PROPOLEOS INMUNOMODULADOR / IMMUNOMODULATORY

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1: Planta Med. 2006 Jan;72(1):20-7.

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Direct and Indirect Mechanism(s) of Antitumour Activity of Propolis and its Polyphenolic Compounds.

Orsolic N, Saranovic AB, Basic I.

Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia.

The immunomodulatory actions of a water-soluble derivative of propolis (WSDP) and two components of propolis, caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) were investigated. Oral administration (50 mg/kg) of WSDP, CA, and CAPE enhanced the weight and cellularity of the spleen (p < 0.05, p < 0.01) of treated mice. The response of spleen cells to polyclonal mitogens (PHA, Con A, PWM) was also increased in mice treated with WSDP as compared to control (p < 0.01); in contrast, the response of spleen cells of mice treated with CA were significantly suppressed (p < 0.001). The colony forming ability of HeLa cells plated on monolayers of macrophages was completely inhibited by peritoneal macrophages from mice receiving either WSDP, CAPE, or CA. Macrophages from treated mice also inhibited [ (3)H]TdR incorporation into HeLa cells in vitro. Testing for the possible presence of NO in the supernatants of 24 hours cultured macrophages activated with either compound revealed that the toxicity of these cells to HeLa cells was in part due to the production of NO. Tumour growth was suppressed by WSDP and its polyphenolic compounds given orally to mice. Local presence of CA, and CAPE in the tissue, caused a significant delay of tumour formation. Based on these results, we postulate that the antitumour activity of the test compounds includes pronounced immunomodulatory activity mainly due to the augmentation of non-specific antitumour resistance in mice via macrophage activation and the production of soluble factors by those cells which may interfere with either cells of the immune system or directly by tumour cells. Abbreviations. WSDP:water-soluble derivative of propolis CA:caffeic acid CAPE:caffeic acid phenethyl ester NO:nitric oxide NOS:nitric oxide syntase [ (3)H]-TdR:[ (3)H]-thymidine.

PMID: 16450291 [PubMed - in process]


2: Radiat Prot Dosimetry. 2005;115(1-4):461-4.

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Assessment by cytogenetic analysis of the radioprotection properties of propolis extract.

Montoro A, Almonacid M, Serrano J, Saiz M, Barquinero JF, Barrios L, Verdu G, Perez J, Villaescusa JI.

Servicio de Proteccion Radiologica, Hospital la Fe, Av/Campanar no. 21, Valencia, 46009, Spain. almonpas@doctor.upv.es

Propolis obtained from honeybee hives has been used in folk medicine as an anti-inflammatory, anti-carcinogenic or immunomodulatory agent. In animal studies, the radioprotector effect of propolis has been attributed to its free-radical scavenging properties. The present study was carried out to show the protective properties of propolis extract against DNA damage induced by gamma irradiation. The evaluation of the radioprotective effect of propolis has been carried out by the analysis of chromosome aberration induction after several doses of gamma rays. The results of an analysis in the presence of ethanol extract of propolis (EEP) were compared with the dose-effect calibration curve for gamma-rays by analysis of chromosome aberrations without propolis, a decrease in the radiation-induced chromosome aberrations has been observed to be higher than 50% for all the doses.

PMID: 16381767 [PubMed - in process]


3: J Ethnopharmacol. 2005 Nov 14; [Epub ahead of print]

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Propolis: Effect of different concentrations, extracts and intake period on seric biochemical variables.

Mani F, Damasceno HC, Novelli EL, Martins EA, Sforcin JM.

Department of Chemistry and Biochemistry, Biosciences Institute, UNESP, 18600-000 Botucatu, SP, Brazil.

Propolis is a resinous substance produced by honeybees that possesses many biological activities, such as antitumor, antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory, among others. The purpose of the present study was to investigate the biochemical profile of propolis-treated rats to observe whether propolis might lead to side effects after administration. Three different treatments were analyzed: (1) rats were treated with different concentrations of propolis (1, 3 and 6mg/kg/day) during 30 days; (2) rats were treated with 1mg/kg/day of ethanolic or water extracts of propolis (EEP, WEP) during 30 days; (3) rats were treated with 1mg/kg/day of ethanolic extract of propolis during 90 and 150 days. Our results demonstrated no alterations in the seric levels of cholesterol, HDL-cholesterol, total lipids, triglycerides and in the specific activity of aminotransferases (AST) and lactic dehydrogenase (LDH) of propolis-treated groups when compared to controls. On the basis of our findings, since propolis does not induce any significant change in seric parameters, it is claimed that long-term administration of propolis might not have any cardiac injury.

