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Changes in the volume and histology of endometriosis foci in rats treated with copaiba oil (Copaiferalangsdorffii)


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The aim of this study was to analyze the changes that occur in rats with experimental endometriosis after treatment with copaiba oil. Experimental endometriosis was induced in rats. The experimental group received copaiba oil (Copaiferalangsdorffii) orally (0.63 mg/day), and the control group received a 0.9% sodium chloride solution orally (1 ml/100 g of body weight/day). Both groups were treated with gavage for 14 days. After this period, the animals were euthanized, and the implant volume was calculated. The autologous transplants were removed, dyed with hematoxylin-eosin, and analyzed by light microscopy. The average final volumes were significantly different between the groups (p=0.007). There was a significant increase (p=0.012) between the initial and final volumes in the control group, whereas treatment with Copaiferalangsdorffii caused a marked reduction in endometrial growth over time (p=0.016). Histologically, 6/11 (55.00%) rats in the experimental group had a well-preserved epithelial layer, and 3 (45.00%) had mildly preserved epithelium. The control group had seven cases (58.30%) of well-preserved epithelial cells and five cases (41.70%) of mildly preserved epithelial cells (p>0.05). Copaiba oil (Copaiferalangsdorffii) appears to be a promising alternative treatment for endometriosis.
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20 - Acta Cirúrgica Brasileira - Vol. 26 (Suppl. 2) 2011
Changes in the volume and histology of endometriosis foci in rats treated with copaiba
oil (Copaiferalangsdorffii)1
Mudanças no volume e histologia do foco de endometriose em ratas tratadas com óleo de
Copaíba (Copaiferalangsdorffii)
João Nogueira NetoI, Márcio Jorge de Souza LindosoII, Laura Fernandes CoelhoII, Rafael Antonio Freire CarvalhoII,
Taciana Gabrielle Pinheiro de Moura RodriguesII, Ana Gisélia Portela de AraújoIII, Manuel João Batista Castelo GirãoIV,
Eduardo SchorV
IMD, Fellow PhD degree, Federal University of Sao Paulo (UNIFESP), Unit of Endometriosis of HU-UFMA, Brazil. Design the protocol, involved
with technical procedures, responsible for manuscript writing, responsible for intellectual and scientific content of the study, supervised all phases of
the study, and provided guidelines for the surgical interventions.
IIGraduate student, UFMA, Maranhao, Brazil. Involved with technical procedures, responsible for manuscript preparation.
IIIMD, HUUFMA, Maranhao, Brazil. Macroscopic and histopathological examinations.
IVPhD, Department of Ginecology, Paulista School of Medicine, Federal University of Sao Paulo (EPM-UNIFESP), Brazil. Responsible for intellectual
and scientific content of the study, critical revision, provide guidelines for the surgical interventions.
VPhD, Affiliate Professor, UNIFESP, Head of Unit of Pelvic Pain and Endometriosis, EPM-UNIFESP, Sao Paulo, Brazil. Responsible for acquisition
and interpretation of data, statistical analysis, helped with technical procedures, collection and processing of study informations, provide guidelines
for the surgical interventions
PURPOSE: The aim of this study was to analyze the changes that occur in rats with experimental endometriosis after treatment
with copaiba oil.
METHODS: Experimental endometriosis was induced in rats. The experimental group received copaiba oil (Copaiferalangsdorffii)
orally (0.63 mg/day), and the control group received a 0.9% sodium chloride solution orally (1 ml/100 g of body weight/day). Both
groups were treated with gavage for 14 days. After this period, the animals were euthanized, and the implant volume was calculated.
The autologous transplants were removed, dyed with hematoxylin-eosin, and analyzed by light microscopy.
RESULTS: The average final volumes were significantly different between the groups (p=0.007). There was a significant increase
(p=0.012) between the initial and final volumes in the control group, whereas treatment with Copaiferalangsdorffii caused a
marked reduction in endometrial growth over time (p=0.016). Histologically, 6/11 (55.00%) rats in the experimental group had a
well-preserved epithelial layer, and 3 (45.00%) had mildly preserved epithelium. The control group had seven cases (58.30%) of
well-preserved epithelial cells and five cases (41.70%) of mildly preserved epithelial cells (p>0.05).
CONCLUSION: Copaiba oil (Copaiferalangsdorffii) appears to be a promising alternative treatment for endometriosis.
Key words: Phytotherapy. Endometriosis. Drug Therapy. Rats.
OBJETIVO: O objetivo deste estudo foi analisar as mudanças que ocorreram em ratas com endometrioses experimental tratadas
com óleo de copaíba.
MÉTODOS: Foi induzida a endometriose experimental nas ratas. O grupo experimental recebeu óleo de copaíba
(Copaiferalangsdorffii) oralmente (0,63mg/dia) e o grupo controle recebeu oralmente solução salina 0,9% (1mL/100g/dia). Ambos
grupos foram tratados por gavagem por 14 dias. Depois desse período, foi realizada a eutanásia dos animais e calculado o volume
do implante. Os transplantes autólogos foram removidos, corados com Hematoxilina-eosina e realizada a microscopia óptica.
RESULTADOS: A média final dos volumes foi significativamente diferente entre os grupos (p=0,007). Houve um aumente
significante (p=0,12) entre o volume inicial e final do grupo controle, enquanto no grupo tratado com Copaiferalangsdorffii causou
uma redução acentuada no crescimento endometrial ao longo durante o período (p=0,016). Histologicamente,6 das 11 (55%) ratas
do grupo experimental tinha uma camada epitelial bem preservada e 3 (45%) apresentaram epitélio levemente preservado. O grupo
controle apresentou sete casos (58,3%) de células epiteliais bem preservadas e cinco casos (41,7%) de células epiteliais levemente
preservadas (p>0,05).
CONCLUSÃO: O óleo de copaíba (Copaiferalangsdorffii) parece ser um tratamento alternativo promissor para endometriose.
Descritores: Fitoterapia. Endometriose. Quimioterapia. Ratos.
Changes in the volume and histology of endometriosis foci in rats treated with copaiba oil (Copaiferalangsdorffii)
Acta Cirúrgica Brasileira - Vol. 26 (Suppl. 2) 2011 - 21
Endometriosis is a condition that affects 10% of women,
and often causing pelvic pain and infertility. Diagnosis is
sometimes difficult and the optimal treatment is yet to come. Some
events of the pathophysiology of endometriosis are well known,
such as inflammation, immunomodulatory disorders, increased
local and systemic oxidative stress, among others. The search for
new treatments for endometriosis is justified when interfering in
the events mentioned above1.
