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DOI:http://dx.doi.org/10.7314/APJCP.2014.15.21.9341
Acanthopanax trifoliatus (L) Merr Extracts Inhibit NF-κB Activity and Decrease Erk1/2 and Akt Phosphorylation
RESEARCH ARTICLE
Anticancer Activity of Acanthopanax trifoliatus (L) Merr
Extracts is Associated with Inhibition of NF-kB Activity and
Decreased Erk1/2 and Akt Phosphorylation
Hua-Qian Wang1, Dong-Li Li1, Yu-Jing Lu1, Xiao-Xing Cui2, Xiao-Fen Zhou1,
Wei-Ping Lin1, Allan H Conney1, 2, Kun Zhang1, 3, Zhi-Yun Du1*, Xi Zheng1, 2*
Abstract
Acanthopanax trifoliatus (L) Merr (AT) is commonly used as an herbal medicine and edible plant in some
areas of China and other Asian countries. AT is thought to have anticancer effects, but potential mechanisms
remain unknown. To assess the anticancer properties of AT, we exposed prostate cancer cells to AT extracts and
assessed cell proliferation and signaling pathways. An ethanol extract of AT was suspended in water followed by
sequential extraction with petroleum ether, ethyl acetate and n-butanol. PC-3 cells were treated with different
concentrations of each extract and cell viability was determined by the MTT and trypan blue exclusion assays.
The ethyl acetate extract of the ethanol extract had a stronger inhibitory effect on growth and a stronger
stimulatory effect on apoptosis than any of the other extracts. Mechanistic studies demonstrated that the ethyl
acetate extract suppressed the transcriptional activity of NF-kB, increased the level of caspase-3, and decreased
the levels of phospho-Erk1/2 and phospho-Akt. This is the first report on the anticancer activity of AT in cultured
human prostate cancer cells. The results suggest that AT can provide a plant-based medicine for the treatment
or prevention of prostate cancer.
Keywords: Plant extract - prostate cancer - apoptosis - NF-kB - HPLC
Asian Pac J Cancer Prev, 15 (21), 9341-9346
Introduction
Prostate cancer is the second leading cause of cancer
related deaths in males in western countries (Siegel et
al., 2012), but has a relatively low incidence in Asia,
particularly in South East Asia (Baade et al., 2009).
Early stage prostate cancer requires androgen for growth
and thus responds well to androgen deprivation therapy
(Loblaw et al., 2007), but tumors become resistant to this
therapy as disease progresses (Pilat et al., 1998; So et al.,
2005; Schroder, 2008; Chi et al., 2009). Chemotherapy is
the primary treatment option for late-stage prostate cancer
patients, but this has limited efficacy and serious toxic side
effects and the prognosis for these patients is very poor
(Gomella et al., 2009; Neri et al., 2009). Therefore, there
is a need for novel therapeutic approaches for treating and
preventing androgen-independent prostate cancer while
minimizing toxic side effects.
Plant-derived natural products are potential sources for
developing novel anticancer agents. Naturally occurring
compounds in plants have been shown to inhibit multidrug
resistance with minimal side effects (Cragg and Newman,
2005; Meiyanto et al., 2012). Furthermore, many existing
FDA-approved anticancer agents are of natural origin
(Saunders and Wallace, 2010). Acanthopanax trifoliatus
(L) Merr (AT) is a widely available plant in China that
belongs to the Acanthopanax species. Plants of this species
are commonly used as herbal medicines such as Radix
Acanthopanacis Senticosl.
AT is most commonly used as a traditional Chinese
medicine and as a food, tea, and shower additive. AT
is believed to have anti-inflammatory activity, and we
recently observed that AT extract has strong antioxidant
and anti-inflammatory effects (unpublished observations).
Histological, molecular genetics, and epidemiological
studies suggest that inflammation is important for
the development of prostate cancer (De Marzo et al.,
2007; Hanahan and Weinberg, 2011; Ianni et al., 2013).
