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The activity of propolis against pathogenic fungi isolated from human infections

Abstract

Propolis is a resinous hive product collected by bees from the buds or other parts of plants. It is known for having various biological properties, including antifungal activity. Among the substances present in propolis, flavonoids and phenolic acids and their esters are responsible for its antifungal properties. This means that propolis is ideal for use as an antifungal agent in alternative medicine to treat a number of both topical and systemic infections caused by Candida species and other yeast-like fungi, dermatophyte and nondermatophyte moulds, without the serious side effects typical of synthetic treatment. It is also active against strains of fungi that are resistant to polyenes and azoles, the classes of drugs most commonly used to treat fungal infections. In this article, we review current knowledge about the activity of propolis from different parts of the world and its components in vitro and in vivo against pathogenic fungi isolated from human infections. The article also indicates the possible mechanism of antifungal activity of propolis and its components.

Keywords:
Propolis; Antifungal activity; Human infections

INTRODUCTION

Propolis is a resinous mixture produced by bees (Apis mellifera) from secretions collected from various parts of a variety of plants. The name comes from the Greek-pro- meaning in front, and -polis- meaning town or city. Bees use propolis to construct, repair and protect their hives, mainly owing to its mechanical and antimicrobial activity and antiseptic efficacy (Bankova, de Castro, Marcucci, 2000Bankova VS, de Castro SL, Marcucci MC. Propolis: recent advances in chemistry. Apidologie. 2000;31:3-15.).

Propolis has a number of biological effects, including antioxidant, anti-inflammatory, anticarcinogenic, detoxifying, immunomodulatory, and antimicrobial activity (Kujumgiev et al., 1999Kujumgiev A, Tsvetkova I, Serkedjieva Y, Bankova V, Christov R, Popova S. Antibacterial, antifungal and antiviral activity of propolis of different geographic origin. J Ethnopharmacol. 1999;64(3):235-2340.; Soares, Cury, 2001Soares MMSR, Cury AE. In vitro activity of antifungal and antiseptic agents against dermatophyte isolates from patients with tinea pedis. Braz J Microbiol.2001;32:130-134.; Astani et al., 2013Astani A, Zimmermann S, Hassan E, Reichling J, Sensch KH, Schnitzler P. Antimicrobial activity of propolis special extract GH 2002 against multidrug-resistant clinical isolates. Pharmazie. 2013;68(8):695-701.; Wolska, Górska, Adamiak, 2016Wolska K, Górska A, Adamiak A. Antibacterial properties of propolis (In Polish). Post Mikrobiol. 2016;55(4):343-350.; Silva et al., 2019Silva FRG, Matias TMS, Souza LIO, Matos-Rocha TJ, Fonesca SA, Mousinho KC, et al. Phytochemical screening and in vitro antibacterial, antifungal, antioxidant and antitumor activities of the red propolis Alagoas. Braz J Biol. 2019;79(3):452-459.; Wolska et al., 2019Wolska K, Górska A, Antosik K, Ługowska K. Immunomodulatory effects of propolis and its components on basic immune cell functions. Indian J Pharm Sci. 2019;81(4):575-588.). Among these properties of propolis, its antimicrobial activity has been the most extensively investigated. Propolis and propolis extracts exhibit inhibitory or microbicidal activity against bacteria, viruses, fungi, and to some extent protozoa (Kujumgiev et al., 1999Kujumgiev A, Tsvetkova I, Serkedjieva Y, Bankova V, Christov R, Popova S. Antibacterial, antifungal and antiviral activity of propolis of different geographic origin. J Ethnopharmacol. 1999;64(3):235-2340.; Hegazi, El Hadyb, Alla, 2000Hegazi AG, El Hadyb F, Alla F. Chemical composition and antimicrobial activity of european propolis. Z Naturforsch . 2000;55(1-2):70-75.). Its antifungal properties have been associated with the presence of flavonoids and of aromatic, diterpenic and phenolic acids in the composition of propolis (Sawaya et al., 2002Sawaya AC, Palma AM, Caetano FM, Marcucci MC, da Silva Cunha IBS, Araujo CEP, et al. Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida. Lett Appl Microbiol. 2002;35(3):203-207.; Oliveira et al., 2006Oliveira AC, Shinobu CS, Longhini R, Franco SL, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from onychomycosis lesions. Mem Inst Oswaldo Cruz. 2006;101(5):493-497.). These properties of propolis are exploited in alternative medicine as a treatment for local and systemic fungal infections caused by Candida species and other yeast-like fungi, dermatophyte and nondermatophyte molds fungi (Burdock, 1998Burdock GA. Review of the biological properties and toxicity of bee propolis. Food Chem Toxicol. 1998;36(97):347-363.; Castaldo, Capasso, 2002Castaldo S, Capasso F. Propolis, an old remedy used in modern medicine. Fitoterapia. 2002;73(02):1-6.; Khalil, 2006Khalil ML. Biological activity of bee propolis in health and disease. Asian Pac J Cancer Prev. 2006;7(1):22-31.).

The available means of treating fungal infections are limited to polyene antifungals, such as nystatin and amphotericin B and azole antifungals e.g. miconazole, ketoconazole, fluconazole, itraconazole and allylamine derivative i.e. terbinafine (Ghannoum, Rice, 1999Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12(4):501-517.; Dalben-Dota et al., 2011Dalben-Dota KF, Consolaro MEL, Svidzinski TIE, Bruschi ML. Antifungal Activity of Brazilian propolis microparticles against yeasts isolated from vulvovaginal candidiasis. Evid Based Complement Alternat Med Volume 2011, Article ID 201953, 8 pages.). Most of these compounds target the formation and/or function of ergosterol, a basic component of the fungal cell membrane. Conventional antifungal therapy with polyene and azole compounds, however, can produce side effects in patients. Moreover, treatment with existing drugs is known to be toxic and to contribute to the development of drug-resistant strains of fungi, especially Cryptococcus neoformans and C. albicans (Ghannoum, Rice, 1999Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12(4):501-517.).

