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Journal of Ethnopharmacology
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Research Paper
Univ. Estadual Paulista-UNESP Departamento de Fisiologia, Instituto de Biocincias, CEP 18618-970 Botucatu, SP, Brazil
Univ. Estadual Paulista-UNESP Departamento de Qumica Orgnica, Instituto de Qumica, CEP 14800-900, Araraquara, SP, Brazil
c
Univ. Estadual Paulista-UNESP Departamento de Morfologia, Instituto de Biocincias, CEP 18618-970, Botucatu, SP, Brazil
d
Univ. Estadual Paulista-UNESP Campus Experimental do Litoral Paulista, CEP 11330-900 So Vicente, SP, Brazil
e
Universidade Santa Ceclia Ps-Graduao em Sustentabilidade de Ecossistemas Costeiros e Marinhos, Rua Oswaldo Cruz, 266,
Boqueiro, CEP 11045907 Santos, SP, Brazil
f
Univ. Estadual Paulista-UNESP Departamento de Cincias Biolgicas, Faculdade de Cincias Farmacuticas, CEP 14801-902, Araraquara, SP, Brazil
b
art ic l e i nf o
a b s t r a c t
Article history:
Received 22 August 2014
Received in revised form
3 November 2014
Accepted 13 November 2014
Available online 24 November 2014
Keywords:
Terminalia catappa L.
Combretaceae
Gastric healing action
Helicobacter pylori
MMP-9
MMP-2
http://dx.doi.org/10.1016/j.jep.2014.11.025
0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
286
1. Introduction
2.3. Apparatus
The mass spectrometry experiments were performed on LCQ
Fleet equipment (Thermo Scientics) equipped with the dispersal of
the directly introduced sample via ow injection analysis (FIA). The
studied matrix was analyzed by electrospray ionization (ESI), and
multiple stages of fragmentation (MS2, MS3, MSn) were performed at
an ion trap (IT) interface. The negative mode was selected for the
generation and analysis of the mass spectra for the rst order (MS)
and for the remaining multi-stage experiments under the following
conditions: capillary voltage, 25 V; voltage spray, 5 kV; capillary
temperature, 275 1C. A carrier gas (N2) with a ow of 8 arbitrary
units (A.U.) was used, and the collision gas was helium (He). The
track acquisition was 1002000 m/z. Xcalibur version 1.3 software
(Thermo Finigans) was used to acquire and process the data.
For the FIA-ESI-IT-MSn assay, 10 mg of the aqueous fraction was
dissolved in 1 mL of MeOH:H2O (1:1, v/v) after using an ultrasonic
bath for 5 min. The samples were then ltered through a 0.22 mm
PTFE lter, and aliquots of 20 mL were directly injected into the
FIA-ESI-IT-MSn system.
For the HPLCPDA a clean-up step was performed to remove any
contaminants; the solution was puried by solid phase extraction
(SPE) using Phenomenex Strata C18 cartridges (500 mg of stationary
phase) that were previously activated with 5 mL of MeOH and
equilibrated with 5 mL of MeOH:H2O (1:1, v/v). The dried aqueous
fraction was diluted to 10 mg/mL in HPLC solvent. A 20 mL aliquot
was injected directly into the HPLCPDA with detection at 270 nm.
The identication of the different compounds in the chromatographic prole of the aqueous fraction was done by comparing their
retention times (tr) and the UV spectra with those isolates previously described in the literature (Mininel et al., 2014).
2.4. Animals
Male Wistar rats weighing 180250 g were obtained from breeding at the Biotrio Central at the Universidade Estadual Jlio de
Mesquita Filho (UNESP), Botucatu-SP. Animals were fed with a
certied Nuvilab CR-diet, with free access to tap water and were
housed on a 12 h light/dark cycle at 6071% humidity and a
temperature of 2272 1C. The UNESP Institutional Animal Care and
Use Committee, following the recommendations of the Canadian
Council on Animal Care (Olfert et al., 1993), approved all of the
employed protocols under number 18/05.
2.5. Evaluation of the gastroprotection activity of the FrAq
2.5.1. Gastric ulcer induced by absolute ethanol
The rats were divided into ve treatment groups (n 714)
and fasted for 12 h prior to receiving an oral dose of the vehicle
(saline 10 mL/kg), carbenoxolone (100 mg/kg) and FrAq (12.5, 25
and 100 mg/kg). After 60 min, all groups were orally treated with
1 mL of absolute ethanol for the gastric ulcer induction. One hour
later, animals were killed and their stomachs excised. The incision
into each stomach was performed along the greater curvature and
examined for linear hemorrhagic lesions in the glandular region
(Morimoto et al., 1991). Then, the stomachs were photographed and
287
400
n.s.