The copaibas are trees in the Leguminosae-
Caesalpinoideae family, reaching 25-40 feet tall and can live upto
400 years. Copaiba oil, in biological terms, is a product of excretion
or detoxification of the plant organism, and acts as a plant defence
against animals, fungi and bacteria2. The attributed effects to
Copaiba oils in folk medicine are anti-inflammatory, anti-tumour,
anti-tetanus, anti-blenorrhagea, as a urinary anti-septic, to treat
bronchitis, syphilis, skin diseases, ulcers, as well as for healing
Some properties of Copaiba oil are well documented in
the scientific world, which could justify its use in the treatment of
endometriosis. Its anti-inflammatory effect had been observed in
the research, which used kaurenoico acid, extracted from
Coapiferalangsdorffii, and used in Wistar rats with induced colitis.
Furthermore, light microscopy revealed the marked reduction of
inflammatory cell infiltration and submucosal oedema formation
in the colon segments of rats treated with the test compound4. The
anti-inflammatory activity was confirmed in a comparative study
between oils from Copaiferacearensis, Copaifera reticulate and
Copaiferamultijuga in vitro and in vivo5. The study indicated that
Copaiba oils demonstrate peripheral and central antinociceptive
effect and may be useful in the treatment of algesic disorders6.
Another study examined the effects of
Copaiferalangsdorffii resin on intestinal damage associated with
mesenteric ischemia/reperfusion (I/R) in rats. Caused significant
attenuations in I/R – associated increases of myeloperoxidase,
malondialdehyde, catalytic activities and nitrite level.
Copaiferalangsdorffii could effectively prevent the I/R-associated
depletion of glutathione. The data indicate that the copaiba
provided protection against I/R-induced intestinal tissue damage,
which appeared to be, at least in part, due to an antioxidant and
anti-lipid peroxidation mechanism7.
Antimicrobial activity was revealed through disruption
and damage to the cell wall, resulting in the release of cytoplasmic
compounds, alterations in morphology, and a decrease in cell
volume, indicating that copaiba oil may affect the cell wall. Another
effect that suggests anti-cell-proliferation was shown in a study
that showed significant activity against the parasite Leishmania
The development of experimental endometriosis in female
rats through auto-transplantation techniques prompted research on
additional medical treatments for endometriosis. These treatments
were analyzed for their efficacy via macroscopic and histological
parameters, among others9,10.
Because of the known properties of Copaiferalangsdorffii
and its relationship to mechanisms involved in the etiopathogeny
of endometriosis, the present study aimed to analyze its effects on
experimental endometriosis implants in rats.
The study was carried out between March and Julyof
2010, using 40 60-day-old (adult) female Wistar rats (Rattus
norvegicus albinus), weighing 180-250g. The rats were obtained
from the bioterium of the Federal University of Maranhao
The study was developed in the Experimental Surgery
Laboratory of the University Hospital of UFMA, Brazil. Study
procedures followed the regulations of the Brazilian Legislation
for the use of experimental animals (Arouca Act n° 11.794 /2008)
and of the Brazilian Animal Experimentation College (COBEA),
an institution affiliated with the International Council for
Laboratory Animal Science. The study was approved by the Animal
Experimentation Ethics Committee (CEEA-UEMA) under
protocol number 035/2010.
The animals were grouped four per polypropylene cage
(46 cm x 31 cm x 16 cm) with a stainless steel grid lid and a paper
covered floor that was replaced every 48 hours. The animals were
divided into four groups and maintained under constant
environmental conditions. These including rat rations (PURINA®,
São Paulo, Brazil) and water ad libitum for seven days for
adaptation; noise control; 22°C ± 2°C temperature; 40% to 60%
relative humidity; and 12/12 hour light/dark cycles.
The autotransplantation technique was performed
according to the methodology proposed by Nogueira et al.1. Shortly
after the midway incision, the uterine horns were identified;
fragments of the medium third were resected, immersed in saline
solution and cut into 4mm by 4mm fragments. The fragments were
sutured to the mesentery adjacent to the artery that irrigates the
cecum, with the serosa faces turned to the peritoneum and the
endometrial layer turned to the cavity (Figure 1).
After the first surgery, the animals were kept in the lab
for a period of 21 days. Following this period, the rats underwent
an additional operation. An inventory of the peritoneal cavity was
taken using a digital pachymeter to identify the success of the
autotransplantation, followed by a volume calculation using the
following formula: [4
Classification of the experimental endometriosis implant growth
was performed9, and only those animals that progressed to a growth
score of III remained in the study (Figure 2).
FIGURE 1 - Photomicrography showing construction of
autotransplant according to Nogueira et al.1
22 - Acta Cirúrgica Brasileira - Vol. 26 (Suppl. 2) 2011
Nogueira Neto J et al.
FIGURE 2 - Photomicrography showing an autotransplant
with a diameter longer than 4.5 mm, classified as grade III
according to Quereda et al.9
After the surgical approach, the rats were identified and
randomly divided into the Copaiferalangsdorffii (COP group) and
the control group (C group), both containing 12 rats.
The COP group gavaged oil (Óleo de Copaiba® All
Chemistry, lot 34883, São Paulo, Brazil) at 0.63mg/day for 14
days was carried out for Brito et al. in 200012. The C group received
1 ml daily gavage of 0.9% saline solution for 14 days.
After the end of the medical treatments, the rats were
anesthetised using ketamine, and a third laparotomy was
After opening the abdominal wall, an inventory of the
peritoneal cavity and measurements of autotransplant volumes
were performed; the transplant and the middle third of the uterine
horn remaining were then removed. The salvaged tissue was rinsed
with 0.9% saline solution and stored in 10% formaldehyde buffer
for later anatomopathological analysis.
Paraffin tissues were sectioned in 5µm widths and placed
in a warm bath; the slides were incubated with Meyer albumin
and dried afterwards. Tissue sections were stained with
hematoxylin-eosin (HE), and a histological analysis was performed
by a pathologist. The oestrous cycles were analyzed in the middle
third of the uterine horn remaining and drug efficacy was
evaluated10. The persistence of epithelial cells in uterine autografts
was evaluated as follows: a well-preserved epithelial layer = score
3, a moderately-preserved epithelium with leukocyte infiltrate = score
2, a poorly-preserved epithelium (occasional epithelial cell
only) = score 1, and no epithelium = score 0 (Figure 3).
