 Caco-2 TC7 10 µM 18
Ferr oportin ↓
(not direc tly confirmed)
Les jak et a l., 2014 (r ef.
75
)
miR-16 ↑ 1.4 A549 50 µM 24 Claudin-2 ↓
Sonoki et a l. , 2015 (re f.
77
)
↑ 1.45 24
↑ 1.8 48
↑ 2.9 24
↑ 3.5 48
↑ 3.1 MIA-PaCa2
↑ 7.6 Capan-1
↑ 3.4 S2-013
↑ 3.0 SKOV-3
↑ 3.5 A2780
miR-142-3p
MacKenzie et al., 2013 (ref.
79
)
Zhang e t al., 2015 (re f.
78
)
Zhou et al., 2015 (ref.
80
)
Nwa eburu et a l. , 2016 (ref.
73
)
Nwa eburu et a l. , 2017 (ref.
74
)
LAPC-4
10 µM - Que rce tin
LNCaP
10 µM - Que rce tin
no direct confirmat ion
Wang e t al., 2015 (re f.
65
)
48
100 µm/ml
48
K-Ras ↓ (mRNA level)
(prote in level showe d exce ptions
afte r sulforapha ne, querce tin
treatment)
(not direc tly confirmed)
10 µM - Sulforapha ne
200 µM - Que rce tin
200 µM - Que rce tin
Tao e t al., 2015 (re f.
57
)
miR-146a
Appar i e t al., 2014 (re f.
71
)
let-7a
40 µM - green tea extract
200 µM - Que rce tin
72
Bax ↑, C aspase -3 ↑, EGFR ↓
miR-21
Pra theeshkuma r et al., 2017 ( ref.
68
)
no direct confirmat ion
1 µM - Arc tigenin
10 µM - Que rce tin
no direct confirmat ion
1 µM - Arc tigenin
10 µM - Que rce tin
LNCaP
miR-145
24
100 µm/ml
Caspase-3 ↑
(growt h inhibition)
2 µM (+ 0.5 µM Cr
VI+
)
BEAS-2B
miR-217
let -7 c
LAPC-4
no direct confirmat ion
143B
12
5 µM - Quercetin
no direct confirmat ion
no direct confirmat ion
AsPC-1
50 µM
100 µM
24
5 µM - Quercetin
5 µM - Cisp latin
K-Ras ↓
no direct confirmat ion
with quer cet in
(HSP 70 ↓)
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019 Jun; 163(2):95-106.
102
Table 2. Summary of quercetin mediated miRNAs with modulated targets and treatment dose of the compound characteristics
in vivo. The values for miRNA expression were usually estimated from article graphs.
ip = intraperitoneal
x = compared to CrVI+ treated cells
CrT = chromium transformed cells
2 mg quercetin/g diet caused 1.6 to 1.5-fold upregulation,
0.2 mg quercetin/g diet only resulted in non-significant
enhancement85.
Patient samples
The last set of findings is based on an epidemiologic
study of Lung cancer tissues. The question was whether
a quercetin-rich diet can modulate miRNA expression.
Data presented in this study showed that there is a group
of miRNAs which was significantly upregulated (2
miRNAs/4 miRNAs) or downregulated (2 miRNAs /8
miRNAs) in adenocarcinoma/squamous cell carcinoma
between groups consuming high and low quantities of
quercetin-rich food (see Table 3). The authors applied an
advanced complex sorting based on former/current smok-
ing + histology or sorting according to miRNA families in
combined with smoking status and histology86.