These facts have driven the search for new antifungal agents from other sources, including natural compounds (Oliveira et al., 2006Oliveira AC, Shinobu CS, Longhini R, Franco SL, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from onychomycosis lesions. Mem Inst Oswaldo Cruz. 2006;101(5):493-497.). Propolis seems to be an excellent solution to these problems. It is a complex mixture of compounds with only low toxicity compared to synthetic substances. More than 300 different compounds have been identified in propolis, including phenols, tannins, polysaccharides, terpenes, aliphatic acids, esters, aromatic acids, fatty acids, aldehydes, amino acids, ketones, chalcones, dihydrochalcones, vitamins, and inorganic substances. (Bankova et al., 1999Bankova VS, Boudourova-Krasteva G, Sforcin JM, Frete X, Kujumgiev A, Maimoni-Rodella R, et al. Phytochemical evidence for the plant origin of Brazilian propolis from São Paulo State. Z Naturforsch. 1999;54(5-6):401-405.; Bankova, de Castro, Marcucci, 2000Bankova VS, de Castro SL, Marcucci MC. Propolis: recent advances in chemistry. Apidologie. 2000;31:3-15.). Propolis has been used as a monotherapy or in association with other pharmaceutical products, having demonstrated marked activity against pathogenic fungi (Burdock, 1998Burdock GA. Review of the biological properties and toxicity of bee propolis. Food Chem Toxicol. 1998;36(97):347-363.; Castaldo, Capasso, 2002Castaldo S, Capasso F. Propolis, an old remedy used in modern medicine. Fitoterapia. 2002;73(02):1-6.). Studies on the simultaneous use of conventional antimycotic drugs and propolis have shown that their use in combination enhanced the inhibitory effect on C. albicans (Holderna, Kędzia, 1987Holderna E, Kędzia B. Investigation upon the combined action of propolis and antimycotic drugs on Candida albicans. Herba Pol.1987;33:145-151.; Gucwa et al., 2018Gucwa K, Kusznierewicz B, Milewski S, Van Dijck P, Szweda P. Antifungal activity and synergism with azoles of polish propolis. Pathogens. 2018;7(02):56.).

ANTIFUNGAL ACTIVITY OF ETHANOLIC EXTRACTS OF PROPOLIS AND ITS COMPONENTS

The inhibitory activity of propolis against pathogenic fungi has been described by many research studies (Koo et al., 2000Koo H, Gomes BP, Rosalen PL, Ambrosano GM, Park YK, Cury JA. In vitro antimicrobial activity of propolis and Arnica montana against oral pathogens. Arch Oral Biol. 2000;45(2):141-148.; Chee, 2002Chee HY. In vitro evaluation of the antifungal activity of propolis extract on Cryptococcus neoformans and Candida albicans. Mycobiology. 2002;30(2):93-95.; D’Auria et al., 2003D’Auria FD, Tecca M, Scazzocchio F, Renzini V, Strippoli V. Effect of propolis on virulence factors of Candida albicans. J Chemother. 2003;15(05):454-460.; Santos et al., 2005Santos VR, Pimenta FJGS, Aguiar MCF, Do Carmo MAV, Naves MD, Mesquita RA. Oral candidiasis treatment with Brazilian ethanol propolis extract. Phytother Res. 2005;19(7):652-654.; Buchta, Černý, Opletalová, 2011Buchta V, Černý J, Opletalová V. In vitro antifungal activity of propolis samples of Czech and Slovak origin. Cent Eur J Biol. 2011;6(2):160-166.; Dalben-Dota et al., 2011Dalben-Dota KF, Consolaro MEL, Svidzinski TIE, Bruschi ML. Antifungal Activity of Brazilian propolis microparticles against yeasts isolated from vulvovaginal candidiasis. Evid Based Complement Alternat Med Volume 2011, Article ID 201953, 8 pages.; Capistrano et al., 2013Capistrano HM, de Assis EM, Leal RM, Alvarez-Leite ME, Brener S, Bastos EMAF. Brazilian green propolis compared to miconazole gel in the treatment of Candida-associated denture stomatitis. Evid Based Complement Alternat Med Volume 2013, Article ID 947980, 6 pages.). Most were conducted in vitro, but in vivo studies will also be discussed.

This effect in vitro has been assessed using a variety of microbial tests, including dilution in tubes or plates, agar diffusion in plates, and bioautography (Sawaya et al., 2002Sawaya AC, Palma AM, Caetano FM, Marcucci MC, da Silva Cunha IBS, Araujo CEP, et al. Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida. Lett Appl Microbiol. 2002;35(3):203-207.). The plate dilution method is the most satisfactory of these tests. There are three reasons for this: it evaluates the inhibitory/fungicidal effect of propolis extracts against the fungal strains tested; its results are sensitive to differences in composition between extracts which result in different MIC (minimal inhibitory concentration)/ MFC (minimal fungicidal concentration) values; and finally, the low hydro-solubility of the active substances in propolis does not interfere with the test. The second commonly used test is agar diffusion in plates. However, the results of the agar diffusion tests are less satisfactory due to the low hydro-solubility of the active substances of propolis, which are therefore poorly diffused in agar. In consequence, the growth inhibition zones are small (Sawaya et al., 2002Sawaya AC, Palma AM, Caetano FM, Marcucci MC, da Silva Cunha IBS, Araujo CEP, et al. Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida. Lett Appl Microbiol. 2002;35(3):203-207.).

Variation in the activity of propolis also depends on the types of ethanolic or aqueous extracts, types of microbes and inoculum concentration, as well as the propolis concentration in the medium (Yusoff et al., 2016Yusoff NYN, Mohamad S, Abdullah HN, Rahmana NA. Antifungal Activity of Malaysian honey and propolis extracts against pathogens implicated in denture stomatitis. AIP Conf Proc. 2016;1791:020006-1-020006-7; doi: 10.1063/1.4968861
https://doi.org/10.1063/1.4968861...
). Most biological properties of propolis, including its antimicrobial activity, are observed in alcoholic extracts, because this results in extraction of larger quantities of active compounds and thus a stronger inhibitory effect against microorganisms (Mello, Petrus, Hubinger, 2010Mello BCBS, Petrus JCC, Hubinger MD. Concentration of flavonoids and phenolic compounds in aqueous and ethanolic propolis extracts through nanofiltration. J Food Eng. 2010;96(4):533-539.).

Table I illustrates the most widespread types of propolis according to their plant origin (poplar propolis from Europe and non-tropical regions of Asia, green and red propolis from Brazil), and their chemical composition. According to the literature the fungicidal properties of ethanolic extract of propolis are attributed to its chemical components, such as flavonoids and phenolic acids and their esters (Mello, Petrus, Hubinger, 2010Mello BCBS, Petrus JCC, Hubinger MD. Concentration of flavonoids and phenolic compounds in aqueous and ethanolic propolis extracts through nanofiltration. J Food Eng. 2010;96(4):533-539.). Ghisalberti (1979Ghisalberti EL. Propolis: A review. Bee World. 1979;60:59-84.) reported that 3-acetylpinobanksin, pinobanksin-3-acetate, pinocembrin, caffeic acid and p-coumaric acid isolated from propolis extract showed a considerable antimycoticic effect. Other substances contained in propolis that may contribute to its antifungal properties include hydroxyl-and methoxyl-substituted derivatives of cinnamic acid (E-3-phenylprop-2-enoic), benzoic acid, and chalcones (E-1,3-diphenylprop-2-en-1-ones) (Bankova et al., 1999Bankova VS, Boudourova-Krasteva G, Sforcin JM, Frete X, Kujumgiev A, Maimoni-Rodella R, et al. Phytochemical evidence for the plant origin of Brazilian propolis from São Paulo State. Z Naturforsch. 1999;54(5-6):401-405.; López et al., 2001López SN, Castelli MV, Zacchino SA, Dominguez JN, Lobo G, Charris-Charris J, et al. In vitro antifungal evaluation and structure activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorg Med Chem. 2001;9(8):1999-2013.; Sawaya et al., 2002Sawaya AC, Palma AM, Caetano FM, Marcucci MC, da Silva Cunha IBS, Araujo CEP, et al. Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida. Lett Appl Microbiol. 2002;35(3):203-207.; Mello, Petrus, Hubinger, 2010Mello BCBS, Petrus JCC, Hubinger MD. Concentration of flavonoids and phenolic compounds in aqueous and ethanolic propolis extracts through nanofiltration. J Food Eng. 2010;96(4):533-539.).

