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Propolis Polyphenols
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This entry is adapted from the peer-reviewed paper 10.3390/plants10020420

Propolis is a resinous substance produced by bees that exhibits antimicrobial, immunostimulatory and antioxidant activity. Its use is common in functional foods, cosmetics and traditional medicine despite the fact that it demonstrates low extraction yields and inconsistency in non-toxic solvents. In this work, a new encapsulation and delivery system consisting of liposomes and cyclodextrins incorporating propolis polyphenols has been developed and characterized. The antioxidant, antimutagenic and antiaging properties of the system under normal and UVB-induced oxidative stress conditions were investigated in cultured skin cells and/or reconstituted skin model. Furthermore, the transcript accumulation for an array of genes involved in many skin-related processes was studied. The system exhibits significant polyphenol encapsulation efficiency, physicochemical stability as well as controlled release rate in appropriate conditions. The delivery system can retain the anti-mutagenic, anti-oxidative and anti-ageing effects of propolis polyphenols to levels similar and comparable to those of propolis methanolic extracts, making the system ideal for applications where non-toxic solvents are required and controlled release of the polyphenol content is desired.

propolis controlled release liposome polyphenols

1. Introduction

Nowadays, there is a huge interest on natural products that can promote the state of health and well-being for humans. Bee products represent a significant category of natural products that exhibit specific health benefits. All bee products—honey, royal jelly, propolis, bee pollen, beeswax and even bee venom—have been largely investigated for their healing properties [1][2][3][4].

Propolis is a resinous substance which is produced by bees and presents many challenges in respect to its extraction and formulation process. It exhibits antimicrobial, immunostimulatory and antioxidant activity and is employed in the preparation of functional foods and cosmetics as well as in traditional medicine [2][5][6][7]. Its composition varies depending on the flora of the foraging region of the bees and the collection season. It contains approximately 50% resins, 30% waxes, 10% aromatic components, 5% pollen and 5% various other components [2][8][9]. The bioactive components of propolis are polyphenols, terpenes, steroids, as well as sugars and aminoacids [10][11][12][13][14][15]. Major polyphenols are flavonoids and phenolic acids. The complexity of the structure of propolis combined with the variable composition depending on the region and the collection season make both raw propolis and its extracts particularly difficult to formulate into products for per os or skin applications [6][16]. The extraction of propolis usually has a low yield in active component concentration [17][18], especially when natural solvents, as water or vegetable glycerol are used. The reason is mainly the hydrophobicity of the majority of propolis’ active ingredients.

In order to increase the extraction yield, various extraction methods have been developed [19][20] as well as methods of encapsulating its components in various carriers [21][22].

As far as the encapsulation of propolis is concerned, Zhang et al. [23] developed propolis loaded zein/caseinate/alginate nanoparticles that demonstrated a promising clean and scalable strategy to encapsulate propolis for applications in foods, supplements and pharmaceuticals. Ong et al. [24] prepared a chitosan-propolis nanoformulation based on optimum physicochemical properties such as particle size, zeta potential, polydispersity index, encapsulation efficiency and the rate of release of the active ingredients for biofilm applications. Do Nascimento et al. [25] developed nanoparticles (200–800 nm) loaded with red propolis extract. This copolymeric matrix system was able to encapsulate different flavonoids from red propolis extract with interesting characteristics of solubility and antioxidant activity demonstrating activity against leishmaniasis.

Liposomes is another form of carrier that has been investigated for propolis encapsulation. Aytekin et al. [26], developed a propolis loaded liposomal system that showed interesting results as a topical application in wound treatment having antioxidant and antimicrobial effects. Tao et al. [27], investigated the immune modulatory function of propolis flavonoids encapsulated in liposomes and showed the potential of the application of the formulation as an adjuvant. Arafa et al. [28], prepared oromuco-adhesive films for buccal delivery of propolis entrapped in niosomes. The results demonstrated controlled and targeted delivery of active ingredients against oral ulcers.

Cyclodextrins have been also used in order to encapsulate propolis ingredients [29][30][31][32]. Vasilaki et al. [33], prepared extracts of propolis by using aqueous solution of hydroxypropyl-beta-cyclodextrins as an alternative for food preservation. Ishida et al. [34], complexed caffeic acid phenethyl ester from propolis with γ-cyclodextrin in order to increase the stability of the former that gets easily degraded by esterases. The complex demonstrated significant in vitro activity against a range of cancer cells. γ-cyclodextrin was also used by Rimbach et al. [35] for the encapsulation of Brazilian green propolis supercritical extract. The system demonstrated promising properties for hepatoprotection helping the combat of chronic inflammation.

Liposomes loaded with cyclodextrin-bioactive molecule complexes are widely used as drug delivery systems, enhancing low aqueous solubility and stability [36][37]. Though such system has been never used for the encapsulation of propolis.

In the present study, an extraction and encapsulation of components of propolis in a combinatorial liposome–cyclodextrin system is performed. The particular properties of both carriers that were taken in advantage are: The ability of the cyclodextrins to enclose polyphenols and enhance their permeability through the skin [38][39] as well as the ability of the liposomes to encapsulate large quantities of components of various degrees of polarities, for topical transport of components and control of their release rate [40][41][42].

Based on our previous studies we have identified promising propolis extracts collected from different areas in Greece. The extracts demonstrated significant in vitro antioxidant activity due to their high total phenolic and flavonoid content. A sample collected from the area of Olympus mountain exhibited significant protection against the cytotoxic effects of UVB radiation by remarkably reducing DNA and protein oxidation damage levels in human immortalized keratinocyte (HaCaT). It also demonstrated significant antiaging efficacy as it decreased histological damage and lowered the induced expression of certain metalloproteinases (MMPs) following exposure to UVB in a reconstituted skin model [43].

