Propolis como produto natural anti-protozoário

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Vol.:(0123456789)1 3
Acta Parasitologica 
https://doi.org/10.1007/s11686-020-00254-7
REVIEW
Promising Anti‑Protozoan Activities of Propolis (Bee Glue) as Natural 
Product: A Review
Shabnam Asfaram1,2 · Mahdi Fakhar2  · Masoud Keighobadi2 · Javad Akhtari3
Received: 12 March 2020 / Accepted: 9 July 2020 
© Witold Stefański Institute of Parasitology, Polish Academy of Sciences 2020
Abstract
Purpose Propolis (bee glue) is a resinous mixture of different plant exudates that possesses a wide range of biological 
and antimicrobial activities and has been used as a food supplement and in complementary medicine for centuries. Some 
researchers have proposed that propolis could be a potential curative compound against microbial agents such as protozoan 
parasitic infections by different and occasionally unknown mechanisms due to the immunoregulatory function and antioxi-
dant capacity of this natural product.
Methods In this review, we concentrate on in vitro and in vivo anti-protozoan activities of propolis extracts/fractions in the 
published literature.
Results In Leishmania, propolis inhibits the proliferation of promastigotes and produces an anti-inflammatory effect via the 
inhibition of nitric oxide (NO) production. In addition, it increases macrophage activation, TLR-2, TNF-α, IL-4, IL-17 pro-
duction, and downregulation of IL-12. In Plasmodium and Trypanosoma, propolis inhibits the parasitemia, improving anemia 
and increasing the IFN-γ, TNF-α, and GM-CSF cytokines levels, most likely due to its strong immunomodulatory activity. 
Moreover, propolis extract arrests proliferation of T. cruzi, because it has aromatic acids and flavonoids. In toxoplasmosis, 
propolis increases the specific IgM and IgG titers via decreasing the serum IFN-γ, IL-1, and IL-6 cytokines levels in the rats 
infected with T. gondii. In Cryptosporidium and Giardia, it decreases oocysts shedding due to phytochemical constituents, 
particularly phenolic compounds, and increases the number of goblet cells. Propolis inhibits the growth of Blastocystis, 
possibly by apoptotic mechanisms like metronidazole. Unfortunately, the mechanism action of propolis’ anti-Trichomonas 
and anti-Acanthamoeba is not well-known yet.
Conclusion Reviewing the related literature could highlight promising antimicrobial activities of propolis against intracel-
lular and extracellular protozoan parasites; this could shed light on the exploration of more effective drugs for the treatment 
of protozoan parasitic infections in the near future.
Keywords Propolis · Bee glue · Natural product · Anti-protozoan activities · Immunoregulatory
Introduction
Propolis (bee glue) is an adhesive natural compound created 
by honeybees; it is produced by mixing salivary and enzy-
matic secretions and the beeswax with resins collected from 
parts of various plant species [1, 2]. The chemical composi-
tion of propolis depends on the native flora of the region and 
collection season, which makes it difficult and challenging 
to standardize [3]. In general, propolis, as a source of bio-
logically active compounds, contains 50% resin and plant 
balsam, 30% beeswax, 10% important and aromatic oils, 
5% pollen, and 5% of other constituents including organic 
debris [4]. In the hive, it has several functions as follows: 
to close the holes, as an anti-infective substance to prevent 
 * Mahdi Fakhar 
 mahdif53@yahoo.com
 * Masoud Keighobadi 
 keighobadi216@yahoo.com
1 Research Center for Zoonoses, Parasitic and Microbial 
Diseases, Ardabil University of Medical Sciences, Ardabil, 
Iran
2 Toxoplasmosis Research Center, Communicable Diseases 
Institute, Iranian National Registry Center for Lophomoniasis 
and Toxoplasmosis, Department of Parasitology, School 
of Medicine, Mazandaran University of Medical Sciences, 
Farah-Abad Road, P.O Box: 48471-91971, Sari, Iran
3 Toxoplasmosis Research Center, Communicable Diseases 
Institute, Department of Medical Nanotechnology, School 
of Medicine, Mazandaran University of Medical Sciences, 
Sari, Iran
http://orcid.org/0000-0002-4690-6938
http://crossmark.crossref.org/dialog/?doi=10.1007/s11686-020-00254-7&domain=pdf
 Acta Parasitologica
1 3
infection of the hive by germs, and guard the entrance 
against invaders and keep dead microorganisms inside the 
hive, thus stopping rottenness and the expansion of odors 
[5–7]. Propolis has a wide range of biological properties 
and its valuable effects against infectious pathogens have 
been proven for decades; for example, it has been used as 
a food supplement and in traditional medical applications 
as an antimicrobial agent to treat respiratory tract infec-
tions, gastric, and skin illnesses [8–10]. Propolis has over 
300 active biological compositions, including terpenoids, 
polyphenols, steroids, flavonoids, amino acids, and phenolic 
acids; the anti-viral, anti-inflammatory, anti-bacterial [11], 
anti-oxidant [12], anti-fungal [13], anticancer [14], preserv-
ing corpses from decomposition [15], wound healing [16], 
immunoregulatory, antibacterial, and anti-protozoal [17, 18] 
activities of propolis have been attributed to these constitu-
ents. The antimicrobial activity of propolis is mainly due to 
the effect of caffeic acid derivatives and flavonoids [19, 20]. 
Therefore, there is increasing attention on it as a source of 
new treatments [21]. Parasitic infections are a serious global 
public health issue, because the available drugs are limited 
and ineffective; in addition, they have toxic side effects that 
contribute to the spread of the infection [22]. Therefore, the 
role of propolis as a traditional medicine has been described 
in parasitic protozoan infections such as Leishmania spp., 
Giardia duodenalis, Blastocystis spp., Toxoplasma gondii, 
Plasmodium spp., Trichomonas vaginalis, Acanthamoeba, 
Cryptosporidium, and Trypanosoma spp. According to pre-
vious studies, one of the best solvents for extracting propolis 
is ethanol, because the extraction procedure directly affects 
the product and values of some compounds [23–25]. Since 
the extract of propolis has an effect on both innate and adap-
tive immune systems by increasing natural killer (NK) cell 
activity [26], the present study attempted to review the anti-
parasitic role of propolis against parasitic protozoan infec-
tions. A summary of several studies assessing the role of 
propolis in protozoan parasites is shown in Table 1.
Leishmania and Propolis
Protozoan parasite of the genus Leishmania is the causative 
agent of leishmaniasis, a zoonotic and neglected parasitic 
disease with significant morbidity and mortality, therapeutic 
failure, and varied spectrum of clinical forms that can cause 
self-limiting skin lesions or fatal visceral involvement [58, 
59]. Leishmania has many escape mechanisms, the activi-
ties of which depend on the CD4 T cell subsets [60, 61]. 
Production of Th2 immune response leads to the spread and 
proliferation of the parasite [62], whereas host resistance 
is established by Th1 lymphocytes, which produces TNF-α 
and IFN-γ, and activates macrophages. Macrophages are 
immune cells that have main roles in the immune system 
and are involved in the killing of intracellular Leishmania 
spp. by the generation of intermediate metabolites, such as 
hydrogen peroxide (H2O2) and NO [62–64]. Among the 
leishmanicidal mechanisms, NO production has been one of 
the most important factors for destroying the parasites [65, 
66]. Alternative compounds and drugs such as Amphotericin 
B, Pentamidine, Miltefosine, and paromomycin are second-
line anti-leishmaniasis drugs; however, these drugs are 
expensive and toxic [67, 68]. On the other hand, emergence 
of drug-resistant parasites as a major problem limits the use 
of long-term treatment [69]. Therefore, the production of a 
new, inexpensive, and safe drug for treatment of leishma-
niasis seems necessary. Accordingly, using natural products 
derived from plants is a good option for this purpose [70]. 
Propolis has been used for many years incomplementary 
medicine and all its extracts can act directly against the pro-
liferation of promastigotes and produce an anti-inflammatory 
effect through the inhibition of NO production. Moreover, 
propolis increases macrophage activation and production of 
TLR-2 and eventually significant development of TLR- 4, 
which is involved in the production of TNF-α [71]. Several 
studies have shown that propolis extracts extracted from dif-
ferent sources, generally alcoholic extracts, show prominent 
antileishmanial effects in vitro and in vivo against Leishma-
nia parasites. Experimental infection using murine animal 
models showed that propolis extracts create a high decrease 
in the lesion size compared to treatment with Glucantime 
[32, 33, 38, 72]. Additionally, it reduces the liver para-
site load, vascular changes, and inflammation in the mice 
infected with Leishmania infantum [33]. In most studies, 
the maximum decrease of parasite growth was detected in 
cultures exposed to 125, 250, and 500 μ/ml of propolis. This 
effect increases in higher concentrations [35, 73], but no 
toxic effects were reported on the animal cells at the selected 
concentrations. A comparison of the difference between 
anti-leishmanial activities of the propolis samples found 
from different regions showed that some types of propolis 
were more effective than others against Leishmania species. 
It is possibly due to the various geographical locations, local 
flora, and plant variety. Some propolis compounds such as 
aromatic acid esters, aromatic acids, cinnamic acid esters, 
and flavanols can be responsible for the significant anti-
leishmanial activity of propolis [34].
Trypanosoma and Propolis
Both African and American trypanosomiases are fatal dis-
eases among vertebrates; and few parasitic species in human 
hosts are caused by a haemoflagellate protozoan parasite of 
the genus Trypanosoma. The parasite escapes the immune 
responses with the aid of multiple molecules on the surface 
and causes death unless treated. Anemia and emaciation 
Acta Parasitologica 
1 3
Ta
bl
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/m
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[3
5]
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m
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on
en
si
s
–
Et
ha
no
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b/
c
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 d
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yp
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xy
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om
bi
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w
ith
 