300
2
ULA (mm )
288
**
***
200
100
2.8. Minimum inhibitory concentration (MIC)
0
Vehicle Carbenoxolone
100 mg/kg
12.5
25
100
FrAq (mg/kg)
Fig. 1. Effect of pretreatment with the aqueous fraction (FrAq) obtained from the
leaves of Terminalia catappa on ethanol-induced gastric ulcers in rats. The animals
orally received saline solution (vehicle), carbenoxolone or FrAq. The results are
expressed as the mean 7 S.E.M. (n 714), and statistical signicance was determined by one-way analysis of variance (ANOVA) followed by Dunnett's test
(nn p o0.01, nnn p o0.001 and n.s. no signicant differences).
80
60
ULA (mm)
***
40
20
0
Vehicle
Lansoprazole
30 mg/kg
FrAq
25 mg/kg
3. Results
Fig. 2. Effect of pretreatment with the aqueous fraction (FrAq) obtained from the
leaves of Terminalia catappa on ischemiareperfusion induced gastric ulcers in rats.
The animals orally received saline solution (vehicle), lansoprazole or FrAq. The
results are expressed as the mean 7 S.E.M. (n 79), and statistical signicance was
determined by one-way analysis of variance (ANOVA) followed by Dunnett's test,
with the level of signicance set at nnp o 0.01 and nnnp o0.001.
Table 1
Effects of the aqueous fraction (FrAq) from the leaves of Terminalia catappa (25 mg/kg)
administered through the intraduodenal (i.d.) or oral (p.o.) route on the biochemical
parameters of gastric juice obtained from pylorus-ligature rats (n68).
Treatment
Route
Dose (mg/kg)
[H ] (Eq/mL/4 h)
Vehicle
Cimetidine
FrAq
i.d.
100
25
7.02 7 2.25
4.29 7 1.19nn
8.02 7 2.18
6.99 7 1.84
2.777 1.30nn
7.34 7 0.65
Vehicle
Cimetidine
FrAq
p.o.
100
25
3.747 1.01
2.63 7 0.67
5.30 7 1.67 n
5.25 7 1.51
1.94 7 0.87nn
6.337 0.43
Data represents the means7 S.E.M. The asterisks denote the signicance levels,
when compared with the control group.
n
po 0.05.
p o0.01 by one-way ANOVA followed by Dunnett's test.
nn
n.s.
Alcian blue
(mg/g wet tissue)
3000
2000
1000
0
Vehicle
Carbenoxolone
100 mg/kg
FrAq
25 mg/kg
Fig. 3. Effects of the aqueous fraction (FrAq) obtained from the leaves of Terminalia
catappa (25 mg/kg) on the production of adherent gastric mucus (measured as the
amount of bound Alcian blue) in pylorus-ligated rats relative to the control values
(n 6). The results are the mean7 S.E.M. Statistical signicance was determined by
ANOVA followed by Dunnett's t test (np o0.05; nnn p o0.01 and n.s. no signicant
differences).
289
4. Discussion
The development of gastric ulcers is a complex and multifactorial process including bacterial infections, the increase of acid
secretion, generation of reactive oxygen species (ROS), inhibition
of the endogenous PGs, and the degradation of the extracellular
matrix (ECM) (Laine et al., 2008; Mei et al., 2013). Research during
the last decade has offered new insights in the preventative
therapy and the healing of gastric ulcers and the synergistic
efciency of a multi-target approach based on individual mechanisms of action could be the new perspective for treatment of this
disease (Wagner, 2011; de Carvalho et al., 2014).
Terminalia catappa, is a medicinal plant widely distributed in
tropical and subtropical regions and it has been previously reported
that this species exhibits a variety of biological effects. However, the
290
Fig. 4. The ulcerative lesion area (ULA-mm2) for gastric ulcers induced by ethanol in rats pretreated with L-NAME (panel a) with vehicle or together with carbenoxolone
(100 mg/kg) or the aqueous fraction (FrAq) obtained from leaves of Terminalia catappa (25 mg/kg), pretreated with N-ethylmaleimide (panel b) with vehicle or together with
carbenoxolone (100 mg/kg) and FrAq (25 mg/kg), or pretreated with INDO indomethacin (panel c) with vehicle or together with carbenoxolone (100 mg/kg) or FrAq
(25 mg/kg). The results are reported as the mean7 S.E.M. Statistical signicance was determined by ANOVA followed by Dunnett's test. np o0.05; nnp o 0.01; nnnp o 0.001
compared to the corresponding vehicle group. # o 0.05; ##p o 0.01 compared to the corresponding NEM vehicle, L-Name vehicle or INDO vehicle. N.S. no signicant
differences.
