Article

Human and Experimental Toxicology

1–8
Sodium tanshinone IIA sulfate protects ª The Author(s) 2018
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myocardium against paraquat-induced DOI: 10.1177/0960327118792051
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toxicity through activating the Nrf2
signaling pathway in rats

Zhang WX, Xiao XY , Peng CG, Chen WL, Xie S and

Wang DW

Abstract
Objective: To investigate the therapeutic effect and mechanism of sodium tanshinone IIA sulfate (STS) on
paraquat (PQ)-induced myocardial injuries in a rat model.
Methods: Healthy adult Sprague Dawley rats were randomly divided into normal control, PQ, and PQ þ STS
groups. PQ group was given a single intragastric administration of PQ (80 mg/kg). PQ þ STS group was
intraperitoneally injected with STS (1 ml/kg) at 30 min following PQ exposure. Rats in control and PQ groups
were injected with equal amount of saline. After 12, 24, 48, and 72 h, rats were killed, and the apoptosis of
myocardial cells was detected. Myocardial expression of Bax and Bcl-2 was measured. The activity of the
nuclear erythroid 2-related factor 2 (Nrf2) pathway was assessed by Western blot.
Results: The apoptotic cells in PQ group were significantly increased in a time-dependent manner compared
with the control group (p < 0.01). The rats in PQ group exhibited significantly lower Bcl-2 expression, but
notably higher Bax expression at 12, 24, 48, and 72 h after PQ exposure (p < 0.05 or 0.01). STS intervention
markedly reduced the proportion of apoptotic myocardial cells, increased Bcl-2 expression, and decreased Bax
expression at 24, 48, and 72 h after treatment (p < 0.05 or 0.01). The expression of phosphorylated Nrf2 and
heme oxygenase 1 in PQ þ STS group was significantly increased compared with PQ and control groups
(p < 0.05 or 0.01).
Conclusion: STS effectively inhibits PQ-induced myocardial cell apoptosis in rats via modulating the Nrf2
pathway, suggesting its potential as a promising therapeutic agent for PQ-induced myocardium damage.

Keywords
Danshen, anti-inflammatory compound, traditional Chinese medicine, apoptosis, Bcl-2, Bax