Quercetin glycosides and its derivatives
Scientists are interested in derivatives of quercetin
such as rhamnetin that modulates miR-34a in different
cell lines87-89. Finally, we found an article, which reversed
the usual logic. The authors used miR-143 as a molecule
that increases chemosensitivity to quercetin in gastric can-
miRNA
Modulation
of miRNA
[folds of control]
Model
Quercetin treatment
[highest concentration]
Length of treatment
Involved proteins
Reference
miR-146a ↑ over 1.75
female BALB/c
athymic nude
mouse ( xenogra ft)
10 mg/kg per day 8 w eeks
authors only c ompare
size of tumor a nd
miR-146a e xpression
Tao e t al., 2015 (re f.57)
↓ 1.5
Cr T ce lls inje cte d int o fla nk
10 mg/kg per day
ip a dmin ist ra tion
30 days
↓ 1.7x
pretreated BEAS-2B cells
injected into fla nk
2 µM (+ 0.5 µM CrVI+)
pretreatment of
BEAS-2B cells
6 months
miR-125b-3p ↓ 9
γ-glutamyl hydrolase
(not direc tly confirmed)
miR-133b ↓ 7
miR-505 ↓ 7
miR-1 ↓ 6
miR-342-3p ↓ 5
miR-298 ↓ 5
miR-503 ↓ 4
miR-206 ↓ 4
miR-33 ↓ 4
miR-216a ↓ 4
miR-301a ↓ 3
miR-21 ↓ 3
miR-205 ↓ 3
miR-125a-3p ↑ 5
miR-132 ↑ 5
miR-411 ↑ 4
miR-484 ↑ 3
25 miRNAs ↑ over 1.5
22 miRNAs ↓ over 1.5
↑ 1.2
100 µg/day
↑ 1.85
100 µg/day + exe rcise
↓ 1.12
100 µg/day
↑ 2.0
100 µg/day + exe rcise
↓ 1.1
100 µg/day
↑ 1.79
100 µg/day + exe rcise
↓ 1.26
100 µg/day
↑ 2.77
100 µg/day + exe rcise
STAT3 ↓ and NF-κB ↑
(Da ta not shown,
discuss ed in the te xt)
↑ 2.0
100 µg/day
↓ 1.1
100 µg/day + exe rcise
↓ 1.4
100 µg/day
↓ 2.03
100 µg/day + exe rcise
miR-122 ↑ 1.6
acyloxya cyl hydrolase ↓
(not direc tly confirmed)
miR-125b ↑ 1.5
TNF-α ↓ (spec ulation)
several pathway discused
(not direc tly confirmed)
7 wee ks
Wein et al., 2015 (r ef.81)
not stated
miR-21
Pra theeshkuma r et al., 2017 ( ref.68)
PDCD4 ↑
female NU/NU Athymic
nude mouse
Milenkovic et a l., 2012 (r ef.83)
fema le C57BL/6J
mouse ( liver)
0.2 a nd 2 mg/g diet
6 wee ks
male Wistar rat
10 mg/kg per day
(100-ppm que rce tin)
In vivo
Boes ch-Saada tmandi et al., 2012 ( ref.85)
wild-type a nd apoE
knock-out mous e
(male, C 57BL/6)
0.006 % (w/w)
(
human equivalent
intake 30 mg/day)
Gare lnabi et al., 2014 (ref.84)
miR-125b
live r
miR-451
aorta
miR-451
live r
male C57B L/6J LDL−/−
mouse
30 days
miR-21
aorta
miR-125b
aorta
miR-21
live r
no direct confirmat ion
no direct confirmat ion
2 wee ks
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019 Jun; 163(2):95-106.
103
cer cells via autophagy inhibition. The autophagy inhibi-
tion was mediated by GABARAPL1, a miR-143 target90.
CONCLUSION
We found a total of ninety-five different species of
miRNA affected by quercetin in our literature research.
Of these, 18 miRNAs were revealed as deregulated in in
vitro experiments, 66 through in vivo experiments and fi-
nally, 15 were discovered in human tissue samples. Several
miRNA molecules were expressed with a common pattern
among in vitro and in vivo experiments as a result of quer-
cetin treatment. miR-21 in particular was deregulated in
the same manner (downregulation) in MCF-7, BEAS-2B
and HK-2 cell lines and in two in vivo models (mouse/
rat)67-69,81. The literature search identified a few exceptions
in two articles that reported quercetin mediated upregula-
tion of miR-21 in the majority of samples65,84. Interestingly,
quercetin causes modulation of let-7c and miR-200b in the
same cell line and it seems that these miRNAs cooper-
ate73,74. The data suggest synergy in potential anti-cancer
effects against pancreatic ductal cell adenocarcinoma.