10
20
8
ULA (mm)
ULA (mm)
15
10
5
***
***
**
***
2
0
0
Vehicle
Lansoprazole
30 mg/kg
FrAq
25 mg/kg
Vehicle
Lansoprazole
30 mg/kg
FrAq
25 mg/kg
Fig. 5. Effect of the oral administration of the aqueous fraction (FrAq) obtained from the leaves of Terminalia catappa (25 mg/kg) on the healing of ulcers produced by the
introduction of acetic acid solution into the stomachs of rats. The ulceration was scored on the 7th day (panel a) and 14th day (panel b) after surgery. The results are reported
as the mean7 S.E.M. Statistical signicance was determined by ANOVA followed by Dunnett's test. nnp o 0.01;nnnpo 0.001 compared to the corresponding vehicle group.
Fig. 6. Representative zymography results of the gastric ulcers from the different
groups illustrating MMP-2 and MMP-9 activity. Treatment for 7 days vehicle (line 1),
lansoprazole (line 2), aqueous fraction (FrAq) obtained from leaves of Terminalia
catappa at dose of 25 mg/kg (line 3) and sham (line 4). Treatment for 14 days vehicle
(line 5), lansoprazole (line 6), aqueous fraction (FrAq) obtained from leaves of
Terminalia catappa at dose of 25 mg/kg (line 7) and sham (line 8). Gelatinolytic bands
of 92, 72, 64 and 57 kDa were observed, which correspond to active-MMP-9,
pro-enzyme, intermediate and active-MMP-2, respectively.
Fig. 7. Effect of treatment with the vehicle, lansoprazole (30 mg/kg) or the aqueous
fraction (FrAq) obtained from Terminalia catappa (FrAq) on the gelatinolytic activity
of MMP-9 (black column) and MMP-2 (white column) in the gastric mucosa after 7
(panel a) and 14 days (panel b) of treatment. Values show the ratio of the IOD from
the treatment groups to the control group (vehicle) IOD value.
291
292
Table 2
Effects of the aqueous fraction (FrAq) obtained from leaves of Terminalia catappa (25 mg/kg) and lansoprazole (30 mg/kg) administered orally for 14 consecutive days on
selected toxicological parameters (n 56).
Treatment (p.o.)
Vehicle
Organ weights (g)
Heart
Lung
Kidney
Liver
Spleen
Lansoprazole
3.85 7 0.48
4.497 0.64
5.147 0.63
10.107 1.23
2.69 7 0.28
Biochemical parameter
Glucose
Creatinine
Urea
-GT
AST
ALT
136.90 7 7.00
0.56 7 0.02
38.107 1.12
0.96 7 0.17
157.117 13.4
44.337 2.51
3.88 7 0.32
5.34 7 1.43
4.917 0.18
9.99 7 0.28
2.83 7 0.24
136.40 7 5.80
0.56 7 0.03
39.40 7 5.35
2.02 7 0.55
181.20 7 17.51
48.007 5.04
FrAq
3.677 0.13
4.20 7 0.40
4.917 0.07
9.707 0.17
2.677 0.27
151.007 8.50
0.53 7 0.04
39.60 7 4.23
1.247 0.25
190.60 7 14.50
43.17 3.11
Results are expressed as the means 7S.E.M. obtained from different groups. The units for the biochemical parameters of serum are U/L (ALT alanine aminotransferase,
AST aspartate aminotransferase, GT gamma-glutamyl transpeptidase) and mg/dL (urea and creatinine).
Table 3
Identication of the substances obtained in the aqueous fraction (FrAq) from the
leaves of Terminalia catappa by FIA-ESI-IT-MSn.
[MH]
1083
781
601
301
MSn ions
781
601
601
409
257
229
Identication
[M-152-152-H]
[M-152-152-180-H]
[M-180-H]
[M-191-H]
[M-44-H]
[M-44-28-H]
Punicalagin (1)
Punicalin (2)
Gallagic acid (3)
Ellagic acid (4)
mucosal architecture (Okabe and Amagase, 2005). Chronic treatment with FrAq (25 mg/kg) demonstrated a dramatic reduction in
the ulcerative lesion area by treatment for 7 days (80%), which was
more effective than 14 days of treatment (37%). This result
demonstrated the FrAq (25 mg/kg) accelerates the healing within
7 days of treatment and the healing effect remains after treatment
of 14 days when compared to control group or lansoprazole group.
The injection of acetic acid into gastric mucosa induces the
development of deep gastric ulceration and gastric mucosal damage
directly associated with ECM degradation, in which the zincdependent matrix metalloproteinases (MMPs) play a crucial role.
In several animal studies of gastric ulcer, attention has focused
on the role of MMPs, mainly MMP-2 and MMP-9 (Li et al., 2013).
