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Meta-analysis on Copaiba Oil: Its Functions in Metabolism and Its Properties as an Anti-inflammatory Agent

September 2018
Journal of Morphological Sciences 35(3)

DOI:10.1055/s-0038-1669390

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CC BY-NC-ND 4.0

Authors:

Romeu Rodrigues de Souza

Universidade Nove de Julho

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Many medicinal plants are sought as alternative therapies for various conditions, as opposed to synthetic alternatives. The Brazilian Amazon provides a plethora of plants with various therapeutic and medicinal properties. One of them is copaiba oil, a natural product of the biodiversity of the Amazon. The anti-inflammatory and antimicrobial properties of copaiba oil have been drawing the attention of the scientific community as a great alternative in the treatment of illnesses associated with inflammatory and infectious processes. The purpose of the present study is to evaluate and analyze the latest publications on the use of copaiba oil in the PubMed/Medline database from 2014 to 2017. Forty-two articles were collected, verifying anti-inflammatory activity, antimicrobial activity, healing, and antitumor activity. The results found on researches with copaiba oil according to publication dates were 11.9% in 2014, 38.1% in 2015, 16.7% in 2016, and 33.3% in 2017. In the analyzed studies, the proposed administration of copaiba oil was 50% topical, 28.6% oral, 9.5% enteral, 4.8% subcutaneous, and 7.1% others. In the objectives of the presente study in relation to the administration of copaiba oil, the result was 31% antimicrobial, 28.6% anti-inflammatory, 9.5% antitumor, 9.5% healing, and 21% others. Regarding the types of research, we have found 50% in vitro, 40.4% in vivo animals, 2.4% in vivo human, 2.4% review and 4.8% others. Regarding the significance factor evaluation, the result was 100% positive in antitumor activity, 84% positive in infection and inflammation pathology, 62% positive in others, like dental processes, food technology application support and as a drug absorption vehicle, and 50% in healing. The results presented in the current meta-analysis show that copaiba oil is an effective alternative to treatments of illnesses such as chronic inflammation, infectious diseases, various types of cancer, autoimmune diseases, and as a vehicle for the absorption of other drugs. Thus, more studies regarding the benefits of copaiba oil could provide a great contribution to the medical community in the treatment of the aforementioned illnesses.

Objectives of research on the use of copaiba oil

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Meta-analysis on Copaiba Oil: Its Functions in Metabolism

and Its Properties as an Anti-inﬂammatory Agent

Marcelo Ferro1S. Masso2R. R. de Souza1M. Moreno1E. Moreira1

1Department of Aging S ciences, Universidade São Judas Tadeu –USJT,

São Paulo, SP, Brazil

2Departamente of Biological Science, Florida International University

-FIU,Florida,UnitedStatesofAmerica

J Morphol Sci 2018;35:161–166.

Address for correspondence MarceloFerro,Departamentode

Ciências do Envelhecimento, Universidade São Judas Tadeu–USJT,

Rua Taquari, 546, Mooca, São Paulo, SP 03166-000, Brazil

(e-mail: marceloferro26@gmail.com).

Introduction

A great number of Brazilian/Amazonian ﬂora has shown to

provide effective treatment for a multitude of aliments. One

derivative of these plants is copaiba oil found in Copaifera

reticulata Ducke, a natural product of the Amazon’s biodi-

versity.1It has been used for more than 390 years as an anti-

inﬂammatory, antimicrobial, and antifungal agent, and to

prevent various types of cancer.2,3

Recent studies demonstrated that one of the major compo-

nents of the copaiba oil, β-caryophyllene, has an anti-inﬂam-

matory effect.4Copaiba oil is extracted from the copaifera, a

Keywords

►copaiba oil

►anti-inﬂammatory

►antimicrobial

►antitumor

►healing

Abstract Many medicinal plants are sought as alternative therapies for various conditions, as

opposed to synthetic alternatives. The Brazilian Amazon provides a plethora of plants

with various therapeutic and medicinal properties. One of them is copaiba oil, a natural

product of the biodiversity of the Amazon. The anti-inﬂammatory and antimicrobial

properties of copaiba oil have been drawing the attention of the scientiﬁc community

as a great alternative in the treatment of illnesses associated with inﬂammatory and

infectious processes. The purpose of the present study is to evaluate and analyze the latest

publications on the use of copaiba oil in the PubMed/Medline database from 2014 to 2017.

Forty-two articles were collected, verifying anti-inﬂammatory activity, antimicrobial

activity, healing, and antitumor activity. The results found on researches with copaiba

oil according to publication dates were 11.9% in 2014, 38.1% in 2015, 16.7% in 2016, and

33.3% in 2017. In the analyzed studies, the proposed administration of copaiba oil was 50%

topical, 28.6% oral, 9.5% enteral, 4.8% subcutaneous, and 7.1% others. In the objectives of

the presente study in relation to the administration of copaiba oil, the result was 31%

antimicrobial, 28.6% anti-inﬂammatory, 9.5% antitumor, 9.5% healing, and 21% others.

Regarding the types of research, we have found 50% in vitro, 40.4% in vivo animals, 2.4%

in vivo human, 2.4% review and 4.8% others. Regarding the signiﬁcance factor evaluation,

the result was 100% positive in antitumor activity, 84% positive in infection and inﬂamma-

tion pathology, 62% positive in others, like dental processes, food technology application

support and as a drug absorption vehicle, and 50% in healing. The results presented in the

current meta-analysis show that copaiba oil is an effective alternative to treatments of

illnesses such as chronic inﬂammation, infectious diseases, various types of cancer,

autoimmune diseases, and as a vehicle for the absorption of other drugs. Thus, more

studies regarding the beneﬁts of copaiba oil could provide a great contribution to the

medical community in the treatment of the aforementioned illnesses.

received

March 4, 2018

accepted

April 18, 2018

published online

September 24, 2018

DOI https://doi.org/

10.1055/s-0038-1669390.

ISSN 2177-0298.