Further, the patient samples described in Lam et al.86
study, displayed ambiguous expression of miR-502 that
was upregulated in lung adenocarcinoma tissues but lung
squamous cell carcinoma tissues showed downregulation
of the expression when tissues from highest/lowest quer-
cetin-rich food consumers were compared86.
Some miRNA molecules can serve as predictive mark-
ers of cancers, especially miR-21 and let-7 family91 that
are modulated by quercetin. MiR-21 is commonly recog-
nized as oncogenic and as an unfavorable prognostic fac-
tor91,92. As expected, its expression was evaluated in many
studies and quercetin or combination treatment usually
downregulate miR-21 expression regardless of the tested
model (in vitro/in vivo). The let-7 family, on the other
hand, is widely viewed as a tumor suppressor miRNAs91,93.
Different members of the miRNA family are often upregu-
lated by quercetin treatment. Shin et al.91 discuss miR-27a
as a diagnostic marker of gastric cancer and miR-146a
as gastric cancer-associated miRNA (ref.91). Both miR-
NAs are modulated by quercetin. These results suggest
that quercetin could function prophylactically in cancer
prevention (e.g. in nutraceutics) with minor exceptions,
e.g. Wang et al.65 - quercetin only treatment enhanced
expression of miR-21.
Many of the studies published used high concentra-
tions, usually several tens of µM that are not physiologi-
cally achievable per os from a regular diet. The data could
be viewed as an interesting option for adjuvant therapies.
ABBREVIATIONS
DMSO, Dimethyl sulfoxide; PBS, Phosphate-buffered
saline; ROS, Reactive oxygen species; LPH, Lactase phlo-
ridzin hydrolase; RISC, RNA-induced silencing complex;
DGCR8, DiGeorge syndrome critical region 8; LPS,
Lipopolysaccharide; AhR, Aryl hydrocarbon receptor;
miRNA, micro ribonucleic acid; CYP, Cytochrome P450;
mRNA, messenger ribonucleic acid; GAE/L, Gallic acid
equivalents per liter; TGF-β, Transforming growth factor
β; TCDD, 2,3,7,8-Tetrachlorodibenzodioxin; TRBP, Trans-
Activation Responsive RNA-Binding Protein; BRCA1/2,
Breast cancer type 1/2 susceptibility protein; EGFR,
Epidermal growth factor receptor; IRAK-1, Interleukin-1
receptor associated kinase 1; TRAF-6, Tumor necrosis
factor receptor associated factor 6; TLR pathway, Toll-
like receptor pathway; ZBTB10, Zinc Finger And BTB
Domain-Containing Protein 10; Sp transcription fac-
tors, Specificity protein transcription factors; PDCD4,
Programmed cell death protein 4; PTEN, Phosphatase
and tensin homolog; Maspin, Mammary serine prote-
ase inhibitor; NF-κB, Nuclear Factor Kappa B; PCR,
Polymerase chain reaction; RT, Room temperature.
Table 3. Summary of quercetin mediated miRNAs with modulated targets and treatment characteristics – patient samples.
miRNA
Modulation
of miRNA
[folds of control]
Model
Quercetin treatment
[highest concentration]
Length of treatment
Involved proteins
Reference
miR-502 ↑ 1.124
miR-125a ↑ 1.505
miR-564
↓ 1.124
miR-124a
↓ 1.174
miR-155 ↑ 1.399
miR-18b ↑ 1.483
miR-612 ↑ 1.069
miR-363* ↑ 1.222
miR-510
↓ 1.147
miR-605
↓ 2.315
miR-373
↓ 1.091
miR-453
↓ 1.112
miR-502
↓ 1.248
miR-183
↓ 1.464
miR-573
↓ 1.151
miR-524* ↓ 1.170
Lam et al., 2012 (ref.