Wound formation and the following healing are dynamic processes
of ECM remodeling that are mainly inuenced by MMP-2 and
MMP-9 (Gyenge et al., 2013).
According to Yeh et al. (2012) MMP-9 is the protease most
signicantly involved in the degradation of the basement membrane
and is associated with pathological states that include inammation
and cancer. Li et al. (2013) described enhanced expression of MMP-9
in the margin of the ulcer in patients with this disease. Their study
suggested that the presence of MMP-9 at the margin of the ulcer may
be indicative of inammation and poor wound healing. Ulcerogenic
agents, such as indomethacin, exhibited 12-fold higher pro-MMP-9
activity and ethanol exhibited 22-fold higher pro-MMP-9 activity in
rat gastric tissues relative to untreated tissues (Mei et al., 2013). Our
results showed MMP-9 activity only after treatments with the vehicle
and lansoprazole (7 days). These results determined that the presence
of MMP-9 activity at the gastric mucosa in groups treated with the
vehicle was related with the absence of healing in ulcers of the gastric
mucosa. Our results also show that the seemingly healing macroscopic ulcer observed by treating animals with lansoprazole (7 days)
may not represent a good wound healing because the presence of
MMP-9 activity in gastric damage further demonstrates the persistence of the inammatory process at the gastric mucosa. Our results
shown that treatment of the acetic acid induced chronic ulcers with
FrAq (25 mg/kg) for 7 and 14 days inhibited the MMP-9 activity. Our
results could be strengthened by the study from Yeh et al. (2012) in
which extract from Terminalia catappa leaves exerts an antimetastic
effect by attenuating MMP-9 mediated inammation in hepatocellular carcinoma. In addition to our results obtained regarding MMP-9,
our results also reported high MMP-2 activity in gastric ulcers of the
control group treated with vehicle (7 and 14 days), and lower MMP-2
activity was observed after the treatment of animals with
293
1083.39
100
95
90
85
80
75
Relative Abundance
70
65
60
55
50
45
40
35
541.15
30
781.45
1013.13
954.49
25
1132.91
639.27
20
1349.87
312.07
15
1397.19
1562.07
10
5
1712.29
0
500
1000
1500
2000
m/z
Fig. 8. First-order mass spectrum of the aqueous fraction (FrAq) obtained from Terminalia catappa (FrAq) at the negative mode. Range of ions with m/z 1002000 Da.
Relative Abundance
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
300
400
500
600
700
800
900
1000
1100
1200
m/z
Fig. 9. Mass spectrum of the second order (MS2) of the precursor ion m/z 1083 from the aqueous fraction (FrAq) obtained in the negative mode of leaves from Terminalia
catappa. Range of ions with m/z 300-1200 Da.
294
1 - e punicalagin
T. catappa FrAq - CH5
References
2000000
Intensity [V]
1000000
2 - e punicalin
0
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
lansoprazole or the FrAq over 14 days. Important toxicity parameters, including changes in body weight, mortality and weight of
the vital organs, were determined as shown in Table 2. Treatment
with FrAq for 14 days with 25 mg/kg did not signicantly alter the
body weight of animals compared to the vehicle control over the
14-days treatment period (data not shown) and the average
weights of the major organs of the FrAq-treated subjects were
comparable to those of the control group. Table 2 also shows that
FrAq did not affect several biochemical parameters. Treatment did
not signicantly alter the body weight, the weight of vital organs
and biochemical parameters of serum. However, Mininel et al.
(2014) evaluated the mutagenicity of the hydroalcoholic extract
from the leaves of Terminalia catappa with the Ames test and
illustrated that this extract exhibited mutagenic activity in vitro at
high concentrations, leading them to recommend caution when
using this compound for medicinal purposes.
This study also evaluated the activity of aqueous fraction (FrAq)
against Helicobacter pylori and determination of minimal inhibitory
concentration (MIC) of 125.0 mg/mL considered an important antimicrobial activity. The literature do not show a consensus in relation
to MIC values obtained for natural products. Aligannis et al. (2001)
consider MICs with values equal to or less than 500 mg/mL as potent
inhibitors; MICs between 600 and 1500 mg/mL and MIC moderate
inhibitors as above 1600 mg/mL as weak inhibitors. Webster et al.
(2008) established as another satisfactory MIC value equal to or less
than 1000 mg/mL. In this sense, the result reported in this investigation demonstrated the inhibitory potential of Terminalia catappa
against this important bacteria responsible to gastric ulcer.