gl
uc
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pr
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ev
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cu
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an
d 
th
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le
si
on
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le
ss
 e
xu
da
tiv
e
[3
6]
 Acta Parasitologica
1 3
Ta
bl
e 
1 
 (c
on
tin
ue
d)
Pa
ra
si
te
 te
ste
d
In
 v
itr
o
In
 v
iv
o
M
ai
n 
re
su
lts
Re
fe
re
nc
e
Pr
ep
ar
at
io
n/
co
nc
en
tra
tio
n
Pr
ep
ar
at
io
n/
do
se
L.
 b
ra
zi
lie
ns
is
Et
ha
no
lic
5,
 1
0,
 2
5,
 5
0,
10
0 
μg
/m
L
H
um
an
 p
er
ip
he
ra
l b
lo
od
 m
on
on
uc
le
ar
 c
el
ls
 (P
B
M
C
)
–
N
o 
eff
ec
t o
n 
ce
ll 
vi
ab
ili
ty
 w
as
 o
bs
er
ve
d 
fo
r p
ro
po
lis
 
co
nc
en
tra
tio
ns
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p 
to
 5
0 
m
g/
m
l. 
Pr
op
ol
is
 m
od
er
at
es
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e 
im
m
un
e 
re
sp
on
se
 o
f p
at
ie
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s a
nd
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ffe
ct
in
g 
C
C
L5
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nd
 