Publicações Ltda, Rio de Janeiro, Brazil

THIEME

Review Article 161

type of tree. Previous studies have claimed that copaiba oil,

extracted from the copaibeira, could befound in more than 60

species cataloged worldwide.1However, in later studies it has

been reported that there are currently 72 species of copai-

beiras in the world, all exclusively in Brazilian soil.3

The anti-inﬂammatory and antimicrobial properties of

copaiba oil have been drawing the attention of the scientiﬁc

community as alternatives in the treatment for illnesses

associated with inﬂammatory and infectious processes

within the body.5Currently, the most common use of copaiba

oil is topical.4Other, newer studies are being performed to

ﬁnd other forms of administration.6,7

In vitro experiments have shown direct damage to the DNA

of cancerous stomach cells with the administration of copaiba

oil. The responsible agent in copaiba oil was found to be

kaurenoic acid. The administration of copaiba oil showed a

reduction to the damage caused by cancerous cells in the

stomach tissue during in vitro testing. This was due to the

kaurenoic acid that makes up, in part, copaiba oil.8Likewise,

the administration of nanoencapsulated copaiba oil signiﬁ-

cantly reducedthe right ventricular hypertrophyof Wistar rats

as well as the oxidative stress.9In another study, the admin-

istration of copaiba oil by gavage reduced the amount of

abdominal adhesions and accelerated the formation of col-

lagen ﬁbers without damaging the early stages of healing.10

Although a large part of the studies showed positive

results with the use of copaiba oil, a small part showed

that copaiba oil did not show signiﬁcant resu lts in the applied

objectives.3Tobouti et al afﬁrmed that, reported that essen-

tial copaiba oil is a proven efﬁcient medicine against some

microorganisms. However, unlike other well established

herbal medicines, antimicrobial studies on copaiba oil may

show some bias due to lack of standa rdization. Therefore, the

purpose of the presen t meta-analysis is to verify publications

on copaiba oil and its uses as a therapy in the Pubmed/

Medline database between 2014 and 2017.

Materials and Methods

The analyzed material consists of journal articles on the

copaiba oil index in PubMed, seeking the relationship of

copaiba oil with anti-inﬂammatory activity, antimicrobial

activity, healing and antitumor effects. The data were col-

lected between 2014 and 2017, totaling 42 items. The search

for these articles was made using the keywords: copaiba oil,

anti-inﬂammatory, antimicrobial, antitumor, and healing.

Results and Discussion

In ►Table 1, we have found 42 articles published in the last

4 years, with 5 articles published in 2014, 16 articles

published in 2015, 7 articles published in 2016, and 14

articles published in 2017. This shows a proportion of

11.9% of publications in 2014, 38.1% in 2015, 16.7% in

2016, and 33.3% in 2017. With this, we can observe a

seasonality in copaiba oil research. Interestingly, there is

an increase in publications in odd-numbered years when

compared with even-numbered years.

In ►Table 2,weﬁnd a 50% proportion of copaiba admin-

istration in topical use in comparison to other administration

methods. In 2014, we did not ﬁnd any publication adminis-

tering topical use. In 2015, there were 3 times more publica-

tions reporting on the topical use in relation to the oral use. By

2016, those numbers had fallen to nearly half as many. On the

other hand, in 2017, we have found only 1.4 times more

publications for the topical use as compared with the oral

use. It seems that the oral administration of copaiba oil has

been drawing attention in the last year due to its low toxicity

and its antimicrobial and anti-inﬂammatory power.

These numbers initially demonstrate the potential of

copaiba oil in the aid of the healing process.11,12 Because

of the beneﬁts of applying copaiba oil as a topical use based

on empirical evidence in the past, it is probable that the

scientiﬁc community was inﬂuenced in researching the use

of copaiba oil in the form most used by local Amazonian

people, who used copaiba oil on the skin. According to Brito

et al,13 the practice of using medicinal plants is common in

developing countries. The Amazon is a nursery of medicinal

plants, and many studies have been made with copaiba oil as

an alternative for aiding in inﬂammatory processes, such as

healing skin ulcers and infections, with very satisfactory

results in the form of topical use. According to Tobouti

et al,3in 1840, copaiba oil was used in combination with

purgatives for gonorrhea treatments, reporting that the

treatment did not exceed 5 days, when the permanent

cure of the disease was observed. This information was

published by the Provincial Medical & Surgical Journal in a

note written by the Gazette Médicale, and the Edinburgh

Medical and Surgical Journal suggested a combination of

copaiba with purgatives in the treatment of gonorrhea.

Following this publication concerning the properties of the

balsam, the copaiba has received attention from many

explorers and travelers since the early years of its discovery.

The oral administration of copaiba has been used as

another form of alternative therapy with controversial

results. With 28.6%, in the present meta-analysis, the oral

administration of copaiba has been shown to be an effective

agent against certain parasites,14 gastrointestinal cancer,8

Table 1 Scientiﬁc publications about copaiba oil between 2014

and 2017

2014 2015 2016 2017 Total

5 16 7 14 42

This table shows the number of articles published each year.

Table 2 Proposal of administration of copaiba oil according to

the articles studied

2014 2015 2016 2017 Total %

Top i ca l –9572150.0

Oral 23251228.6

Enteral 1 2 –1049.5

Subcutaneous –2––02 4.8

Others 2 ––1037.1

Journal of Morphological Sciences Vol. 35 No. 3/2018

Meta-analysis on Copaiba Oil Ferro et al.162

endometriosis,6,7,15 arthritis,16 and other conditions. Con-

trary to w hat was thought, the o ral administration of copa iba

was shown to be non-toxic to rat liver when used as a carrier

for amphotericin B.14

In contrast, in another study, the results revealed that

copaiba oil showed anti-inﬂammatory and systemic antiox-

idant actions in arthritic rats. These beneﬁcial effects, how-

ever, were counterbalanced by deleterious modiﬁcations in

the metabolism and morphology of hepatic cells of healthy

control rats. Thus, the administration of oral copaiba oil16

demonstrates great potential as an alternative treatment to

the aforementioned pathologies.