5. Conclusions
We determined that the FrAq from Terminalia catappa leaves
has an important anti-Helicobacter pylori activity, excellent preventive and curative effects on acute and chronically induced
gastric ulcers. The mechanisms involved in the gastroprotection
are related to the NO pathway, an increase in the mucus and the
endogenous prostaglandins, and this fraction was able to heal
ulcers through the inhibition of MMP-9 and MMP-2 activities.
Acknowledgments
This study was supported by the Biota-FAPESP project (Fundao
de Amparo Pesquisa do Estado de So Paulo), CNPq (Conselho
Aligannis, N., Kalpotzakis, E., Mitaku, S., Chinou, I.B., 2001. Composition and
antimicrobial activity of the essential oils of two Origanum species. Journal of
Agricultural and Food Chemistry 49, 41684170.
Al-Jiboury, H., Kaunitz, J.D., 2012. Gastroduodenal mucosal defense. Current
Opinion of Gastroenterology 28, 594601.
Arakawa, T., Watanabe, T., Tanigawa, T., Tominaga, K., Fujiwara, Y., Morimoto, K.,
2012. Quality of ulcer healing in gastrointestinal tract: its pathophysiology and
clinical relevance. World Journal of Gastroenterology 18, 48114822.
Arrieta, J., Benitez, J., Flores, E., Castillo, C., Navarrete, A., 2003. Purication of
gastroprotective triterpenoids from stem bark of Amphipterygium adstringens;
roles of prostaglandins, sulfhydryls, nitric oxide and capsaicin neurons. Planta
Medica 69, 905909.
Bradford, M.M., 1976. A rapid and sensitive method for the quantization of
microgram quantities of protein utilizing the principle of protein-dye binding.
Analytical Biochemistry 72, 248254.
Brzozowska, I., Strzalka, M., Drozdowicz, D., Konturek, S.J., Brzozowski, T., 2013.
Mechanisms of esophageal protection, gastroprotection and ulcer healing by
melatonin. Implications for the therapeutic use of melatonin in gastroesophageal reux disease (GERD) and peptic ulcer disease. Current Pharmaceutical
Design , http://dx.doi.org/10.2174/1381612819666131119110258 (Epub ahead of
print).
Brzozowski, T., Konturek, P.C., Konturek, S.J., Pajdo, R., Schuppan, D., Drozdowicz, D.,
Ptak, A., Pawlik, M., Nakamura, T., Hahn, E.G., 2000. Involvement of cyclooxygenase (COX)-2 products in acceleration of ulcer healing by gastrin and
hepatocyte growth factor. Journal of Physiology and Pharmacology 51, 751773.
Brzozowski, T., Konturek, P.C., Sliwowski, Z., Pajdo, R., Drozdowicz, D., Kwiecien, S.,
Burnat, G., Konturek, S.J., Pawlik, W.W., 2006. Prostaglandin/cyclooxygenase
pathway in ghrelin-induced gastroprotection against ischemia-reperfusion
injury. Journal of Pharmacology and Experimental Therapeutics 319, 477487.
Camargo, M.C., Garca, A., Riquelme, A., Otero, W., Camargo, C.A., Garca, T.H.,
Candia, R., Bruce, M.G., Rabkin, C.S., 2014. The problem of Helicobacter pylori
resistance to antibiotics: a systematic review in Latin America. Clinical and
Systematic Reviews 109, 485495.
Chatterjee, A., Chatterjee, S., Das, S., Saha, A., Chattopadhyay, S., Bandyopadhyay, S.K.,
2012. Ellagic acid facilitates indomethacin-induced gastric ulcer healing via COX2 up-regulation. Acta Biochimica et Biophysica Sinica 44, 565576.
Chen, P.S., Li, J.H., 2005. Chemopreventive effect of punicalagin, a novel tannin
component isolated from Terminalia catappa, on H-ras-transformed NIH3T3
cells. Toxicology Letter 163, 4453.
Chen, P.S., Li, J.H., Liu, T.Y., Lin, T.C., 2000. Folk medicine Terminalia catappa and its
major tannin component, punicalagin, are effective against bleomycin-induced
genotoxicity in Chinese hamster ovary cells. Cancer Letter 152, 115122.
Chen, B., Tuuli, M.G., Longtine, M.S., Shin, J.S., Lawrence, R., Inder, T., Michael, N.D.,
2012. Pomegranate juice and punicalagin attenuate oxidative stress and
apoptosis in human placenta and in human placental trophoblasts. American
Journal of Physiology and Endocrinology Metabolism 302, E1142E1152.
CLSI Manual Clinical and Laboratory Standards Institute., 2006. Methods for
dilution antimicrobial susceptibility tests for bacteria that grow aerobically:
approved standards. 6 ed. Performance standards for antimicrobial susceptibility testing. Sixteenth informational supplement M100-S16 (tab 2J). Clinical
and Laboratory Standards Institute, Wayne, PA.