86
)
St at istic ally dif fe ren t
expre ssion betwe en high
and low Que die t only
(Highes t/lowes t querce tin-
rich food c onsumers )
Lung ade nocar cinoma
tissues
Lung squa mous c ell
carcinoma tissues
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019 Jun; 163(2):95-106.
104
Search strategy and selection criteria
Our article focuses on the miRNA modulation as
impact of quercetin treatment or combination of com-
pounds containing quercetin. Minor emphasis was placed
on pharmacokinetics of quercetin and miRNA biogenesis.
The scientific articles from 1972 to 2019 were searched
using the PubMed and Google Scholar. All the documents
were searched through keywords such as “Quercetin,
miRNA, modulation, microRNA, regulation and poly-
phenols”. Only English language articles were reviewed.
Acknowledgement: This work was supported by IGA_
LF_2019_015 and the Institutional Support of Palacký
University in Olomouc RVO 61989592. The authors are
thankful to Dr. A.V. Zholobenko for proofreading of the
manuscript.
Author contribution: All authors contributed equally to
preparing the manuscript.
Conflict of interest statement: The authors state that there
are no conflicts of interest regarding the publication of
this article.
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... This finding is in line with Boone et al. [23] who reported that herbs added to honey can treat sore throats and coughs. Besides, Boone et al. [23] documented that a mixture of 1 teaspoon of honey with 1 teaspoon of dried orange peel and ginger can boost innate immunity to reduce infection hazards associated with CoV. ...
... This finding is in line with Boone et al. [23] who reported that herbs added to honey can treat sore throats and coughs. Besides, Boone et al. [23] documented that a mixture of 1 teaspoon of honey with 1 teaspoon of dried orange peel and ginger can boost innate immunity to reduce infection hazards associated with CoV. Furthermore, it was documented that respiratory symptoms associated with coronavirus can be treated naturally, using traditional Chinese medicine or herbal Boone et al. [23]. ...
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Background Cancer stem cells are suggested to contribute to the extremely poor prognosis of pancreatic ductal adenocarcinoma and dysregulation of symmetric and asymmetric stem cell division may be involved. Anticancer benefits of phytochemicals like the polyphenol quercetin, present in many fruits, nuts and vegetables, could be expedited by microRNAs, which orchestrate cell-fate decisions and tissue homeostasis. The mechanisms regulating the division mode of cancer stem cells in relation to phytochemical-induced microRNAs are poorly understood. Methods Patient-derived pancreas tissue and 3 established pancreatic cancer cell lines were examined by immunofluorescence and time-lapse microscopy, microRNA microarray analysis, bioinformatics and computational analysis, qRT-PCR, Western blot analysis, self-renewal and differentiation assays. ResultsWe show that symmetric and asymmetric division occurred in patient tissues and in vitro, whereas symmetric divisions were more extensive. By microarray analysis, bioinformatics prediction and qRT-PCR, we identified and validated quercetin-induced microRNAs involved in Notch signaling/cell-fate determination. Further computational analysis distinguished miR-200b-3p as strong candidate for cell-fate determinant. Mechanistically, miR-200b-3p switched symmetric to asymmetric cell division by reversing the Notch/Numb ratio, inhibition of the self-renewal and activation of the potential to differentiate to adipocytes, osteocytes and chondrocytes. Low miR-200b-3p levels fostered Notch signaling and promoted daughter cells to become symmetric while high miR-200b-3p levels lessened Notch signaling and promoted daughter cells to become asymmetric. Conclusions Our findings provide a better understanding of the cross talk between phytochemicals, microRNAs and Notch signaling in the regulation of self-renewing cancer stem cell divisions.