FIGURE 3 - Photomicrography of moderately-preserved
epithelium, with mildly-preserved (40X) cytoplasm from the group
of rats treated with 0,63 mg/day Copaiferalangsdorffii, administered
for a 14-day period.
Biostat 3.0 Windows XP was used for statistical analysis,
where the significance level (
) used to reject the null hypothesis
was 5% (p<0.05). The Mann-Whitney test was used for
independent samplings, and the Wicoxon test was performed for
related samples. Fisher’s exact test was used to analyze the
histopathologic score.
Initially there were 12 samples in each group. Due to
technical problems, one sample of the experimental group was
lost. This left 11 samples in the experimental group. All of the
middle third of the uterine horn remaining was in either the
proestrus or oestrus phase of oestrous cycle.
There was no significant difference between the mean
volume (38.09 mm3) in the C group and (47.00mm3) that in the
COP group at 21 days following the induction of endometriosis
(p=0.470). Two weeks after administering copaiba oil and saline
solution, the final average volumes were 65.40mm3 for the C group
and 23.38mm3 for the COP group (p=0.007).
Average volumes for the initial control group and the
saline-treated group two weeks later were 38.09mm3 and
65.70mm3, respectively. This increase in average volume was
significantly different (p=0.012). For the COP group, the initial
average volume was 47.00mm3, in contrast to the 23.38mm3
final average, and these measurements were also significant
(p=0.016) (Table 1).
Changes in the volume and histology of endometriosis foci in rats treated with copaiba oil (Copaiferalangsdorffii)
Acta Cirúrgica Brasileira - Vol. 26 (Suppl. 2) 2011 - 23
TABLE 1- Characteristics and results for a group of rats treated orally for 14 days with
Copaiba oil (0,63 mg/day) or saline solution (1 ml/100 g body weight).
Regarding preservation of the epithelial layer, upon
histological evaluation of the autotransplant focus the experimental
group (n=11) contained six cases (55.00%) with a well-preserved
epithelial layers (Figure 2), and five cases (45.00%) with
mildly-preserved epitheliums. The control group (n=12) included
seven cases (58.30%) with well-preserved epithelial cells and five
cases (41.70%) of mildly-preserved epithelial cells. No significant
differences were presented (p>0.05).
The treatment of endometriosis is either clinical or surgical
or both. The drugs commonly used interfere with the menstrual
cycle, and after the drug taking is suspended, there is a
reoccurrence of the pathology. Although the surgeries can be
simple, they are often mutilating. It is important to do the
experimental tests with therapeutic options that go against what
has happened in pathogenesis of endometriosis, mainly in the
interference of the inflammatory process and oxidative stress1.
The copaiba oil is extracted from trees of the species
Copaifera, popularly known as “copaiba”, “copaíva” or “pau-de-
óleo”. It is known to have the following medicinal qualities: anti-
inflammatory; anti-tumoral against Walker sarcoma and melanoma
cell line; anti-ulcerogenic, antioxidant and anti-lipoperoxidative;
cercaricide and anti- helmintic; insect repellent and antimicrobial.
The cosmetic industry uses copaiba oil in shampoos, capillary
lotion and bathing foams6.
The copaiba oil used in this research was extracted from
the species Copaiferalangsdorffii, which has scientifically
confirmed anti-inflammatory and antioxidant effects4,7, justifying
its experimental use in endometriosis.
The doses used in this research were based on studies
that used the copaiba oil in different doses (0.63 ml/kg and 0.06
ml/kg during 14 days), followed by microscopic hepatic evaluation
of the rats, in which no hepatocelular alteration was found. The
volume used in the pilot plan was 1.26 ml/kg during 14 days, where
on the 5th day 90 % of the samples died. The volume was fractioned
to 0.98 ml/kg ((3/4 de 1.26 ml/kg), 0.63 ml/kg (1/2 of 1.26 ml/kg)
and 0.31 ml//kg ¼ de 1, 26 ml/kg). This way, the doses of 0.63
ml/kg was standardized, representing the highest volume from
which there were no mortalities in the period of 14 days, and
considered sufficient to realize the major part of the experiment
that used copaiba oil12. Our research reassured the security of the
Group Average Initial Volume Average Final Volume p*
Oil copaiba 47.00 mm3 23.38 mm3 0.016
38.09 mm³
65.40 mm³
p* The Wilcoxon Test for samples (with p<0.05 for rejecting the null hypothesis) comparing
averages of the initial and final volumes between the groups.
p** Mann-Whitney test for independent samples (with p<0.05 for rejecting the null
hypothesis) comparing averages of the initial and final volumes between the oil copaiba
and the control treated groups.
mentioned doses as there were no mortalities in our study.
Statins represent a class of drugs that can effectively
decrease the serum level of cholesterol and is largely used in the
treatment of hypercholesterolemia. Experimental studies show
that these drugs effectively decreased the inflammatory processes
and are anti-oxidant, and so were used in endometriosis
experiments with similar methodology employed in this research.
The sinvastatin used in the dose of 20 mg/kg/day during 14 days
showed a significant regression of the focus of autotransplants
when comparing the final volumes between the experimental and
the control group1. Studies that used atorvastatin in high doses
showed similar results13; results that are compatible with our
research on copaiba oil.
Melatonin is the product of the secretion of the pineal
gland whose main function is regulating sleep, but also has
anti-inflammatory, antioxidant and immunomodulator properties.
It was used in an experimental endometriosis rat model treated
with melatonin (10 mg/kg) intraperitoneally, with the evaluation
of the morphology of the autotransplants, the expression of
COX-2 and antioxidants enzymes. After four weeks of treatment
it showed significant reduction of the autotransplant volumes,
COX-2 and antioxidant activities in the experimental group14. The
morphological evaluation with the significant reduction in volume
agreed with our results.
Strong evidence of the anti-inflammatory effect in the
reduction of the volume of the focus of the autotransplants in rat
model endometriosis is proven in studies that use dexametason
(0.8 mg/kg/day) for 13 days in Wistar rats. The dexametason
significantly reduced inflammatory processes, the amount of
collagen in the stroma, and the area occupied by the glands of the
The histological evaluation didn’t show compatible
alterations with what was seen macroscopically without significant
alterations. The use of melatonin showed significant histological
changes in the experimental group when compared to the control
group, but the author himself criticizes this type of evaluation
because it is semi quantitative14.