De Foneska, A., Kaunitz, J.D., 2010. Gastroduodenal mucosal defense. Current
Opinion Gastroenterology 26, 604610.
de Carvalho, K.I., Bonamin, F., Dos Santos, R.C., Prico, L.L., Beserra, F.P., de Sousa, D.P.,
Filho, J.M., da Rocha, L.R., Hiruma-Lima, C.A., 2014. Geraniol-a avoring agent
with multifunctional effects in protecting the gastric and duodenal mucosa.
Naunyn Schmiedebergs Archieves of Pharmacology 387, 355365.
Eom, C.S., Park, S.M., Myung, S.K., Yun, J.M., Ahn, J.S., 2011. Use of acid-suppressive
drugs and risk of fracture: a meta-analysis of observational studies. Annals
Family Medicine 9, 257267.
Fan, Y.M., Xu, L.Z., Gao, J., Wang, Y., Tang, X.H., Zhao, X.N., Zhang, Z.X., 2004.
Phytochemical and antiinammatory studies on Terminalia catappa. Fitoterapia
75, 253260.
Fyhrquist, P., Mwasumbi, L., Haeggstrm, C.A., Vuorela, H., Hiltunen, R., Vuorela, P.,
2002. Ethnobotanical and antimicrobial investigation on some species of
Terminalia and Combretum (Combretaceae) growing in Tanzania. Journal of
Ethnopharmacology 79, 169177.
Genestra, M., 2007. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signalling 19, 18071819.
Germosn-Robineau, L., 2014. Farmacopea Vegetal Carbea. CICY editorial, Yucatn,
Mexico p. 360.
Gyenge, M., Amagase, K., Kunimi, S., Matsuoka, R., Takeuchi, K., 2013. Roles of proangiogenic and anti-angiogenic factors as well as matrix metalloproteinases in
healing of NSAID-induced small intestinal ulcers in rats. Life Science 93,
441447.
Iino, T., Nakahara, K., Miki, W., Kiso, Y., Ogawa, Y., Kato, S., Takeuchi, K., 2001. Less
damaging effect of whisky in rat stomachs in comparison with pure ethanol.
Digestion 64 (214221), 2001.
Iino, T., Tashima, K., Umeda, M., Ogawa, Y., Kato, S., Takata, K., Takeuchi, K., 2002.
Effect of ellagic acid on gastric damage induced in ischemic rat stomachs
following ammonia or reperfusion. Life Science 70, 11391150.
Khalifa, M.A., Hassan, M.K.A., Ashour, O.M., Heeba, G., 2002. Evaluation of the
antiulcer activity of pibutidine hydrochloride (IT-066); the new histamine
H2-receptor antagonist, in cold-restraint stressand ethanol-induced ulcer
models in rats. Al Azhar Medical Journal 31, 3347.
Kinoshita, S., Inoue, Y., Nakama, S., Ichiba, T., Aniya, Y., 2007. Antioxidant and
hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa
Island and its tannin corilagin. Phytomedicine 14, 755762.
Kumar, B.G., Kumari, D., RAjeshwar, G., Umadevi, V., Kotla, N.G., 2014. Antiulcer
activity of ethanolic extract of Terminalia catappa leaves against gastric ulcers
by pyrolic ligation induced model in rats. International Journal of Pharmaceutical Sciences and Drug Research 6, 3840.
Laine, L., Takeuchi, K., Tarnawski, A., 2008. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 135, 4160.
Lin, C.C., Chen, Y.L., Lin, J.M., Ujiie, T., 1997. Evaluation of the antioxidant and
hepatoprotective activity of Terminalia catappa. The American Journal of
Chinese Medicine 25 (153161), 1997.
Li, S.L., Zhao, J.R., Ren, X.Y., Xie, J.P., Ma, Q.Z., Rong, Q.H., 2013. Increased expression
of matrix metalloproteinase-9 associated with gastric ulcer recurrence. World
Journal of Gastroenterology 19, 45904595.
Lin, C.C., Hsu, Y.F., Lin, T.C., 1999. Effects of punicalagin and punicalin on
carrageenan-induced inammation in rats. The American Journal of Chinese
Medicine 27, 371376.
Masuda, T., Yonemori, S., Oyama, Y., Takeda, Y., Tanaka, T., Andoh, T., Shinohara, A.,
Nakata, M., 1999. Evaluation of the antioxidant activity of environmental
plants: activity of the leaf extracts from seashore plants. Journal of Agriculture
Food and Chemistry 47, 17491754.
Mei, X.T., Xu, D.H., Xu, S.K., Zheng, Y.P., Xu, S.B., 2013. Zinc(II)-curcumin accelerates
the healing of acetic acid-induced chronic gastric ulcers in rats by decreasing
oxidative stress and downregulation of matrix metalloproteinase-9. Food
Chemistry and Toxicology 60, 448454.
