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Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, 8, 85-94 85

Immunomodulatory Properties of Green Propolis

Sônia M. de Figueiredoa,b,*, José A. Nogueira-Machadoa, Bruno de M. Almeidad, Sheila R.L.

Abreuc, José A.S. de Abreud, Sidney A.V. Filhoe, Nancy S. Bindaa and Rachel B. Caligiornea

a
Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte (IEP/SCBH), rua Domingos Vieira, 590, Belo Hori-
zonte 30150-240, Minas Gerais, Brazil; bDepartamento de Alimentos, Escola de Nutrição, Universidade Federal de
Ouro Preto-Campus Morro do Cruzeiro, Ouro Preto 35400-000, Minas Gerais, Brazil; cPharmanectar, Rua Pernambuco
1066, Belo Horizonte 30130-151, Minas Gerais, Brazil; dNectar Pharmaceuticals, the MG 435 - 2.5 Km. Caeté, Minas
Gerais 34800-000, Brazil; eDEFAR, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Morro do
Cruzeiro, Ouro Preto 35400-000, Minas Gerais, Brazil

Received: March 7, 2014; Accepted: June 18, 2014; Revised: June 18, 2014

Abstract: Propolis is a resinous material collected by honeybees from numerous plants and serves as a defense against in-
truders. Because of its relevant curative properties, it is now gaining popularity in health foods and in cosmetic products.
Understanding the underlying molecular mechanisms of phytochemicals has become a good strategy in bioprospection for
new anti-inflammatory compounds. The biological activity of propolis derives from its high levels of phenolic acids,
while flavonoids are thought to account for the activity of propolis extracts. The comprehension of the relationship be-
tween propolis and the immune system has progressed in the last years, recent articles have provided important contribu-
tions to this investigation field. Studies have shown that propolis suppressed the “IL-6-induced phosphorylation of signal
transducer and STAT3”, an essential cytokine-activated transcription factor in Th17 development. Therefore, action
mechanisms of “propolis on Th17 differentiation could be instrumental in controlling disturbed cytokine networks in in-
flammation, autoimmune diseases, and infections.” The use of propolis has been proposed in some patents as:
WO2013163714; CN102885854, WO2013142936, US20130266521, and US20130129808, which are related to the treat-
ment of dental diseases; adjuvant in anti-cancer treatment; in cosmetic products; as an anti-inflammatory agent and natural
antibiotic. Although there are many publications regarding the propolis efficacy, its applicability to human health and
mechanisms of action are not completely understood, creating opportunities for new studies.
Keywords: Cytokines, immunomodulation, interleukins, PAMPs, propolis, toll-like receptors.

1. INTRODUCTION biological properties including, antimicrobial, anti-cancer,

antioxidant, antiviral, anti-inflammatory, antiprotozoan, he-
Propolis is a resinous material collected by honeybees in
patoprotective, cytotoxic, antiulcer activity and protective of
numerous plants as a defense against intruders [1, 2]. Be-
the heart [2, 4, 9-16].
cause of its relevant therapeutic application, it has been used
in folk medicine for centuries, and is now gaining popularity Due to these health-promoting characteristics, propolis is
in health foods as well as in cosmetic products [1, 3, 4]. regarded as a functional component, and thus can used in
cosmetics, medicines, toothpastes, in the treatment of gingi-
Also known as “bee glue”, propolis plays an important
vitis, cheilitis and stomatitis. It can be presented in the form
role in ensuring bee colony health [5]. Honeybees exploit
of gels, creams, beverages or foods to prevent diseases and
nectar and pollen from nature to fulfill their nutritional
improve health [1, 2, 17].
needs, and use propolis to maintain the antiseptic environ-
ment in the hive [1]. In fact, the expression propolis derives Though more than 400 different chemical constituents
from the Greek pro (in defense of, or in front of) and polis have been recognized in propolis during the past few years,
(city or hive), and thus denotes a substance that is useful for these properties are primarily due to a few compounds in-
the protection of the hive [6, 7]. cluding polyphenols, flavonoids, terpenes, essential oils,
inorganic compounds, caffeic, ferulic and cumaric acids,
Propolis is gathered by honeybees from resinous exu-
aldehydes and esters [14, 18, 19]. Some organic constituents
dates of buds, leaves, branches, and barks found in the vicin-
isolated from green propolis are presented in Fig. (1).
ity of the beehive [3, 8]. Propolis samples have shown many
Green propolis is well known for its color [3, 9]. The
plant Baccharis dracunculifolia DC (Asteraceae) is the
*Address correspondence to this author at the Escola de Nutrição, Universidade,
Federal de Ouro Preto, Campus Morro do Cruzeiro, Ouro Preto Minas, Gerais, primary subtract for it, a common species found in the Bra-
Brazil. CEP 35400-000; Tel: +55 31 3559 1844; Fax: +55 31 3559 1828; zilian cerrado [2, 17]. The biological activity of propolis
Mobile: +55 31 8896 4089; E-mail: [email protected] derives from its high levels of phenolic acids, while fla-