We can observe that the enteral administration by gavage

was the third most used form in the present meta-analysis,

with 9.5%. Campos et al9administered copaiba in natura and

in nanoencapsulated form and both reported a signiﬁcant

reduction in the sizes of their right ventricles in induced

pulmonary arterial hypertension (PAH). The same authors

afﬁrm that copaiba oil can be an alternative medicine for the

reduction of hypertrophy of the right ventricle, as well as for

the reduction of oxidative stress.

Researching the other copaiba administration routes, we

have found the subcutaneous form to be effective 4.8% of the

time, and other forms to be effective 7.1% of the time. Accord-

ing to Venturini et al,17 the subcutaneous administration of

copaiba in association with drugs for the treatment of carci-

noma in the skin of pigs brought beneﬁts by the increase in

drug retention on theskin layer. The author states that copaiba

is considered the most promising nanoformulation for the

treatment of skin carcinoma by assisting the absorption of the

drugs applied.

In ►Table 3, we can observe a predominance of the studies

of copaibaoil as an antimicrobial agent with an effectiveness of

31%. As mentioned above, copaiba oil has been drawing the

attention of the scientiﬁc community as an antimicrobial

agent for a few years. According to Mizuno et al,18 copaiba

oil is one of the most popular naturalmedicines in the Amazon.

The same authors reported positive effects in both antileish-

manial activity as well as in antitrypanosomal activity with

copaiba oil in topical administrations. In another study, Sven-

tichny et al19 demonstrated positive effects with antifungal

activity in the administration of copaiba oil. Effects of anti-

microbial activity have also been observed in many other

studies, such as the inhibition of Staphylococcus aureus,as

an antileishmanial agent,2the inhibition of Staphylococcus

agalactiae,20 and the inhibition of Streptococcus sp.21 Accord-

ing Otaquiri et al,20 the results of the antibacterial activity of

copaiba oil demonstrated a new alternative as a strategy in the

control of S. agalactiae in neonatal infections. In another study,

Alencar et al22 showed signiﬁcant antimicrobial and antibio-

ﬁlm activities withthe administration of copaiba oil, reporting

it to be a promising candidate in the treatment of infections

and in the incorporation of other antimicrobial drugs.

As with the antimicrobial activity of copaiba oil, the anti-

inﬂammatory activity was present in the present study with

28.6% effectiveness. In a study to investigate the action of the

oral administration of copaiba oil on the systemic inﬂamma-

tion, the oxidative status, and liver cell metabolism of rats with

adjuvant-induced arthritis, Ghizoni et al16 demonstrated that

copaiba oil presented systemic anti-inﬂammatory and anti-

oxidant actions in arthritic rats when compared with the

control group. Lucca et al4attribute the anti-inﬂammatory

action of copaiba oil to β-caryophyllene, a component of the

oil. The anti-inﬂammatory action of β-caryophyllene is due to

its agonistaction at the cannabinoid receptorsknown as CB2.23

Thus, the anti-inﬂammatory activity of copaiba oil occurs

because β-caryophyllene binds selectively to CB2 receptors,

being a CB2 agonist.31 When this occurs, there is an inhibition

of adenylate cyclase, triggering a cascade of biochemical

reactions that contribute to the systemic anti-inﬂammatory

activity.23 Likewise, Teixeira et al1reported an increased

efﬁciency in the modulation of inﬂammatory processes,

mainly in the number of macrophages observed. According

to the author,therapies with copaibaoil have been shownto be

of low toxicity when administered in the oral form.

Another purpose of copaiba oil that drew attention in the

present studywas its antitumor action, with 9.5% of the studies

ﬁnding that copaiba oil demonstrated a high antitumor capa-

city. In a study on gastric cancer, Cardoso et al8demonstrated

that the administration of caurenoic acid, extracted from

copaiba oil, signiﬁcantly reduced mitosis in gastric cancer cells

by inducing apoptosis in these tissue types when compared to

the control group. However, Cavalcante et al24 demonstrated a

genotoxicity in the use of kaurenoic acid using 2.5, 5, 10, 30,

and 50 μg/mL in lung ﬁbroblast cells of hamsters. Likewise,

Ghizoni et al16 reported that although copaiba oil showed

positive results in the treatment of inﬂammations at doses

between 0.58 and 1.15 g/kg, detrimental changes were found

in the liver metabolism and in the liver morphology. Interest-

ingly, in another study, Campos et al25 demonstrated that the

use of trans-caryophyllene extracted from copaiba oil asso-

ciated with atorvastatin presented signiﬁcant leukocyte

counts compared with the control group in chemotherapy

treatments in Wistar rats, reporting a potential preventative

effect for secondary leukopenia in induced chemotherapy.

These differences in toxicity reported in the use of copaiba

oil were even more evident when Teixeira et al1demonstrated

that 200 mg/kg/day presented low toxicityand positive results

in inﬂammatory processes. Similarly, Silva et al6,7 demon-

strated that 50 μg/mL of nanocomposite system (Nano COR)

was developed and a toxicity test was performed. The tests

showed that Nano COR has a greater impact on the behavior of

human endometriotic stromal cells than on the behavior of

eutopic endometrium stromal cells, supporting the idea that

Nano COR, a form of copaiba oil, should be further investigated

Table 3 Objectives of research on the use of copaiba oil

2014 2015 2016 2017 Total %

Antimicrobial 1 7 2 3 13 31.0

Anti-

inﬂammatory

3 4 2 3 12 28.6

Antitumor –2–249.5

Healing –11249.5

Others 1224921.4

Journal of Morphological Sciences Vol. 35 No. 3/2018

Meta-analysis on Copaiba Oil Ferro et al. 163

as a novel and valuable alternative to treat endometriosis.

These controversies between the toxicity of copaiba oil and of

its components still require further study. Perhaps a dose

adjustment by weight is a path in the search for a safer

treatment with a product as promising as shown in ►Table 4.

We have reviewed the pertinent articles to evaluate the

healing properties of copaiba oil. A curious fact is that,

empirically, in the past, native Amazonians used copaiba

oil for healing. However, in the present study, we have

observed that only 9.5% of the publications aimed to study

this property. Thus, we have looked at some works with

copaiba oil administered via gavage for abdominal adhesion

in rats corrected with Vicryl (Ethicon Inc., Somerville, NJ,

USA) mesh.26 The authors demonstrated that although the

gavage administration showed no statistically signiﬁcant

difference in adhesions and collagen ﬁbers, the inﬂamma-

tory response was better in the group that used copaiba oil.