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Oxidative stress is viewed as an imbalance between the production of reactive oxygen species (ROS) and their elimination by protective mechanisms, which can lead to chronic inflammation. Oxidative stress can activate a variety of transcription factors, which lead to the differential expression of some genes involved in inflammatory pathways. The inflammation triggered by oxidative stress is the cause of many chronic diseases. Polyphenols have been proposed to be useful as adjuvant therapy for their potential anti-inflammatory effect, associated with antioxidant activity, and inhibition of enzymes involved in the production of eicosanoids. This review aims at exploring the properties of polyphenols in anti-inflammation and oxidation and the mechanisms of polyphenols inhibiting molecular signaling pathways which are activated by oxidative stress, as well as the possible roles of polyphenols in inflammation-mediated chronic disorders. Such data can be helpful for the development of future antioxidant therapeutics and new anti-inflammatory drugs.
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The present study aimed to investigate whether rhamnetin induced apoptosis in human breast cancer cells and the underlying molecular mechanism of this anti cancer effect. The treatment of MCF-7 cells with rhamnetin was able to significantly inhibit cell proliferation and induce caspase-3/9 activity in a dose- and time-dependent manner, compared with untreated cells. In addition, treatment with rhamnetin was able to significantly promote the expression of p53 protein and microRNA (miR-)34a compared with untreated cells. The treatment with rhamnetin also suppressed the expression of Notch1 protein in MCF-7 cells compared with untreated cells. Subsequently, miR-24a expression was promoted in rhamnetin-treated MCF-7 cells using a miR-34a plasmid. The overexpression of miR-34a was able to significantly inhibit cell viability and induce caspase-3/9 activity in MCF-7 cells following treatment with rhamnetin. Furthermore, the overexpression of miR-34a was able to significantly promote the expression of p53 protein and miR-34a, and suppress the expression of Notch1 protein in rhamnetin-treated MCF-7 cells. Therefore, the results of the present study demonstrated that rhamnetin induced apoptosis in human breast cancer cells via the miR-34a/Notch-1 signaling pathway.
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Etoposide is commonly used as a monotherapy or in combination with other drugs for cancer treatments. In order to increase the drug efficacy, ceaseless search for novel combinations of drugs and supporting molecules is under way. MiRNAs are natural candidates for facilitating drug effect in various cell types. We used several systems to evaluate the effect of miR-29 family on etoposide toxicity in HeLa cells. We show that miR-29b significantly increases etoposide toxicity in HeLa cells. Because Mcl-1 protein has been recognized as a miR-29 family target, we evaluated downregulation of Mcl-1 protein splicing variant expression induced by miR-29 precursors and confirmed a key role of Mcl-1 protein in enhancing etoposide toxicity. Despite downregulation of Mcl-1 by all three miR-29 family members, only miR-29b significantly enhanced etoposide toxicity. We hypothesized that this difference may be linked to the change in Mcl-1L/Mcl-1S ratio induced by miR-29b. We hypothesized that the change could be due to miR-29b nuclear shuttling. Using specifically modified miR-29b sequences with enhanced cytosolic and nuclear localization we show that there is a difference, albeit statistically non-significant. In conclusion, we show that miR-29b has the synergistic effect with etoposide treatment in the HeLa cells and that this effect is linked to Mcl-1 protein expression and nuclear shuttling of miR-29b.
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MicroRNAs (miRs) are a class of single-stranded RNA molecules of 15–27 nucleotides in length that regulate gene expression at the post-translational level. miR-21 is one of the earliest identified cancer-promoting ‘oncomiRs’, targeting numerous tumor suppressor genes associated with proliferation, apoptosis and invasion. The regulation of miR-21 and its role in carcinogenesis have been extensively investigated. Recent studies have focused on the diagnostic and prognostic value of miR-21 as well as its implication in the drug resistance of human malignancies. The further use of miR-21 as a biomarker and target for cancer treatments is likely to improve the outcome for patients with cancer. The present review highlights recent findings associated with the importance of miR-21 in hematological and non-hematological malignancies.