Introduction The incident of PQ poisoning due to accidental or

Paraquat (PQ; 1,10 -dimethyl-4,40 -bipyridinium) is an
important fast-acting broad-spectrum contact herbi-
cide that has been widely used since 1960s.1 The
chemical is toxic through ingestion, inhalation, or
dermal exposure.2 PQ, when ingested orally, is highly
toxic to mammals including humans, leading to lung,
heart, liver, and kidney failure and even death.3 The
reported oral lethal dose (LD50) value of PQ ranges
from 30 mg/kg to 150 mg/kg in mammals.4 PQ is
easily available and inexpensive, and there are cur-
rently no specific medical treatments available, which
makes poisoning management extremely difficult.5
intentional ingestion has been reported each year,
leading to a fatality rate between 60% and 80%.6,7
Although the mechanism of PQ toxicity has not
been fully elucidated, it has been suggested that the
Department of Emergency, Jiangxi Provincial People’s Hospital,
Nanchang, Jiangxi, China
Corresponding author:
Xiao XY, Department of Emergency, Jiangxi Provincial People’s
Hospital, 92 Aiguo Road, East Lake District, Nanchang, Jiangxi
330006, China.
Email: x71657013shic@yeah.net
2 Human and Experimental Toxicology XX(X)
chemical initiates a sustained redox-cycling reaction
to generate a large amount of reactive oxygen species
(ROS), leading to oxidative stress and extensive
inflammation.8 Excess ROS and the resulting oxida-
tive stress induce oxidative modification of cellular
macromolecules, inhibit protein function, and ulti-
mately promote apoptosis; increasing evidences sup-
port that oxidative stress and apoptosis are closely
associated with physiological phenomena; Bcl-2, a
member of the Bcl family, has been shown to prevent
cell apoptosis via an anti-oxidative mechanism.9,10
Recent studies have also shown that PQ impairs
myocardial contractile function through the genera-
tion of ROS, which ultimately results in cardiopul-
monary failure. 11,12 Numerous researches have
attempted to develop efficient treatments for PQ
poisoning, but so far have achieved disappointing
clinical therapeutics. 13–16 Therefore, alternative
treatment agents for acute PQ poisoning are urgently
required for clinical practice.
Medicinal plants have provided a rich source for
the screening of novel therapeutic agents.17–19 Salvia
miltiorrhiza, also known as Danshen, is a traditional
Chinese medicine that has been commonly used for
centuries for improving microcirculation.20,21 Tanshi-
none IIA (TIIA), one of the active components of
Salvia miltiorrhiza, might exert a wide range of strong
biochemical effects, including anti-oxidant and anti-
inflammatory effects.22–24 Sodium tanshinone IIA
sulfate (STS), a clinical formulation of TIIA, is sug-
gested to protect myocardium and blood vessels
against ischemia/reperfusion injury during ischemic
heart diseases and ischemic stroke.25,26 However,
whether STS produces protective effects on myocar-
dium against PQ-induced toxicity is not yet clear. In
this study, we aimed to evaluate the therapeutic effect
of STS on PQ-induced myocardial dysfunction in a rat
model after PQ ingestion. We further investigated the
underlying mechanism of the effects of STS in this
model by analyzing the key apoptosis-related markers
(Bax and Bcl-2) and the proteins in the nuclear ery-
throid 2-related factor 2 (Nrf2) pathway.
Material and methods
Main reagents
STS injection (Nuoxinkang) was purchased from
Shanghai No. 1 Biochemical & Pharmaceutical Co.,
Ltd (Shanghai, China). PQ solution (20%) was pur-
chased from Biobest Biotech (Chongqing, China).
Terminal deoxynucleotidyl transferase dUTP nick-
end labeling (TUNEL) assay kit was purchased from
Beyotime Institute of Biotechnology (Shanghai,
China). RNA extraction kit, PrimeScript RT-PCR kit,
and polymerase chain reaction (PCR) amplification
kit were purchased from Takara (Japan). The primers
used for PCR amplification were synthesized by Pro-
mega (Shanghai, China): b-actin-forward: 50 -GGC
TGTATTCCCCTCCATCG-3 0 , b-actin-reverse:
50 -CCAGTTGGTAACAATGCCATGT-30 ; Bax-F:
50 -CCAGGATGCGTCCACCAA-30 , Bax-R: 50 -AA
AGTAGAAGAGGGCAACCAC-3 0 ; and Bcl-2-F:
50 -GTGGCCTTCTTTGAGTTCG-30 , Bcl-2-R: 50 -AC
CCAGCCTCCGTTATCC-30 . Protein extraction kit
and BCA kit were purchased from Beyotime Institute
of Biotechnology. Mouse anti-rat Bcl-2 and Bax
monoclonal antibody, mouse anti-rat b-actin poly-
clonal antibody, and horseradish peroxidase (HRP)-
labeled rabbit anti-mouse immunoglobulin G (IgG)
were purchased from Abcam (Cambridge, Massa-
chusetts, USA).
Animals and grouping
This animal study was approved by the Research
Ethics Committee at our hospital. Healthy adult
Sprague Dawley male rats weighting 220 + 40 g
were purchased from the Department of Animal
Science of the School of Medicine, Nanchang Uni-
versity and housed in standard laboratory condi-
tions. These rats were randomly divided into
three groups: control (n ¼ 24), PQ (n ¼ 40), and
PQ þ STS group (n ¼ 40). The rats in PQ group
were given a single intragastric administration of