2212-3334/14 $100.00+.00 © 2014 Bentham Science Publishers

86 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 de Figueiredo et al.

Compound R1 R2 R3 R4

Chrysin H OH H H

Tectochrysin H OCH3 H H
R3
R4 Pinobanksin OH OAc H H

R2 O Galangin OH OH H H

Apigenin H OH H OH
R1
Kaempferide OH OH H OCH3
OH O
Quercetine OH OH OH OH

Rutin OGluMan OH OH OH

O O O

O
O O COOH COOH
OH

O HO
O
Cinnamic acid
OH

Baccharin
HO
Artepillin C
O
HO
O

Caffeic Acid phenylethyl ester (CAPE)

Fig. (1). Chemical structure of compounds isolated from propolis.

vonoids are thought to account for the activity of propolis Szliszka et al. (2013) [29] proposed that the immuno-
extracts [20, 21]. modulatory properties of propolis can be attributed to its
flavonoids and phenolic acids. Among the flavonoids, the
Wang et al. (2013) [15] reported that numerous varieties
Artepilin C and the CAPE are associated in the immuno-
of propolis have a wide spectrum of pharmacological activity,
modulatory actions. Addictionally, the artepillin C presents
and emphasized the fact that the main constituent of pro-
several proven activities, such as antioxidant and antitumor
polis varies widely when gathered from different geographic
[3] Caffeic acid phenethyl ester (CAPE) has a polyphenolic
locations. Consequently, different aspects, such as the geo-
ring that networks with several molecules of the human
graphical origin, plant resources, collecting season, bee spe-
body, see Fig. (1). This compound is known to have antitu-
cies, and solvents used in the extraction, have an influence
moral, anti-inflammatory, antineoplastic and, to some extent,
on the chemical constitution of propolis [18, 22]. Therefore,
antioxidant properties [29].
it is necessary to distinguish between specific propolis types
and their corresponding composition [2, 23]. In the present review, the role of propolis on immuno-
modulation and the signaling pathways associated with innate
Information on the underlying molecular mechanisms of
immunity is discussed [31]. In addition, the current literature
phytochemicals has become a good strategy in the bio-
and recent patents related to propolis effects on the immune
prospection of new anti-inflammatory compounds [24, 25].
system and metabolic signaling pathways are highlighted.
Until the 1990s, the knowledge of the immunomodulatory
action of propolis has been scarce [6]. But, in the last years,
2. PROPOLIS AND IMMUNOMODULATION
new articles have provided an important contribution to this
investigation field, showing that the immunomodulatory According to some studies, the artepillin C that has
properties of propolis are attributed to the flavonoids and demonstrated antitumor effects, antioxidant protection and exert
phenolic acids [4, 26]. Regarding the Brazilian green propo- an immunosuppressive function on T-lymphocyte subsets,
lis, the constituents are cinnamic acid, coumaric acid, quer- while paradoxically activating macrophages [32]. Therefore,
cetin, rutin, pinobanksin-3-acetate, kaempferide, apigenin, Chan et al. (2013) [33] and Ahn et al. (2009) [34] investi-
galangin, artepillin C, tectochrysin, baccharin, pinobanksin, gated a potential immunomodulatory properties of the cin-
chrysin, among others, see Fig. (1) [19, 24-29, 30]. namic acid, since these acids have a significant role in the
Properties of Green Propolis Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 87