TABLE I
The most popular propolis types according to their plant origin and their chemical composition (Hegazi, El Hadyb, Alla, 2000Hegazi AG, El Hadyb F, Alla F. Chemical composition and antimicrobial activity of european propolis. Z Naturforsch . 2000;55(1-2):70-75.; Bankova et al., 1999Bankova VS, Boudourova-Krasteva G, Sforcin JM, Frete X, Kujumgiev A, Maimoni-Rodella R, et al. Phytochemical evidence for the plant origin of Brazilian propolis from São Paulo State. Z Naturforsch. 1999;54(5-6):401-405.; Sforcin, Bankova 2011Sforcin JM, Bankova V. Propolis: is there a potential for the development of new drugs. J Ethnopharmacol . 2011;133(2):253-260.)

Table II illustrates the antifungal effect of propolis against pathogenic fungi. Included in this review article were the following: C. albicans and other Candida species, responsible for topical infections (e.g. oral infections, skin infections or vaginitis), and systemic infections (e.g. respiratory tract infections); yeast-like fungi: C. neoformans, a pathogen with a polysaccharide capsule and responsible for meningitis and pneumonia; as well as dermatophyte moulds, i.e. species of the genus Trichophyton and Epidermophyton, which cause skin, hair and nail infections; and nondermatophyte moulds, e.g. Aspergillus species causing bronchopulmonary aspergillosis.

TABLE II
The antifungal effect of propolis against pathogenic fungi

Antifungal activity of Brazilian propolis and its components

Sforcin et al. (2001Sforcin JM, Fernandes Jr A, Lopes CAM, Bankova V, Funari SRC. Seasonal effect on Brazilian propolis antibacterial activity. J Ethnopharmacol . 2001;73(1-2):243-249.) studied the in vitro antimicrobial activity of Brazilian green propolis from the Southeast of the country in all collected four seasons against yeast pathogens isolated from human infections. They concluded that C. tropicalis and C. albicans were susceptible to low concentrations of propolis, but the latter showed greater susceptibility (with values of 3.22-4.22% (v/v) for C. tropicalis and 2.32-3.33% (v/v) for C. albicans. No differences were seen in relation to seasonal effects in the minimal inhibitory concentration of propolis. These results were in agreement with a study by Ota et al. (2001Ota C, Unterkircher C, Fantinato V, Shimizu MT. Antifungal activity of propolis on different species of Candida. Mycoses. 2001;44(9-10):375-378.), in which Candida isolates from the saliva of patients with dentures were found to be susceptible to an alcoholic solution of Brazilian green propolis. C. albicans was the most susceptible, followed by C. tropicalis, C. krusei, and C. guilliermondii. Moreover, they reported the fungicidal activity of EEP at concentrations of 1 - 12 mg/ml against all Candida species tested. The same authors, in an in vivo study, demonstrated a reduction in Candida in patients with full dentures who had used a hydroalcoholic propolis extract as a mouth-rinse, whereas no difference in the yeast count was noted in controls. Dias et al. (2009Dias SMD, Gomes RT, Santiago WK, Paula AMB, Cortés ME, Santos VR. Antifungal activity of commercial ethanolic and aqueous extracts of Brazilian propolis against Candida spp. Rev Ciênc Farm Básica Apl. 2009;28(3):259-263.) demonstrated the activity of an ethanolic extract of Brazilian propolis (10%) against Candida spp. using agar diffusion tests. The results of this study showed that strains of the species C. albicans, C. tropicalis and C. krusei were the most susceptible, while C. parapsilosis, C. glabrata and C. guillermondii were the least susceptible (the growth inhibition zone of C. tropicalis was 17.3 mm; C. albicans - 16.9 mm; C. krusei - 16.2 mm; C. guillermondii - 13.5 mm; C. glabrata - 13.28 mm; C. parapsilosis - 12.3; control with ethanol - 7 - 9 mm).

The ethanolic extract of Brazilian green propolis (20%) was found to reduce oral candidiasis in twelve denture-wearing patients with Candida-associated denture stomatitis (Santos et al., 2005Santos VR, Pimenta FJGS, Aguiar MCF, Do Carmo MAV, Naves MD, Mesquita RA. Oral candidiasis treatment with Brazilian ethanol propolis extract. Phytother Res. 2005;19(7):652-654.). In this study, patients treated with a commercial ethanol propolis extract showed lesion regression similar to that observed in patients treated with nystatin. Therefore the 20% EEP used in this research can be effective in treating oral Candida-associated denture stomatitis. Other in vivo studies have confirmed that patients with Candida-associated denture stomatitis who received propolis in the form of a mouthwash showed a statistical reduction or complete clinical remission of symptoms such as palatal oedema and erythema, and a decrease or elimination of the yeast count after treatment. The authors concluded that Brazilian green propolis (2.5% of extract) has a similar effect to miconazole in the treatment of Candida-associated denture stomatitis as an alternative treatment for this condition (Santos et al., 2008Santos VR, Gomes RT, de Mesquita RA, de Moura MD, França EC, de Aguiar EG, et al. Efficacy of Brazilian propolis gel for the management of denture stomatitis: a pilot study. Phytother Res . 2008;22(11):1544-1547.; Capistrano et al., 2013Capistrano HM, de Assis EM, Leal RM, Alvarez-Leite ME, Brener S, Bastos EMAF. Brazilian green propolis compared to miconazole gel in the treatment of Candida-associated denture stomatitis. Evid Based Complement Alternat Med Volume 2013, Article ID 947980, 6 pages.). According to Koo et al. (2000Koo H, Gomes BP, Rosalen PL, Ambrosano GM, Park YK, Cury JA. In vitro antimicrobial activity of propolis and Arnica montana against oral pathogens. Arch Oral Biol. 2000;45(2):141-148.), the extract of propolis (10%) may be effective in treating periodontal disease owing to its antifungal effect on species such as C. albicans. Moreover, it was shown to inhibit biofilm formation in vitro.