Thus, the anti-inflammatory activity of AT may provide
anticancer benefits for prostate cancer patients. Here we
present a study investigating the effects of AT extracts on
prostate cancer cells. To our knowledge, this is the first
report investigating the anticancer activity of AT against
prostate cells
Allan H Conney Laboratory for Anticancer Research, School of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou, 3Wuyi University, Jiangmen, Guangdong, China, 2Susan Lehman Cullman Laboratory for Cancer Research,
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Jersey, USA
*For correspondence: xizheng@pharmacy.rutgers.edu, zhiyundu@gdut.edu.cn
1
Asian Pacific Journal of Cancer Prevention, Vol 15, 2014
9341
Hua-Qian Wang et al
Materials and Methods
Preparation of AT extracts
AT plants were collected from Jiangmen City in
the southwestern part of Guangdong Province, China.
Stems and leaves were collected together according to
the procedures used for making AT dietary supplements
and traditional teas. Plant material was air dried and then
ground into a fine powder. The powder (100 g) was boiled
with either distilled water (1:10 w/v) or ethanol (1:10 w/v)
for 2 hours before filtration. The water extract (WE) was
freeze-dried, while the ethanol extract (EE) was vacuum
dried, resuspended in distilled water (1:10 w/v) and
extracted sequentially with petroleum ether, ethyl acetate
and n-butanol (Figure 1). All fractions were stored at 4°C
until analyzed. Each fraction was dissolved in dimethyl
sulfoxide (DMSO) for functional assays.
Cell culture and reagents
PC-3 cells, a commonly used human prostate cancer
cell line in chemotherapeutic studies, were obtained from
the American Type Culture Collection (ATCC, Rockville,
MD, USA) PC-3 cells were maintained in RPMI-1640
culture medium, supplemented with 10% FBS, penicillin
(100 units/ml)-streptomycin (0.1 mg/ml) (Gibco, Grand
Island NY).
Cytotoxic activity assay
PC-3 cells were seeded in 96-well dishes at a density
of 1.5×103 cells/well and incubated at 37°C for 24 hours
(h). The cells were then treated with various concentrations
(10~160 μg/ml) of each AT extracts for 72h. To measure
cell viability, the MTT assay was performed as described
earlier (Wei et al., 2012). The effect of different AT extracts
on growth was assessed as percent cell growth as compared
to the DMSO-treated cells. The cytotoxic effects of the
AT extracts was measured by the trypan blue exclusion
assay as previously described (Hansson et al., 2005)
using a hemocytometer under a light microscope (Nikon
Optiphot). For all treatments, the DMSO concentration
did not exceed 0.1%, and no effects on cell growth were
observed at this solvent concentration.
Figure 1. Extraction Procedure. Acanthopanax trifoliatus
(L) Merr (AT) was air dried and then ground into a fine powder.
The powder (100g) was added to boiling distilled water (1:10
w/v) or boiling ethanol (1:10 w/v) for 2h before filtration. The
water extract (WE) was freeze-dried while the ethanol extract
(EE) was vacuum dried, resuspended in water and extracted
sequentially with petroleum ether, ethyl acetate and n-butanol.
Fractions were obtained after removal of solvent, and stored for
3-4 days at 4℃ until analysis
9342 Asian Pacific Journal of Cancer Prevention, Vol 15, 2014
Assessment of apoptotic cells by morphology and
caspase-3 activation
Apoptosis following AT extract treatment was
determined by morphologic assessment of propidium
iodide stained cells, as described previously (Zheng et
al., 2004). Briefly, PC-3 cells were seeded at a density
of 0.2×105 cells/ml in 35-mm tissue culture dishes and
incubated for 24h. The cells were then treated with AT
extracts (80 μg/ml) or DMSO (1 μL/ml final concentration)
for 96h. The cells were fixed with methanol/acetone (1:1)
for 10 min and stained with propidium iodide (1 μg/ml)
for 10 min. Stained cells were then visualized under a
fluorescent microscope to identify apoptotic cells. A
minimum of 200 cells were counted to determine the
percentage of apoptotic cells in each sample. Caspase-3
activation was measured using an EnzoLyte AMC
Caspase-3 Assay Fluorimetric kit (AnaSpec, Fremont,
CA, USA) following the manufacturer’s instructions
(Wei et al., 2012). Fluorescence intensity was measured
using a Tecan Infinite M200 plate reader (Tecan US Inc.,
Durham, NC, USA).