Copaiba oil also showed positive effects on bladder healing,11

and skin healing processes.27

In ►Table 5, we see a predominance of in vitro research,

with 50%, followed closely by the publications of clinical

studies in animals, with 40.4%. In the papers evaluated in the

present meta-analysis, we could see that copaiba oil is

promising in the medical ﬁeld as a very great potential

alternative therapy as an antimicrobial,19 anti-inﬂamma-

tory,1as well as an antitumor agent.17 These numbers

show that, until now, the researchers working with copaiba

oil seem to want to corroborate the empiric act of the local

natives with the use of this medicinal plant.

On the other hand, human studies are still lacking to

validate the therapeutic effects of copaiba oil. The publica-

tions with human subjects corresponded to only 2.4% of the

works evaluated in 2017. Observing the anti-inﬂammatory

potential of copaiba oil, we believe that in the coming years

the scientiﬁc community will focus more on publications

with humans, especially in the sports ﬁeld, because the

inﬂammatory processes in sports, such as tendinitis, mus-

cular contractures, stretching, and dislocations, are very

common. However, we must not forget the elderly, who

also present with a high incidence of i nﬂammatory processes

due to their age.

Regarding the publications in review form, we have found

the same percentage of clinical studies in humans, w hich was

of 2.4%. Of these, 4.8% were studies on the chemical compo-

sition of copaiba oil.

In ►Table 4, we can observe the comparative results

presented in these 42 studies on the administration of

copaiba oil. With 84% of positive results and inﬂammation,

copaiba oil has been shown to have a therapeutic potential

for both conditions. Cont roversial results s till appear because

of the great diversity of copaifera that exists in various parts

of the continent. According to Tobouti et al,3in the scientiﬁc

literature about copaiba oil, many articles do not specify

which exact strain is being studied. This makes it difﬁcult to

compare results between studies. Studies with β-caryophyl-

lene present in copaiba oil have been demonstrating its anti-

inﬂammatory properties and its therapeutic effects.4There-

fore, the use of copaiba oil extracted from trees with low β-

caryophyllene concentration may compromise the results of

the studies.3

Another component from copaiba oil with potent anti-

oxidant and anti-inﬂammatory properties is kaurenoic

acid.6,7 According to Silva et al16, the results of their research

demonstrated a signiﬁcant decrease in tumor necrosis factor

α(TNF-α) and Interleukin-1 (IL-1) expression and myeloper-

oxidase (MPO) activity at the T1/T2 time point.

In the results reported by other studies with copaiba oil,

there are uses of copaiba oil as a vehicle for administration of

medicaments, for topical and oral treatment28,29,infood

technology30, dental procedures30, and cardiorespiratory pro-

cesses.9Here we can observe a positive result in the use of

copaiba oil of 78% according to ►Table 4. This can demonstrate

versatility in the use of copaiba oil for different purposes.

In the studiesusing copaiba oil with a focus on its antitumor

action, the results were promising. Of the 4 studies published

in the database that were collected for the present meta-

analysis, 100% of the results showed a decrease in tumor

activity in the presence of copaiba oil in any form of

Table 4 The results with signiﬁcance, evaluated

2014 2015 2016 2017 Total %

Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative

Cancer –– 2–––2–100.0 –

Infections and

inﬂammation

3 1 10 1 3 1 5 1 84.0 19.0

Others –1–22–3–62.5 37.5

Healing –– –11–1 1 50.0 50.0

Total 3 2 12 4 6 1 11 2 78.0 22.0

Table 5 Publication types

2014 2015 2016 2017 Total %

In vitro 1 10 6 4 21 50.0

In vitro

animal

37161740.4

In vitro

human

–––112.4

Review –––112.4

Others 1 ––124.8

Journal of Morphological Sciences Vol. 35 No. 3/2018

Meta-analysis on Copaiba Oil Ferro et al.164

administration, whether oral, topical or in vitro. Although we

have found few studies on antitumor activity in our present

study, the use of copaiba oil in cancer therapies have

shown great results. Further clinical studies with copaiba oil

in humans are required for future development of dosages,

toxicity, and pharmacokinetic and pharmacodynamic

activities.

Interestingly, differently from the results on antitumor

activity, the percentages presented with respect to the

healing properties of copaiba oil were different than

expected, with only 50% of positive results found. Consider-

ing the empirical use of local people in the use of copaiba oil

as a healing agent, this result was a surprise. However, we

cannot fail to report that the studies found on the healing

properties of copaiba did not involve its application oil on

the skin exclusively. Yasoshima et al26 used copaiba oil via

gavage in rats that underwent hernia repair with Vicryl

mesh. According to the authors, there were no signiﬁcant

results in the postoperative healing process when compared

with the control group. Wagner et al12 used copaiba oil in

local ulcers in the mouth of rats and did not obtain

signiﬁcant results.

Conclusion

The proposed administration of copaiba oil in pathological

processes seems promising. The results presented in this

meta-analysis show that copaiba oil is an interesting alter-

native for treatments in pathologies such as chronic inﬂam-

mation, infectious processes, various type of cancer,

autoimmune diseases, and as a vehicle for the absorption

of other drugs. However, more studies on copaiba oil would

bring a great contribution to the medical community in the

search for alternative treatments. We have not found studies

related to age-ﬁghting properties of copaiba oil. Therefore,

there is an open gap here.

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25 Campos MI, Vieira WD, Campos CN, Aarestrup FM, Aarestrup BJ.