2. Discussion

The standardization and consistency of metabolite content of natural products is a key issue concerning their bioactivity. Bee products and especially propolis demonstrate high inconsistency because of their dependance on various parameters, such as the flora of the foraging region of the bees, the collection season and the overall health of bee organisms.

We have recently demonstrated the anti-oxidative, anti-mutagenic and anti-ageing properties of propolis extracts, foraged from different parts of Greece, on skin models. In particular, methanolic propolis extracts, exhibited significant antioxidant capacity, as tested by (2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid))(ABTS) and DPPH in vitro assays. Furthermore, they could protect human keratinocytes from UVB-induced DNA double-strand breaks and decrease the total protein carbonyl content. Interestingly, treatment of a reconstituted skin tissue model with these propolis extracts could prevent the UV-induced upregulation of MMPs at both mRNA and protein level and ultimately alleviate from cellular damages [43]. Thus, propolis and its components are ideal candidates for developing encapsulation and delivery systems with protective and health promoting properties that could be safely applied to human skin.

In the present study we developed a system consisting of liposomes and cyclodextrins incorporating propolis polyphenols, mainly for skin applications. The physicochemical characteristics of the system remain stable over time and when it is stored at a temperature of 6 °C. Furthermore, the antioxidant activity and total phenolic compounds remained stable. The cumulative release of total phenolic compounds was 23.99 ± 1.18% at 8 h and 26.04 ± 2.54% at 48 h. The antioxidant activity, as assessed by DPPH assay, follows this pattern too.

These assays indicate that the system is a stable form of encapsulating and protecting propolis polyphenols. The release rate of the polyphenols that the system demonstrated is suitable for applications where a prolonged provision of polyphenols is desired, such as antioxidant and antiaging targeting.

Next, we examined the anti-mutagenic and anti-oxidative potential of CRPP on a human immortalized skin cell line by employing single cell electrophoresis and measuring the protein carbonyl levels upon UV irradiation and application of the CRPP. Our results demonstrate that CRPP can readily protect HaCaT cells against the mutagenic effects of UV radiation and lower the UV-induced protein carbonyl content, respectively. We further investigated the photoprotective and anti-ageing role of CRPP in a reconstituted human skin tissue model. Application of the CRPP protected the reconstituted skin tissues from UVB-induced lesions and decreased the UVB-induced expression of matrix metalloproteinases, a molecular marker of photoaging, at both mRNA and protein level.

ATP intracellular levels in NHDF cells in vitro were increased by CRPP under or no UVB irradiation, indicating that CRPP enhanced cell viability, cell proliferation and energy metabolism of dermal fibroblasts. According to previous reports, increased intracellular ATP is associated with higher levels of mitochondrial activity, energy metabolism and cell proliferation and is also indicative of a lack of cytotoxicity [44][45]. Furthermore, in order to explore the gene candidates of biological process related to the addition of CRPP in NHDF cells, we proceed on a differential gene transcription analysis. Specifically, transcripts analysis revealed that the presence of CRPP modified the expression of genes that are associated with cell proliferation, antiaging and antimicrobial response. In our study, we observed that transcripts of TNFα were up-regulated in in NHDF cells treated with CRPP in contrast to control cells. TNF-α is a pleiotropic cytokine with diverse cellular responses [46][47]. Recently, it has been reported that increase expression levels of TNF-α were associated with an antiaging effect on dermal fibroblasts by mediating in ERK/AP--1 signaling pathway [48]. This outcome indicates that CRPP may serve a critical role in the attenuation of skin aging.

Transcripts of Vascular endothelial growth factor (VEGF) were found to be significantly up-regulated in NHDF cells treated with CRPP in contrast to control cells. VEGF is a angiogenesis as well as vasculogenesis related key growth factor indicating that it might also be involved in the regulation of angiogenesis during wound healing [49][50]. These results which are in agreement with a previous study [51], are indicative of a possible positive effect of the CRPP in tissue healing processes, as it is in accordance with previous reports demonstrating that the induction of VEGFA expression correlates with wound healing process [52][53].

Moreover, transcript of AQP3 were upregulated in NHDF cells treated with CRPP in contrast to control cells. This outcome potentially underlines the stimulatory role of CRPP in cell proliferation in an AQP3-dependent manner. It has been reported that transcripts of AQP3 promote cell proliferation related to cell migration process [54][55]. Specifically, Cao C et al. [55]. demonstrated that up-regulation of AQP3 plays an important role in cell proliferation related to wound healing process through facilitating of fibroblasts migration by EGF/EGFR signaling.

IL-4, a multifunctional pleiotropic cytokine mediating in different cellular pathways such as cell proliferation, inflammation, apoptosis [56]. In our study we observed that the transcript levels of il4 are upregulated in NHDF treated with CRPP compared to control. According to a previous report, the increased levels of transcripts of IL4 correlates with the activation of the defense pathways against pathogenic microbes on skin fibroblasts emphasizing the protective role of CRPP against pathogenic microbes of skin [57]. Finally, we observed that the transcript of ITGB2 were upregulated in NHDF treated with CRPP compared to control which potentially demonstrates the in vitro immune protective role of CRPP in human fibroblasts, as increased levels of transcripts of ITGB2 were correlated with immune response [58][59].

Additionally, the reconstituted human skin model was utilized to further confirm the protective properties of CRPP on human epidermis. In our study, the incorporation of CRPP in a cosmetic formulation was proven non-irritant for the epidermis which is an essential step during the development of new skin care related products.

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