IF
N
-γ
 e
xp
re
ss
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n 
PB
M
C
[1
0]
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zi
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ns
is
Et
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5,
 1
0,
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5,
 5
0,
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0 
μg
/m
L
M
ur
in
e 
m
ac
ro
ph
ag
es
Et
ha
no
lic
B
al
b/
c
2.
5,
 5
, 1
0 
m
g/
kg
M
ac
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ph
ag
es
 in
cu
ba
te
d 
w
ith
 p
ro
po
lis
 o
bs
er
ve
d 
a 
co
ns
id
er
-
ab
le
 e
nh
an
ce
m
en
t i
n 
in
te
rio
riz
at
io
n 
an
d 
fu
rth
er
 k
ill
in
g 
of
 p
ar
as
ite
s. 
In
cr
ea
se
d 
TNF-
α 
pr
od
uc
tio
n 
an
d 
al
so
 d
ow
n 
re
gu
la
tio
n 
of
 IL
-1
2 
du
rin
g 
th
e 
in
fe
ct
io
n 
w
as
 o
bs
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ve
d
[3
7]
L.
 b
ra
zi
lie
ns
is
H
yd
ro
al
co
ho
lic
1,
 1
0,
 3
0,
 5
0,
 1
00
, 2
50
, 5
00
, 7
50
 μ
g/
m
L
Ve
ro
 c
el
ls
 li
ne
H
yd
ro
al
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lic
B
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b/
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00
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50
 μ
g/
m
L
In
 th
e 
in
 v
itr
o,
 p
ro
po
lis
 h
yd
ro
al
co
ho
lic
 e
xt
ra
ct
 d
id
 n
ot
 sh
ow
 
cy
to
to
xi
ci
ty
 in
 th
e 
m
ax
im
um
 d
os
es
 e
xa
m
in
ed
. I
n 
in
 v
iv
o,
 
pr
op
ol
is
 e
xt
ra
ct
 o
ra
lly
 a
nd
 to
pi
ca
lly
 o
r b
ot
h 
in
 c
om
bi
na
-
tio
n 
de
cr
ea
se
d 
le
si
on
 d
ev
el
op
m
en
t
[3
8]
L.
 b
ra
zi
lie
ns
is
H
yd
ro
al
co
ho
lic
H
um
an
-d
er
iv
ed
 p
er
ip
he
ra
l b
lo
od
 m
on
on
uc
le
ar
 c
el
ls
 
(P
B
M
C
)
5,
 2
5 
μg
/m
L
–
Pr
op
ol
is
 p
re
tre
at
m
en
t d
is
pl
ay
s i
m
m
un
om
od
ul
at
or
y 
eff
ec
ts
 
on
 b
ot
h 
he
al
th
y 
do
no
rs
 a
nd
 p
at
ie
nt
s a
dh
er
en
t c
el
ls
. 
En
ha
nc
em
en
t I
L-
4 
an
d 
IL
-1
7 
an
d 
re
du
ce
 IL
-1
0,
 in
 e
ith
er
 
th
e 
pr
es
en
ce
 o
r a
bs
en
ce
 o
f t
he
 L
. b
ra
zi
lie
ns
is
 in
fe
ct
io
n,
 
sh
ow
in
g 
th
at
 p
ro
po
lis
 c
on
tro
ls
 th
e 
pa
ra
si
te
 b
y 
re
du
ci
ng
 
in
fla
m
m
at
io
n
[3
9]
C
ry
pt
os
po
ri
di
um
 sp
p.
–
Et
ha
no
lic
 a
nd
 a
qu
eo
us
O
oc
yt
e
R
at
50
 m
g/
kg
Th
e 
hi
gh
es
t d
ec
re
as
e 
of
 o
oc
ys
ts
 sh
ed
di
ng
 in
 fe
ca
l s
am
pl
es
 
w
as
 o
bs
er
ve
d 
in
 ra
ts
 tr
ea
te
d 
w
ith
 p
ro
po
lis
 e
xt
ra
ct
s. 
A
 
si
gn
ifi
ca
nt
 in
cr
ea
se
 in
 n
eu
tro
ph
ils
 c
ou
nt
 a
nd
 α
2-
 a
nd
 
β-
gl
ob
ul
in
s l
ev
el
s i
n 
ra
ts
 tr
ea
te
d 
w
ith
 b
ot
h 
ex
tra
ct
s w
as
 