PQ (80 mg/kg). The control group was intragastri-
cally administered with equal amount of saline.
The PQ þ STS group was given a single intraper-
itoneal injection of STS (1 ml/kg) at 30 min fol-
lowing PQ exposure. Rats in control and PQ groups
were intraperitoneally injected with equal amount
of saline. Based on our preliminary experiments
and previous studies,27,28 rats exhibit severe car-
diac oxidative damage at approximately 72 h after
intragastric exposure to 80 mg/kg PQ, and death
rate begins to increase thereafter. We, therefore,
monitored the condition of rats within the first 72
h after PQ toxicity. At 12, 24, 48, and 72 h after
PQ exposure, six randomly selected rats from each
group were anesthetized and killed by abdominal
aorta bloodletting. The heart was obtained from
each rat and stored at 70 C until use.
WX et al.
TUNEL assay
The heart tissue in each group was fixed in 10% for-
malin, treated with xylene, and dehydrated with serial
ethanol. The middle part of the left ventricle coronal
was cleared in chloroform, embedded in paraffin, and
cut into 4-mm sections. The sections were stained
using TUNEL assay kit following the manufacturer’s
instructions. The number of positive cells in randomly
selected five visual fields was counted and the apop-
totic index was calculated as the mean percentage of
positive cells.
Western blot analysis
The expression of Bax, Bcl-2, and proteins in the
Nrf2 pathway including phosphorylated Nrf2
(p-Nrf2) and heme oxygenase 1 (HO-1) in the heart
tissues was detected by Western blot. Briefly, the
heart tissue was homogenized. Total protein was
extracted using protein extraction kit and quantified
using a BCA kit following the manufacture’s
instruction. Equal amounts of total protein (10 mg)
were separated by 10% sodium dodecyl sulphate
polyacrylamide gel electrophoresis (SDS-PAGE)
electrophoresis and transferred to polyvinylidene
difluoride membranes. The membrane was blocked
with 5% skim milk overnight at 4 C and incubated
with the appropriate primary antibody (Abcam) at
37 C for 4 h. The membranes were washed with
tris-buffered saline plus Tween 20 and incubated
with HRP-labeled secondary antibody (1:100) at
37  C for 1 h. The membrane was subjected to
enhanced chemiluminescence detection. The inten-
sity of bands was detected by a Molecular Imager®
ChemiDocTM XRS System (Bio-Rad Laboratories)
and analyzed by Image Lab 2.0 software (Bio-Rad
Laboratories, Hercules, CA, USA). The experiment
was performed in triplicates. The relative expression
of protein was calculated using b-actin as the inter-
nal control.
Reverse transcription PCR
The expression of Bax and Bcl-2 mRNA in the heart
tissues was measured by reverse transcription PCR
(RT-PCR). Briefly, total RNA was extracted using
RNA extraction kit and reverse transcribed into
cDNA using reverse transcription kit according to the
manufacture’s instructions. PCR amplification was
performed using cDNA as a template and PCR Master
Mix (TaKaRa, Japan) following the manual. The
3
reaction condition is 95 C for 5 min, followed by 35
cycles of 95 C 10 s, 49 C 30 s, and 72 C 30 s, and
72 C for 10 min. PCR products were analyzed by 1%
agarose gel electrophoresis. The relative expression
of mRNA was expressed as its intensity to that of
b-actin. The experiment was performed in triplicates.
Statistical analysis
All data were represented as mean + standard devia-
tion and analyzed using SPSS 13.0 (SPSS Inc,
Chicago, Illinois, USA). Difference among groups
was analyzed by one-way analysis of variance fol-
lowed by Student-Newman-Keuls tests (SNK) in
case of significant difference. The value of p <
0.05 is considered statistically significant.
Results
STS reduced the apoptosis of myocardial cells
induced by PQ exposure
The apoptosis index of myocardial cells in different
groups was compared by TUNEL assay. As shown in
Figure 1, the apoptotic cells in PQ group was signif-
icantly increased in a time-dependent manner com-
pared with the control group (p < 0.01). STS
intervention markedly reduced the proportion of
apoptotic cells induced by PQ toxicity at 24, 48, and
72 h after treatment (p < 0.05 or 0.01). The apoptosis
index in PQ þ STS group was similar to that in con-
trol group at 48 and 72 h (p > 0.05).
STS modulated the expression of Bax and
Bcl-2 protein
The expression of apoptosis-related proteins (Bax and
Bcl-2) was compared by Western blot. As shown in
Figure 2, the rats in PQ group exhibited significantly
lower Bcl-2 expression but notably higher Bax
expression at 12, 24, 48, and 72 h after PQ exposure
(p < 0.05 or 0.01). Bcl-2 expression in PQ þ STS
group was significantly higher, but Bax expression
was substantially lower compared with PQ group at
the same time point (p < 0.05 or 0.01), suggesting that
STS treatment time-dependently increased Bcl-2
expression and decreased Bax expression.
STS regulated the expression of Bax and
Bcl-2 mRNA
The expression of Bax and Bcl-2 mRNA was further
determined by RT-PCR. As shown in Figure 3, the
4 Human and Experimental Toxicology XX(X)