PMID: 16293383 [PubMed - as supplied by publisher]


4: Vet Res Commun. 2005 Oct;29(7):575-93.

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Peroral application of water-soluble derivative of propolis (WSDP) and its related polyphenolic compounds and their influence on immunological and antitumour activity.

Orsolic N, Sver L, Terzic S, Basic I.

Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia. norsolic@yahoo.com

Polyphenolic compounds are widely distributed in the plant kingdom and display a variety of biological activities, including chemoprevention and growth inhibition of tumours. Propolis contains a conglomerate of polyphenolic compounds. We investigated the effect of propolis and polyphenolic compounds, components of propolis, on the growth and metastatic potential of a transplantable mammary carcinoma (MCa) of the mouse. Metastases in the lung were generated by 2 x 10(5) tumour cells injected intravenously (i.v.). A water-soluble derivative of propolis (WSDP) and the polyphenolic compounds (caffeic acid (CA) and caffeic acid phenethyl ester (CAPE)) were given to mice perorally before or after tumour cell inoculation. WSDP, CA and CAPE reduced the number of metastases in the lung. This implies that the antitumour activities of the compounds used in these studies are mostly related to the immunomodulatory properties of the compounds, their cytotoxicity to tumour cells, and their ability to induce apoptosis and/or necrosis.

PMID: 16142606 [PubMed - in process]


5: Leuk Res. 2005 Nov;29(11):1343-6.

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Evaluation of Manisa propolis effect on leukemia cell line by telomerase activity.

Gunduz C, Biray C, Kosova B, Yilmaz B, Eroglu Z, Sahin F, Omay SB, Cogulu O.

Ege University, Faculty of Medicine, Department of Medical Biology, Izmir, Turkey.

Propolis is a resinous substance which is used by bees to repair and maintain their hives. It has more than 180 compounds including flavonoids, phenolic acids and its esters which have anti-inflammatory, antibacterial, antiviral, immunomodulatory, antioxidant and antiproliferative effects. Propolis is shown to inhibit cell division and protein synthesis. However the exact mechanism underlying antitumor effect is not clearly described. On the other hand progressive telomere shortening to a critical level results with senescence of normal cells by inducing apoptosis and telomerase prevents erosion of telomeres. In this study we aimed to evaluate hTERT ratios in propolis-treated T-cell acute lymphoblastic leukemia (CCFR-CEM) cell line. Cell counts and cell viability of propolis-treated and propolis-free T-cell acute lymphoblastic leukemia (CCFR-CEM) cell line were assessed by trypan blue dye exclusion test and MTT assay. The LightCycler instrument was used (online real-time PCR) for the quantification of hTERT in CCFR-CEM cell line. The hTERT ratio significantly decreased 60 and 93% after 24 and 72 h respectively compared to the initial value of the cells incubated with propolis. It had almost no cytotoxic effect and caused 30, 30, 22 and 12% decrease in cell counts after 24, 48, 72 and 96 h respectively which is statistically significant. In conclusion propolis may show antitumor and apoptotic effect via inhibiting telomerase expression besides the mechanisms which have been described previously.

PMID: 16055186 [PubMed - indexed for MEDLINE]


6: Pulm Pharmacol Ther. 2006;19(2):90-5. Epub 2005 Jun 13.

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Effects of caffeic acid phenethyl ester on lipopolysaccharide-induced lung injury in rats.

Koksel O, Ozdulger A, Tamer L, Cinel L, Ercil M, Degirmenci U, Unlu S, Kanik A.

Department of Thoracic Surgery, Mersin University School of Medicine, Zeytinabahce Caddesi, 33079 Mersin, Turkey.

