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Biomedicine & Pharmacotherapy 96 (2017) 466–470
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Original article
Inhibitory effect of Triperygium wilfordii polyglucoside on dipeptidyl peptidase
I in vivo and in vitro
Jingjing Wang, Yi Chu, Xiaoying Zhou
MARK
⁎
School of Pharmaceutical Engineering and Life Science, Changzhou University, 213164, Jiangsu, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
DPPI activity
Triperygium Wilfordii Polyglucoside
Triptolide
CIA rat model
Backgroud: Dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease is derived from granule immune cells
including mast cell, neutrophils, and toxicity T cells. DPPI can activate serine proteases by removal of dipeptides
from N-termini of the pro-proteases, resulting in granule immune cells activation which involved in physiological or pathological responses. Triperygium Wilfordii Polyglucoside (TWP) is one of the traditional Chinese
medicines, and commonly used in rheumatoid arthritis (RA) treatment. The present study intended to evaluate
the effects of TWP on DPPI activity.
Methods: In vivo and in vitro studies were carried out to investigate the functions of TWP or triptolide (TP) on
DPPI activities in serum, tissues of CIA rats. Rats were divided into five groups randomly: normal group, untreated CIA rat group, TWP treatment CIA groups (the low dose 2.5 mg/100 g body-weight and high dose 5 mg/
100 g body-weight), and TP treatment CIA group (4 μg/100 g body-weight). Arthritis development was monitored visually, and joint pathology was examined radiologically. Total protein concentrations in synovial fluids
(SFs) were determined by BCA method. Serums and tissue homogenates from CIA rats were collected and DPPI
activities were detected using fluorescence substrate GF-AFC. The in vitro interactions between DPPI in serums or
in tissue homogenates and TWP or TP were assessed.
Results: TWP-treated CIA rats showed a significant improvement in bone erosion. TWP significantly suppressed
paw swelling and total protein concentration in the SFs of CIA rats compared with untreated CIA rats. The
elevated activities of DPPI in serums or tissues of CIA rats were significantly inhibited by TWP, but not by TP in
vivo. The inhibitory effects of TWP on DPPI activities were also confirm by in vitro study.
Conclusion: One of the therapeutic functions of TWP in RA treatment could be inhibiting DPPI activity in serums
and synovial tissue produced during RA development, and then reducing inflammatory serine proteases activities and further recovering CIA rats from RA symptoms.
1. Introduction
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease derived from granule immune cells [1]. DPPI is constitutively expressed
by granule immune cells in a variety of tissues, such as lung, serum,
liver and spleen [2] and plays an important role in the activation of
serine proteases, such as mast cell chymase, neutrophil elastase, and T
cells granulase A and B by removing dipeptides from N-termini of proserine-proteases [3–5]. Our previous study established a DPPI specific
fluorescent substrate Gly-Phe-AFC (GF-AFC) which can be hydrolyzed
by DPPI. The cleaved AFC from GF-AFC displayed strong fluorescence
enhancement at Ex400 nm/Em492 nm in a linear relationship with the
levels of DPPI activity [6]. Our studies showed a direct correlation
between increased DPPI activities in serum samples and arthritis severities in collagen induced arthritis (CIA) rats during the progress of
⁎
disease [6]. The previous study reported that DPPI−/− mice were
highly resistant to the development of RA in CIA rats and DPPI regulates the development of collagen-induced arthritis [7,8]. Thus, we
hypothesized that the inhibition of elevated DPPI activities would be
beneficial for RA treatment.
Triperygium Wilfordii Polyglucoside (TWP), a mixed extracts from the
effective parts of Tripterygium wilfordii Hook F, is reported as the
useful traditional Chinese medicine for RA treatment [9–11]. Triptolide
(TP) is a monomer composition included within TWP. A great amount
of clinical data have shown that TWP has anti‐inflammatory and immuno-suppressive activities in human clinical trials for inflammatory
and autoimmune diseases, and been historically used for RA treatment
[12,13]. Numerous studies indicated that TWP suppressed production
of cytokines, including TNF-α, interleukin-2 (IL-2), interferon (IFN)-γ,
IL-6 and IL-8 in serum, and inhibited endothelial growth factor (VEGF)
Corresponding author.