The similar volume reduction of the copaiba oil when
compared to anti-inflammatory, anti-oxidants and even
imunommodulators confirmed the theoretical suspicion of the
possible action against the development of focus of experimental
endometriosis and opens one more possible line of research for
the treatment of endometriosis.
24 - Acta Cirúrgica Brasileira - Vol. 26 (Suppl. 2) 2011
Nogueira Neto J et al.
The copaiba oil, at least of the species
Copaiferalangsdorfii, seems to be a promising therapeutic option
in the clinical treatment of endometriosis.
1. Nogueira NJ, Torres OJM, Borges MOR, Coelho TM, Nascimento
AGPAC, Nunes JJNN. Changes in the volume and histology of focus of
endometriosis in rats treated with sinvastatin. Rev Bras Ginecol Obstet.
2. Montes LV, Broseghini LP, Andreatta FS, Sant‘Anna ES, Neves VM,
Silve AG. Evidences for the use of copaiba oil-resin in wound healing- a
systematic review. Natureza Online. 2009;7:61-7.
3. Paiva LAF, Alencar Cunha KM, Santos FA, Gramosa NV, Silveira ER,
Rao VSN. Investigation on the wound healing activity of oleo-resin from
Copaiferalangsdorffii in rats. Phytother Res. 2002;16:737-9.
4. Paiva LAF, Gurgel LA, Silva RM, Tomé AR, Gramosa NV, Silveira
ER, Santos FA, Roa VSN. Anti-inflamatory effect of kaurenoic acid, a
diterpene from Copaiferalangsdorffii on acetic acid-induced colitis in
rats. Vasc Pharmacol. 2003;39:303-7.
5. Vieira Junior VF, Rosas EC, Carvalho MV, Henriques MGMO, Pinto
AC. Chemical composition and anti-inflammatory activity of copaíba
oils from Copaiferacearensis Huber ex Ducker, Coipaifera reticulate
Ducker and Copaiferamultijura Hayne – A comparative study. J
Ethnopharmacol. 2007;112:248-54.
6. Gomes NM, Rezende CM, Fontes SP, Matheus ME, Fernandes PD.
Antinociceptive activity of Amazonian Copiaba oils. J Ethnopharmacol.
7. Paiva LAF, Gurgel LA, Campos AR, Silveira ER, Roa VSN.
Attennuation of ischemia/reperfusion-induced intestinal injury by
oleo-resin from Copaiferalangsdorffii in rats. Life Sci. 2004;75:1979-87.
8. Santos SO, Ueda-Nakamura T, Dias Filho BP, Viegas Junior VF, Pinto
AC, Nakamura CV. Effect of Brazilian copaíba oils on
Leishmaniaamazonensis. J Ethnopharmacol. 2008;120:204-8.
9. Quereda F, Barroso J, Acien P. Individual and combined effects of
triptoreline and gestrinone on experimental endometriosis in rat. Eur J
Obstet Gynecol Reprod Biol. 1996;67:35-40.
10. Keenan JA, William-Boyce PK, Massey PJ, Chen TT, Caudle MR,
Bukovsky A. Regression of endometrial explants in a rat model of
endometriosis treated with the immune modulators loxoribine and
levamisole. Fertil Steril. 1999;72:135-41.
11. Kudon M, Susuki Y, Ideyama Y, Nanya T, Mori M, Shikama H.
Inhibitory effects of a novel aromatase inhibitor, YM511, on growth of
endometrial explants and insulin-like growth factor –I gene expression
in rats with experimental endometriosis. J Steroid Biochem Mol Biol.
12. Brito MVH, Oliveira RVBO, Silveira EL, Reis JMC, Noguchi A,
Epaminodas WA, Morais MR. Microscopic aspects of the rats liver after
copaíba oil administration. Acta Cir Bras. 2000;15:29-33.
13. Oktem M, Esinler L, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu
HB. High-dose atorvastatin causes regression of endometriotic implants:
a rat model. Hum Reprod. 2007;22:1474-80.
14. Guney M, Oral B, Karahan N, Mungan T. Regression of endometrial
explants in a rat model of endometriosis treated melatonin. Fertil Steril.
15. Batista APB, Medeiros PL, Texeira AAC, Teixeira VW. Histochemical
and morphometric analysis of endometriotic lesions induced in female
rats and treated with dexametasona. J Bras Patol. 2009;45:147-53.
João Nogueira Neto
Av. dos Holandeses S/N Qd 24 Lote 05/901
65071-380 São Luís – MA Brasil
Conflict of interest: none
Financial source: none
1Research performed at Experimental Surgery Laboratory, University Hospital, Federal University of Maranhao (LACEMA-HUUFMA), Brazil.
Presented at the XII National Congress on Experimental Surgery of the Brazilian Society for Development of Research in Surgery-SOBRADPEC,
2011 October 26-29 Ribeirao Preto-SP, Brazil.
... CPO is a natural substance derived from the Copaifera genus of plants. It possesses antioxidant, anti-inflammatory, and antinociceptive properties, all of which might be useful in the treatment of endometriosis [121]. PLGA/CPO nanoparticles decreased cell viability in both the eutopic and ectopic endometriums of women with endometriosis in a time-dependent manner after 48 hours of exposure in cell cultures.In the eutopic endometrium of women without endometriosis, a modest and delayed decrease in cell availability was found. ...
Contraception has previously provided alternative medication delivery techniques for the treatment of endometriosis. Only LNG-IUSs and depot formulation (DMPA), however, have been studied in numerous RCTs to treat patients. These approaches tend to enhance patient compliance and satisfaction when compared to other conventional treatment alternatives. Nanotechnologies are potential new drug delivery techniques that have been shown to deliver compounds with a particular therapeutic impact. However, the information is limited and preliminary. Endometriosis research has identified the patients who could benefit most from this kind of medication administration. No one has ever been used in a clinical study to treat endometria. Alternative medication delivery techniques may help to enhance compliance, effectiveness, and the development of novel treatment approaches. The use of vaginal rings as a unique and alternative medication delivery route for AIs, as well as the experience with danazol, are examples. The vaginal ring has been studied as a new medication delivery mechanism for danazol and aromatase inhibitors. Nanotechnologies are made up of bioconjugates that deliver anti-inflammatory, antioxidant, anti-angiogenic, and immunomodulating chemicals directly to the illness site. At this early stage of proof-of-concept, the evidence is limited and tentative. Clinical effectiveness can not be predicted using mouse models.