ob
se
rv
ed
. B
ut
 th
e 
ly
m
ph
oc
yt
es
 si
gn
ifi
ca
nt
ly
 d
ec
re
as
ed
[4
0]
C
ry
pt
os
po
ri
di
um
 sp
p.
Et
ha
no
lic
 a
nd
 a
qu
eo
us
0.
12
5,
 0
.2
5,
 0
.5
, 1
, 2
 m
g/
m
L
Et
ha
no
lic
 a
nd
 a
qu
eo
us
 im
m
un
o-
su
pp
re
ss
ed
 ra
t
50
 m
g/
kg
7 
da
ys
A
qu
eo
us
 e
xt
ra
ct
 p
os
se
ss
ed
 h
ig
h 
an
tio
xi
da
nt
 e
ffi
ci
en
cy
 th
an
 
et
ha
no
lic
 e
xt
ra
ct
. I
n 
th
e 
ra
ts
 tr
ea
te
d 
w
ith
 a
qu
eo
us
 e
xt
ra
ct
, 
th
e 
m
or
ta
lit
y 
ra
te
 w
as
 th
e 
lo
w
es
t (
30
%
)
[4
1]
P.
 c
ha
ba
ud
i
–
M
et
ha
no
lic
 S
w
is
s m
ic
e
25
, 5
0,
 1
00
 m
g/
kg
7 
da
ys
Si
gn
ifi
ca
nt
ly
 in
hi
bi
te
d 
th
e 
pa
ra
si
te
m
ia
 a
nd
 sh
ow
ed
 m
aj
or
 
effi
ca
cy
 in
 im
pr
ov
in
g 
an
em
ic
 a
nd
 in
cr
ea
se
d 
th
e 
le
ve
l 
cy
to
ki
ne
s s
uc
h 
as
 IF
N
-γ
, T
N
F-
α,
 G
M
-C
SF
 a
nd
 G
-C
SF
[4
2]
P.
 b
er
gh
ei
–
H
yd
ro
al
co
ho
lic
B
al
b/
c
25
, 5
0,
 1
00
 m
g/
kg
5 
da
ys
Pr
op
ol
is
 h
yd
ro
al
co
ho
lic
 so
lu
tio
n 
ha
d 
a 
str
on
g 
im
m
un
om
od
-
ul
at
or
y 
ac
tiv
ity
 b
ut
 w
ea
k 
an
tip
la
sm
od
ia
l a
ct
iv
ity
[4
3]
T.
 b
ru
ce
i
–
M
et
ha
no
lic
R
at
60
0,
 4
00
,2
00
 m
g/
kg
5 
da
ys
R
at
s t
re
at
ed
 w
ith
 p
ro
po
lis
 (6
00
 a
nd
 4
00
 m
g/
kg
) h
ad
 a
 
si
gn
ifi
ca
nt
 re
du
ct
io
n 
in
 p
ar
as
ite
m
ia
, h
ig
he
r p
ac
ke
d 
ce
ll 
vo
lu
m
es
, h
em
og
lo
bi
n 
co
nc
en
tra
tio
ns
 a
nd
 w
ei
gh
t g
ai
n 
th
an
 th
e 
D
M
SO
 c
on
tro
l
[4
4]
Acta Parasitologica 
1 3
Ta
bl
e 
1 
 (c
on
tin
ue
d)
Pa
ra
si
te
 te
ste
d
In
 v
itr
o
In
 v
iv
o
M
ai
n 
re
su
lts
Re
fe
re
nc
e
Pr
ep
ar
at
io
n/
co
nc
en
tra
tio
n
Pr
ep
ar
at
io
n/
do
se
T.
 c
ru
zi
Et
ha
no
lic
Pe
rit
on
ea
l m
ac
ro
ph
ag
es
 m
ic
e
15
–6
0 
μg
/m
L
Et
ha
no
lic
Sw
is
s m
ic
e
25
, 5
0,
 1
00
, 1
50
, 2
00
, 3
00
 m
g/
kg
10
 d
ay
s
Th
e 
ex
tra
ct
 (2
5–
30
0 
m
g 
kg
) d
ec
re
as
ed
 th
e 
pa
ra
si
te
m
ia
, 
al
th
ou
gh
 n
ot
 a
t c
on
si
de
ra
bl
e 
le
ve
ls
. A
ni
m
al
 su
rv
iv
al
 is
 
in
cr
ea
se
d 
an
d 
di
d 
no
t i
nd
uc
e 
an
y 
he
pa
tic
, m
us
cu
la
r l
es
io
n 
or
 re
na
l t
ox
ic
ity
[4
5]
T.
 c
ru
zi
Et
ha
no
lic
75
, 3
00
 m
g/
m
L
–
In
hi
bi
te
d 
th
e 
gr
ow
th
 o
f T
. c
ru
zi
 e
pi
m
as
tig
ot
e 
at
 th
es
e 
co
nc
en
tra
tio
ns
[4
6]
L.
 in
fa
nt
um
T.
 c
ru
zi
p.
 fa
lc
ip
ar
um
M
et
ha
no
lic
M
C
R-
5 
ce
ll 
lin
es
64
–0
.2
5 
μg
/m
L
–
Th
e 
m
ai
n 
ac
tiv
ity
 o
f t
he
 e
xt
ra
ct
s w
as
 o
bt
ai
ne
d 
ag
ai
ns
t t
he
se
 
te
ste
d 
pr
ot
oz
oa
. T
he
 h
ig
he
st 
ac
tiv
ity
 a
ga
in
st 
P.
 fa
lc
ip
ar
um
 