E-mail address: xiaoyingzhou@cczu.edu.cn (X. Zhou).
http://dx.doi.org/10.1016/j.biopha.2017.09.139
Received 21 May 2017; Received in revised form 19 September 2017; Accepted 26 September 2017
0753-3322/ © 2017 Published by Elsevier Masson SAS.
Biomedicine & Pharmacotherapy 96 (2017) 466–470
J. Wang et al.
2.3. Clinical assessment of arthritis
mRNA expression in CIA rats, also TWP can induce apoptosis of synoviocytes in RA [14–16]. TP was also reported as an immune-suppressor
in the treatment of some inflammatory and autoimmune diseases
[17–19]. But, the mechanisms of TWP or TP in RA treatment were still
not fully understood. Our study has firstly explored the function of TWP
or TP in inhibition of serum DPPI activities and investigated the association of the reductions of DPPI activities with the recoveries of CIA rat
from RA symptoms in vivo using CIA rat model, a widely used animal
model that shares many features with human RA especially [20,21].
Also, our study employed the molecular models to evaluate the enzymatic interactions between TWP or TP and DPPI activities (in serum or
tissue) in vitro. The human recombinant DPPI (hrDPPI) and specific
DPPI inhibitor Gly-Phe-CHN2 (Gly-Phe-diazomethane) were used as the
control compounds [22,23], aiming to explore the potential mechanisms of TWP in the treatment of RA.
The thickness of hind paws of each rats in different groups were
measured every 2 days using a vernier caliper from the 7th day after
intragastrically administered with TWP, the body weight of each individual animals was also recorded.
2.4. SFs and serums samples preparation
After two weeks of administration, all rats were sacrificed; the
canthus blood samples and synovial membranes were collected. The
canthus blood samples were stood at room temperature for 2 h, then
centrifuged at 4000 rpm for 20 min, the serums were isolated and
stored at −80 °C for later analysis. Synovial membranes were cut into
pieces, and mixed (1: 9) with PBS buffer containing protease inhibitors
(0.1 mM), and then homogenized for 2–3 min. The homogenates of SFs
were obtained after centrifugation in 3000 rpm for 20 min at 4 °C.
2. Materials and methods
Six-week wistar rats (male, 250–300 g) were purchased from
Changzhou Cavens Lab Animal Company (China). Bovine type II collagen (CII) (Chondrex, USA) and Freund's incomplete adjuvant (IFA)
(Sigma, USA) were used for rat immunization. TWP pills (containing
10 mg of TWP per pill) were obtained from DND Pharmaceuticals
(Zhejiang Province, China). TP, purity (HPLC) > 99%, were from ZiyiReagent of China. Vernier caliper was obtained from Harbin
Measuring & Cutting Tool Group Co., Ltd. Fluorescence spectra were
recorded on LS55 (Perkin Elmer, USA) and the slits for excitation and
emission were both set to 10 nm. Fluorescent substrate GF-AFC was
made in our laboratory, The School of Pharmaceutical Engineering and
Life Science, Changzhou University, Jiangsu, China [6]. The hrDPPI
used as a positive control was from R & D Systems (USA) and DPPI
specific inhibitor Gly-Phe-CHN2 was purchased from Sigma (USA).
Total protein concentrations in serums or SFs were determined using
BCA assay kit (Pierce Chemical Co., Rockland, IL).
2.5. Determination of total protein concentration in SFs by BCA method
The protein concentrations in SFs of all rats were determined using
BCA Protein Concentration Assay Kit. A standard curve was generated
by a series of dilutions of bovine serum albumin (BSA). The total protein concentrations in SFs were calculated based on the standard curve
according to the OD value obtained from each SF samples.
2.6. DPPI activity assay
As previous described [6], briefly, 90 μl of assay buffer (25 mM citric acid, 10 mM NaCl, pH6.0, and 0.5 mM GF-AFC) was mixed with
10 μl of serums or SFs collected from different groups. The fluorescence
intensity was monitored at Ex400/Em492 nm by fluorescence spectrometer. Maximum speed of kinetic reaction (Vmax) was calculated as the
changes in florescent intensity per min over 10 min in each reaction.
Michaelis-Menten equation: v = Vmax[S]/(Km + [S]) where v is the
initial velocity of the enzyme reaction, Vmax is the maximal velocity,
[S] is the substrate concentration, and Km is the Michaelis-Menten
constant (concentration of substrate at 0.5 of Vmax).