Extracts of propolis, a natural beehive product, have been known for centuries to have a variety of beneficial medical properties, among which their anti-inflammatory effect is a major one. Caffeic acid phenethyl ester (CAPE), an active propolis component, has antimicrobial, anti-inflammatory, antioxidant, carcinostatic and immunomodulatory properties. In this study, we aimed to investigate the efficacy of CAPE in endotoxin-induced lung injury in rats. Lung injury was induced by a footpad injection of lipopolysaccharide (LPS). In the treatment group, 10mumolkg(-1) CAPE was injected intraperitoneally immediately after LPS injection. At 24h after LPS and/or CAPE injection, blood and lung tissue specimens were collected. MDA levels and MPO activity in serum and lung tissue, serum total antioxidant levels, lung tissue Na(+)/K(+) ATP-ase activity and histopathological evaluation were determined to assess the efficacy of CAPE treatment. CAPE was found to be efficient in reducing inflammation and lung tissue damage induced by LPS in rats.

PMID: 15953745 [PubMed - in process]


7: Neurosci Lett. 2005 Jul 22-29;383(1-2):39-43.

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The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity.

Noelker C, Bacher M, Gocke P, Wei X, Klockgether T, Du Y, Dodel R.

Department of Neurology, Friedrich-Wilhelms-University, Bonn, Germany.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons of the substantia nigra pars compacta. 6-Hydroxydopamine (6-OHDA) is specific to dopaminergic neurons in intrastriatal rodent models. It induces neuronal death either via uncoupling mitochondrial oxidative phosphorylation resulting in energy deprivation or alternatively, is associated with its ability to produce hydrogen peroxide, hydroxyl and superoxide radicals. Caffeic acid phenethyl ester (CAPE), an antioxidant flavanoid, has antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties. Recent studies have shown that CAPE has also a neuroprotective effects in ischemia and low potassium-induced neuronal apoptotic models. In cerebellar granule neurons CAPE significantly blocks 6-OHDA mediated cell death (70 microM) in a dose-dependent manner. Furthermore, CAPE was able to modulate the Ca(2+)-induced release of cyctochrome c in isolated liver mitochondria. Caspase-3 activation following 6-OHDA treatment was markedly inhibited in the presence of CAPE. Although the molecular mechanisms associated with CAPE's neuroprotective effects remain to be elucidated in more detail, our results clearly demonstrate a considerable neuroprotective effect of CAPE. Since a mitochondrial insult is a major cause for the degeneration of nigral neurons in PD, we hypothesize that propolis derivatives, in particular CAPE, may have a neuroprotective effect on those cells and may be a promising drug candidate to be taken into in vivo models of PD.

PMID: 15894425 [PubMed - indexed for MEDLINE]


8: J Ethnopharmacol. 2005 Apr 26;98(3):301-5.

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Effect of propolis, some isolated compounds and its source plant on antibody production.

Sforcin JM, Orsi RO, Bankova V.

Department of Microbiology and Immunology, Biosciences Institute, UNESP, 18618-000 Botucatu, S.P., Brazil.

Propolis is a beehive product with a very complex chemical composition, widely used in folk medicine because of its several therapeutic activities. Its biological properties and chemical composition may vary according to the geographic location and to the different plant sources. The possible mechanism of action of propolis as well as of its active compounds has been the subject of researchers in recent years. In this work, first we reported the results of our study on the seasonal effect of the immunomodulatory action of propolis on antibody production in bovine serum albumin (BSA)-immunized rats. Then, we compared the effect of Brazilian and Bulgarian propolis, some isolated compounds and Baccharis extract on anti-BSA antibody levels. Based on the results, we conclude that propolis stimulates antibody production, independently of the season and geographic origin. Caffeic acid, quercetin and Baccharis extract had no effect on antibody production, although the importance of isolated compounds is well reported in other biological assays. Propolis action is a consequence of plant-derived products with synergic effects, while isolated compounds or extracts from its plant sources had no effect in this assay.

PMID: 15814263 [PubMed - indexed for MEDLINE]


9: Int Immunopharmacol. 2005 Feb;5(2):359-68.

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Effects of Brazilian and Bulgarian propolis on bactericidal activity of macrophages against Salmonella Typhimurium.

Orsi RO, Sforcin JM, Funari SR, Bankova V.

Department of Production and Animal Exploration-School of Veterinary Medicine and Animal Husbandry-UNESP, 18618-000 Botucatu, SP, Brazil.