Ethanolic extract of Brazilian green propolis showed high in vitro efficacy against vaginal yeasts (C. glabrata, C. albicans, C. guilliermondii and C. parapsilosis). EEP was also active against strains resistant to azole drugs (fluconazole, voriconazole, itraconazole, ketoconazole and miconazole) and amphotericin B. Most of the C. albicans and non-C. albicans isolates (96.63%) from vulvovaginal candidiasis (VVC) were inhibited by EEP with a TPC (total phenol content) concentration of 550.30 μg/ml. Propolis microparticles (PMs) also inhibited both C. albicans and non-C. albicans, to a maximum TPC of about 5570 μg/ml (on average 696.31 μg/ml) (Dalben-Dota et al., 2011Dalben-Dota KF, Consolaro MEL, Svidzinski TIE, Bruschi ML. Antifungal Activity of Brazilian propolis microparticles against yeasts isolated from vulvovaginal candidiasis. Evid Based Complement Alternat Med Volume 2011, Article ID 201953, 8 pages.). The results provided important information on the potential use of propolis microparticles obtained without a high concentration of ethanol in treating VVC, involving prolonged release of propolis.

According to many authors (De Carvalho Duailibe, Goncalves, Mendes Ahid, 2007De Carvalho Duailibe SA, Goncalves AG, Mendes Ahid FJ. Effect of a propolis extract on Streptococcus mutans counts in vivo. J Appl Oral Sci. 2007;15(05):420-423.; Sforcin, Bankova, 2011Sforcin JM, Bankova V. Propolis: is there a potential for the development of new drugs. J Ethnopharmacol . 2011;133(2):253-260.; Montero, Mori, 2012Montero JC, Mori GG. Assessment of ion diffusion from a calcium hydroxide propolis paste through dentin. Braz Oral Res. 2012;26(4):318-322.), the antifungal activity of ethanolic extract of green Brazilian propolis is attributed to the presence of flavonoids, aromatic acids, and esters present in resins. The most effective flavonoids in Brazilian propolis include galangin, quercetin, kaempferol, and pinocembrin, which are important fungicidal agents in the ethanol extract (De Carvalho Duailibe, Goncalves, Mendes Ahid, 2007De Carvalho Duailibe SA, Goncalves AG, Mendes Ahid FJ. Effect of a propolis extract on Streptococcus mutans counts in vivo. J Appl Oral Sci. 2007;15(05):420-423.; Sforcin, Bankova, 2011Sforcin JM, Bankova V. Propolis: is there a potential for the development of new drugs. J Ethnopharmacol . 2011;133(2):253-260.; Montero, Mori, 2012Montero JC, Mori GG. Assessment of ion diffusion from a calcium hydroxide propolis paste through dentin. Braz Oral Res. 2012;26(4):318-322.). Pinocembrin is thought to be the primary inhibitory agent against Candida species (Metzner, Schneidewind, Friedrich, 1977Metzner J, Schneidewind EM, Friedrich E. Effect of propolis and pinocembrin on fungi. Pharmazie. 1977;32(11):730.). In a study by Sawaya et al. (2002Sawaya AC, Palma AM, Caetano FM, Marcucci MC, da Silva Cunha IBS, Araujo CEP, et al. Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida. Lett Appl Microbiol. 2002;35(3):203-207.), the results of HPLC (high performance liquid chromatography) plate analysis showed ten compounds that inhibited growth of C. albicans in the presence of Brazilian propolis extracts obtained using 70% or higher ethanol. Of the ten substances, six were identified: p-coumaric acid, 3-prenyl-4-hydroxycinnamic acid, 3,5-diprenyl-4 hydroxycinnamic acid, 2,2-dimethyl-8- prenyl-2H-1-benzopyran-6-propenoic acid, 2,2-dimethyl-6-carboxyethenyl-2H-1-benzopyran and pinobanksin. The other four compounds, which were not fully identified, included derivatives of kaempferol and cinnamic acid and two 3,5-diprenyl-4-hydroxycinnamic acid derivatives.

The antifungal effect of an EEP of green Brazilian propolis from south-eastern Brazil corresponds with the results of other research in which red Brazilian propolis from the north-east was tested. The ethanolic extract of Brazilian red propolis showed significant results for inhibitory activity for C. krusei; 50 mg/ml was the concentration which was in the greatest inhibitory zone - 12.4 mm. In this research, observed as chemical constituents of red propolis were red flavanones, xanthones and chalcones aurones, catechins, and leucoanthocyanidins (Silva et al., 2019Silva FRG, Matias TMS, Souza LIO, Matos-Rocha TJ, Fonesca SA, Mousinho KC, et al. Phytochemical screening and in vitro antibacterial, antifungal, antioxidant and antitumor activities of the red propolis Alagoas. Braz J Biol. 2019;79(3):452-459.). Siqueira et al. (2015Siqueira ABS, de Araújo Rodriquez LRN, Santos RKB, Marinho RRB, Sheila Abreu S, Peixoto RF, et al. Antifungal activity of propolis against Candida species isolated from cases of chronic periodontitis. Braz Oral Res . 2015;29(1):1-6.) reported that an ethanolic extract of Brazilian red propolis exhibited higher activity than chlorhexidine against Candida species isolated from chronic periodontitis cases, where fluconazole was used as a control. All Candida species were susceptible to propolis and chlorhexidine, while five samples of C. albicans, C. tropicalis and C. glabrata were resistant to the antifungal activity of fluconazole. Propolis was found to exhibit fungistatic activity against C. tropicalis and C. albicans at 32-64 μg/ml and against C. glabrata at 64 μg/ ml. Fungicidal activity was observed at 64-256 μg/ml for C. tropicalis, 64-512 μg/ml for C. albicans, and 64 μg/ml for C. glabrata.