Nuclear factor-kB (NF-kB)-dependent reporter gene
expression assay
NF-kB transcriptional activity was measured as
described previously (Zheng et al., 2008). Following
transduction of the reporter construct, a single stable clone,
PC-3/N, was generated for use in the present study. Briefly,
PC-3/N cells were seeded at a density of 0.2×105 cells/ml
and incubated for 24h. PC-3/N cells were then treated with
AT extracts for 24h, and the NF-kB-luciferase activity was
measured using a luciferase assay kit (Promega, Madison,
WI, U.S.A) (Zheng et al., 2008). Luciferase activity was
normalized against the sample protein concentration as
determined using the Bio-Rad protein assay kit (Bio-Rad,
Hercules, CA, USA). Luciferase activity was expressed
as a percentage of the luciferase activity in DMSO treated
control cells.
Western blotting
For biochemical analysis, PC-3 cells were seeded at a
density of 1×105 cells/ml of medium and incubated at 37°C
for 24h, then cells were treated with different AT extracts
(80 μg/ml) or DMSO (1 μl/ml) as a negative control for
24h. After treatment the cells were washed with ice-cold
phosphate buffered saline (PBS) and lysed with lysis buffer
(10 mM Tris-HCl (pH 7.4), 50 mM sodium chloride, 30
mM sodium pyrophosphate, 50 mM sodium fluoride, 100
μM sodium orthovanadate, 2 mM iodoacetic acid, 5 mM
ZnCl2, 1 mM phenylmethylsulfonyl fluoride, and 0.5%
Triton X-100). Erk 1/2 and Akt expression were measured
by western blot analysis with anti-phosphorylated-Erk1/2
antibodies (#4376, Cell Signaling Technology, Danvers,
MA, USA) and anti-phosphorylated-Akt antibodies,
respectively (#4501, Cell Signaling Technology, Danvers,
MA, USA).
β-Actin was used as a loading control to normalize
protein levels. Expression was detected with fluorochromeconjugated secondary antibody (Santa Cruz Biotechnology
Inc., USA) using the Odyssey infrared imaging system
(LiCor, Biosciences, Lincoln, NE, USA).
DOI:http://dx.doi.org/10.7314/APJCP.2014.15.21.9341
Acanthopanax trifoliatus (L) Merr Extracts Inhibit NF-κB Activity and Decrease Erk1/2 and Akt Phosphorylation
HPLC analysis of AT extracts
Prior to HPLC analysis, 50 mg portions of extract
were dissolved in 25 mL methanol and filtered through
0.45 μm filters. The injection volume was 10 μL. Elution
of AT compounds was detected by monitoring the eluate
at 254 nm.
Statistical analysis
Results were expressed as the mean±standard error
of the mean (SEM). The Analysis of Variance (ANOVA)
method with the Tukey-Kramer multiple comparison
test (Hsu, 1996) was used for the comparison of number
of viable and apoptotic cells among different treatment
groups at the end of the treatment.
Results
HPLC fingerprinting analysis of AT extracts
The HPLC fingerprint profile standardized with known
marker compounds served as standards for comparisons
with subsequent preparations of AT extracts. The HPLC
chromatogram of EE was found to contain constituents
with major peaks at 18.73 min, 26.52 min and 28.22 min.
The presence of chlorogenic acid in EE at RT 18.73 min
was confirmed by comparing its retention time and UV
spectra with that of the reference standard chlorogenic
acid. Additional characterization of the peak by mass
spectrometry confirmed the peak as chlorogenic acid
(data not presented). The major peak at RT around 26.5
min in EAT had the same mobility and the same UV
absorption spectra (not shown) as isochlorogenic acid A
(C25H24O12). The identity of this compound was further
verified by Q-TOF mass spectrometry (data not presented).
Results of the HPLC analysis of PEL, EAL and NBL
showed that each extract produced a distinct fingerprint
profile (Figure 2) that may be used for standardizing the
preparation of the each extracts.
Figure 3. Effects of AT Extracts on Human Prostate
Cancer PC-3 Cells. A) PC-3 cells were seeded at a density of
0.2×105 cells /ml in 35-mm tissue culture dishes and incubated
for 24h. The cells were then treated with DMSO (0.1%, final
concentration, control) or the indicated AT-extracts (80μg/ml in
DMSO) for 96h. The number of viable cells after treatment with
AT extracts is expressed as percent of control. Both viable and
dead cells were determined by a trypan blue exclusion assay.