Propolis has been used in folk medicine since ancient times due to its many biological properties, such as antimicrobial, antiinflammatory, antioxidant, immunomodulatory activities, among others. Macrophages play an important role in the early phase of Salmonella infection. In this work, macrophages were prestimulated with Brazilian or Bulgarian propolis and subsequently challenged with Salmonella Typhimurium at different macrophage/bacteria ratio. After 60 min of incubation, cells were harvested with Triton-X to lyse the macrophages. To assess the bactericidal activity, the number of colony-forming units (CFU) of S. typhimurium was determined by plating 0.1 mL in Mueller Hinton agar. After 24 h, CFU were counted, and the percentage of bactericidal activity was obtained. Propolis from Brazil and Bulgaria enhanced the bactericidal activity of macrophages, depending on its concentration. Brazilian propolis seemed to be more efficient than that from Bulgaria, because of their different chemical composition. In Bulgaria, bees collect the material mainly from the bud exudate of poplar trees, while in Brazil, Baccharis dracunculifolia DC. was shown to be the main propolis source. Our data also showed that the increased bactericidal activity of macrophages involved the participation of oxygen (H(2)O(2)) and nitrogen (NO) intermediate metabolites.

PMID: 15652765 [PubMed - indexed for MEDLINE]


10: Clin Biochem. 2005 Feb;38(2):191-6.

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Effects of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart.

Okutan H, Ozcelik N, Yilmaz HR, Uz E.

Department of Cardiovascular Surgery, Suleyman Demirel University Medical School, 6 Mart Ataturk C. Istiklal M. Oztunc A., No:1 D:4 32050 Isparta, Turkey. okutanh@yahoo.com

OBJECTIVES: The risk for cardiovascular disease is significantly high in diabetes mellitus. Experimental evidence suggests that oxidative stress plays a dominant role in the pathogenesis of diabetes mellitus. Caffeic acid phenethyl ester (CAPE), an active component of propolis, has several biological and pharmacological properties, including antioxidant, anti-inflammatory, anti-carcinogenic, antiviral, and immunomodulatory activities. In light of the antioxidant ability of CAPE, the effects of CAPE on the antioxidative status of cardiac tissue were investigated in streptozotocin (STZ)-induced diabetic rats. DESIGN AND METHODS: Twenty-six rats were randomly divided into three groups: group I, control, nondiabetic rats (n = 9); group II, STZ-induced, untreated diabetic rats (n = 7); and group III, STZ-induced, CAPE-treated diabetic rats (n = 10). In groups II and III, diabetes developed 3 days after intraperitoneal (ip) administration of a single 35 mg kg(-1) dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10 mumol kg(-1) ip dose of CAPE per day. After 8 weeks, the levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the cardiac tissues of all groups were analyzed. RESULTS: In untreated diabetic rats, MDA markedly increased in the cardiac tissue compared with the control rats (P < 0.05). However, MDA levels were reduced to the control level by CAPE. The activities of SOD and CAT in the untreated diabetic group and the CAPE-treated diabetic group were higher than those of the control group (P < 0.05). Rats in the CAPE-treated diabetic group had reduced activities of SOD and CAT in comparison with the rats in the untreated diabetic group (P < 0.05). There were no significant differences in the activity of GSH-Px between the rats in the untreated diabetic group and the control group. However, the activity of GSH-Px was increased in CAPE-treated diabetic rats compared with the control and untreated diabetic rats (P < 0.05). CONCLUSION: These results reveal that diabetes mellitus increases oxidative stress in cardiac tissue and CAPE has an ameliorating effect on the oxidative stress via its antioxidant property.

PMID: 15642285 [PubMed - indexed for MEDLINE]


11: J Sep Sci. 2004 May;27(7-8):619-23.

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Quantitative analysis of caffeic acid phenethyl ester in crude propolis by liquid chromatography-electrospray ionization mass spectrometry.

Del Boccio P, Rotilio D.

Gennaro Paone Environmental Health Center, Mario Negri Institute for Pharmacological Research, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have antimitogenic, anticarcinogenic, antinflammatory, and immunomodulatory properties. The paper describes a rapid and simple liquid chromatography-electrospray ionisation mass spectrometry method for qualitative and quantitative determination of CAPE. The chromatographic separation was performed with a Luna RP-C18 column using a water-acetonitrile linear gradient. The method was linear over a 0.125-80 ng/mL range (LOD = 62.5 pg/mL). The method was applied for the quantitation of caffeic acid phenethyl ester in crude propolis samples, which were analysed directly after extraction with ethyl acetate solution.