mixture of compounds, among then the artepillin C [15, 32, There are several studies around the antitumoral actions
35]. of propolis. In assays in vivo, Missima et al. (2010) [42]
showed that propolis could be associated to immune regula-
Macrophages play an important role in the immune system
tion by stimulates IL-10 expression and production, and may
as well as in the inflammation process. When stimulated
be associated to its antitumoral action [42]. Regarding the
by lipopolysaccharides (LPS), macrophages can secrete a
anti-inflammatory action of propolis, Orsatti et al. (2010)
variety of inflammatory mediators, including NO, IL-1, and
[43] had previously found that propolis administration to
IL-6 [15, 36]. According to Wang (2013) [15], an increase of
mice for three consecutive days increased proinflammatory
these mediators will break immune equilibrium and origin
cytokines (IL-1 and IL-6) production and stimulated the
numerous inflammatory conditions, including septic shock, expression of toll-like receptors (TLR-2 and TLR-4), which
arteriosclerosis, and cancer and they suggest that the green implies that propolis may balancing the components of the
propolis acts a suppressive influence on the expression of the immune response [43, 44]. Additionally, propolis constitu-
inflammation-related genes at the transcriptional level. ents could interact with diverse receptors in different cells,
Researchers like Neiva et al. (2014) [36] verified that but further investigation is still needed to understand the
propolis decreased the LPS-induced cytokines and/or involvement of isolated compounds [43].
chemokines expression in odontoblast-like cells, in macro- Toll-like receptors (TLR) have a crucial role in the detec-
phages and in osteoclasts. Also, Bachiega et al. (2012) [37] tion of microbial infection in mammals and insects [44].
researched the immunomodulatory effect of propolis on cy- TLR are capable to discriminate different domains of patho-
tokine production (IL-6, IL-1b and IL-10) by peritoneal gen-associated molecular patterns (PAMPs) [44, 45] through
macrophages in vitro and verified that propolis may modu- pathogen recognition receptors (PRRs), and it is essential for
late the immune/inflammatory response, depending on its microbial survival, thus playing an important function in
concentration, thanks to the synergic action of its constitu- host innate immunity with further activation of adaptive im-
ents. munity [44]. TLR-2 and TLR-4 are transmembrane proteins
Propolis dose-dependently controls the immune/inflam- that present a domain with a leucine-rich repetition in their
matory response; its efficacy may be due to the synergistic extracellular region, which allows the recognition of diverse
effect of its compounds [38]. Marwaha et al. (2012) [39] PAMPs [14, 44].
suggested that depending on the environment T helper 17 TLR-2 recognizes mechanism from Gram-positive bacte-
cells (Th17 cells) can alter their differentiation program, ria and zymosan while TLR-4 recognizes Gram-negative
ultimately giving rise to either protective or pro-inflammatory bacteria LPS [44]. Human antigen-presenting cells (APCs)
cells [39]. Okamoto et al. (2013) [40] also found that reveal both HLA-DR molecules, responsible for presenting
“Brazilian propolis restricts Th1 and Th17 differentiation peptides and CD80 (B7-1), which is a costimulatory mole-
and may prevent autoimmune and inflammatory diseases. cule for T-cell activation [14]. In addition, subsequent to
The Brazilian propolis used in their study contained high activation and signal transduction, signaling cascades might
levels of artepillin C as the major compound in the Brazilian activate transcription factors and these in turn direct to the
green propolis from Baccharis dracunculifolia [9, 35]. gene expression of cytokines, proinflammatory chemokines
Artepillin C has been reported to inhibit the expression of and antimicrobial peptides [14, 44].
IFN and IL-17 in alloreactive human CD4+ T cells, and In a study using chronically stressed mice, Orsatti and
may be related to the inhibition of Th1 differentiation [39]. Sforcin (2012) [46] showed that propolis modulates the im-
This finding is important to better understand the synergies mune mechanisms, as it upregulates the TLR-2 and TLR-4
of Th1-differentiation inhibition by propolis. mRNA expression, promoting the recognition of microor-
Tanaka (2013) [38] and Okamoto et al. (2013) [40] found ganisms and the early stages of the immune response during
that the protective effect of propolis on collagen-induced stress [46].
arthritis (CIA) was related to the suppression of interleukin- Some studies indicated that propolis may reduce the risk
17 (IL-17) production in CIA mice. Okamoto et al. (2013) of Atherosclerosis (AS) and it is potentially anti-AS [47-49].
demonstrated that propolis inhibited IL-6 plus transforming Fang et al. (2013) [47], working with the administration of
growth factor- induced for Th17 differentiation in vitro an ethanolic extract of propolis, observed significantly de-
and reported that propolis suppressed the IL-6-induced creased levels of IL-6 and increased levels of IL-17 in
phosphorylation of signal transducer - STAT3 , an essential ApoE
/
mice on a high-fat diet. Those authors [47], also
cytokine-activated transcription factor in Th17 development noted that elevated levels of IL-17 were associated with a
[39]. better outcome in patients with acute myocardial infarction a
Cheung et al. (2013) [41] indicated that Brazilian green finding that supports a protective regulatory role of IL-17 in
propolis or the artepillin C isolated can suppress alloreactive anti-Atherosclerosis effects [47].
CD4 T-cell responses in vitro, which suggests that artepillin Koya-Miyata et al. (2009) [48] reported that propolis
C could be used as a potential immune suppressant, either extract avoids weight gain. In addition, reduced levels of
alone or as an adjunct agent in treating graft versus host glucose, triglycerides, cholesterol, non-esteri ed fatty acids
disease. serum in diet-induced obesity in C57BL/6 N mice. In another
88 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 de Figueiredo et al.