w
as
 w
ith
 IC
50
 ≤
 0.
2 
μg
/m
L
[4
7]
T.
 b
ru
ce
i,
L.
 d
on
ov
an
i,
P.
 fa
lc
ip
ar
um
C
ri
th
id
ia
 fa
sc
ic
ul
at
a
Et
ha
no
lic
M
am
m
al
ia
n 
ce
ll 
lin
es
0.
1–
20
0 
μg
/m
L
–
A
ll 
th
e 
ex
tra
ct
s w
er
e 
ac
tiv
e 
ne
ar
ly
 a
ga
in
st 
al
l o
f t
he
se
 te
ste
d 
pr
ot
oz
oa
 a
nd
 d
is
pl
ay
 a
 ra
ng
e 
of
 E
C
50
 v
al
ue
s b
et
w
ee
n 
1.
65
 a
nd
 5
3.
6 
μg
/m
L.
 T
he
 to
xi
ci
ty
 a
ga
in
st 
an
im
al
 c
el
ls
 
w
as
 m
od
er
at
e
[4
8]
Bl
as
to
cy
st
is
 sp
p.
Et
ha
no
lic
12
5,
25
0,
50
0,
10
00
 μ
g/
m
L
–
W
as
 re
str
ai
ne
d 
th
e 
gr
ow
th
 o
f B
la
sto
cy
st
is
 sp
p.
 in
 b
ot
h 
of
 
th
e 
de
te
ct
ed
 su
bt
yp
es
 (S
T1
, S
T3
)
[4
9]
Ac
an
th
am
oe
ba
Sp
Et
ha
no
lic
1,
 2
, 4
, 5
, 6
, 7
, 8
 m
g/
m
L
–
Th
e 
tro
ph
oz
oi
te
 g
ro
w
th
 st
op
pe
d 
at
 th
e 
co
nc
en
tra
tio
ns
 o
f 
5 
m
g/
m
L.
 th
e 
str
on
ge
r i
nh
ib
ito
ry
 e
ffe
ct
 w
as
 a
t t
he
 c
on
ce
n-
tra
tio
ns
 o
f 7
 m
g/
m
L
[5
0]
A.
 c
as
te
lla
ni
i
Et
ha
no
lic
12
5,
 6
2.
5,
 3
1.
25
, 1
5.
62
, 7
.8
1,
 3
.9
0,
 1
.9
5,
 0
.7
8 
m
g/
m
L
M
on
ol
ay
er
 o
f r
at
 c
or
ne
al
 e
pi
th
el
ia
l c
el
ls
R
at
10
 d
ay
s
C
on
ce
nt
ra
tio
ns
 o
f p
ro
po
lis
 h
ig
he
r t
ha
n 
7.
81
 m
g/
m
L 
ca
us
e 
da
m
ag
e 
to
 c
or
ne
al
 e
pi
th
el
ia
l c
el
ls
. T
he
 k
er
at
iti
s g
ra
de
s 
w
ith
 p
ro
po
lis
 e
xt
ra
ct
 w
er
e 
si
gn
ifi
ca
nt
ly
 lo
w
er
 o
ve
r t
im
e 
th
an
 th
e 
ea
rly
 d
ay
s (
P 
<
 0.
05
)
[5
1]
G
. l
am
bl
ia
Et
ha
no
lic
25
0,
 5
00
 μ
g/
m
L
tro
ph
oz
oi
te
s
–
N
o 
in
hi
bi
tio
n 
w
as
 re
po
rte
d 
on
 p
ro
te
as
e 
ac
tiv
ity
 o
f p
ro
po
lis
 
tre
at
ed
 tr
op
ho
zo
ite
s
[5
2]
G
. l
am
bl
ia
M
et
ha
no
lic
0,
 2
5,
 5
0,
 1
00
, 2
00
 μ
g/
m
L
Tr
op
ho
zo
ite
–
Pr
op
ol
is
 d
em
on
str
at
ed
 th
e 
hi
gh
es
t i
nh
ib
ito
ry
 a
ct
iv
ity
 
ag
ai
ns
t G
. l
am
bl
ia
. T
he
 se
as
on
 h
ad
 a
 si
gn
ifi
ca
nt
 e
ffe
ct
 o
n 
th
e 
an
ti-
G
ia
rd
ia
 a
ct
iv
ity
 o
f p
ro
po
lis
. S
um
m
er
 p
ro
po
lis
 
sh
ow
ed
 th
e 
hi
gh
es
t i
nh
ib
ito
ry
 e
ffe
ct
 o
n 
th
e 
G
ia
rd
ia
 
tro
ph
oz
oi
te
 g
ro
w
th
 th
an
 o
th
er
 se
as
on
s
[5
3]
T.
 v
ag
in
al
is
Es
se
nt
ia
l o
il
25
, 5
0,
 1
00
, 2
00
, 3
00
, 4
00
,5
00
 μ
g/
m
L
Tr
op
ho
zo
ite
s
–
Ex
po
su
re
 to
 p
ro
po
lis
 in
hi
bi
te
d 
th
e 
gr
ow
th
 o
f T
. v
ag
in
al
is
. 
A
 c
on
ce
nt
ra
tio
n 
of
 5
00
 μ
g/
m
L 
ca
n 
ki
ll 
10
0%
 o
f t
he
 T
. 
va
gi
na
lis
 tr
op
ho
zo
ite
s
[5
4]
T.
 v
ag
in
al
is
Et
ha
no
lic
 a
nd
 h
yd
ro
et
ha
no
lic
10
0,
50
0 
μg
/m
L
TY
M
–
Pr
op
ol
is
-f
ra
ct
io
ns
 sh
ow
ed
 a
ct
iv
ity
 a
ga
in
st 
T.
 v
ag
in
al
is
 a
nd
 