PMID: 15335050 [PubMed - indexed for MEDLINE]


12: J Ethnopharmacol. 2004 Oct;94(2-3):307-15.

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Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds.

Orsolic N, Knezevic AH, Sver L, Terzic S, Basic I.

Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000, Croatia. norsolic@yahoo.com

The effect of polyphenolic compounds isolated from propolis and propolis itself was investigated on the growth and metastatic potential of a transplantable mammary carcinoma (MCa) of CBA mouse. Metastases in the lung were generated by intravenous injection of tumor cells (2 x 10(5)). A water-soluble derivative of proplis (WSDP), caffeic acid (CA), caffeic acid phenethyl ester (CAPE) and quercetin (QU) were given to mice per os before tumor cells inoculation. Tested compounds significantly decreased the number of tumor nodules in the lung. According to the results obtained the antitumor activity of tested compounds can be related to the immunomodulatory properties of the compounds, their cytotoxicity to tumor cells, and their capacity to induce apoptosis and necrosis. The experimental data support that WSDP, CA, CAPE and QU could be potentially useful in the control of tumor growth in experimental models.

PMID: 15325736 [PubMed - indexed for MEDLINE]


13: Nutr Cancer. 2003;47(2):156-63.

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Inhibitory effect of water-soluble derivative of propolis and its polyphenolic compounds on tumor growth and metastasizing ability: a possible mode of antitumor action.

Orsolic N, Sver L, Terzic S, Tadic Z, Basic I.

Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia. norsolic@yahoo.com

Polyphenolic compounds are widely distributed in the plant kingdom and display a variety of biological activities, including chemoprevention and tumor growth inhibition. Propolis is made up of a variety of polyphenolic compounds. We compared how the routes of administration of polyphenolic compounds deriving from propolis and of propolis itself affect the growth and metastatic potential of a transplantable mammary carcinoma (MCa) of the CBA mouse. The influence of tested compounds on local tumor growth was also studied. Metastases in the lung were generated by 2 x 10(5) tumor cells injected intravenously (IV). A water-soluble derivative of propolis (WSDP) and polyphenolic compounds (caffeic acid, CA, and CA phenethyl ester, CAPE) were given to mice per os (PO) or intraperitoneally (IP) before or after tumor cell inoculation. Tested compounds significantly decreased the number of lung colonies. When mice were inoculated with 10(5) MCa cells in the exact site of subcutaneous injection of different doses of WSDP, CA, or CAPE, tumor growth was inhibited, and survival of treated mice was prolonged. Antitumor activity, according to the results obtained, is mostly related to the immunomodulatory properties of the compounds and their capacity to induce apoptosis and necrosis. In conclusion, results presented here indicate that WSDP, CA, and CAPE could be potential useful tools in the control of tumor growth in experimental tumor models when administrated PO; because PO administration is the easiest way of introducing a compound used for prevention and/or cure of any disease, it is likely that this article has reached the goal of the investigation.

PMID: 15087268 [PubMed - indexed for MEDLINE]


14: Int Immunopharmacol. 2004 Mar;4(3):429-36.

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Immunomodulatory effect of caffeic acid phenethyl ester in Balb/c mice.

Park JH, Lee JK, Kim HS, Chung ST, Eom JH, Kim KA, Chung SJ, Paik SY, Oh HY.

Immunotoxicology Division, Department of Toxicology, National Institute of Toxicological Research, KFDA, Nokbun-Dong, Eunpyung-Gu, Seoul 122-704, South Korea. jaehyun@kfda.go.kr