... A previous report already validated that an oral formulation of copaiba oil can inhibit the growth of endometriotic lesions in rats. [197] Therefore, several research groups proposed that encapsulating copaiba oil extracts within nanomaterials may provide advantages for their bioavailability, delivery, safety, and therapeutic effect. [198][199][200] A 2016 study by de Almeida Borges et al. evaluated the effects of copaiba oleoresin, containing 5.05% w/w of β-caryophyllene, on endometrial cells when delivered using a PLGA nanoparticle formulation. ...
Endometriosis is an incurable gynecological disease characterized by the abnormal growth of endometrium‐like tissue, characteristic of the uterine lining, outside of the uterine cavity. Millions of people with endometriosis suffer from pelvic pain and infertility. This review aims to discuss whether nanomedicines that are promising therapeutic approaches for various diseases have the potential to create a paradigm shift in endometriosis management. For the first time, the available reports and achievements in the field of endometriosis nanomedicine are critically evaluated, and a summary of how nanoparticle‐based systems can improve endometriosis treatment and diagnosis is provided. Parallels between cancer and endometriosis are also drawn to understand whether some fundamental principles of the well‐established cancer nanomedicine field can be adopted for the development of novel nanoparticle‐based strategies for endometriosis. This review provides the state of the art of endometriosis nanomedicine and perspective for researchers aiming to realize and exploit the full potential of nanoparticles for treatment and imaging of the disorder.
... Thus, rendering the oleoresin an important natural remedy for people without access to commercial drugs (Ohsaki et al., 1994;Veiga Junior and Pinto, 2002;Leandro et al., 2012;Boaroto, 2014). Based on the comprehensive application in folk medicine, the oleoresin has been subject of various scientific studies aiming to prove its activity in different in vitro and in vivo models (Basile et al., 1988;Ohsaki et al., 1994;Veiga Junior et al., 2001Lima et al., 2003;Paiva et al., 2004;Carvalho et al., 2005;Gomes et al., 2007Gomes et al., , 2008Gomes et al., , 2010Santos et al., 2008aSantos et al., , 2008bBrito et al., 2010;Santos Junior et al., 2010;Neto et al., 2011;Almeida et al., 2012;Dias et al., 2014;Bardají et al., 2016). ...
Ethnopharmacological relevance: The oleoresin of Brazilian Copaifera reticulata is a traditional remedy used for the treatment of skin and urinary tract infections, respiratory diseases, rheumatism, ulcer and tumours; thus, playing an important role in the primary health care of the indigenous population. Aim: As most previous pharmacological tests used the crude oleoresin and only a few studies so far dealt with enriched fractions or pure chemically defined compounds, the aim of this study was to systematically evaluate the antimicrobial and cytotoxic properties of the Copaifera reticulata oleoresin and to assign traditional uses to specific secondary metabolites. Materials and methods: The oleoresin, as well as its neutral and acidic fractions were tested for their activity against six cancer cell lines, two clinically relevant bacterial strains, and two dermatophytes. Both fractions were analysed by GC-MS and UHPLC-ELSD, respectively. The antibacterial acidic phase was further fractionated by preparative chromatography to purify and characterize the compounds responsible for the observed pharmacological effect. Results: Whereas no cytotoxic activity was detected, the crude oleoresin and its acidic fraction showed antibacterial activity against gram-positive bacteria Enterococcus faecium (IC50 values 4.2 and 4.8 µg/mL, respectively) and methicillin-resistant Staphylococcus aureus (MRSA, IC50 values 5.3 and 7.2 µg/mL, respectively). Purification of the acidic fraction of the C. reticulata oleoresin yielded two dicarboxylic diterpene acids and the four main diterpene acids, comprising three different diterpene scaffolds. Interestingly, the activity was not restricted to a particular diterpene-type but rather depended on the compounds’ lipophilicity, with the most active constituent showing IC50 values of 1.6 (E. faecium) and 2.5 µg/mL (MRSA), respectively. Furthermore, ent-polyalthic acid, the major diterpenoid, was significantly active against dermatophytes with IC50 values of 6.8 µg/mL (Trichophyton rubrum) and 4.3 µg/mL against (T. mentagrophytes). Conclusion: The present study proved the antimicrobial effects of the C. reticulata oleoresin and its diterpenoid constituents, confirming its wide use in folk medicine for the treatment of skin and urinary tract infections. The inhibitory activity of copaiba diterpenoids against dermatophytic fungi as well as the gram-positive bacteria E. faecium and MRSA is being reported for the first time, providing potential lead structures for the treatment of these clinically relevant bacterial strains.
... While acute inflammation is a normal part of the healing process, chronic inflammation often plays a role in chronic diseases such as osteoarthritis, lupus, and inflammatory bowel disease, and can be problematic. Several copaiba oleoresins have shown anti-inflammatory activity, including C. cearensis [13], C. duckei [84], C. langsdorffii [50,91], C. multijuga [13,58,61,100], C. officinalis [62], and C. reticulata [13] (Table 3). ...
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The oleoresin of Copaifera trees has been widely used as a traditional medicine in Neotropical regions for thousands of years and remains a popular treatment for a variety of ailments. The copaiba resins are generally composed of a volatile oil made up largely of sesquiterpene hydrocarbons, such as β-caryophyllene, α-copaene, β-elemene, α-humulene, and germacrene D. In addition, the oleoresin is also made up of several biologically active diterpene acids, including copalic acid, kaurenoic acid, alepterolic acid, and polyalthic acid. This review presents a summary of the ecology and distribution of Copaifera species, the traditional uses, the biological activities, and the phytochemistry of copaiba oleoresins. In addition, several biomolecular targets relevant to the bioactivities have been implicated by molecular docking methods.