Figure 1. Comparison of apoptosis index of myocardial cells in different groups by TUNEL assay at 12, 24, 48, and
72 h after PQ exposure (n ¼ 6). *p < 0.05 and **p < 0.01 compared with control group; #p < 0.05 and ##p < 0.01 compared
with PQ group.
TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; PQ: paraquat.

Figure 2. Comparison of the expression of apoptosis-related proteins in different groups by Western blot at 12, 24, 48,
and 72 h after PQ exposure (n ¼ 6). (a) A representative image of Western blot, (b) Bcl-2 protein, and (c) Bax protein.
*p < 0.05 and **p < 0.01 compared with control group; #p < 0.05 and ##p < 0.01 compared with PQ group.
PQ: paraquat.
WX et al.
Figure 3. Comparison of the expression of (a) Bcl-2
mRNA and (b) Bax mRNA in different groups by RT-PCR
at 12, 24, 48, and 72 h after PQ exposure (n ¼ 6). *p < 0.05
and **p < 0.01 compared with control group; #p < 0.05 and
##
p < 0.01 compared with PQ group.
RT-PCR: reverse transcription PCR; PQ: paraquat.
change trend of Bax and Bcl-2 mRNA expression in
PQ and PQ þ STS groups was similar to that of their
corresponding proteins during the experiment, indi-
cating that STS intervention significantly increased
Bcl-2 expression and decreased Bax expression in a
time-dependent manner.
STS activated the Nrf2 signaling pathway
The expression of key proteins in the Nrf2 signaling
pathway (p-Nrf2 and HO-1) in different groups was
measured by Western blot. As shown in Figure 4, the
expression of p-Nrf2 and HO-1 in PQ þ STS group
was significantly increased compared with PQ and
control groups at 24, 48, and 72 h (p < 0.05 or
0.01), whereas the expression of both proteins in PQ
group was only slightly higher than that in control
group at all time points (all p > 0.05). The results
5
indicated that the STS treatment had activated the Nrf2
signaling pathway to protect the mice against PQ-
induced toxicity.
Discussion
PQ is a widely used herbicide, but may lead to mul-
tiple organ damage and failure in humans and animals
through ingestion, inhalation, or dermal exposure.2
Once entering the body, PQ acts as a redox cycling
agent, producing a large amount of ROS including
superoxide anion radical and hydrogen peroxide and
hydroxyl radical.29 The PQ-induced oxidative stress
interrupts several essential biochemical processes in
the body and thus impairs the cellular functions in
target organs.30 Multiple studies have shown that
PQ can severely damage myocardial functions.11,12
Consistently, we found that the apoptosis index of
myocardial cells in rats was significantly increased
at 12, 24, 48, and 72 h after PQ exposure, confirming
that PQ had induced myocardial damages.
STS has been suggested as an anti-inflammatory,
anti-oxidative, and antiapoptotic agent.22–24 Although
the protective effect of STS on myocardium against
ischemia/reperfusion injury has been frequently
studied, 31–33 whether STS protects myocardium
against PQ-induced toxicity remains largely unclear.
In this study, we assessed the therapeutic effects of
STS on myocardium in a rat model with PQ toxicity.
It was found that STS intervention significantly
reduced the proportion of PQ-induced apoptotic cells
at 24, 48, and 72 h after treatment (p < 0.05 or 0.01).
The apoptosis index in PQ þ STS group was close to
that in control group at 48 and 72 h, suggesting that
STS exerted protective effects on myocardial cells.
The Bcl-2 protein family has been well known for
its regulation on apoptosis.34 The mitochondrial apop-
tosis pathway is controlled by the Bcl-2 family. Bcl-2
(an antiapoptotic member) and Bax (a proapoptotic
member) are two major important players in modulat-
ing the mitochondrial apoptosis pathway. 35 We,
therefore, further investigated the mechanism behind
the inhibitory effect of STS on the apoptosis of myo-
cardial cells. We measured the expression of Bcl-2
and Bax and found that STS reduced myocardial cell
apoptosis through the enhancement of Bcl-2 and the
inhibition of Bax (Figures 2 and 3). These results
suggested that the therapeutic effect of STS against
PQ-induced myocardial damage was achieved
through the inhibition of apoptosis.
6 Human and Experimental Toxicology XX(X)