study, Nader et al. (2010) [49] suggest that the extract of CAPE inhibits NFB activation by suppressing nuclear
propolis produced the potential beneficial effects, inhibiting translocation and DNA binding of p65, which may be
the development of AS in hypercholesterolemic rabbits [49]. dependent or independent of IB
protein degradation in the
cytosol [29]. Furthermore, the artepillin C, the major com-
Concerning the antimicrobial actions of propolis, Conti
et al. (2013) [14] showed that TNF-
and IL-10 production pound identified from Brazilian propolis, reduced NFB
expression during acute inflammation [50].
by human monocytes was inhibited by high concentrations
of cinnamic acid (Ci) while increased fungicidal activity was Ozturk et al. (2012) [51] reported that CAPE is a specific
observed against C. albicans. Using a mouse model for inhibitor of NFB and can inhibit NFB activation in
vulvovaginal candidiasis, Castro et al. (2013) [19] showed prostatic cancer-3 (PC-3) cells by blocking the ability of
that a propolis-based topical pharmaceutical preparation was paclitaxel and tumor necrosis factor-alpha (TNF-
) to
able to control infections caused by Candida albicans, and activate NFB. However, according Conti et al. (2014) [14],
the authors strongly indicate that propolis could be used as a further investigations about molecular targets and structural
strategy for controlling candidiasis. analysis of CAPE, artepillin C and its inhibition of NFB are
necessary [14].
The propolis immunomodulatory mechanisms described
above, like the antitumoral, anti-inflammatory and antimi-
crobial are frequently attributed to the two main chemical 3. PATENTS
constituents identified as Caffeic acid phenethyl ester A large number of green propolis patents have been
(CAPE) and artepillin C, and are well-documented as NFB recorded, and multiple technical articles are available to
inhibitor [2, 35, 50]. Previous reports have demonstrated that describe biological profiles of propolis (Table 1).