si
gn
ifi
ca
nt
 a
nt
io
xi
da
nt
 c
ap
ac
ity
[5
5]
T.
 g
on
di
i
Et
ha
no
lic
10
0,
 5
0,
 2
5,
 1
0,
 9
, 8
, 7
, 6
, 5
, 4
, 3
,1
 n
m
Ta
ch
yz
oi
te
s
R
H
 st
ra
in
–
Pr
op
ol
ise
xt
ra
ct
 sh
ow
ed
 a
 d
es
tru
ct
iv
e 
eff
ec
t o
n 
vi
ab
le
 ta
ch
y-
zo
ite
s i
n 
th
e 
di
ffe
re
nt
 d
ilu
tio
ns
[5
6]
 Acta Parasitologica
1 3
are main clinical signs of both types of trypanosomiasis. 
Fexinidazole is used to treat both stages of the disease in 
adults and children [74]. Resistance to melarsoprol and pen-
tamidine has also been reported, that can lead to recurrent 
parasitemia and treatment failures [75]. Therefore, new tryp-
anocidal drugs, that are nontoxic and affordable, are urgently 
needed. Oral treatment with a methanolic extract of propolis 
significantly increased weight, survivability, packed cell vol-
umes, and hemoglobin concentrations. Although, it is not 
capable to clear the parasitemia, but it can limit the infec-
tion by reducing the rate of parasite proliferation through 
immunomodulation [44]. Intracellular amastigote is clini-
cally more important than epimastigotes, and more suscep-
tible to extract. Moreover, the effect of the extract was much 
more on the non-multiplicative stage (trypomastigotes) [76]. 
Epimastigotes treated with extracts displayed ultrastructural 
alterations in the Golgi complex, reservosomes and mito-
chondrion (target organelles for propolis) that these metabo-
lism alterations will lead to the death of the parasite [77]. 
Besides, in vitro experiments showed that ethanolic propolis 
extract has a high inhibitory activity against Trypanosoma 
cruzi epimastigote [46] due to the content of aromatic acids 
and flavonoids present in propolis extracts [76].
Plasmodium and Propolis
Malaria is one of the most important infectious diseases caused 
by an ancient and formidable organism called the Plasmo-
dium parasite; it is transmitted to humans by the bite of female 
Anopheles mosquitoes. This blood disease is a life-threatening 
issue in nearly half of the world’s population (91 countries). 
The first line of anti-malarial drugs is sulfadoxine–pyrimeth-
amine, chloroquine, artemisinin, and its derivatives, all of 
which are toxic [78]. At present, the parasite is now resistant to 
most advanced drugs [79]. Therefore, many researchers have 
attempted to develop novel antimalarial drugs and have found 
that many natural products can have the potential for antima-
larial activity [80]. The decrease in red blood cells (RBCs) 
production due to malarial parasites and the destruction of par-
asitized RBCs causes severe anemia. Malaria-related anemia is 
fatal; therefore the prevention of anemia and the reduction of 
the percentage of parasitemia are an important step in the treat-
ment of malaria infection [81]. The complications of malarial 
infection on the spleen tissue are important, because the spleen 
plays a key role in inducing an immune response against this 
disease [82]. Flavonoid compounds motivate the prolifera-
tion of human peripheral blood leukocytes and increase the 
activity of cytokines, helper T cells, g-interferon, interleukin 
2, and macrophages that are useful in the treatment of immune 
deficiency diseases [83]. Activated macrophages can induce 
lysozyme enzymes, increase the phagocytosis process, and 
eradicate Plasmodium, especially in the erythrocyte stage Ta
bl
e 
1 
 (c
on
tin
ue
d)
Pa
ra
si
te
 te
ste
d
In
 v
itr
o
In
 v
iv
o
M
ai
n 
re
su
lts
Re
fe
re
nc
e
Pr
ep
ar
at
io
n/
co
nc
en
tra
tio
n
Pr
ep
ar
at
io
n/
do
se
T.
 g
on
di
i
–
Et
ha
no
lic
R
at
0.
1 
m
L
28
 d
ay
s
Tr
ea
tm
en
t w
ith
 p
ro
po
lis
 sh
ow
ed
 th
at
 si
gn
ifi
ca
nt
ly
 in
cr
ea
se
d 
th
e 
sp
ec
ifi
c 
an
tib
od
y 
in
 ra
ts
[5
7]
Acta Parasitologica 
1 3
[84]. The effect of the propolis extract has been proven on 
anti-inflammatory activity in macrophages and the enhance-
ment and modulation of the immune system both in vivo and 
in vitro methods [8, 85–87]. Propolis methanol extract showed 
a remarkable decrease in the percentage of the parasitemia of 
mice that were experimentally infected with Plasmodium [42, 
88]; this could be correlated with the activation of the immune 
system through the generation of pro-inflammatory cytokines 
allowing the release of the parasite. Furthermore, several stud-
ies reported that there was a considerable enhancement in the 
number of RBCs, as well as a recovery in the hemoglobin level 
and a reduction in the number of white blood cells (WBCs) 
after treatment with the methanol extract propolis [8, 42, 
89–91]. After the effectiveness of propolis extract, spleen his-
tological examination showed a significant recovery in spleen 
tissue against Plasmodium infection [42, 89].
Cryptosporidium and Propolis
Cryptosporidiosis is an emerging highly infectious threat; it 
is known as a global health problem, which can cause diar-
rhea and even death if left untreated, especially in children 
and immunodeficient individuals [92]. Potential molecules 
such as phospholipases, proteases, and hemolysins cause 
tissue damage [93]. There is no effective treatment against 
cryptosporidiosis, and nitazoxanide shortens diarrhea dura-