The chemical composition of Copaifera langsdorffii Desf. is rich in sesquiterpenes and diterpenes, and is mainly indicated for healing and inflammation in general. Considering the medicinal importance of this species and the lack of research that gathers and analyzes the available information, this study aimed to verify if there is consensus on the medicinal use, chemical components and biological activities. A search was conducted in Pub Med, Science Direct, Scielo, Web of Science, Google Scholar and Institutional Repository of the Universidade Estadual Paulista. A total of 96 health problems were catalogued, of which inflammation in general and healing were the most cited, along with resin-oil and stem bark. Of the 277 compounds recorded, 91 were specific to the essential oil, 58 to the crude resin, and 57 to the extract. Caryophyllene oxide was the most frequent constituent. The major constituents presented variation in the essential oil, crude resin, extract and different parts of the plant. A total of 28 proven activities were recorded, of which the most tested were antioxidant, cytotoxic, anti-inflammatory and antibacterial. C. langsdorffii shows important sources of active principles in the combat of diseases which affect human health, mainly regarding the Skin, General, and Nonspecific systems. Its chemical composition is responsible for the biological activities demonstrated for the species. Further investigations are necessary, mainly regarding in vitro and in vivo pharmacological properties, isolation of substances, mechanism of action, and bioavailability, in order to provide subsidies for the development of new drugs.
Introduction: Pharmacotherapy has a key role in the management of endometriosis. However, a significant proportion of patients gains only intermittent or limited benefits. In this regard, alternative and novel drug delivery methods are of paramount importance to improve efficacy and compliance of available treatments and develop alternative medical approaches. Areas covered: This review aims to provide the reader with a complete overview of available evidence about alternative and novel drug delivery methods for endometriosis pharmacotherapy and highlight new research lines. Expert opinion: Progestins and estroprogestins, which represent the first-line therapy, are already available in different formulations, being employed for contraception. Nevertheless, evidence on their adoption is still limited for some drug delivery methods, such as vaginal rings, patches, and subcutaneous implants. Further research is needed to define better their clinical utility in patients with endometriosis. Nanotechnologies have been investigated as novel drug delivery methods able to target the drug at the disease level. However, data are very limited and preliminary, and further research is needed to consider a possible clinical application in endometriosis.
Ethnopharmacological relevance Achillea cretica (AC) is a medicinal plant emphasized for treatment of gynecological disorders and pathological symptoms similar to endometriosis in traditional Persian medicine. Since information about its chemical constituents is limited, the aim of this study is to investigate phenolic composition of AC extract as well as its effect on experimental model of endometriosis. Materials and methods RP-HPLC-PDA-ESI-MS/MS analysis was used for the determination of polyphenolic compounds. Endometriosis was induced in rats by suturing of uterus segments to abdominal wall of same rat, after eight weeks when the model was induced, it was followed by 28 days of treatment with 100, 200, and 400 mg/kg/day of hydroethanolic extract of the plant. Blood samples and implanted tissues were collected in the final day, and area of foci, tumor necrosis factor-α, vascular endothelial growth factor, interleukin-6, and serum total thiol molecules were measured and compared with positive group (0.2 mg/kg/day letrozole) and control group (solvent of extract: normal saline). Implanted tissue sections of the sacrificed rats were also assessed histopathologically. Results Nine polyphenolic compounds were identified in AC extract including 7 flavonoids and 2 phenolic acids. Plant extract decreased area of foci and cytokine levels in serum and local tissue. Histopathological assessments confirmed the effectiveness of treatments by decreasing the thickness of epithelial layer and increasing the infiltration of leukocytes into this layer. Doses of 100 mg/kg and 400 mg/kg of extract showed better effects in comparison with the dose of 200 mg/kg in reduction of cytokine levels and size of implanted tissue. Extract and letrozole did not demonstrate significant effect on thiol level. Conclusion AC aerial extract may be a favorable medicine for management of endometriosis by modulating inflammatory cytokines; however, further studies are needed for more conclusive and reliable decision about its efficacy and safety.
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Summary. This study was aimed to develop an approach allowing pain behavior estimation of rats with experimental endometriosis. The histological score was design to assess the degree of changes observed in the endometrial tissues. Experimental endometriosis was carried out on anesthetized sexually mature intact females of outbred rats aged 10–11 weeks by autotransplantation of a segment of the horn of the uterus. Implant was placed between the peritoneum and muscle. The pain behavior was estimated 2, 4 and 8 weeks after surgery. Sensitivity to abdominal probing was assessed by pressing the lower abdomen against a rod attached to a gram force meter, and measuring the force producing withdrawal/escape behaviors. The pain response to the mechanical stimulation of the abdominal wall was significantly higher in the animals with endometriosis compared to the sham-operated rats. 50% of the animals were euthanatized 4 weeks after the pathology induction, 50% – after 8 weeks. A morphological study indicated the presence of endometrioticlike implants exceeding in size of implanted segments. The histological examination showed morphological changes indicating endometriosis development. The ectopic endometrium was characterized by the coexistence of both glands and stromal structures. Glandular epithelia were observed to have an appearance similar to that of the eutopic epithelial glands. The degree of pathological changes was estimated using specially design grading system (score range – 0–3). As a result, the approach for both histological evaluation and pain behavior assessment in rats with experimental endometriosis was developed. This model can be used to study the pharmacological action of new medicines. Keywords: endometrios, pain behavior, rat.
Endometriosis and uterine fibroids (also known as uterine leiomyomas) are serious medical conditions affecting large numbers of women worldwide. Many women are asymptomatic but those with symptoms require medical intervention to relieve chronic pain and dysmenorrhea and to address infertility. Drug delivery has played a role in reducing some of the symptoms associated with endometriosis and uterine fibroids. Use of drug delivery systems for both conditions can roughly be divided into two categories: (1) existing systems designed for other indications such as contraception for symptomatic relief and (2) development of novel systems aimed at addressing some of the underlying biochemical changes associated with endometriosis and uterine fibroids such as oxidative stress, angiogenesis, and matrix degradation. The latter drug delivery approaches rely heavily on nanotechnology. Existing systems that deliver estrogens and/or progestins include vaginal rings, transdermal patches, and intrauterine systems. Long-acting implantable contraceptives such as Implanon® and injectables such as Depo-Provera® have found use in treating endometriosis. Similarly, long-acting GnRH products (e.g., Lupron Depot®) are used to treat endometriosis. Other drugs formulated in long-acting formulations include intravaginal rings capable of delivering selective progesterone receptor modulators, androgens such as danazol, and aromatase inhibitors (e.g., anastrozole). Nanoparticles composed of silica, poly(lactic-co-glycolic acid), cerium oxide, dendrimers, and chitosan/polyethyleneamine have all been investigated to improve treatment of endometriosis and to a lesser extent, uterine fibroids.