Table 1. Summary of Recent Patents Targeting Propolis.

Publication Number* Description / Title Inventors (Company) Summary Reference

WO2013163714 Green propolis pharmaceutical Bastos, E.F., Alves, M., The present invention relates to the process for pre- [52]
formulation for use in human Fialho, S.L. paring a pharmaceutical formulation based on green
odontology propolis with antimicrobial properties, which can
treat various odontological diseases. The formulation
can be used via buccal administration

CN102885854 Taiwanese green propolis ex- Huang, Y., Chen, J., The invention provides a nutritious supplement [58]
tractants used for the purpose of Jane, Y., Huan, X., Qiao, which enhances life quality of a cancer patient. The
slowing down progression of H., Lin, J., Yang, Y.Z. nutritious supplement contains Taiwanese green
patient disease propolis extractants and is used in combination with
one or more anti-cancer drugs or components

CN102908287 Chinese and western medicine Zhonghua, M. The invention discloses a Chinese and Western medicine [59]
composite preparation tooth- composite preparation toothpaste with propolis and a
paste with propolis and prepara- preparation method of the Chinese and western medicine
tion method thereof composite preparation toothpaste with the propolis

WO2013042932 Food production method capa- Kim, J.T., Kim, J.-T. The food production method capable of reducing the [60]
ble of reducing the time re- time required for radiation detoxification comprises
quired for radiation detoxifica- obtaining fine powders of propolis, seaweeds, or
tion other useful plants; extracting effective ingredients
from said plants, and mixing the effective ingredients

CN203111738 Propolis antioxidant package Li, H., In, E. The utility model relates to the field of agricultural [61]
product deep processing, and particularly relates to
the field of propolis capsules

WO2013142936 Scalp cleansing and treating Dios, M. Invention patent to cosmetics, shampoos, nutrients, [62]
composition moisturisers; special customised conditioners with
propolis

WO2013147409 Natural extract for preventing Oh, M.H., Kim, W.H., The present invention relates to an extract having the [63]
and treating oral disease Kim, G.J., Choi, H.A., activity of preventing and treating oral disease, wherein
Kim, Y.K. the extract is isolated from natural substances
Properties of Green Propolis Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 89

Table (1) contd….

Publication Number* Description / Title Inventors (Company) Summary Reference

US20130266521 Oral compositions comprising Fetissova, N., Blanvalet, Oral compositions are provided that comprise a pro- [64]
propolis C., Lambert, P. polis extract

CN102994296 Propolis ginger juice no-alcohol Wang, R. The invention provides a bee glue ginger juice no- [65]
wine alcohol wine beverage, which comprises natural bee
glue, fresh ginger juice and no-alcohol wine

CN103300372 Propolis capsules wolfberry Wang, J. The invention discloses a capsule propolis wolfberry, [66]
wolfberry extracts from, almond powder, propolis,
pine pollen, dextrin is made, characterized in that: the
weight ratio of raw material: 20-40 wolfberry extract,
almond powder 20 -30, propolis 10-15, pine pollen
20-30, dextrin 6-15

CN101361757 Combination containing brown Hao, S.Z. The present invention discloses a composition of [67]
alga polysaccharide sulfuric fucoidan and the application in the regulation of the
ester and propolis and use immune system, said composition comprising fu-
thereof coidan or flavonoids and propolis extract as an active
ingredient adjusted

EP2633862 Compositions based on propolis Brandão, H.M. The present invention relates to a process for obtain- [68]
nanocapsules which can be used ing compositions constituted by propolis nanoparti-
as carriers for substances of cles and to the use thereof. Said nanoparticles being
interest, methods for producing optionally associated to one or more substances of
same and use thereof interest such as active ingredients, as well as, option-
ally, substances of secondary effect such as syner-
gists and adjuvants