2.1. Induction of CIA rats and treatments using TWP or TP in-vivo
All animal works were taken with the approval of the Changzhou
University Ethics Committee. The animals were housed in controlled
environment under the Guidelines of Animal Ethics and Welfare. CIA
rat models were set up twice (30 wistar rats each time) using the
modified method described previously [6,24,25]. Rats were divided
into five groups randomly (six rats in each group). Control groups:
normal group and untreated CIA rat group; three CIA treatment group:
TWP treatment groups including low-dose group (2.5 mg/100 g bodyweight) and high-dose group (5 mg/100 g body-weight), TP treatment
group (4 μg/100 g body-weight). For CIA rat groups, including untreated CIA control group and TWP or TP treatment groups, 300 μl of
collagen II-IFA emulsified liquid (1 mg/ml) was intra-dermal injected at
the base of each rat tail on day 0. The boosting injections were at day 3
and 7 in same method. After two weeks post-injections, the CIA rats of
treatment groups were intragastrically administered with TWP or TP
every day for 14 days (TWP and TP dissolved in 0.5% sodium carboxymethyl cellulose (CMC) in required concentrations). The rats in untreated CIA rat group were administered with equal volume of 0.5%
CMC only for same period.
2.7. The interactions between DPPI and TWP or TP in-vivo
TWP or TP were dissolved in dimethysulphoxide (DMSO) to give
stock solution of 4000 μg/ml, and different concentrations (0, 250, 500,
1000, 2000 μg/ml) were prepared with PBS. 1 μl of different concentrations of TWP, TP or DPPI (20 mM) [26] were separately added
into hrDPPI (0.5 mU), or into serums or SFs of CIA rats with high DPPI
levels. The interactions of the mixtures were left in shaker at 35 °C for
2 h. After incubation, the DPPI activities in each interation-condition
were determined using GF-AFC by fluorescence spectrometer at Ex400/
Em492 nm. The inhibition rate relative to untreated sample in percentage was calculated as: Inhibition rate (%) = [Vmax (TWPtreatedsample)
– Vmax (untreatedsample)]/Vmax (untreatedsample) × 100%. The concentration
of TWP resulting in 50% inhibition rate of enzyme activity (IC50) was
determined by SPSS software.
2.8. Statistical analysis
2.2. Radiography
Statistical analyses and graphs were performed using GrapPad Prism
7 package. All the results were expressed as mean ± SEM. The MannWhitney non-parametric test for unpaired variables was used to compare differences between groups. *P < 0.05 was taken as statistically
significant, **P < 0.01, statistically very significant.
Radiography analysis of the hind limbs of rats in different groups
was carried out using a HP Faxitron (Faxitron X-Ray LLC, Wheeling, IL,
USA). Images were visualized using a standard light box and photographed.
467
Biomedicine & Pharmacotherapy 96 (2017) 466–470
J. Wang et al.
Fig. 1. Inhibition of bone degradation in the joint by
TWP treatment. A. normal rat; B. untreated CIA rat; C.
TWP (5 mg/100 g body weight) treated CIA rat.
3. Results
Table 2
Total protein concentration in SFs of rats from different groups.
3.1. Radiological observation
Bone erosion is one of the major features of joint damage caused by
RA. Joint narrowing was observed in most of the arthritis-bearing rats
[27]. The X-ray results (Fig. 1) showed that the toes joints could barely
be seen in untreated CIA rats (Fig. 1B). With TWP treatment, TWP
significantly improved on joint destruction of CIA rat (Fig. 1C).
3.4. TWP reduced DPPI activities in serum or SFs elevated over RA
development of CIA Rats in vivo
The results from fluorescent kinetic activity assay (Fig. 2) demonstrated the activities of DPPI in SFs or serums of CIA rats after 2wks
administration of TWP or TP. The value of DPPI activity in SFs of CIA
Table 1
The clinical assessment variables of rat paw swollen thickness (cm) in untreated CIA
group and TWP treatment CIA rats group.