Figure 4. Comparison of the expression of apoptosis-related proteins in different groups by Western blot at 12, 24, 48,
and 72 h after PQ exposure (n ¼ 6). (a) A representative image of Western blot, (b) Nrf2 protein, and (c) HO-1 protein.
*p < 0.05 and **p < 0.01 compared with control group; #p < 0.05 and ##p < 0.01 compared with PQ group.
PQ: paraquat; Nrf2: nuclear erythroid 2-related factor 2; HO-1: heme oxygenase 1.

Nrf2 is an NF-E2-like basic leucine zipper tran-
scription activator that plays an important role in
the defense against oxidative stress.36 Under normal
physiological conditions, the cytoplasmic adapter
protein Keap1 binds to Nrf2 and prevents its translo-
cation to the nucleus, whereas oxidative stresses
trigger the phosphorylation of Nrf2, leading to its
dissociation from Keap1 and translocation into the
nucleus, where it activates the expression of down-
stream cytoprotective genes such as HO-1, NQO1
(NAD(P)H: quinone oxidoreductase 1), and so on.37
The protective effect of the Nrf2 pathway in the
defense against oxidative stress-induced injury
including PQ toxicity has been frequently
reported.38,39 We, therefore, examined the activity
of Nrf2 pathway by Western blot and found that the
expression of p-Nrf2 and HO-1 in PQ þ STS group
was markedly increased compared with PQ and con-
trol groups, suggesting that STS had activated the
Nrf2 signaling pathway to protect the mice myocar-
dium against PQ-induced toxicity. Our study herein
provided a preliminary mechanistic study on the ther-
apeutic effects of STS against PQ toxicity, despite
that further in-depth studies are needed.
In summary, our study has shown that STS thera-
peutically inhibits PQ-induced myocardial cell apop-
tosis in rats. The associated mechanism was achieved
via the enhancement of Bcl-2 and the inhibition of
Bax. Our results provide a theoretic basis for the
application of STS in the treatment of acute PQ toxi-
city, despite that further in-depth studies are needed.
STS might be a promising therapeutic agent for
PQ-induced myocardial damage and failure.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest
with respect to the research, authorship, and/or publication
of this article.
Funding
The author(s) disclosed receipt of the following financial
support for the research, authorship, and/or publication of
WX et al.
this article: This work was supported by the Natural Sci-
ence Foundation in Science and Technology Department of
Jiangxi Province (no: 20142BBG70092).
ORCID iD
Xiao XY http://orcid.org/0000-0002-9217-3747
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