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based NLC containing lidocaine: from pre-formulation to in vivo

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Exsudatos de espécies arbóreas amazônicas: diversidade e potencialidades

Article

Full-text available

May 2022

A floresta Amazônica possui uma alta diversidade de Produtos Florestais Não Madeireiros, que fornecem suporte considerável para comunidades locais através de alimentos, medicamentos, plantas de importância cultural, material para abrigo e como fonte de renda, a exploração sustentável desses produtos podem contribuir para o desenvolvimento econômico da região e para o bem-estar das populações que dependem desses recursos para sua sobrevivência, além disso, são produtos importantes para o desenvolvimento da bioeconomia na Amazônia. Os exsudatos estão entre esses produtos e podem ser de grande valor econômico, social e cultural. O objetivo deste trabalho foi identificar, caracterizar o estado atual de informações disponíveis para uma série de espécies e discutir o potencial de uso para diferentes tipos de exsudatos. Utilizando como metodologia revisão bibliográfica. Quanto ao tipo, podem ser classificados como resina, látex, goma e seiva. Seus principais usos são na medicina popular, alimentação e cosméticos. São encontrados em abundância nas florestas e apresentam várias potencialidades, sendo necessário mais estudos científicos para direcionar sua exploração de forma sustentável e trazer retorno econômico principalmente para as populações tradicionais que habitam nessas regiões.

Fast-Acting and Receptor-Mediated Regulation of Neuronal Signaling Pathways by Copaiba Essential Oil

Article

Full-text available

Mar 2020
INT J MOL SCI

This study examined the biological activities of copaiba essential oil via measurement of its effects on signaling pathways in the SH-SY5Y neuronal cell line. Nanofluidic proteomic technologies were deployed to measure the phosphorylation of biomarker proteins within the signaling cascades. Interestingly, copaiba essential oil upregulated the pI3K/Akt/mTOR, MAPK, and JAK/STAT signaling pathways in neuronal cells. The effects of copaiba essential oil peaked at 30 min post-treatment, with a half-maximal effective concentration (EC50) of approximately 80 ng/mL. Treatment with cannabinoid receptor 2 (CB2) agonist AM1241 or the inverse agonist BML190 abrogated the regulatory effects of copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. Surprisingly, copaiba essential oil also activated the apoptosis signaling pathway and reduced the viability of SH-SY5Y cells with an EC50 of approximately 400 ng/mL. Furthermore, β-caryophyllene, a principal constituent of copaiba essential oil, downregulated the pI3K/Akt/mTOR signaling pathway. Taken together, the findings indicated that copaiba essential oil upregulated signaling pathways associated with cell metabolism, growth, immunity, and apoptosis. The biological activities of copaiba essential oil were determined to be fast acting, CB2 mediated, and dependent on multiple chemical constituents of the oil. Nanofluidic proteomics provided a powerful means to assess the biological activities of copaiba essential oil.

An integrated in vitro approach on the enzymatic and antioxidant mechanisms of four commercially available essential oils (Copaifera officinalis, Gaultheria fragrantissima, Helichrysum italicum, and Syzygium aromaticum) traditionally used topically for their anti-inflammatory effects

Article

Full-text available

Jan 2024

Introduction: Despite the increasing number of essential oils being reported on their potential therapeutic effects, some remain relatively unknown on their biological properties. That is the case of the essential oils obtained from copaiba (Copaifera officinalis L.), wintergreen (Gaultheria fragrantissima Wall.), everlasting (Helichrysum italicum (Roth) G.Don) and clove (Syzygium aromaticum (L.) Merr. & L.M.Perry), commonly labelled as being useful on the amelioration of conditions with an inflammatory background. Methods: To further broaden the current knowledge on the four essential oils, commercially available samples were approached on their effects upon a series of mediators that are involved on the inflammatory and oxidative response, both through in vitro cell-free and cell-based assays (5-lipoxygenase activity, lipid peroxidation, free radical and nitric oxide radical scavenging properties or tyrosinase inhibition). Results: The four oils proved to be active at some of the concentrations tested in most of the performed assays. Significant differences were found between the essential oils, S. aromaticum proving to tbe the most active, followed by G. fragrantissima against 5-lipoxygenase (5-LOX) and linoleic acid peroxidation, proving their potential use as antioxidants and anti-inflammatory agents. In fact, the IC50 value of S. aromaticum in the 5-LOX assay was 62.30 μg mL⁻¹. Besides S. aromaticum efficiently scavenged superoxide radicals generated by xanthine/xanthine oxidase, displaying an IC50 value of 135.26 μg mL⁻¹. The essential oil obtained from H. italicum exhibited a significant decrease in the nitric oxide levels on BV-2 cells, showing its potential as a cytoprotective agent against toxic damage. Copaiba oil ranked first as the most potent tyrosinase inhibitor, exhibiting an IC50 98.22 μg mL⁻¹. Conclusion: More studies are needed to describe the essential oils properties, but these results confirm the potential of these essential oils as anti-inflammatory and antioxidant agents.

Toxicological Effects of Copaiba Oil (Copaifera spp.) and Its Active Components

Article

Full-text available

Feb 2023

Vegetable oils are among the most important traditional resources of Amazonia. Oleoresins are a type of oil that have interesting characteristics and highly bioactive properties with pharmacological potential. Oleoresins produced in the trunks of Copaifera (Fabaceae) spp. trees, known as copaiba oils, are made up of terpenes from the sesquiterpene (volatile) and diterpene (resinous) classes, but in amounts that vary between species and depending on several factors, such as soil type. Despite being used for medicinal purposes, via topical and oral application, the toxic effects of copaiba oils and their constituents are little known. The current paper reviews the toxicological studies, both in vitro and in vivo, described in the literature for copaiba oils, as well as the cytotoxic characteristics (against microorganisms and tumor cells) in in silico, in vitro and in vivo models for the sesquiterpenes and diterpenes that make up these oils.