The antifungal activity of the Brazilian red and green propolis ethanolic extracts has also shown high efficacy against dermatophytes such as Trichophyton rubrum, T. tonsurans and T. mentagrophytes. The green propolis showed fungistatic activity against T. rubrum at 64 - 512 μg/ml and against T. tonsurans and T. mentagrophytes at 128 - 1024 μg/ml. Fungicidal activity of green propolis was observed at an MFC of 1024 μg/ml in the case of T. rubrum and T. tonsurans and at 512 μg/ml for T. mentagrophytes. Red propolis also exhibited fungistatic activity against T. rubrum at 8 - 128 μg/ml, against T. mentagrophytes at 16 - 128 μg/ml, and against T. tonsurans at 32 - 128 μg/ml. The red propolis extract exerted a fungicidal effect on these species at concentrations ranging from 128 to 256 μg/ml, 256 to 512 μg/ml and 128 to 1024 μg/ml, respectively, for the same species. In vivo tests were performed as well and showed that propolis treatment was more effective than classical therapy with terbinafine and itraconazole (Siqueira et al., 2009Siqueira AB, Gomes BS, Cambuim I, Maia R, Abreu S, Souza-Motta CM, et al. Trichophyton species susceptibility to green and red propolis from Brazil. Lett Appl Microbiol . 2009;48(1):90-96.). The results are consistent with findings by Soares and Cury (2001Soares MMSR, Cury AE. In vitro activity of antifungal and antiseptic agents against dermatophyte isolates from patients with tinea pedis. Braz J Microbiol.2001;32:130-134.). They studied the in vitro activity of Brazilian propolis alcoholic extract against dermatophytes isolated from patients with tinea pedis. The minimum inhibitory concentration of the extract ranged from about 8 μg/ml to > 2000 μg/ml. The MIC was 125 μg/ml in the case of most T. rubrum strains (about 55%), up to 250 μg/ml for about 70% of T. mentagrophytes strains, and > 2000 μg/ml for only one strain. The propolis extract inhibited two strains of Epidrmophyton floccosum at 125 μg/ml and the other two at 250 μg/ml. The MFCs of this agent ranged from 1000 μg/ml to more than 2000 μg/ml for the three fungal species.

The results of Veiga et al. (2018Veiga FF, Gadelha MC, da Silva MRT, Costa MI, Kischkel B, de Castro-Hoshino LV, et al. Propolis extract for onychomycosis topical treatment: from bench to clinic. Front Microbiol. 9:779.doi:10.3389/fmicb. 2018.00779. eCollection. 2018.
https://doi.org/10.3389/fmicb. 2018.0077...
) showed that 30% ethanolic extract of green Brazilian propolis was efficient in vitro against both the planktonic cells and the biofilm formed by Trichophyton spp., which is the most common agent of onychomycosis and is usually resistant to conventional antifungals. The results in vivo showed that EEP was able to penetrate the human nail and to treat onychomycosis. The majority of the isolates showed MIC50 and MFC50 below the concentration of 0.088% total phenol content in propolis extract. Another study (Oliveira et al., 2006Oliveira AC, Shinobu CS, Longhini R, Franco SL, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from onychomycosis lesions. Mem Inst Oswaldo Cruz. 2006;101(5):493-497.) showed high level of activity of ethanolic extract of green Brazilian propolis obtained from eucalyptus against Trichosporon, C. albicans, and C. non-albicans isolated from onychomycosis patients. All of the yeasts (35% C. parapsilosis, 23% C. tropicalis, 13% C. albicans, and 29% other species) were inhibited by a concentration of 500 μg/ml of flavonoids and 200 μg/ml of flavonoids stimulated their cellular death. Trichosporon spp. were the most sensitive species, showing MIC50 and MIC90 of 125 μg/ml of flavonoids, and C. tropicalis was the most resistant, with MIC50 of 500 μg/ml of flavonoids and MIC90 of 1000 μg/ml.

Antifungal activity of European propolis and its components

The ethanolic extracts of propolis from different regions of Romania used in the study of Stan et al. (2017Stan T, Teodor ED, Gatea F, Chifiriuc MC, Lazar V. Antioxidant and antifungal activity of Romanian propolis. Roman Biotechnol Lett. 2017;22(6):13116-13124.) exhibited antifungal (growth inhibition zones with diameters between 6 and 20 mm) and antibiofilm activity (the inhibition of adhesion on the inert substratum at minimum biofilm eradication concentration values between 0.23 and 15 mg/ml) against C. albicans strains isolated from tracheal secretions in hospitalized patients with respiratory tract associated infections. The ethanolic extracts of Polish propolis also showed activity with MFC in the range of 0.08-1.25% (v/v) on clinical isolates of C. albicans strains (Gucwa et al., 2018Gucwa K, Kusznierewicz B, Milewski S, Van Dijck P, Szweda P. Antifungal activity and synergism with azoles of polish propolis. Pathogens. 2018;7(02):56.). In this study, a synergistic effect was observed for the action of propolis and azole antifungals (fluconazole and voriconazole) against C. albicans. These results were in agreement with a study of Sariguzel et al. (2016Sariguzel FM, Berk E, Koc AN, Sav H, Demir G. Antifungal activity of propolis against yeasts isolated from blood culture: in vitro evaluation. J Clin Lab Anal. 2016;30(5):513-516). They demonstrated that Turkish propolis showed significant in vitro antifungal activity, which was comparable with fluconazole and itraconazole against yeast isolates from blood cultures. The propolis MIC range of eight C. albicans strains was found as 0.006 to 0.5 μg/ml. Similarly, D’Auria et al. (2003D’Auria FD, Tecca M, Scazzocchio F, Renzini V, Strippoli V. Effect of propolis on virulence factors of Candida albicans. J Chemother. 2003;15(05):454-460.) demonstrated that ethanolic extract of Italian propolis significantly inhibited the C. albicans strains tested, showing rapid (between 30 seconds and 15 minutes), dose-dependent cytocidal activity and an inhibitory effect at a concentration of about 0.20 mg/ml. German propolis (special extract GH 2002) concentrations between 0.6 and 2.4 mg/ml displayed fungicidal activity against different clinical isolates of Candida (Astani et al., 2013Astani A, Zimmermann S, Hassan E, Reichling J, Sensch KH, Schnitzler P. Antimicrobial activity of propolis special extract GH 2002 against multidrug-resistant clinical isolates. Pharmazie. 2013;68(8):695-701.).

Petroleum ether extract of Slovak and Czech propolis has exhibited excellent inhibitory effects against clinical fungal strains of C. albicans and T. mentagrophytes (MIC 8 - 64 μg/ml). These extracts had the least effect on non- albicans species of Candida (C. krusei, C. tropicalis and C. glabrata) and on T. asahii (MIC 64 - >128 μg/ ml). This study showed lower antifungal potency for the ethanolic extract, but it was relatively effective against two C. albicans and T. mentagrophytes strains (MIC ≤ 64 μg/ml) (Buchta, Černý, Opletalová, 2011Buchta V, Černý J, Opletalová V. In vitro antifungal activity of propolis samples of Czech and Slovak origin. Cent Eur J Biol. 2011;6(2):160-166.). Antifungal activity was not fully correlated with the content of flavonoids in the extracts. These findings indicate that it was not flavonoids alone but also other components of the mixture and/or their proportions in it that resulted in its antifungal activity. The correlation between the total phenolic acids and flavonoids content and antifungal activity was reported for propolis from Croatia. Especially, p-coumaric acid, apigenin, and kaempferol were significantly correlated with the activity of propolis against C. albicans (Tlak Gajger et al., 2017Tlak Gajger I, Pavlovic I, Bojic M, Kosalec I, Sreces S, Vlainic T, et al. The components responsible for the antimicrobial activity of propolis from continental and mediterranean regions in Croatia. Czech J Food Sci. 2017;35(5):376-385.).