Caffeic acid phenethyl ester (CAPE), an the active component of propolis, is known to have anticarcinogenic, antiviral and various biological activities; however, the effect of CAPE on the immunomodulatory activity in vivo remains unknown. We have investigated the effect of CAPE on the immune system in female Balb/c mice. CAPE (0, 5, 10, 20 mg/kg) was given to mice orally for 14 days. Immunomodulatory activity was evaluated by assessment of body and organ weight, lymphocyte blastogenesis, plaque-forming cell (PFC) assay, lymphocyte subpopulation by flow cytometry and cytokine production. Even though the change of body weight was not observed in CAPE-administered group, thymus weight and/or cellularity of thymus and spleen are decreased at the all dose groups of CAPE (5, 10, 20 mg/kg). On the other hand, CAPE had no effect on B lymphocyte proliferation induced by lipopolysaccharide (LPS) but increased T lymphocyte blastogenesis induced by concanavalin A (Con A) at the dose of 20 mg/kg. In the case of lymphocyte subpopulation, the population of T and B cells was not changed but CD4(+) T cell subsets are significantly increased in exposure to CAPE. The antibody responses to T lymphocyte dependent antigen, sheep red blood cell and keyhole limpet hemocyanin (KLH) were increased more than 10 mg/kg in CAPE-treated group. Likewise, the cytokine, IL-2, IL-4 and IFN-gamma were significantly increased at the dose of 20 mg/kg CAPE group. These results suggest that CAPE could have immunomodulatory effects in vivo.

PMID: 15037220 [PubMed - indexed for MEDLINE]


15: J Ethnopharmacol. 2004 Mar;91(1):25-30.

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Effects of ethanol extract of propolis (EEP) and its flavones on inducible gene expression in J774A.1 macrophages.

Blonska M, Bronikowska J, Pietsz G, Czuba ZP, Scheller S, Krol W.

Department of Microbiology and Immunology, Medical University of Silesia, ul Jordana 19, Zabrze-Rokitnica 41-808, Poland.

Propolis, a bee-hive product, has been used in folk medicine for centuries, and recently in modern medicine as an anti-inflammatory and immunomodulatory agent. These activities would be mainly due to phenolic compounds such as flavonoids, especially flavone derivatives. The present study examined the effect of ethanol extract of propolis (EEP) and selected flavone derivatives (chrysin, galangin, kaempferol and quercetin) on interleukin-1beta (IL-1beta) and inducible nitric oxide synthase (iNOS) gene expression in lipopolysaccharide (LPS)-induced J774A.1 macrophages. Treatment of cells with EEP significantly suppressed both IL-1beta mRNA (P<0.02) and iNOS mRNA (P<0.001) expression. The concentrations of cytokine in cell culture supernatants and cell lysates and nitric oxide (NO) generation were reduced in a dose-dependent manner. The tested phenolic compounds significantly decreased the IL-1beta mRNA level and IL-1beta protein concentration (P<0.05) (excluding galangin), iNOS mRNA level and NO production (P<0.001). The most potent inhibitor of the IL-1beta synthesis and NO generation was chrysin. These results indicate that EEP exerts its inhibitory effect on the IL-1beta and iNOS gene expression in J774A.1 macrophages at the transcriptional level. Tested flavone derivatives contribute to the anti-inflammatory activity of propolis.

PMID: 15036463 [PubMed - indexed for MEDLINE]


16: J Pharmacol Exp Ther. 2004 Mar;308(3):993-1001. Epub 2003 Nov 14.

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Caffeic acid phenethyl ester inhibits T-cell activation by targeting both nuclear factor of activated T-cells and NF-kappaB transcription factors.

Marquez N, Sancho R, Macho A, Calzado MA, Fiebich BL, Munoz E.

Departamento de Biologia Celular, Fisiologia e Inmunologia. Facultad de Medicina, Cordoba, Spain.

Caffeic acid phenethyl ester (CAPE), which is derived from the propolis of honeybee hives, has been shown to reveal anti-inflammatory properties. Since T-cells play a key role in the onset of several inflammatory diseases, we have evaluated the immunosuppressive activity of CAPE in human T-cells, discovering that this phenolic compound is a potent inhibitor of early and late events in T-cell receptor-mediated T-cell activation. Moreover, we found that CAPE specifically inhibited both interleukin (IL)-2 gene transcription and IL-2 synthesis in stimulated T-cells. To further characterize the inhibitory mechanisms of CAPE at the transcriptional level, we examined the DNA binding and transcriptional activities of nuclear factor (NF)-kappaB, nuclear factor of activated cells (NFAT), and activator protein-1 (AP-1) transcription factors in Jurkat cells. We found that CAPE inhibited NF-kappaB-dependent transcriptional activity without affecting the degradation of the cytoplasmic NF-kappaB inhibitory protein, IkappaBalpha. However, both NF-kappaB binding to DNA and transcriptional activity of a Gal4-p65 hybrid protein were clearly prevented in CAPE-treated Jurkat cells. Moreover, CAPE inhibited both the DNA-binding and transcriptional activity of NFAT, a result that correlated with its ability to inhibit phorbol 12-myristate 13-acetate plus ionomycin-induced NFAT1 dephosphorylation. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory activities of this natural compound.