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Copaiba oleoresin (CPO) obtained from Copaifera landgroffii, is described as active to a large number of diseases and more recently in the endometriosis treatment. In this work poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing CPO were obtained using the design of experiments (DOE) as a tool to optimize the production process. The nanoparticles optimized by means of DOE presented an activity in relation to the cellular viability of endometrial cells. The DOE showed that higher amounts of CPO combined with higher surfactant concentrations resulted in better encapsulation efficiency and size distribution along with good stability after freeze drying. The encapsulation efficiency was over 80% for all produced nanoparticles, which also presented sizes below 300 nm and spherical shape. A decrease in viability of endometrial stromal cells from ectopic endometrium of patients with endometriosis and from eutopic endometriotic lesions was demonstrated after 48h of incubation with the CPO nanoparticles. The nanoparticles without CPO were not able to alter the cell viability of the same cells, indicating that this material was not cytotoxic to the tested cells and suggesting that the effect was specific to CPO. The results indicate that the use of CPO nanoparticles may represent a promising alternative for the treatment of endometriosis.
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INTRODUÇÃO: A literatura relata que os implantes endometriais possuem receptores para hormônios esteroides, sendo estimulados principalmente pelo estrógeno, e que algumas estratégicas de tratamento têm sido propostas em modelos experimentais, tais como a utilização de glicocorticoides sintéticos, como a dexametasona. OBJETIVO: analisar histoquímica e morfometricamente lesões endometrióticas induzidas em ratas e tratadas com 0,8 mg/kg/dia de dexametasona. MATERIAL E MÉTODOS: Quarenta ratas albinas (linhagem Wistar) com 90 dias de vida, pesando aproximadamente 150 g, foram induzidas à endometriose e divididas em grupos: 1. ratas com endometriose e avaliadas após 34 dias (G1); 2. ratas com endometriose e avaliadas após 47 dias (G2); 3. ratas com endometriose e, após 21 dias do pós-operatório, tratadas com dexametasona por 13 dias (G3) e 4. ratas com endometriose e, após 21 dias do pós-operatório, tratadas com dexametasona por 13 dias e eutanasiadas após um período de 13 dias, contados a partir do término do tratamento com dexametasona (G4). Os fragmentos dos implantes endometriais foram fixados em Bouin, incluídos em paraplast e corados por hematoxilina-eosina e tricrômico de Mallory. As médias do número de glândulas foram submetidas ao teste não-paramétrico de Tukey-Kramer (p < 0,05). RESULTADOS: A dexametasona reduziu a inflamação nos implantes endometriais, o teor de colágeno no estroma e significativamente a área ocupada pelas glândulas (G1= 123,25 ± 6,44ª; G2= 113 ± 6,27ª; G3= 81,66 ± 3,05b; e G4= 94 ± 6,24b). CONCLUSÃO: A dexametasona, na dosagem utilizada, reduz os efeitos estrogênicos em implantes endometriais em ratas.
INTRODUCTION: The literature reports that endometrial implants have receptors for steroid hormones primarily stimulated by estrogen and that some treatment strategies have been proposed in experimental models such as the use of synthetic glucocorticoids, for example, dexamethasone. OBJECTIVE: to analyze histochemically and morphometrically endometriotic lesions induced in rats and treated with dexamethasone (0.8 mg/kg/day). MATERIAL AND METHODS: Forty albino female rats (Wistar strain), with 90 days of age, weighing approximately 150 g, were induced with endometriosis and divided into groups: I - rats with endometriosis and evaluated after 34 days, II - rats with endometriosis and evaluated after 47 days, III - rats with endometriosis and 21 days post-surgery treated with dexamethasone for 13 days and IV - rats with endometriosis and 21 days post-surgery treated with dexamethasone for 13 days and euthanized after a period of 13 days starting from the end of treatment. The fragments of endometrial implants were fixed in Bouin, embedded in Paraplast and stained with hematoxylin-eosin and Mallory trichrome. The mean number of glands was compared through nonparametric Tukey-Kramer test (p < 0,05). RESULTS: Dexamethasone reduced inflammation in the endometrial implants, the collagen content in the stroma and decreased significantly the area occupied by glands (GI - 123.25 ± 6.44ª; IGI - 113 ± 6.27ª; GIII - 81.66 ± 3.05b and GIV - 94 ± 6.24b). CONCLUSION: The applied dexamethasone dosage reduces estrogenic effects in endometrial implants in rats.
Copaiba oil has been used in folk medicine since the 19th century. The use of copaiba oils to treat leishmaniasis is cited in several ethnopharmacological studies. Nevertheless, the potential antileishmania of copaiba oils had not been studied. Eight different kinds of Brazilian copaiba oils were screened for antileishmanial activity. The antiproliferative effect of copaiba oil on promastigote and amastigote axenic were determined. To determine the survival index peritoneal macrophage were infected with promastigotes of Leishmania amazonensis and treated with copaiba oil. The cytotoxic effect of copaiba oil was assessed on macrophage strain J774G8 by assay of sulforhodamine B. Copaiba oils showed variable levels of activity against promastigote forms with IC(50) values in the range between 5 and 22microg/mL. The most active oil was that from Copaifera reticulata (collected in Pará State, Brazil) with IC(50) values of 5, 15, and 20microg/mL for promastigote, axenic amastigote and intracellular amastigote forms, respectively. Amphotericin B showed IC(50) of 0.058 and 0.231microg/mL against promastigote and amastigote forms, respectively. Cytotoxicity assay showed that this copaiba oil obtained from Copaifera reticulata showed low cytotoxicity against J774G8 macrophages. Copaiba oils showed significant activity against the parasite Leishmania amazonensis.
To evaluate the effects of triptoreline, gestrinone, and both, on experimental endometriosis in rats. Experimental endometriosis was surgically induced in 225 Wistar rats. Of these, 202 rats showed at least one grown implant, 22 of which composed the control group, while 180 were treated with triptoreline, gestrinone, or both, for 28 days. The implants were evaluated again after 25 days. There were no changes in size in the control group. About 73% of the implants treated with triptoreline showed a high reduction (> 50%), vs. 51% with gestrinone (P < 0.0005) and 65% with both (P < 0.005). Triptoreline caused macroscopic resolution in 40% of the implants vs. 31% for gestrinone (not significant) and 26% for both substances (P < 0.05). In the triptoreline group, the mean size of the implants decreased by 65% between the 25th and 28th days, 58% between the 29th and the 35th, and 39% after the 36th day. This reduction was 51%, 36%, and 33%, respectively, in gestrinone group. Triptoreline was more effective than gestrinone, but perhaps not in the long run. Their association did not improve the results.