Antifungal activity of Asian propolis and its components

Propolis from Saffareh in Lebanon showed antimicrobial activity towards C. albicans with average inhibition zone diameters of 25 mm, MIC of 12.5 mg/ ml and MFC of 25 mg/ml (Chamandi, Olama, Holail, 2015Chamandi G, Olama Z, Holail H. Antimicrobial effect of propolis from different geographic origins in Lebanon. Int J Curr Microbiol App Sci. 2015;4(4):328-342.). Qualitative analysis of this propolis showed that it contained alkaloids, flavonoids, phenols, saponins, steroids, tannins, and terepenoids. In another study, the alcoholic extract of Iranian propolis at the concentration of 250 mg/ml showed an inhibitory and cidal effect on more than 50% of clinical Candida and Aspergillus isolates (Diba, Mahmoudi, Hashemi, 2018Diba K, Mahmoudi M, Hashemi J. In vitro activity of propolis alcoholic extract on opportunistic pathogenic fungi. Int J Res Appl Basic Med Sci. 2018;4(2):68-73.). Chee (2002Chee HY. In vitro evaluation of the antifungal activity of propolis extract on Cryptococcus neoformans and Candida albicans. Mycobiology. 2002;30(2):93-95.) assessed the antifungal effect of propolis from Korea (EEP) on two clinically important fungi, C. albicans and C. neoformans. In a microbroth culture assay, the MICs for C. albicans and C. neoformans were 16 and 2 mg/ml, respectively. Propolis showed fungicidal activity against C. neoformans (MFC=8 mg/ml), but only fungistatic activity against C. albicans. Moreover, under a scanning electron microscope, rupture of C. neoformans cells could be observed following treatment with propolis. Studies by other authors (Roh, Kim, 2018Roh J, Kim KR. Antimicrobial Activity of Korean Propolis Extracts on Oral Pathogenic Microorganisms. J Dent Hyg Sci. 2018;18(1):18-23.) also showed significant antifungal activity of ethanolic extract of Korean propolis (10 mg/ml) on oral pathogenic C. albicans strains.

Similarly, propolis (EEP) from Malaysia, produced by stingless bees of the species Trigona thoracica, exhibited high antifungal properties against C. albicans (ATCC 25987) and C. neoformans (a local clinical isolate), which was explained by its high content of phenolic acids (about 1754 mg gallic acid/kg) and flavonoids (about 83 mg quercetin/kg). The visually assessed MIC of propolis was 1.56 mg/ml against both C. albicans and C. neoformans, while the MICs determined by spectrophotometry were 3.13 mg/ml and 1.56 mg/ml, respectively. The MFCs of propolis were 3.13 mg/ml for C. neoformans and 6.25 mg/ ml against C. albicans (Shehu et al., 2006Shehu A, Ismail S, Rohin MAK, Harun A, Aziz AA, Haque M. Antifungal properties of Malaysian Tualang honey and stingless bee propolis against Candida albicans and Cryptococcus neoformans. J Appl Pharm Sci. 2006;6(02):044-050.). Antimicrobial activity of propolis from Yemen against upper respiratory tract infections has been reported by El-Shouny et al. (2012El-Shouny W, Muagam F, Sadik Z, Hamza W. Antimicrobial activity of propolis extract on URT infections in pediatric patients admitted to Al-Thowrah Hospital, Hodeidah City, Yemen. World J Med Sci. 2012;7(3):172-177.). Throat swabs were collected from 17 children up to 11 years of age and six tested positive for C. albicans (35.3 %) with the most isolates found in children ≤ 3 years old. Nystatin (50 μg) showed antifungal activity against C. albicans isolates. Propolis used at a concentration of 200 mg/ml inhibited growth of C. albicans, resulting in 19 mm zones of inhibition. A mixture of propolis with goat milk enhanced the antifungal effect in vivo; full remission of Candida symptoms was attained in all children in less time (2 to 5 days) than in the case of either agent applied separately.

Based on the available literature the antifungal activity of propolis is weaker in aqueous extracts than alcoholic extracts. Both Malaysian propolis (water extract) produced by Apis mellifera and propolis produced by Trigona spp. have shown weak activity against oral fungi, especially Candida spp. For the MIC value of the propolis extracts, both Apis mellifera and Trigona spp. propolis have shown an inhibitory effect at 500 mg/ml. Neither propolis showed activity against Candida spp., based on the absence of inhibition zones (Yusoff et al., 2016Yusoff NYN, Mohamad S, Abdullah HN, Rahmana NA. Antifungal Activity of Malaysian honey and propolis extracts against pathogens implicated in denture stomatitis. AIP Conf Proc. 2016;1791:020006-1-020006-7; doi: 10.1063/1.4968861
https://doi.org/10.1063/1.4968861...
). Similarly, aqueous extracts of Brazilian propolis have demonstrated little or no effectiveness in inhibiting the growth of Candida albicans at 5.0±0.00 mm (Dias et al., 2009Dias SMD, Gomes RT, Santiago WK, Paula AMB, Cortés ME, Santos VR. Antifungal activity of commercial ethanolic and aqueous extracts of Brazilian propolis against Candida spp. Rev Ciênc Farm Básica Apl. 2009;28(3):259-263.).