Day 33
untreated rats
swollen
thickness
TWP(5 mg/ml)
swollen
thickness
0.86 ± 0.02
0.86 ± 0.02
0.84 ± 0.02
0.83 ± 0.01
0.51 ± 0.05
0.51 ± 0.047
0.44 ± 0.03
0.39 ± 0.01
Total protein concentration
526 ± 145
1652 ± 32.8
932 ± 105
Serums and tissue homogenates were prepared as described above
and the effects of TWP in vitro on DPPI activities were determined. The
data showed the increased inhibitory rates of TWP on DPPI activities in
different tissues (serums, SFs, liver, spleen, and lung) and all in dosedependent manners(Fig. 3). However, After incubation with different
TWP doses of 25, 50, 100 and 200 μg/ml, the activities of hrDPPI were
inhibited by 15.1, 36.1, 43.6 and 55.2%. The serums containing high
DPPI activity collected from CIA rats were incubated with TWP (25, 50,
100 and 200 μg/ml), serums DPPI activities were inhibited by 22.3,
34.2, 45.1% and 75.6% respectively. After incubation of TWP (25, 50,
100 and 200 μg/ml) with SFs of CIA rats, DPPI activities were inhibited
by 8.84, 11.5, 22.1%, 34.0%. In vitro study demonstrated that TWP has
a direct inhibitory effects on DPPI activity in serums or in SFs. The IC50
of TWP against hrDPPI activity, serums DPPI activity and SFs DPPI
activity were 158 μg/ml; 112 μg/ml and 266 μg/ml. The lower the IC50
values for TWP toward DPPI, the stronger the inhibition of DPPI.
Gly-Phe-CHN2 is a DPPI specific inhibitor and used in our study to
assess the strength of inhibitory effects between Gly-Phe-CHN2, TWP,
TP and solvent (0.01% DMSO) by adding them separately into hrDPPI
(Fig. 4A) or SFs (Fig. 4B) and serums (Fig. 4C) from CIA rats. As shown
in Fig. 4, compared with untreated controls, the effects of Gly-PheCHN2 significantly decreased DPPI activities of hrDPPI (P = 0.001), SFs
(P = 0.004) and serums (P = 0.006) of CIA rats; TWP also significantly
reduced DPPI activities of hrDPPI (P = 0.021), SFs (P = 0.016) and
serums (P = 0.02) of CIA rats. However, there was no significant difference between TP and untreated controls in all of hrDPPI, SFs or
serums in vitro.
Total protein concentrations in SFs of rats were shown in Table 2. In
untreated CIA rat group, the total protein concentration in SFs were
68.1% (P = 0.01) higher than that in the normal group. In contrast, CIA
rats treated with TWP (5 mg/100 g body weight) exhibited a marked
decrease of total protein concentration by 43.5% compared with untreated CIA rat group. There was no significant difference between TWP
treatment group and normal group.
Day 31
TWP
3.5. TWP inhibited DPPI activity in vitro
3.3. TWP recovered total protein concentration that elevated in SFs over RA
development of CIA rats
Day 29
Untreated
rat group was 16.4 folds higher (P = 0.03) than that in the normal
group. The activity of DPPI was decreased 1.3 times in TWP treatment
(5 mg/100 g body-weight) group (P = 0.18) compared with the untreated CIA rat group (Fig. 2A). In the serums of untreated CIA rat
group the DPPI activity was increased by 63% compared to the normal
rat group. Compared with the untreated CIA rat group, the DPPI activity of TWP treatment (5 mg/100 g body-weight) CIA rat group was
significantly dropped by 58.9% (P = 0.002) (Fig. 2B). There were no
significant difference in serums DPPI activities between untreated CIA
rat group and TP treatment CIA rat group (Fig. 2C).
Rat paws swollen and the changes of the thickness are typical
symptom over RA development. The data in Table 1 from pathological
assessments have shown the paw swollen thickness of CIA rats with or
without TWP treatment. The paw swollen thickness was kept a high
level in untreated CIA rats. TWP treatment decreased the severity of
paw swelling of CIA rats in comparison with the untreated CIA rats.
TWP (5 mg/100 g body weight) exhibited recovery effects from the
development of arthritis. At the same time, TWP treatment could effectively suppress the loss of body weight of CIA rats.
Day 27
Normal
Data are expressed as Mean ± SEM (n = 6).
3.2. Pathological changes in CIA rat after treatment with TWP
CIA rat group
Group
Data are expressed as Mean ± SEM (n = 6).