B-D) PC-3 cells were seeded at a density of 0.2×105 cells /ml
in a 96-well plate and incubated for 24h. The cells were then
treated with DMSO (0.1%, final concentration, control) or the
indicated AT extracts (10-160μg/ml in DMSO) for 72h, and the
relative cell growth was determined by the MTT assay. Data are
expressed as mean±SEM of percent of viable cells from triplicate
experiments. Differences between AT-extract treated groups and
the DMSO-treated (control) group were analyzed by the TukeyKramer multiple comparison test. ***p<0.001
Inhibitory effects of AT extracts on the growth of cultured
human prostate cancer cells
To assess the effects of AT extracts on the growth of
human prostate cancer cells, we assessed cell viability
Figure 4. Effects of AT Extracts on Apoptosis of PC-3
Cells. A-B) Morphological assessment of propidium iodide
Figure 2. HPLC Chromatograms of AT Extracts. Fifty
mg portions of each AT extract was dissolved in 25mL methanol
and filtered through 0.45μm filters before HPLC analysis. A)
water extract; B) ethanol extract (EE); C) petroleum ether layer
(PEL); D) ethyl acetate layer (EAL); E) n-butanol layer (NBL);
F) remaining water layer (WL) obtained as described in Figure 1
stained PC-3 cells after treatment with DMSO (A) or the EAL AT
extract (B). Apoptotic cells were determined by morphological
assessment using a fluorescence microscope. Arrows indicate
apoptotic cells. C) Quantification of the percentage of apoptotic
cells by morphological assessment. D) Quantification of
caspase-3 activity as measured by fluorescence intensity in PC-3
cells treated with the indicated AT-extracts. Caspase-3 activity is
expressed as arbitrary units relative to the control. Columns are
the mean±SEM of 3 separate experiments. Differences between
AT-extract treated groups and the DMSO-treated (control) group
were analyzed by the Tukey-Kramer multiple comparison test.
***p<0.001
Asian Pacific Journal of Cancer Prevention, Vol 15, 2014
9343
Hua-Qian Wang et al
Figure 5. Effects of AT Extracts on NF-kB
Transcriptional Activity in PC-3/N Cells. Quantification
of NF-kB luciferase reporter activity in PC-3/N cells after
treatment with AT extracts. Cells were seeded at a density
of 0.2×105 cells/ml of medium in 35mm culture dishes and
incubated for 24h. The cells were treated with 0.1% DMSO
final concentration (Control) or with the indicated AT extracts
(80 μg/ml in DMSO) for 24h. NF-kB transcriptional activity
was measured by a luciferase activity assay as described in
the Materials and Methods section. Differences between ATextract treated groups and the DMSO-treated (control) group
were analyzed by the Tukey-Kramer multiple comparison test.
*p<0.05; **p<0.01
after treatment with each AT extract. PC-3 cells were
treated with PEL, EAL, and NBL AT extracts for 72h,
and viability was assessed using MTT and trypan blue
exclusion assays. We found that EAL had the strongest
inhibitory effect on the growth of PC-3 cells, followed by
the PEL and NBL extracts (Figure 3A). All three extracts
inhibited cell growth in a dose-dependent manner (Figure
3B-D). The other extracts (WE, EE, NBL and WL) had
only a small inhibitory effect on the viability of PC-3 cells
that was not dose-dependent (data not shown).
Effects of AT extracts on apoptosis in PC-3 cells
Given the strong inhibitory effect of EAL on PC-3 cell
viability, we investigated whether this extract promoted
apoptosis in PC-3 cells. Treatment of PC-3 cells with EAL
resulted in apoptosis, as determined by morphological
assessment (Figure 4A-B). Treatment of PC-3 cells with
80 µM EAL resulted in a 43% increase in morphologically
distinct apoptotic cells, compared to only 10% in NBL
treated cells (Figure 4C). Equivalent doses of WE, EE,
PEL or WL alone caused little or no increase in apoptosis.
We further assessed apoptosis induction in PC-3 cells
using the caspase-3 activation assay. Consistent with the
morphological assessment, EAL stimulated caspase-3
activity more dramatically than other extracts, suggesting
that this extract efficiently stimulates apoptosis in PC-3
cells (Figure 4D).