tion in normal people and is ineffective in immunosuppres-
sive and HIV individuals [94]. Evaluating the efficacy of 
both propolis extracts (ethanol and water) in immunosup-
pressed rat models infected with Cryptosporidium spp. 
showed that stimulating immune system with propolis could 
lead to the enhancement of antibody titers [95]. This was 
positively correlated with the reduced oocysts shedding and 
excretion patterns, but none of them was able to completely 
inhibit the parasite [40, 95]. Additionally, histopathologi-
cal examination of the ileum revealed that both extracts 
increased the number of goblet cells, which play a main 
role in the production of anti-microbial antibodies. However, 
it could not revive the symmetrical architecture of ileal villi 
and mucosa [96]. The anti-cryptosporidial activity of propo-
lis extracts is possibly due to the phytochemical constituents, 
particularly phenolic compounds [95]. These compounds are 
the major antioxidants that act through increasing oxidative 
defense mechanisms [97, 98].
Toxoplasma gondii and Propolis
Toxoplasma gondii (T. gondii) is an opportunistic zoonotic 
protozoan and the forth deadly pathogen in immunosup-
pressed patients worldwide. There are acute tachyzoite and 
chronic bradyzoite stages in its life cycle [99]. Treatment of 
acute human toxoplasmosis is so difficult, but it is possible 
with intracellular antibiotics or sulfonamides at higher doses 
[100]. An ethanol extract of propolis possesses obvious in vitro 
anti-Toxoplasma activity in macrophages. Adding 7% of prop-
olis extract on the preservative cold saline is responsible for 
the longer viable persisting time of tachyzoites; it can also be 
used in liquid nitrogen cryopreservation of the Toxoplasma 
RH strain tachyzoites for research purposes and exact golden 
Methylene Blue Dye Test for confirming animal and human 
toxoplasmosis. In addition, 7% diluted propolis extract can 
maintain the Toxoplasma RH strain tachyzoites antigen used 
for manufacturing various types of serological kits. Propolis 
nutritional components probably act similar to calf serum as 
a feeding supplement for tachyzoites. It seems that higher 
propolis concentrations at 4 ℃ could directly increase in vitro 
precipitating factor, and trapping some heavier compounds 
effectively destructs tachyzoites [56]. Treatment with propo-
lis through the in vivo model significantly increased the spe-
cific antibody (IgM and IgG) titers and decreased the serum 
cytokines (IFN-γ, IL-1, and IL-6) level in rats infected with 
T. gondii [57].
Giardia and Propolis
Giardia lamblia (G. lamblia) is a flagellated protozoan and 
one of the main causes of non-viral diarrhea in humans. The 
5-nitroimidazole compounds (metronidazole, tinidazole, and 
secnidazole) are used to control giardiasis as a first-line treat-
ment worldwide [101]. Propolis is a potential alternative and 
in vitro experiments have shownthe inhibitory effect of propo-
lis on the growth and adherence of Giardia trophozoites [73]. 
Excreted-secreted proteins are pathogenesis factors in Giardia 
and have been considered as chemotherapeutic targets in the 
parasite. Propolis ethanolic extract could not inhibit tropho-
zoites proteinase activities [52], but this extract inhibited the 
in vitro proliferation of Giardia trophozoites [73]. Experiments 
on mouse model of giardiasis showed the enhancing effect of 
propolis on immune response and reduction of the parasite 
load [102]. Alday-Provencio [53] reported that season had an 
important effect on the anti-Giardia activity of propolis so that 
the highest parasite growth-inhibitory activity was observed 
in summer followed by winter, spring, and autumn, respec-
tively. However, the season did not have a significant effect 
on the chemical composition of propolis [103]. The caffeic 
acid phenethyl ester, as a compound found in propolis, has 
an anti-Giardia activity but albendazole was more effective 
in the treatment of giardiasis than chemical constituents of 
propolis [52].
 Acta Parasitologica
1 3
Trichomonas vaginalis and Propolis
Trichomoniasis is the most common non-viral and sexu-
ally transmitted infection in all countries with complica-
tions including infertility, pregnancy outcomes, and cervi-
cal and prostate cancers [104]. The most important drugs 
used for treatment are metronidazole and tinidazole; the 
number of resistant isolates of these drugs has increased 
[105]. The hydroalcoholic extract of propolis, as an adju-
vant in a veterinary vaccine formulation, reduced viscos-
ity, reactivity, and toxicity. Furthermore, it could induce 
good stability and robust humoral and cellular response 
[106, 107]. Cytotoxicity is a limiting factor for the use of 
propolis so that propolis extract at high concentrations had 
anti-Trichomonas activity and damaged all trophozoites. A 
higher cytotoxicity level was detected in the in vitro test; 
but the lower concentrations were not toxic for cells and 
they decreased parasite proliferation only by 70% [54]. 
Therefore, its use in topical vaginal forms for the treat-
ment of trichomoniasis appears to be an exciting alterna-