THE MECHANISM OF ANTIFUNGAL ACTION OF PROPOLIS AND ITS COMPONENTS

Various compounds present in propolis, such as phenolics and flavonoids, are responsible for their antifungal activity. There are reports indicating that phenolic acids can increase cell membrane permeability, resulting in the loss of cellular proteins and nucleic acids, as well as inorganic ions such as potassium and phosphate, thereby causing the death of the cell (Farnesi et al., 2009Farnesi AP, Aquino Ferreira R, De Jong D, Bastos JK, Soares AE. Effects of stingless bee and honey bee propolis on four species of bacteria. Genet Mol Res. 2009;8(2):635-640.).The antifungal activity of flavonoids and other alpha- and beta-unsaturated oxo-compounds is most likely due to a vinylene double bond reacting with sulfanyl groups in enzymes, thereby impeding synthesis of the cell wall of the fungus (López et al., 2001López SN, Castelli MV, Zacchino SA, Dominguez JN, Lobo G, Charris-Charris J, et al. In vitro antifungal evaluation and structure activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorg Med Chem. 2001;9(8):1999-2013.). It has been shown that chemical components of propolis may harbour dose-dependent cytocidal activity and an inhibitory effect on yeast-mycelial conversion, and that they may inhibit extracellular phospholipase activity and fungal adhesion to epithelial cells (D’Auria et al., 2003D’Auria FD, Tecca M, Scazzocchio F, Renzini V, Strippoli V. Effect of propolis on virulence factors of Candida albicans. J Chemother. 2003;15(05):454-460.). Mello et al. (2006Mello AM, Gomes RT, Lara SR, Gomes Silva L, Alve JB, Cortes ME, et al. The effect of Brazilian propolis on the germ tube formation and cell wall of Candida albicans. Pharmacology online. 2006;3:352-358.) suggested that Brazilian propolis antifungal activity is based on inducing changes in the cell wall (alteration of cellular permeability) that have as consequence an increasing volume of the cell and cellular membrane rupture. The inhibition of fungal growth and germination tube formation of C. albicans could be attributed to the interaction of propolis with proteins sulfhydryl groups. The antifungal activity of pinocembrin, an important flavonoid isolated from propolis against Penicillium italicum was investigated by Peng et al. (2012Peng L, Yang S, Cheng YJ, Chen F, Pan S, Fan G. Antifungal activity and action mode of pinocembrin from propolis against Penicillium italicum. Food Sci Biotechnol. 2012;21(6):1533-1539.). Pinocembrin inhibited the mycelial growth of P. italicum by interfering energy homeostasis and cell membrane damage of the pathogen. Takaisi-Kikuni and Schilcher (1994Takaisi-Kikuni NB, Schilcher H. Electron microscopic and microcalorimetric investigations of the possible mechanism of the antibacterial action of a defined propolis provenance. Planta Med. 1994;60(3):222-227.) have investigated another potential mechanism of the antifungal and antibacterial action of propolis. They noted that cell division was inhibited in the presence of propolis, which indicated that the action of propolis could involve inhibition of DNA replication and, consequently, of cell division.

CONCLUSION

Propolis from Brazil, Europe and Asia is effective against pathogenic fungi, Candida species and other yeast-like fungi, dermatophyte and nondermatophyte moulds. Its antifungal properties are a resultant of the action of phenolic acids and their esters, and flavonoids. However, propolis from different geographic and climatic zones and the plant sources has a high variation in both the qualitative and quantitative chemical composition. This can be seen in this paper. Therefore, it is more reliable to compare the results of studies relating to one type of propolis. In summary, due to its common antimicrobial properties, including antifungal, and due to the fact that propolis is a low-toxic product compared to many synthetic drugs, it can be used in conventional medicine. But for this happen, propolis needs chemical standarisation that guarantees its quality, safety, and efficacy.