US20130129808 Medical product containing Chang, J.H, Lee, H.S., A medical product containing either an active ingre- [69]
active component of propolis or Lee, J.H. dient of propolis which is a natural antibiotic or a
grapefruit seed extract and grapefruit seed extract, and a manufacturing method
manufacturing method thereof thereof are provided

US20130280183 Anticariogenic dentifrice com- Navarrete, L.A.S., From these 3 components, propolis is the major com- [70]
position comprising propolis as Rizzardinni, G.D.C.M. ponent, which is reinforced in its activity for a
anticariogenic active ingredient smaller amount of methylparaben and propylparaben
obtaining a composition with a high anticariogenic
composition without side effects

WO2013091053 Polymer composition containing Cabrera, W.I.R., The present invention refers to a polymer composi- [71]
natural bioactive principles for Nakajima, K., Bendo, L. tion containing natural bioactive principles, in par-
use in pharmaceutical and cos- ticular Propolis extract
metic formulations

CN302509436 Bottle (Propolis) Xiao, Y. Name of the product design: bottle (propolis); design [72]
uses of products: transportation of goods, loading or
unloading of packaging and containers used to hold
propolis; design features: the product's overall shape;
points that best describe the design drawings or pho-
tographs: three-dimensional map

CN102356799 Propolis Sugar Gao, Y.L., Zhao, L., The present invention discloses a sugar propolis [73]
Zhao, P., Zhao, Q.D., containing propolis extract, ganoderma extract, sugar,
Europe, Y., Zhao, Q.-C., Vitamin C
Wang, R.Z., Fan, K.
90 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 de Figueiredo et al.

Table (1) contd….

Publication Number* Description / Title Inventors (Company) Summary Reference

EP2646041 Extraction and formation of Mourtzinos, I., Koutsia- The extraction of propolis is effected at room tem- [74]
inclusion complexes of propolis nas, N., Dragani, A.P. perature, without the use of ultrasound or micro-
active components with hy- waves, by adding hydroxypropyl-
-cyclodextrin in
droxypropyl-beta-cyclodextrin the extraction solvent system

CN102961410 Oral spray of propolis Liu, M.W., Sunde, G. The invention relates to an oral spray of propolis, [75]
aims at providing an oral spray product of the propo-
lis, and provides the oral spray of the propolis for
playing an inhibitional role on coliform and Staphy-
lococcus aureus

CN102940648 Bee propolis soft capsule and Liu, M.W., Sunde, G. The invention aims to overcome the defect that poly- [76]
manufacturing process thereof ethylene glycol is added into bee propolis to influ-
ence an effective component in the bee propolis

EP2612667 Anticaries dentifrice composi- Navarrete, L.A.S., Riz- The invention is referred to a new dentifrice composi- [77]
tion that includes anticaries zardinni, G.D.C.M. tion with anticariogenic properties, which has as
propolis as an active principle active anticariogenic ingredients a combination of
propolis, methylparaben and propylparaben

WO2013132456 Prebiotic mixture Mercati, V., Mercati, V., The present invention refers to a prebiotic mixture [78]
Lugli, A., Maidecchi, A. comprising at least one plant polysaccharide fibre and
at least one of Propolis and/or Olea europaea and/or
Aloe vera extracts, optionally comprising also Thy-
mus vulgaris and/or Agrimoniaeupatoria extracts

CN102894246 Water-soluble propolis liquid Liu, M.W., Sunde, G. The invention aims to provide a water-soluble propo- [79]
and preparation method thereof lis liquid product. According to the water-soluble
propolis liquid, capryliccapric triglyceride is used as
a cosolvent originally

CN103054906 Propolis ethanol extract for Zhou, B., Ji, F., Ji, J. The invention relates to a propolis ethanol extract for [80]
alleviating hangover and prepa- alleviating a hangover and a preparation method
ration method thereof, and thereof, and application of the propolis ethanol ex-
application of propolis ethanol tract in producing buccal tablets, belonging to the
extract in producing buccal technical field of techniques for extracting effective
tablets substances from propolis