Anti-inflammatory and wound healing effect of Copaiba Oleoresin on the oral cavity: A systematic review

Article

Full-text available

Feb 2022

Copaiba oleoresin has been related to properties including healing and anti-inflammatory effects, making it a potential candidate to treat oral lesions. We aimed to define the benefits related to the anti-inflammatory and healing capacity of Copaiba-based formulations on the oral cavity. This is a systematic review, conducted in PubMed, Web of Science, Scopus, Embase, Scielo, Cochrane Library, BVS, and Google Scholar databases selecting full articles in English, Portuguese, or Spanish, until March 3rd, 2021. Pre-clinical, clinical, or randomized clinical trials, cohort and case-control in vivo studies were included; studies with other designs, in vitro, and those that did not match the PICO question were excluded (PROSPERO: CRD42021244938). Data was collected and synthesized descriptively through a specific form. The risk of bias was evaluated by SYRCLE´s RoB Tool. So, five studies were included. Two reported beneficial wound healing effects, such as early reduction in the wound area and greater immature bone formation in the rats' mandibles; and two related benefic anti-inflammatory effects, like reduced acute inflammatory reaction and more advanced tissue repair stage, early formation of collagen fibrils, with greater quantity, thickness and better organization, and more expressive anti-inflammatory activity, reduction of the edema intensity and the CD68+ macrophages concentration. Based on the articles, benefits related to the wound healing and anti-inflammatory effects in the oral cavity of rats treated with Copaiba oleoresin were suggested. However, due to the limited data, future studies are necessary, especially clinical ones.

Revestimento bioativo à base de fécula de mandioca (Manihot esculenta) e beterraba acrescido de óleo de copaíba bálsamo (Copaifera officinalis) para conservação de carne bovina in natura

Article

Full-text available

Feb 2021

O mercado agropecuário brasileiro tem crescido e ocupado cada vez mais espaço na economia mundial. O Brasil é o segundo maior produtor e consumidor de carne bovina, atrás apenas dos Estados Unidos. Os fatores intrínsecos da carne contribuem para a proliferação microbiana e rápida deterioração, surgindo a necessidade produzir uma alternativa natural para a conservação de alimentos, sendo acessível e com baixo custo para a população. O trabalho teve por objetivo avaliar o potencial de conservação do gel da Manihot esculenta adicionado óleo essencial de copaíba (Copaifera officinalis) e extrato de beterraba (Beta vulgaris L.) na extensão da vida de prateleira da carne bovina. O potencial antimicrobiano do óleo de copaíba foi determinado com a difusão em disco, determinação das concentrações inibitórias e bactericidas mínimas do óleo por microdiluição, composição química, vida de prateleira através da cor, pH e microbiota durante o período de armazenamento das amostras controles e tratamento. Dentre os resultados, o pH inicial da amostra controle foi 5,25 ± 0,05 e final 5,93 ± 0,03, a amostra OCB 5,28 ± 0,01 ao final 5,37 ± 0,008 e a amostra BET entre 5,21 ± 0,08 a 5,39 ± 0,05. Já, a análise microbiológica inicial da amostra controle dos mesófilos aos 20 minutos de 3,06 para 5,27 log UFC/g no 7º dia, a amostra OCB iniciou 3,26 para 5,14 log UFC/g e a amostra BET, partiu de 3,39 a 4,73 log UFC/g. Os resultados obtidos despertam próximos estudos para exploração de novas dosagens nesta matriz.

Akt3 Regulates the Tissue-Specific Response to Copaiba Essential Oil

Article

Full-text available

Apr 2020
INT J MOL SCI

This study reports a relationship between Akt3 expression and tissue-specific regulation of the pI3K/Akt/mTOR signaling pathway by copaiba essential oil. Akt3, a protein kinase B isoform important for the regulation of neuronal development, exhibited differential expression levels in cells of various origins. In neuronal and microglial cells, where Akt3 is present, copaiba essential oil positively regulated the pI3K/Akt/mTOR signaling pathway. In contrast, in liver cells and T lymphocytes, where Akt3 is absent, copaiba essential oil negatively regulated the pI3K/Akt/mTOR signaling pathway. The expression of Akt3 via plasmid DNA in liver cells led to positive regulatory effects by copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. In contrast, inhibition of Akt3 expression in neuronal cells via small interfering RNA molecules targeting Akt3 transcripts abrogated the regulatory effects of copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. Interestingly, Akt3 expression did not impact the regulatory effects of copaiba essential oil on other signaling pathways. For example, copaiba essential oil consistently upregulated the MAPK and JAK/STAT signaling pathways in all evaluated cell types, independent of the Akt3 expression level. Collectively, the data indicated that Akt3 expression was required for the positive regulatory effects of copaiba essential oil, specifically on the pI3K/Akt/mTOR signaling pathway.

Copaiba oil-resin (Copaifera reticulata Ducke) modulates the inflammation in a model of injury to rats’ tongues

Article

Full-text available

Jun 2017
BMC Compl Alternative Med

Background The regeneration of integrity and tissue homeostasis after injury is a fundamental property and involves complex biological processes fully dynamic and interconnected. Although there are medications prescribed to accelerate the process of wound healing by reducing the exaggerated inflammatory response, comes the need to search for different compounds of Amazonian biodiversity that can contribute to the acceleration of the healing process. Among these products, the copaiba oil-resin is one of the most prominent feature in this scenario, as they have been reported its medicinal properties. Methods Aiming to evaluate the anti-inflammatory and healing effect of copaiba oil-resin (Copaifera reticulata Ducke) in transfixing injury of rats’ tongues first proceeded up the copaiba oil-resin oral toxicity test in 5 male mice to stipulate the therapeutic dose which was established at 200 mg/kg/day. Then it was induced transfixing injury in a total of 15 Wistar rats. The animals were randomly divided into three groups based on the treatment: control group, dexamethasone group and copaiba oil-resin group. After 7 days of treatment, histological slides stained with hematoxylin and eosin was prepared. Immunohistochemistry for CD68 (macrophage marker) was performed and analyzed by the cell counter Image J. Results The acute toxicity test showed that the oil-resin copal has low toxicity. Furthermore, copaiba oil-resin therapy modulates the inflammatory response by decreasing the chronic inflammatory infiltrate, edema and specifically the number of macrophages. Conclusions The results indicate the potential of the Amazon region and showed up relevant because therapy with this extract modulates the inflammatory process.