Megraud, F., Coenen, S., Versporten, A., Kist, M., Lopez-Brea, M., Hirschl, A.M.,
Andersen, L.P., Goossens, H., Glupczynski, Y., 2013. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption.
Gut 62, 3442.
Mininel, F.J., Leonardo Junior, C.S., Espanha, L.G., Resende, F.A., Varanda, E.A., Leite,
C.Q., Vilegas, W., Dos Santos, L.C., 2014. Characterization and quantication
of compounds in the hydroalcoholic extract of the leaves from Terminalia
catappa Linn. (Combretaceae) and their mutagenic activity. Evidence-Based
Complementary and Alternative Medicine , http://dx.doi.org/10.1155/2014/
676902 (Epub ahead of print).
Mishra, V., Agrawal, M., Onasanwo, S.A., Madhur, G., Rastogi, P., Pandey, H.P., Palit, G.,
Narender, T., 2013. Anti-secretory and cyto-protective effects of chebulinic acid
isolated from the fruits of Terminalia chebula on gastric ulcers. Phytomedicine 20,
506511.
Morimoto, Y., Shimohara, K., Oshima, S., Sukamoto, T., 1991. Effects of the new antiulcer agent KB-5492 on experimental gastric mucosal lesions and gastric
mucosal defensive factors, compared to those of teprenone and cimetidine.
Japanese Journal of Pharmacology 57, 495505.
Nagappa, A.N., Thakurdesai, P.A., Venkat Rao, N., Singh, J., 2003. Antidiabetic activity
of Terminalia catappa Linn fruits. Journal of Ethnopharmacology 88, 4550.
Nunes, P.H., Martins, M., do, C., Oliveira, R., de, C., Chaves, M.H., Sousa, E.A., Leite, J.R.,
Vras, L.M., Almeida, F.R., 2014. Gastric antiulcerogenic and hypokinetic activities
of Terminalia fagifolia Mart. Zucc. (Combretaceae). Biomed Research International ,
http://dx.doi.org/10.1155/2014/26174 ([Epub ahead of print]).
Nunes, A.F., Viana, V.S.L., Brito Junior, E.C., Rabelo, R.S., Nunes Filho, D.M., Nunes, P.H.M.,
Martins, M.C.C., 2012. Antiulcerogenic activity of ethanol extract of the bark from
Terminalia catappa in gastric ulcer model induced by ethanol in Rattus norgegicus.
Pharmacologyonline 9, 98101.
Okabe, S., Roth, J.L., Pfeiffer, C.J., 1971. A method for experimental, penetrating
gastric and duodenal ulcers in rats. Observations on normal healing. American
Journal of Digestive Diseases 16, 277284.
Okabe, S., Amagase, K., 2005. An overview of acetic acid ulcer modelsthe history
and state of the art of peptic ulcer research. Biological and Pharmaceutical
Bulletin 28, 13211341.
Olfert, E.D., Cross, B.M., McWilliam, A.A., 1993. Guide to the Care and Use of Experimental
Animals. Canadian Council on Animal Care, Ottawa, Ontario, pp. 1213.
295
Oyagi, A., Ogawa, K., Kakino, M., Hara, H., 2010. Protective effects of a gastrointestinal agent containing Korean red ginseng on gastric ulcer models in mice.
BMC Complementary and Alternative Medicine , http://dx.doi.org/10.1186/
1472-6882-10-45 (Published online August 18, 2010).
Ozdil, K., Kahraman, R., Sahin, A., Calhan, T., Gozden, E.H., Akyuz, U., Erer, B.,
Sokmen, M.H., 2013. Bone density in proton pump inhibitors users: a prospective study. Rheumatology International 33, 22552260.
Pandya, N.B., Tigari, P., Dupadahalli, K., Kamurthy, H., Nadendla, R.R., 2013.
Antitumor and antioxidant status of Terminalia catappa against Ehrlich ascites
carcinoma in Swiss albino mice. Indian Journal of Pharmacology 45, 464469.
Pawlik, M., Ptak, A., Pajdo, R., Konturek, P.C., Brzozowski, T., Konturek, S.J., 2001.
Sensory nerves and calcitonin gene related peptide in the effect of ischemic
preconditioning on acute and chronic gastric lesions induced by ischemiareperfusion. Journal of Physiology and Pharmacology 52, 569581.
Parreira, P., Duarte, M.F., Reis, C.A., Martins, M.C., 2014. Helicobacter pylori infection:
a brief overview on alternative natural treatments to conventional therapy.
Critical Reviews in Microbiology 10, 112.