CN102283794 Toothpaste including radix Li, J., Luo, S., Susa, Y.L. The invention is a propolis toothpaste containing [81]
notoginseng and propolis and thirty-seven and its preparation method
preparation method thereof

US8455007 Method Flurin, C.B. The method applies to the production of extracts of [82]
to treat propolis propolis for use in the fabrication of hygiene, cos-
metic products, food supplements and others

CN102824371 Propolis lycopene composition Estrela W. H., Jingjing The invention is propolis lycopene soft capsule and [83]
and preparation method L., Xuan Z., Passou L., its preparation .
Huan Z., Gang L.

US20130309218 Process for producing aqueous Terao, K., Fukumi, H., The purpose of the present invention is to provide a [84]
solution containing fat-soluble Nakata, D., Uekaji, Y., process for producing an aqueous solution containing
substance Jo, A. a fat-soluble substance
Properties of Green Propolis Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 91

Table (1) contd….

Publication Number* Description / Title Inventors (Company) Summary Reference

CN102499338 Hydrophilic propolis powder Zhou, P. The present invention relates to a hydrophilic capsule [85]
capsule composition and pro- composition of propolis powder and its production
duction method thereof method

WO2013155715 Stomach health-preserving Chen, H., Chen, H., Disclosed is a stomach health-preserving capsule, [86]
capsule Zheng, H., Zheng, H., consisting of components in the following weight
Chen, Y., Chen, Y., Lu, ratios: 16% Ganoderma lucidum extract, 12% milk
H., Luhan, P., Chen, vetch root extract, 42.2% Hericium erinaceus extract,
C.N., Weijie, W.U., 7% propolis and 22.8% Lentinus edodes
Wu, W. extract

CN102961314 Propolis cutin removal paste for Liu, H.S. The invention relates to a propolis cutin removal [87]
lips paste for lips, belonging to the field of cosmetics

WO2013012477 Propolis and caffeic acid Omene, C., O'Connor, Methods for treating a subject with cancer using a [88]
phenethyl ester and uses thereof O., Frenkel, K. combined therapeutic regimen comprising adminis-
tering propolis or caffeic acid phenethyl ester
(CAPE) in conjunction with other cancer therapeutics
are described herein

US20120004389 Method for extracting propolis Lee, Y.K. A method for extracting propolis by using far infra- [89]
using far-infrared rays from red ray from pottery
earthenware

CN101669556 Method for preparing blueberry Week, Z. The granule mainly comprises the following raw [90]
green tea granules materials: green tea, blueberries, propolis, vitamin E,
vitamin C, and dextrin

WO2012057291 Process for production of Kishi, A., Doi, S., Mat- The present invention relates to a process for produc- [91]
phenolic polymerizable sukawa, T., Matsui, T., ing a phenolic polymerizable compound
compound having Yamada, Y., Yamada, I.
physiological activity

WO2011114291 Process for obtaining non- Ricchiuto, G.M., The present invention also relates to a method of [92]
allergic propolis Gardana, C.S., purifying semisolid propolis derivative to
Guglielmetti, S.D. obtain a hydroalcoholic hydrodispersible propolis
derivative

WO2011141007 Propolis and method of its pro- Saroch, J., Holub, M., The invention relates to propolis containing active [93]
duction Krupickova, J. substances, whose composition is specific according
to the season of harvesting and according to the ori-
gin and method of production of such propolis

EUA20120004389 Method for extracting propolis Kwang, Y.L. The described methodology for extracting propolis [94]
using far-infrared rays from using far-infrared rays from earthenware, make
earthenware possible to avoid microorganisms proliferation and
so, the consequent oxidation and deterioration of the
propolis

*This survey was conducted with patents related to the use of green propolis, its use in cancer treatment, and other propolis-related products; the consultation was performed from
January 2011 to November 2013.
92 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 de Figueiredo et al.