468
Biomedicine & Pharmacotherapy 96 (2017) 466–470
J. Wang et al.
Fig. 2. CIA rats model in vivo study after TWP or TP
intragastric administrations for 14 days, the levels of
DPPI activities in (A) SFs and (B) serums of normal
rats, untreated CIA rats and TWP treated CIA rats; (C)
the levels of DPPI activities in serums of normal rats,
untreated CIA rats and TP treated CIA rats, (n = 6).
The values are expressed as mean ± SEM.
4. Discussion
Our both in vivo and in vitro studies highlighted that TWP is able to
inhibit the increasment of DPPI activity in serum, SFs and tissues of CIA
rat and suppress RA development, giving a new insight that the possible
pharmacological mechanism of TWP in treating RA may be related to
the decrease of elevated DPPI activity to keep synovial homeostasis.
In present study, we demonstrated that TWP can ameliorate the
inflammatory condition of arthritis and inhibit the progression of RA in
CIA rats. The major pathological changes of RA are chronic inflammatory responses of synovial joints. Our radiological observation
indicated that TWP treatment lead to reduced cartilage destruction and
bone erosion, contributing to a protective effect against RA. Our results
showed that the total protein concentrations in SFs of untreated CIA rat
group were significantly higher than that in the normal group, while
the total protein concentration in the SFs of TWP treatment group were
recovered to the level of normal group. It was also observed that the
paw’s swollen thickness of CIA rats in TWP treatment group were also
recovered to normal level and well decreased compared with the untreated CIA rats.
DPPI activities in SFs and serum samples of CIA rats in vivo were
much more increased compared with that in normal rats, while TWP
significantly reduced DPPI activity in SFs and serum samples of CIA rats
in dose-dependent manner after treatment, and significantly recovered
to normal levels.
In our in vitro study, TWP showed the inhibitory effect on hr-DPPI
activity, and was very effective in inhibiting DPPI activity in serum and
in SFs from CIA rats in vitro. However TP had no inhibitory effect on
DPPI activity in vivo and in vitro respectively.
5. Conclusion
In summary, our studies discovered that the elevated DPPI activities
in SFs and serums of CIA rats during RA progress can be decreased by
TWP treatment in vivo; the increased DPPI activities or decreased DPPI
activities were associated with the development of RA progress or recovery from RA development. The inhibitory effects of TWP on DPPI
activities were also confirm by in vitro study. We suggest that a possible
therapeutic function of TWP in treatment of RA might be relating to
inhibition of increments of DPPI activities and then further reduction of
serine proteases activations, as well as indirectly inhibiting and weakening the roles of activated serine proteases in inflammatory symptoms.
However, TP is a very monomer in the components of TWP and had
fewer effects on TWP in this case [28]; also TP did not show the inhibitory function on DPPI activity in vivo and in vitro.
Fig. 3. In vitro study DPPI activities (A) of hrDPPI (0.5mU), (B) in serums, (C) in SFs, (D) in spleen, (E) in liver and (F) in lung of CIA rats were inhibited by addition of TWP (0, 25, 50,
100, 200 μg/ml). The inhibition rate was calculated: Inhibition rate (%) = [Vmax (TWPtreatedsample) – Vmax (untreatedsample)]/Vmax (untreatedsample) × 100%, and expressed as mean ± SEM
(n = 3–6, in triplicates).
469
Biomedicine & Pharmacotherapy 96 (2017) 466–470
J. Wang et al.
Fig. 4. Effects of Gly-Phe-CHN2 (20 μM), TWP
(100 μg/ml) or TP (75 μg/ml) on DPPI activities of
(A) hrDPPI(0.5mU), (B) SFs and (C) serums of CIA
rats in-vitro. Values are expressed as mean ± SEM
(n = 3-6, in triplicates), *P < 0.05, **P < 0.01.
Acknowledgements
We thank Changzhou University Talent Introdution Researh Fund
(ZMF14020066); Start-up Research Laboratory for Over-sea Talent
Fund (Z391405); Changzhou Science and Technology Bureau
International Cooperation Research Fund, China (CZ20150014) and
Postgraduate Research & Practice Innovation Program of Jiangsu
Province (KYCX17-2082) for financial supports.
[14]
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