Rafatullah, S., Tariq, M., Al-Yahya, M.A., Mossa, J.S., Ageel, A.M., 1990. Evaluation of
turmeric (Curcuma longa) for gastric and duodenal antiulcer activity in rats.
Journal of Ethnopharmacology 29, 2534.
Rao, C.V., Vijayakumar, M., 2007. Protective effect of ( )-catechin against gastric
mucosal injury induced by ischaemia-reperfusion in rats. Journal of Pharmacy
and Pharmacology 59, 11031107.
Ratnasooriya, W.D., Dharmasiri, M.G., 2000. Effects of Terminalia catappa seeds on
sexual behaviour and fertility of male rats. Asian Journal of Andrology 2, 213219.
Shay, H., Komarov, S.A., Fels, S.E., Meraze, D., Gruentein, M., Siplet, H., 1945.
A simple method for the uniform production of gastric ulceration in the rat.
Gastroenterology 5, 4361.
Smith, G.S., Mercer, D.W., Cross, J.M., Barreto, J.C., Miller, T.A., 1996. Gastric injury
induced by ethanol and ischemia-reperfusion in the rat. Differing roles for lipid
peroxidation and oxygen radicals. Digestive Diseases and Sciences 41, 11571164.
Takeuchi, K., 2010. Prostaglandin EP receptors and their roles in mucosal protection and
ulcer healing in the gastrointestinal tract. Advances Clinical Chemistry 51, 121144.
Tang, X., Gao, J., Wang, Y., Fan, Y.M., Xu, L.Z., Zhao, X.N., Xu, Q., Qian, Z.M., 2006. Effective
protection of Terminalia catappa L. leaves from damage induced by carbon
tetrachloride in liver mitochondria. Journal of Nutritional Biochemistry 17, 177178.
Tarnawski, A.S., Ahluwalia, A., Jones, M.K., 2014. Increased susceptibility of aging
gastric mucosa to injury: the mechanisms and clinical implications. World
Journal of Gastroenterology 20, 44674482.
Takeuchi, H., Trang, V.T., Morimoto, N., Nishida, Y., Matsumura, Y., Sugiura, T., 2014.
Natural products and food components with anti-Helicobacter pylori activities.
World Journal of Gastroenterology 20, 89718978.
Thomson, L.A.J., Evans, B., 2006. Terminalia catappa (tropical almond), 2.2. In:
Elevitch, C.R. (Ed.). Species proles for pacic Island agroorestry: permanent
agriculture resources (PAR), 2006. http://www.traditionaltree.org.
Ueda, S., Yoshikawa, T., Takahashi, S., Ichikawa, H., Yasuda, M., Oyamada, H.,
Tanigawa, T., Sugino, S., Kondo, M., 1989. Role of free radicals and lipid
peroxidation in gastric mucosal injury induced by ischemia-reperfusion in rats.
Scandinavian Journal of Gastroenterology 162, 5558.
Wagner, H., 2011. Synergy research: approaching a new generation of phytopharmaceuticals. Fitoterapia 82, 3437.
Wallace, J.L., 2008. Prostaglandins, NSAIDs, and gastric mucosal protection: why
doesn't the stomach digest itself? Physiological Review 88, 15471565.
Wallace, J.L., Ma, L., 2001. Inammatory mediators in gastrointestinal defense and
injury. Experimental Biology and Medicine 226, 10031015.
Wang, Y., Zhang, H., Liang, H., Yuan, Q., 2013. Purication, antioxidant activity and
protein-precipitating capacity of punicalin from pomegranate husk. Food
Chemistry 138, 437443.
Webster, D., Taschereau, P., Belland, R.J., Sand Rennie, C.R.P., 2008. Antifungal
activity of medicinal plant extracts preliminary screening studies. Journal of
Ethnopharmacology 115, 140146.
Yeh, C.B., Hsieh, M.J., Hsieh, Y.S., Chien, M.H., Lin, P.Y., Chiou, H.L., Yang, S.F., 2012.
Terminalia catappa exerts antimetastatic effects on hepatocellular carcinoma
through transcriptional inhibition of matrix metalloproteinase-9 by modulating
NF-B and AP-1 Activity. Evidence-Based Complementary and Alternative Medicine , http://dx.doi.org/10.1155/2012/595292 (Published online 2012 November 8).
Yeh, C.B., Yu, Y.L., Lin, C.W., Chiou, H.L., Hsieh, M.J., Yang, S.F., 2014. Terminalia
catappa attenuates urokinase-type plasminogen activator expression through
Erk pathways in Hepatocellular carcinoma. BMC Complementary and Alternative Medicine 14, 141, http://dx.doi.org/10.1186/1472-6882-14-141.