Comparative analysis of the effects of Copaifera multijuga oil-resin and nitrofurazona in the cutaneous wound healing process

Article

Full-text available

Dec 2016

Objectives: to evaluate, histologically and macroscopically, the influence of Copaifera multijuga (Copaíba) oil-resin on the healing process of cutaneous wounds, comparing it with nitrofurazone. Methods: we divided 36 rats into three groups of 12 animals, according to the treatment to be administered. Group SL (control) received saline on the lesion; the Group OIL received topical treatment with Copaíba oil; and the Group NITRO was treated with Nitrofurazone. We inflicted a circular wound of 8mm in diameter on the back of each animal. We subdivided each of the three groups of 12 animals into three subgroups, according to treatment time and euthanasia (7, 14 and 21 days). All animals received the proposed treatment daily. We photographed the lesions for area measurement, as well as for evaluation of macroscopic aspects. We resected and stained the scars to quantify and qualify elastic fibers, collagen, degree of epithelization, neovascularization and inflammation. Results: although the saline solution provided a faster wound closure in its initial phase, after 14 days the wound size of the three groups tested was the same. Levels of inflammation and neovascularization were similar in all three groups. The amount of collagen and elastic fibers was higher in the Nitrofurazone and Copaíba oil groups. Conclusion: in male Wistar rats, Copaifera multijuga oil-resin positively influences the healing process, but it is less effective than nitrofurazone in healing by secondary intention.

Brazilian Amazon Traditional Medicine and the Treatment of Difficult to Heal Leishmaniasis Wounds with Copaifera

Article

Full-text available

Jan 2017
EVID-BASED COMPL ALT

The present study describes the use of the traditional species Copaifera for treating wounds, such as ulcers scarring and antileishmanial wounds. It also relates phytochemical studies, evaluation of the leishmanicidal activity, and toxicity. The species of Copaifera with a higher incidence in the Amazon region are Copaifera officinalis , Copaifera reticulata , Copaifera multijuga Hayne. The copaiba oil is used in the Amazon’s traditional medicine, especially as anti-inflammatory ingredient, in ulcers healing, and in scarring and for leishmaniasis. Chemical studies have shown that these oils contain diterpenes and sesquiterpenes. The copaiba oil and terpenes isolated have antiparasitic activity, more promising in the amastigote form of L. amazonensis . This activity is probably related to changes in the cell membrane and mitochondria. The oil showed low cytotoxicity and genotoxicity. Furthermore, it may interfere with immune response to infection and also has a healing effect. In summary, the copaiba oil is promising as leishmanicidal agent.

Copaiba Oil: Chemical Composition and Influence on In-vitro Cutaneous Permeability of Celecoxib

Article

Aug 2017
Curr Drug Deliv

Background: Use of topical or transdermal administration of Celecoxib (Cxb) is an interesting strategy in cutaneous treatments since it reduces or avoids side effects of the oral route. However, Cxb´s high lipophilicity and the stratum corneum (SC) barrier impair cutaneous penetration. Objective: evaluate copaiba oil (C.O) as a potential skin penetration enhancer (P.E) for Cxb. Methods: The chemical composition of C.O was evaluated by GC-MS. Both in vitro release and permeability assay of Cxb in Polyethylene glycol 400/ propylene glycol (PEG 400/PG) vehicle associated to C.O (1-50% w/w) were determined in a modified diffusion cell fitted with a synthetic hydrophobic membrane and pig ear skin as model, respectively. Results: GC-MS analysis of C.O showed that it is composed of sesquiterpenes (68.65%) and diterpenes (22.26%). Formulations containing 25% C.O (F4) and 50% C.O (F5) have shown in vitro burst release in the first 2 h, but only F4 released 100% of drug after 24 h. The highest Cxb permeation across skin was obtained from F4 and the highest skin retentions for F4 and F5 in the stratum corneum and epidermis plus dermis. Conclusion: The increased Cxb permeability through skin and its retention for an extended time (24h) at 25% C.O suggest that it could be a promising adjuvant for the development of transdermal formulations of Cxb.

Anti-inflammatory Effect from a Hydrogel Containing Nanoemulsified Copaiba oil (Copaifera multijuga Hayne)

Article

Aug 2017
AAPS PHARMSCITECH

Copaiba oil is used as a popular medicine in the Amazonian forest region, especially due to its anti-inflammatory properties. In this paper, we describe the formulation of hydrogel containing copaiba oil nanoemulsions (with positive and negative charges), its skin permeation, and its anti-inflammatory activity in two in vivo models: mouse ear edema and rat paw edema. Three hydrogels were tested (Carbopol(®), hydroxyethylcellulose and chitosan), but only Carbopol(®) and hydroxyethylcellulose hydrogels presented good stability and did not interfere with the nanoemulsions droplet size and polydispersity index. In skin permeation assay, both formulations, positively charged nanoemulsion (PCN) and negatively charged nanoemulsion (NCN), presented a high retention in epidermis (9.76 ± 2.65 μg/g and 7.91 ± 2.46 μg/cm(2), respectively) followed by a smaller retention in the dermis (2.43 ± 0.91 and 1.95 ± 0.56 μg/cm(2), respectively). They also presented permeation to the receptor fluid (0.67 ± 0.22 and 1.80 ± 0.85 μg/cm(2), respectively). In addition, anti-inflammatory effect was observed to NCN and PCN with edema inhibitions of 69 and 67% in mouse ear edema and 32 and 72% in rat paw edema, respectively. Histological cuts showed the decrease of inflammatory factors, such as dermis and epidermis hyperplasia and inflammatory cells infiltration, confirming the anti-inflammatory effect from both copaiba oil nanoemulsions incorporated in hydrogel.

Antimicrobial activity of copaiba oil: A review and a call for further research

Article

Oct 2017

Copaiba oil has been used for more than 390 years, however, considering the time of empirical use, there are a scarce number of publications on its activities. This essential oil is a phytomedicine proven to be efficient against some microorganisms. However, different from other phytomedicines which are well established, antimicrobial studies on copaiba oil can present some bias due to the lack of standardization. This review; summarizes recent works, from 2009 to 2016, into the antibacterial and antifungal activities of copaiba oil; discusses issues affecting studies on this oil; and calls for more in vitro and clinical studies.