tive, because topical treatment allows for the delivery of 
higher drug concentrations with lower treatment doses to 
the vaginal epithelium [107]. The ethanolic extracts of 
propolis were more active than hydroethanolic extracts and 
reduced 99% of Trichomonas trophozoites. Thus, ethanol 
extract propolis can be useful for vaginal trichomoniasis 
[55].
Acanthamoeba and Propolis
Acanthamoeba species are ubiquitous and opportunistic 
protozoa that can cause major human diseases, including 
eye keratitis and fatal granulomatous amoebic encepha-
litis. There are two stages in the life cycle of free-living 
Acanthamoeba spp., a motile trophozoite and a resistant 
cyst [108]. Propolis extract at high concentrations proved 
potent amoebicidal effects on both trophozoite and cyst 
stages of Acanthamoeba castellanii [109]. In the in vitro 
experiment cytotoxicity of propolis, the high concentra-
tions of propolis cause damage to corneal epithelial cells. 
Several agents have been assessed as anti-amoebic, but 
the effective medical therapy for Acanthamoeba keratitis 
has yet to be appointed. Chlorhexidine is effective in some 
patients. Propolis extracts showed comparable ameobicidal 
efficacy to chlorhexidine [51].
Blastocystis and Propolis
Blastocystis spp. is one of the commonest lower intestinal 
protozoans, with a global geographic distribution that has 
unclear clinical significance in animals and humans [110]. 
Blastocystis, as an opportunistic pathogen, can be asymp-
tomatic and self-limiting; however, it may cause gastroin-
testinal disorders for months or years if left untreated in 
immunocompromised patients. Metronidazole, trimetho-
prim–sulfamethoxazole, nitazoxanide, iodoquinol, para-
momycin, ketoconazole, emetine, secnidazole, and tini-
dazole are the common drugs used to treat Blastocystis 
infection [111]. Cysteine proteases of protozoan parasites 
have important biological functions including immune 
evasion, host cell invasion, virulence, and pathogenesis 
that these enzymes are as therapeutic targets for antipro-
tozoal drug development [112]. Blastocystis spp. cysteine 
proteases decline human secretory immunoglobulin A 
(IgA) and modify interleukin 8. Therefore, these are con-
tributing to parasite survival in vivo. The use of ethanol 
(70% and 95%) as a solvent for propolis extract showed no 
activity on the growth of Blastocystis spp.[113]. The high 
concentration of propolis extract (1000 μg/ml) displays a 
strong inhibitory effect on the in vitro growth of Blastocys-
tis spp. and completely destroys the parasite. Microscopic 
examination revealed morphological changes including a 
significant decrease in the vacuolar and granular forms in 
Blastocystis parasites treated with high doses of propolis 
extract [49]. Propolis extract could have similar effects 
to metronidazole on Blastocystis spp. that both activate 
apoptotic mechanisms [114].
Conclusion
At present, apitherapy or the medical uses of bee prod-
ucts as substances have pharmacological potential against 
bacteria, fungi, viruses, and especially parasites. In should 
be noted that even though ethanol extract of propolis is 
frequently used, extracts with other solvents have been 
applied for the detection of constituents. However, etha-
nol extract of propolis increases the inhibition of parasite 
infections and is effective in the destruction or reduction 
of the host’s parasitemia. Moreover, because of the pres-
ence of arginine, bioflavonoids, minerals, and vitamin A, 
C, B complexes, it has wound healing ability and reduces 
the damage. As a whole, due to the potential biological 
properties of propolis against the human pathogen, the 
current review suggests that new propolis compounds be 
characterized for discovering novel antiprotozoal drugs 
with greater efficacy. It is our hope that this review could 
Acta Parasitologica 
1 3
shed a light for researchers and also encourage them to 
establish such studies in the future.
Acknowledgements We also would like to thank of financial support 
by Vice Chancellors for Research of Mazandaran University of Medical 
Sciences, Sari, Iran (Grant number: 6873).
Author contributions MF and MK designed the study and revised the 
manuscript. SA wrote the draft of the manuscript. JA performed paper 
selection processing and critical review. All authors read and approved 
the final manuscript.
Compliance with ethical standards 
Conflict of interest The authors declare there are no competing inter-
ests.
Ethics approval This study was reviewed and approved by the ethi-
cal committee at Mazandaran University of Medical Sciences (IR.
MAZUMS.REC.1398. 6873).
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	Promising Anti-Protozoan Activities of Propolis (Bee Glue) as Natural Product: A Review
	Abstract
	Purpose 
	Methods 
	Results 
	Conclusion 
	Introduction
	Leishmania and Propolis
	Trypanosoma and Propolis
	Plasmodium and Propolis
	Cryptosporidium and Propolis
	Toxoplasma gondii and Propolis
	Giardia and Propolis
	Trichomonas vaginalis and Propolis
	Acanthamoeba and Propolis
	Blastocystis and Propolis
	Conclusion
	Acknowledgements 
	References