Effects of AT extracts on NF-kB activity
To investigate the mechanisms by which AT extracts
stimulate apoptosis in PC-3 cells, we assessed the
activity of NF-kB, an important regulator of cell growth
and apoptosis, in AT extract treated cells. NF-kB
transcriptional activity was assessed using a luciferase
reporter gene expression assay in PC-3/N cells. After
treatment with each AT extract, luciferase activity was
9344
Asian Pacific Journal of Cancer Prevention, Vol 15, 2014
Figure 6. Inhibitory Effects of AT Extracts on
Activation of Akt and Erk1/2. Western blot analysis of
phospho-Akt, phospho Erk 1/2, and β-actin in PC-3 cells treated
with DMSO (Control) or the indicated AT extracts. Cells were
seeded at a density of 1×105 cells/ml and incubated for 24h, then
treated with AT extracts (80µg/ml) for 24h. β-actin was used as a
loading control. The data is representative of three experiments
measured to determine NF-kB activity levels. Using this
assay, we found that only the EAL and PEL fractions
had a strong inhibitory effect on NF-kB transcriptional
activity (Figure 5). This result suggests that EAL may
promote apoptosis through inhibition of NF-kB activity
in PC-3 cells.
Effects of AT extracts on the levels of phospho-Akt and
phospho-Erk 1/2 in PC-3 cells
Activation of Akt and Erk 1/2 plays a role in the
survival and growth of prostate cancer cells (Kaur et al.,
2008; Bhargavan et al., 2012; Ye et al., 2012). Thus, we
assessed Akt and Erk 1/2 activity in PC-3 by western blot
analysis of Akt and Erk 1/2 phosphorylation. PC-3 cells
were treated with DMSO (0.1% final concentration) or
different AT extracts (80 μg/ml) in DMSO for 24h, and
the levels of phospho-Akt, phospho-Erk 1/2, and β-actin
in whole cell lysates were determined by Western blot.
Treatment of PC-3 cells with EAL and PEL caused
a strong decrease in Akt phosphorylation, while the
other AT extracts had a small or negligible effect Akt
phosphorylation (Figure 6). Similarly, EAL treatment
resulted in a strong decrease in Erk 1/2 phosphorylation,
while PEL and NBL also inhibited Erk 1/2 activity to a
lesser degree (Figure 6).
Discussion
Here, we demonstrated for the first time that AT
extracts can suppress the growth of the PC-3 human
prostate cancer cell line. Among the AT extracts, EAL
was the most potent inhibitor of PC-3 cell growth and
stimulator of apoptosis. AT is commonly used as an herbal
medicine in China and in other Asian countries and is also
consumed as a vegetable in areas of southern China such
as Guangdong Province. Although some species of the AT
genus have anti-inflammatory activity (Chi, 1997; Loi,
2000), there have been no studies investigating the anticancer activities of AT extracts. Our results suggest that AT
extracts, in particular the EAL extract can exert anti-cancer
activities in cultured prostate cancer cells by promoting
DOI:http://dx.doi.org/10.7314/APJCP.2014.15.21.9341
Acanthopanax trifoliatus (L) Merr Extracts Inhibit NF-κB Activity and Decrease Erk1/2 and Akt Phosphorylation
apoptosis. Our current results may lay the foundation for
further studies to determine the mechanisms of action by
which AT extracts exert anti-cancer effects on tumor cells.
Since many bioactive constituents in plants are
lipophilic, we prepared an ethanol extract (EE) of AT.
The EE was further extracted sequentially with petroleum
ether, ethyl acetate and n-butanol as described in Figure
1. These extracts, along with the remaining water layer
(WL) fractions were analyzed for their effects on cell
growth and apoptosis. The EE had a modest inhibitory
effect on the growth of PC-3 cells, similar to the WE
fraction (Figure 3), but the effect was not dose-dependent
(data not presented). Among the different fractions of
EE, the EAL extract was the most potent stimulator of
apoptosis, while the other fractions had little to no effect
on apoptosis rates. HPLC analysis showed that EAL,
WE and EE all had a major peak at RT around 26.52 min
which was either small (NBL) or absent (PEL and WL) in
other fractions which had no effect on cell growth (Figure
2). Furthermore, the concentration of this component
was highest in the EAL, consistent with the more higher
potency of this extract. The major peak at RT around 26.5
min in EAT had the same mobility and UV absorption
spectra as isochlorogenic acid A (C25H24O12) (data
not shown). The identity of this compound was further
verified by Q TOF mass spectrometry. Since EAL had the
strongest stimulatory effect on apoptosis, isochlorogenic
acid A is likely the apoptotic AT constituent. However,
further studies using preparative HPLC are needed to
identify the specific AT-derived compounds responsible
for inducing apoptosis.