Effects of Copaiba Oil Topical Administration on Oral Wound Healing

Article

Jun 2017
PHYTOTHER RES

The effects of topical copaiba oil extract and topical corticosteroid were assessed on oral wound healing in an in vivo model using 96 male Wistar rats. Traumatic ulcers were caused in the dorsum of the tongue using a 3-mm punch tool. The animals were divided into: Control; Corticosteroid; Placebo and Copaiba oil Group. The animals received two daily applications of the products. The control group received only daily handling. Six rats in each group were euthanized at days 3, 5, 10 and 14. The animals were monitored daily to determine wound status. The weigh was assessed at day 0 and euthanasia day. The percentage of repair was calculated, and histopathological aspects were analyzed. The Kruskal-Wallis test was used to compare the results between groups and times of evaluation. Closing time was assessed through the log-rank test. The corticosteroid group lost more weight at days 10 and 14 than the control group (p < 0.05). Moreover, the healing time of corticosteroid group was longer than the control group (p = 0.007). No differences were observed between the copaiba oil group and the control group. We concluded that topical copaiba oil, in spite of being safe, did not accelerate the process of oral wound healing. Copyright © 2017 John Wiley & Sons, Ltd.

Natural lipids-based NLC containing lidocaine: From pre-formulation to in vivo studies

Article

Aug 2017
EUR J PHARM SCI

In a nanotechnological approach we have investigated the use of natural lipids in the preparation of nanostructured lipid carriers (NLC). Three different NLC composed of copaiba oil and beeswax, sweet almond oil and shea butter, and sesame oil and cocoa butter as structural matrices were optimized using factorial analysis; Pluronic® 68 and lidocaine (LDC) were used as the colloidal stabilizer and model encapsulated drug, respectively. The optimal formulations were characterized by different techniques (IR-ATR, DSC, and TEM), and their safety and efficacy were also tested. These nanocarriers were able to upload high amounts of the anesthetic with a sustained in vitro release profile for 24 hours. The physicochemical stability in terms of size (nm), PDI, zeta potential (mV), pH, nanoparticle concentration (particles/mL), and visual inspection was followed during 12 months of storage at 25 °C. The formulations exhibited excellent structural properties and stability. They proved to be nontoxic in vitro (cell viability tests with Balb/c 3T3 fibroblasts) and significantly improved the in vivo effects of LDC, over the heart rate of zebra fish larvae and in the blockage of sciatic nerve in mice. The results from this study support that the proper combination of natural excipients is promising in DDS, taking advantage of the biocompatibility, low cost, and diversity of lipids.

Anti-inflammatory and Antioxidant Actions of Copaiba Oil Are Related to Liver Cell Modifications in Arthritic Rats: copaiba oil and hepatic cell metabolism

Article

Mar 2017
J CELL BIOCHEM

The present study investigated the action of copaiba oil (Copaifera reticulata) on the systemic inflammation, oxidative status and liver cell metabolism of rats with adjuvant-induced arthritis. The later is an experimental autoimmune pathology that shares many features with the human rheumatoid arthritis. Holtzman rats were distributed into the following groups: control (healthy) rats; control rats treated with copaiba oil at the doses of 0.58 and 1.15 g · Kg−1, arthritic rats, and arthritic rats treated with copaiba oil (0.58 and 1.15 g · Kg−1). The oil was administrated orally once a day during 18 days after arthritis induction. Both doses of copaiba oil improved the paw edema and the dose of 0.58 mg · Kg−1 improved the swollen adrenals and lymph nodes besides decreasing the plasmatic myeloperoxidase activity (-30%) of arthritic rats. Copaiba oil (1.15 g · Kg−1) abolished the increases of protein carbonyl groups and reactive oxygen species in the liver and both doses increased the liver GSH content and the catalase activity in arthritic rats. Copaiba oil (1.15 g · Kg−1) decreased glycolysis (-65%), glycogenolysis (-58%) and gluconeogenesis (-30%) in the liver of arthritic animals. However, gluconeogenesis was also diminished by the treatment of control rats, which presented lower body weight gain (-45%) and diminished number of hepatocytes per liver area (-20%) associated to higher liver weight (+29%) and increased hepatocyte area (+13%). The results reveal that copaiba oil presented systemic anti-inflammatory and antioxidant actions in arthritic rats. These beneficial effects, however, were counterbalanced by harmful modifications in the liver cell metabolism and morphology of healthy control rats. This article is protected by copyright. All rights reserved

Effect of diterpenoid kaurenoic acid on genotoxicity and cell cycle progression in gastric cancer cell lines

Article

May 2017

The goal of our study was to evaluate the effect of kaurenoic acid, obtained from copaiba oil resin, in gastric cancer (GC) and a normal mucosa of stomach (MNP01) cell lines. The compound was tested at concentrations of 2.5, 5, 10, 30 and 60 μg/mL. Comet and micronucleus assays were used to access its potential genotoxicity in vitro. Moreover, we evaluated the effect of kaurenoic acid in cell cycle progression and in the transcription of genes involved in the control of the cell cycle: MYC, CCND1, BCL2, CASP3, ATM, CHK2 and TP53. Kaurenoic acid induced an increase on cell DNA damage or micronucleus frequencies on GC cell lines in a dose-dependent manner. The GC and MNP01 cell lines entering DNA synthesis and mitosis decreased significantly with kaurenoic acid treatment, and had an increased growth phase compared with non-treated cells. The treatment induced apoptosis (or necrosis) even at a concentration of 2.5 μg/mL in relation to non-treated cells. GC cell lines presented reduced MYC, CCND1, BCL2 and CASP3 transcription while ATM, CHK2 and TP53 increased in transcription in relation to non-treated cells, especially at a concentration above 10 μg/mL. The gene transcription in the MNP01 (non-treated non-cancer cell line) was designated as a calibrator for all the GC cell lines. In conclusion, our results showed that kaurenoic acid obtained from Copaifera induces DNA damage and increases the micronuclei frequency in a dose-dependent manner in GC cells, with a significant genotoxicity observed above the concentration of 5 μg/mL. Moreover, this compound seems to be able to induce cell cycle arrest and apoptosis in GC cells.