REFERENCES

  • Astani A, Zimmermann S, Hassan E, Reichling J, Sensch KH, Schnitzler P. Antimicrobial activity of propolis special extract GH 2002 against multidrug-resistant clinical isolates. Pharmazie. 2013;68(8):695-701.
  • Bankova VS, Boudourova-Krasteva G, Sforcin JM, Frete X, Kujumgiev A, Maimoni-Rodella R, et al. Phytochemical evidence for the plant origin of Brazilian propolis from São Paulo State. Z Naturforsch. 1999;54(5-6):401-405.
  • Bankova VS, de Castro SL, Marcucci MC. Propolis: recent advances in chemistry. Apidologie. 2000;31:3-15.
  • Buchta V, Černý J, Opletalová V. In vitro antifungal activity of propolis samples of Czech and Slovak origin. Cent Eur J Biol. 2011;6(2):160-166.
  • Burdock GA. Review of the biological properties and toxicity of bee propolis. Food Chem Toxicol. 1998;36(97):347-363.
  • Capistrano HM, de Assis EM, Leal RM, Alvarez-Leite ME, Brener S, Bastos EMAF. Brazilian green propolis compared to miconazole gel in the treatment of Candida-associated denture stomatitis. Evid Based Complement Alternat Med Volume 2013, Article ID 947980, 6 pages.
  • Castaldo S, Capasso F. Propolis, an old remedy used in modern medicine. Fitoterapia. 2002;73(02):1-6.
  • Chamandi G, Olama Z, Holail H. Antimicrobial effect of propolis from different geographic origins in Lebanon. Int J Curr Microbiol App Sci. 2015;4(4):328-342.
  • Chee HY. In vitro evaluation of the antifungal activity of propolis extract on Cryptococcus neoformans and Candida albicans Mycobiology. 2002;30(2):93-95.
  • Dalben-Dota KF, Consolaro MEL, Svidzinski TIE, Bruschi ML. Antifungal Activity of Brazilian propolis microparticles against yeasts isolated from vulvovaginal candidiasis Evid Based Complement Alternat Med Volume 2011, Article ID 201953, 8 pages.
  • D’Auria FD, Tecca M, Scazzocchio F, Renzini V, Strippoli V. Effect of propolis on virulence factors of Candida albicans J Chemother. 2003;15(05):454-460.
  • De Carvalho Duailibe SA, Goncalves AG, Mendes Ahid FJ. Effect of a propolis extract on Streptococcus mutans counts in vivo J Appl Oral Sci. 2007;15(05):420-423.
  • Diba K, Mahmoudi M, Hashemi J. In vitro activity of propolis alcoholic extract on opportunistic pathogenic fungi. Int J Res Appl Basic Med Sci. 2018;4(2):68-73.
  • Dias SMD, Gomes RT, Santiago WK, Paula AMB, Cortés ME, Santos VR. Antifungal activity of commercial ethanolic and aqueous extracts of Brazilian propolis against Candida spp. Rev Ciênc Farm Básica Apl. 2009;28(3):259-263.
  • El-Shouny W, Muagam F, Sadik Z, Hamza W. Antimicrobial activity of propolis extract on URT infections in pediatric patients admitted to Al-Thowrah Hospital, Hodeidah City, Yemen. World J Med Sci. 2012;7(3):172-177.
  • Farnesi AP, Aquino Ferreira R, De Jong D, Bastos JK, Soares AE. Effects of stingless bee and honey bee propolis on four species of bacteria. Genet Mol Res. 2009;8(2):635-640.
  • Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12(4):501-517.
  • Ghisalberti EL. Propolis: A review. Bee World. 1979;60:59-84.
  • Gucwa K, Kusznierewicz B, Milewski S, Van Dijck P, Szweda P. Antifungal activity and synergism with azoles of polish propolis. Pathogens. 2018;7(02):56.
  • Hegazi AG, El Hadyb F, Alla F. Chemical composition and antimicrobial activity of european propolis. Z Naturforsch . 2000;55(1-2):70-75.
  • Holderna E, Kędzia B. Investigation upon the combined action of propolis and antimycotic drugs on Candida albicans Herba Pol.1987;33:145-151.
  • Khalil ML. Biological activity of bee propolis in health and disease. Asian Pac J Cancer Prev. 2006;7(1):22-31.
  • Koo H, Gomes BP, Rosalen PL, Ambrosano GM, Park YK, Cury JA. In vitro antimicrobial activity of propolis and Arnica montana against oral pathogens. Arch Oral Biol. 2000;45(2):141-148.
  • Kujumgiev A, Tsvetkova I, Serkedjieva Y, Bankova V, Christov R, Popova S. Antibacterial, antifungal and antiviral activity of propolis of different geographic origin. J Ethnopharmacol. 1999;64(3):235-2340.
  • López SN, Castelli MV, Zacchino SA, Dominguez JN, Lobo G, Charris-Charris J, et al. In vitro antifungal evaluation and structure activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorg Med Chem. 2001;9(8):1999-2013.
  • Mello BCBS, Petrus JCC, Hubinger MD. Concentration of flavonoids and phenolic compounds in aqueous and ethanolic propolis extracts through nanofiltration. J Food Eng. 2010;96(4):533-539.
  • Mello AM, Gomes RT, Lara SR, Gomes Silva L, Alve JB, Cortes ME, et al. The effect of Brazilian propolis on the germ tube formation and cell wall of Candida albicans Pharmacology online. 2006;3:352-358.
  • Metzner J, Schneidewind EM, Friedrich E. Effect of propolis and pinocembrin on fungi. Pharmazie. 1977;32(11):730.
  • Montero JC, Mori GG. Assessment of ion diffusion from a calcium hydroxide propolis paste through dentin. Braz Oral Res. 2012;26(4):318-322.
  • Oliveira AC, Shinobu CS, Longhini R, Franco SL, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from onychomycosis lesions. Mem Inst Oswaldo Cruz. 2006;101(5):493-497.
  • Ota C, Unterkircher C, Fantinato V, Shimizu MT. Antifungal activity of propolis on different species of Candida Mycoses. 2001;44(9-10):375-378.
  • Peng L, Yang S, Cheng YJ, Chen F, Pan S, Fan G. Antifungal activity and action mode of pinocembrin from propolis against Penicillium italicum Food Sci Biotechnol. 2012;21(6):1533-1539.
  • Roh J, Kim KR. Antimicrobial Activity of Korean Propolis Extracts on Oral Pathogenic Microorganisms. J Dent Hyg Sci. 2018;18(1):18-23.
  • Santos VR, Pimenta FJGS, Aguiar MCF, Do Carmo MAV, Naves MD, Mesquita RA. Oral candidiasis treatment with Brazilian ethanol propolis extract. Phytother Res. 2005;19(7):652-654.
  • Santos VR, Gomes RT, de Mesquita RA, de Moura MD, França EC, de Aguiar EG, et al. Efficacy of Brazilian propolis gel for the management of denture stomatitis: a pilot study. Phytother Res . 2008;22(11):1544-1547.
  • Sariguzel FM, Berk E, Koc AN, Sav H, Demir G. Antifungal activity of propolis against yeasts isolated from blood culture: in vitro evaluation. J Clin Lab Anal. 2016;30(5):513-516
  • Sawaya AC, Palma AM, Caetano FM, Marcucci MC, da Silva Cunha IBS, Araujo CEP, et al. Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida Lett Appl Microbiol. 2002;35(3):203-207.
  • Sforcin JM, Fernandes Jr A, Lopes CAM, Bankova V, Funari SRC. Seasonal effect on Brazilian propolis antibacterial activity. J Ethnopharmacol . 2001;73(1-2):243-249.
  • Sforcin JM, Bankova V. Propolis: is there a potential for the development of new drugs. J Ethnopharmacol . 2011;133(2):253-260.
  • Shehu A, Ismail S, Rohin MAK, Harun A, Aziz AA, Haque M. Antifungal properties of Malaysian Tualang honey and stingless bee propolis against Candida albicans and Cryptococcus neoformans J Appl Pharm Sci. 2006;6(02):044-050.
  • Silva FRG, Matias TMS, Souza LIO, Matos-Rocha TJ, Fonesca SA, Mousinho KC, et al. Phytochemical screening and in vitro antibacterial, antifungal, antioxidant and antitumor activities of the red propolis Alagoas. Braz J Biol. 2019;79(3):452-459.
  • Siqueira AB, Gomes BS, Cambuim I, Maia R, Abreu S, Souza-Motta CM, et al. Trichophyton species susceptibility to green and red propolis from Brazil. Lett Appl Microbiol . 2009;48(1):90-96.
  • Siqueira ABS, de Araújo Rodriquez LRN, Santos RKB, Marinho RRB, Sheila Abreu S, Peixoto RF, et al. Antifungal activity of propolis against Candida species isolated from cases of chronic periodontitis Braz Oral Res . 2015;29(1):1-6.
  • Soares MMSR, Cury AE. In vitro activity of antifungal and antiseptic agents against dermatophyte isolates from patients with tinea pedis. Braz J Microbiol.2001;32:130-134.
  • Stan T, Teodor ED, Gatea F, Chifiriuc MC, Lazar V. Antioxidant and antifungal activity of Romanian propolis. Roman Biotechnol Lett. 2017;22(6):13116-13124.
  • Takaisi-Kikuni NB, Schilcher H. Electron microscopic and microcalorimetric investigations of the possible mechanism of the antibacterial action of a defined propolis provenance. Planta Med. 1994;60(3):222-227.
  • Tlak Gajger I, Pavlovic I, Bojic M, Kosalec I, Sreces S, Vlainic T, et al. The components responsible for the antimicrobial activity of propolis from continental and mediterranean regions in Croatia. Czech J Food Sci. 2017;35(5):376-385.
  • Veiga FF, Gadelha MC, da Silva MRT, Costa MI, Kischkel B, de Castro-Hoshino LV, et al. Propolis extract for onychomycosis topical treatment: from bench to clinic. Front Microbiol. 9:779.doi:10.3389/fmicb. 2018.00779. eCollection. 2018.
    » https://doi.org/10.3389/fmicb. 2018.00779
  • Wolska K, Górska A, Adamiak A. Antibacterial properties of propolis (In Polish). Post Mikrobiol. 2016;55(4):343-350.
  • Wolska K, Górska A, Antosik K, Ługowska K. Immunomodulatory effects of propolis and its components on basic immune cell functions. Indian J Pharm Sci. 2019;81(4):575-588.
  • Yusoff NYN, Mohamad S, Abdullah HN, Rahmana NA. Antifungal Activity of Malaysian honey and propolis extracts against pathogens implicated in denture stomatitis AIP Conf Proc. 2016;1791:020006-1-020006-7; doi: 10.1063/1.4968861
    » https://doi.org/10.1063/1.4968861

Publication Dates

  • Publication in this collection
    14 Apr 2023
  • Date of issue
    2023

History

  • Received
    06 Nov 2019
  • Accepted
    15 Feb 2021
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br