To investigate the mechanisms by which AT extracts
inhibit cell growth and promoted apoptosis in PC-3
cells, we analyzed cell-proliferation signaling pathways
after treatment with each extract. NF-kB can regulate
of proliferation and apoptosis in a variety of cells
including prostate cancer cells (Paule et al., 2007; Karin,
2009; Sambantham et al., 2013). Moreover, NF-kB is
commonly activated in invasive prostate cancer (Lessard
et al., 2003; Ross et al., 2004; Shukla et al., 2004) and
of NF-kB-responsive genes are commonly associated
with prostate cancer progression (Shukla et al., 2004).
Thus, NF-kB provides an attractive therapeutic target
for the treatment of prostate cancer. We found that AT
extracts inhibited the transcriptional activity of NF-kB,
inhibition NF-kB by each AT extract correlated with
its inhibition of cell growth. In particular, EAL was a
potent inhibitor of both NF-kB and cell growth, as well
as a strong inducer of apoptosis. A large number of
studies have shown that the LPS-TLR4/NF-kB signaling
pathway regulates the inflammatory response. This is
consistent with our findings, in which AT extracts with
anti-inflamatory properties had an inhibitory effect on
PC-3 cell proliferation.
In addition to inhibiting NF-kB, EAL decreased
phosphor-Erk 1/2 expression, as assessed by Erk 1/2
phosphorylation analysis. Other AT extracts had small
to moderate effects for decreasing the level of phosphoErk1/2 with the exception of WE, which had no effect
relative to controls. Erk 1/2 activity is generally associated
with mitogenesis and suppression of apoptosis (McCubrey
et al., 2007; Junttila et al., 2008), and constitutive
activation of Erk has been observed in prostate cancer
(Gioeli et al., 1999; Uzgare and Isaacs, 2005). Erk 1/2
can activate a number of transcription factors, including
NF-kB, to regulate gene expression (Raman et al., 2007;
Kook et al., 2011). Thus, EAL may suppress PC-3 cell
growth by downregulating Erk 1/2 and subsequent prosurvival signaling through NF-kB.
In addition to Erk 1/2 suppression, we found that
the EAL also suppressed Akt activity in PC-3 cells. Akt
is a serine-threonine protein kinase that regulates cell
proliferation and survival in a wide variety of cancer
types, including prostate cancers (Sarker et al., 2009;
Wegiel et al., 2010). Advanced prostate cancers frequently
have elevated levels of phospho-Akt, and Akt signaling
appears to be critical to prostate cancer cell survival and
proliferation (Antonarakis et al., 2010). Treatment with
NBL and PEL extracts also decreased Akt phosphorylation
while WE, EE and wL had little or no effect, suggesting
that AT may suppress Akt activity through one or more
constituents shared among these extracts. Earlier studies
indicated that some cytokines induced activation of NFkB through Erk1/2 and Akt pathways (Maeda and Omata,
2008). Thus, it is possible that AT, and the EAL extract
in particular, may be able to suppress prostate cancer cell
growth through an Erk/Akt dependent pathway.
In summary, we demonstrate that AT extracts inhibit
cell growth and induce apoptosis in cultured prostate
cancer cells. Among the AT extracts tested, EAL was
the most potent inhibitor of growth and stimulator of
apoptosis. The ability of AT extracts to suppress prostate
cancer cell growth was associated with their ability to
inhibit NF-kB, Erk 1/2 and Akt activity. These results
suggest that the AT, in particular the EAL extract, could
provide a novel therapy for prostate cancer patients.
Further studies are needed to determine the in vivo effects
of these extracts in animal models in order to better
evaluate the therapeutic potential of AT.
Acknowledgements
This work was supported by funds from a leadership
grant From China awarded to AHC, Guangdong Natural
Science Foundation, China (S2012040007488).
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