Estrogen deprivation therapy effectively prevents progress of endometriosis but the precise mechanism by which estrogen stimulates growth of endometriotic implants is still unknown. We examined effects of hypoestrogenic state induced by ovariectomy, gonadotropin-releasing hormone agonist (leuprolide) or aromatase inhibitor (YM511), on growth of experimental endometrial explant, a section of endometrium transplanted under the renal capsule, in rats. Ovariectomy gradually reduced the volume of endometrial explants for 21 days. YM511 (0.1 mg/kg) and leuprolide (1 mg/rat) completely reduced volume of endometrial explants but they differed widely in the onset of inhibitory action. YM511 prevented growth of explants on day 4 but leuprolide had no inhibitory effect until day 15. YM511 dose-dependently reduced volume of endometrial explants and its minimum effective dose was 0.04 mg/kg. Insulin-like growth factor-I (IGF-I) mRNA expression in endometrial explant and uterus was examined on day 4. YM511 decreased IGF-I expression in endometrial explant and uterus by 58% and 48%, respectively. Reductions of the extent of IGF-I expression by YM511 and ovariectomy were comparable. A significant correlation between the volume and IGF-I mRNA expression in endometrial explant suggests that local expression of this gene may play an important role in stimulating growth of endometrial explants.
To investigate the effects of the immune modulators levamisole and loxoribine in a rat model of endometriosis. Prospective, placebo-controlled study. Hospital-based research facility. Nineteen rats with experimentally induced endometriosis. Rats were treated with three weekly intraperitoneal injections of levamisole (2 mg per rat; n = 6), loxoribine (1 mg per rat; n = 6), or saline (control; n = 7) and killed 8 weeks after treatment. Histologic and immunohistochemical analysis of endometriotic explants. The loxoribine-treated group showed marked regression of both epithelial and stromal components. Epithelial regression was noted in the control group, but the epithelium was strikingly preserved in the levamisole group. There were significantly greater numbers of dendritic cells in the explants of animals treated with loxoribine and levamisole. The number of natural killer cells was significantly reduced in loxoribine-treated explants. Loxoribine, a potent immunomodulatory drug, appeared to cause regression in both stromal and epithelium components in a rat model of endometriosis. Further, specific cell-mediated immune responses in this model of endometriosis were elucidated.
The wound healing activity of oleo-resin from Copaifera langsdorffii Desf. (Leguminaceae) bark was evaluated in rats on experimental wounds. The oleo-resin was tested by monitoring wound contraction in excised wounds and by measuring tensile strength in healing incision wounds. The topical application of oleo-resin at a concentration of 4% accelerated wound contraction in open wounds. The mean values of wound contraction in oleo-resin treated rats on day 9 was 84.05% +/- 2.37% as against 51.29% +/- 9.54% seen in controls and the difference was statistically significant (p < 0.05). No significant differences in the rates of wound contraction were observed on days 12, 15, 18 and 21. Also, the tensile strength in healing incised wounds was found to be significantly higher in the group of animals treated with 4% oleo-resin on day 5 but not on days 7 and 12 (controls: 35.95 +/- 7.44 g/cm; oleo-resin: 71.48 +/- 5.77 g/cm; p < 0.05). These results indicate the beneficial effect of C. langsdorffii oleo-resin on wound healing and justify its traditional use for the treatment of wounds.
Kaurenoic acid, a diterpene from Copaifera langsdorffii (Leguminaceae), was evaluated on rat colitis induced by acetic acid. Rats were pretreated orally (15 and 2 h before) or rectally 2 h before induction of colitis with kaurenoic acid (50 and 100 mg/kg) or vehicle (1 ml, 3% DMSO). Colitis was induced by intracolonic instillation of a 2 ml of 4% (v/v) acetic acid solution and, 24 h later, the colonic mucosal damage was analysed macroscopically for the severity of mucosal damage, the myeloperoxidase (MPO) activity and the malondialdehyde (MDA) levels in the colon segments. A marked reduction in gross damage score (52% and 42%) and wet weight of damaged colon tissue (39% and 32%) were observed in rats that received 100 mg/kg kaurenoic acid, respectively, by rectal and oral routes. This effect was confirmed biochemically by a two- to three-fold reduction of colitis associated increase in MPO activity, the marker of neutrophilic infiltration and by a marked decrease in MDA level, an indicator of lipoperoxidation in colon tissue. Furthermore, light microscopy revealed the marked diminution of inflammatory cell infiltration and submucosal edema formation in the colon segments of rats treated with the test compound. These findings indicate the anti-inflammatory potential of kaurenoic acid in acetic acid-induced colitis.
Copaifera langsdorffii oleo-resin (CLOR) is a reputed herbal medicine used to combat gastrointestinal functional disorders. Our previous studies show that CLOR prevents gastric ulceration and promotes wound healing. This study examined the effects of CLOR on intestinal damage associated with mesenteric ischemia/reperfusion in rat. Wistar albino rats were divided into four groups of six in each. Group 1: Sham operated, Group 2: Vehicle + 45 min of ischemia followed by 60 min reperfusion (I/R), Groups 3 and 4: I/R + CLOR (200 and 400 mg /kg, p.o., respectively). All treatments were given 24 h, 12 h and 2 h before I/R. Animals were sacrificed at the end of reperfusion period and ileal tissue samples were obtained for biochemical analysis. Myeloperoxidase (MPO), an index of polymorphonuclear leukocytes; malondialdehyde (MDA), an end product of lipoperoxidation; catalase (CAT), an antioxidant enzyme; reduced glutathione (GSH), a key antioxidant; and nitrite, a marker of nitric oxide (NO) production were determined in ileum homogenates. The results show that I/R produces a significant increase in MDA content, MPO, and CAT activities with a significant decrease in GSH and an elevation in nitrite production, as compared to sham control. CLOR treatment caused significant attenuations in I/R-associated increases of MPO, MDA and CAT activities and on nitrite level. Besides, CLOR could effectively prevent the I/R-associated depletion of GSH. The data indicate that the oleo-resin has a protective action against I/R-induced intestinal tissue damage, which appeared to be, at least in part, due to an antioxidant and anti-lipid peroxidation mechanism.