Those works focus on the relevant compiled results on CONFLICT OF INTEREST

the properties of propolis, its potential mechanisms and
The authors confirm that this article content has no con-
its active constituents. The inventions are related to the
flict of interest.
processes for preparing green propolis-based pharmaceutical
formulations and propolis capsules with antimicrobial
ACKNOWLEDGEMENTS
properties, which can treat various dental diseases such as
mucositis, cancer, and buccal peri-implantitis [52]. This work was supported by the National Council for
Research and Development - CNPq and Research Founda-
Propolis is a cationic antibacterial agent as well as an
tion of the State of Minas Gerais - FAPEMIG.
anti-attachment, anti-inflammatory, and biofilm disruption
agent [2]. Processes for obtaining standardized extracts or
LIST OF ABBREVIATIONS
isolated substances from green propolis; standardized
extracts formulations, fractions and isolated substances of CAPE = Caffeic acid phenethyl ester
propolis are used as sanitizer, antiseptic and/or disinfecting Ci = Cinnamic acid
products for microbiological control in alimentary and similar
industries, fixed surfaces and dairy products [2]. Artepillin C = 3, 5-Diprenyl-4-hydroxycinnamic acid
There are different commercial formulations [52-94], CIA = Collagen-induced arthritis
already patented, that are used as antisepsis of hands and IL-17 = Interleukin-17
skin, nutritional supplements that enhances the quality of life
of cancer patients. Since the first Romanian patent in 1965 STAT3 = Activator of transcription 3
until 1999, 239 propolis-related patents had been filed. Until Th17 cells = T Helper cells 17
the late 1980s, the patents were dominated by the former Th1 cells = T Helper cell (redirect from Th1 cell)
USSR and its satellite countries, especially Romania [53].
According to data obtained from the LATIPAT database on IFN = Interferon gamma
the Instituto Nacional de Propriedade Industrial - INPI [54]. CD4+ T cells = CD4+T helper cells
(National Institute of Industrial Property) website, by January
2014, approximately 2452 patent applications could be found IL-1 = Interleucina 1
in worldwide records of propolis-related patents. Of these, IL-6 = Interleukin 6
110 were Japanese and the first patent from Japan was filed
TLR = Toll-like receptors
in 1987 [55].
PAMPs = Pathogen-associated molecular
Among Japanese patents are those on the isolation and patterns
application of an antitumor compound from Brazilian propolis
produced in the states of Minas Gerais and São Paulo, APCs = Human antigen-presenting cells
Artepillin C [56]; the application of Artepillin C alone and/or HLA-DR = MHC class II cell surface receptor
its salt as an agent for apoptosis [57].
CD80 (B7-1) = Cluster of Differentiation 80
Thousands of patents are mentioned in the literature but
only those associated to effects on the immune system were LPS = Lipopolysaccharide
analyzed (2,452). Thus, we can infer that the propolis is still mRNA = Messenger RNA
treated as a functional food, even though we observed a EEP = Ethanolic extract of propolis
general description of its many properties regarding human
health. NFB = Factor nuclear kappa B
IL-10 = Interleukin-10
4. CURRENT & FUTURE DEVELOPMENTS
IB
protein = Nuclear factor of kappa light polypep-
The present review highlights the potential application of tide gene enhancer in B-cells inhibitor,
propolis as a natural alternative anti-inflammatory agent in alpha
acute and chronic inflammation. It is believed that propolis
p65 = Transcription factor p65
acts through different mechanisms and that its polyphenolic
components are responsible for this activity. IKK = IB kinase complex
The information on the biological properties and bio- PC-3 = Prostatic cancer-3
chemical interactions of propolis on the immune system has TNF-
= Necrosis factor-alpha
advanced a lot in the last years on account of a number of
in vitro and in vivo studies. However, there is not much AS = Atherosclerosis
information about the clinical efficacy of propolis and its LATIPAT = Database on the Instituto Nacional de
impact in human treatment so clinical studies are necessary Propriedade Industrial-INPI
in order to evaluate this potential application.
Properties of Green Propolis Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 2 93

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