PMID: 14617683 [PubMed - indexed for MEDLINE]


17: J Ethnopharmacol. 2003 Jul;87(1):93-7.

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Propolis: lymphocyte proliferation and IFN-gamma production.

Sa-Nunes A, Faccioli LH, Sforcin JM.

Department of Clinical Analysis, Toxicology and Bromatology, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.

We evaluated propolis influence on polyclonal activation of lymphocytes by concanavalin A (Con A). The in vitro experiments showed that propolis decreases splenocyte proliferation both in the absence or presence of Con A. The suppression in mitogen-induced splenocyte proliferation also occurred when mice were treated intraperitoneally with propolis for 3 days. An increased of IFN-gamma production in the culture supernatants of the same cells was observed. A dual action of propolis on lymphocyte activation was proposed: it decreases splenocyte proliferation in the presence or absence of Con A and stimulates IFN-gamma production by spleen cells. These results are important to understand the immunomodulatory action of propolis on the host's specific and non-specific immunity.

PMID: 12787960 [PubMed - indexed for MEDLINE]


18: J Ethnopharmacol. 2003 Feb;84(2-3):265-73.

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Immunomodulation by water-soluble derivative of propolis: a factor of antitumor reactivity.

Orsolic N, Basic I.

Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10 000 Zagreb, Croatia. norsolic@yahoo.com

The antimetastatic efficacy of a water-soluble derivative of propolis (WSDP) was studied. Tumor was a transplantable mammary carcinoma of CBA mouse. Metastases in the lung were generated by 2 x 10(5) viable tumor cells i.v. WSDP was given intraperitoneally at doses of 50 or 150 mg/kg before or after tumor cell inoculation. Therapies reduced the number of metastases in the lung and tumor growth was suppressed significantly by WSDP. It is likely that antimetastatic activity of the WSDP is mainly mediated by immunomodulatory activity. Changes in several immunological parameters such as production of lymphocyte activating factor by peritoneal macrophages and the efficacy of those macrophages to kill tumor cell in vitro, responses of lymphocytes to mitogen, and weight and cellularity of spleen, respectively, correlated well with antimetastatic properties of the WSDP. Based on results we postulate that the antimetastatic activity of propolis includes a pronounced immunomodulatory activity mainly toward augmentation of nonspecific antitumor resistance in mice via macrophage activation. Copyright 2002 Elsevier Science Ireland Ltd.

PMID: 12648825 [PubMed - indexed for MEDLINE]


19: Fitoterapia. 2002 Nov;73 Suppl 1:S1-6.

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Propolis, an old remedy used in modern medicine.

Castaldo S, Capasso F.

Department of I.N.P.S. of Naples, via Medina 63, Naples, Italy.

Propolis is one of the few natural remedies that has maintained its popularity over a long period of time. The pharmacologically active molecules in the propolis are flavonoids and phenolic acids and their esters. These components have multiple effects on bacteria, fungi and viruses. In addition, propolis and its components have anti-inflammatory and immunomodulatory activities. Moreover, propolis has been shown to lower blood pressure and cholesterol levels. However, clinical studies to substantiate these claims are required.

Publication Types:

       Review


PMID: 12495704 [PubMed - indexed for MEDLINE]


20: J Ethnopharmacol. 2002 Oct;82(2-3):89-95.

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Estrogenic effects of ethanol and ether extracts of propolis.

Song YS, Jin C, Jung KJ, Park EH.

Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul, South Korea.

Propolis obtained from honeybee hives has been used in Oriental folk medicine as an anti-inflammatory, anti-carcinogenic, or immunomodulatory agent. The potential estrogenic activity of propolis was investigated in vitro using the MCF-7 human breast cancer cell proliferation, human estrogen receptor (hER) binding and yeast-based steroid receptor transcription, and in vivo using the immature rat uterotrophic effect. Treatments with ethanol extract of propolis (EEP) and ether extract of propolis (REP) enhanced MCF-7 cell proliferation in concentrations ranging from 0.8 to 4 microg/ml. Both EEP and REP competed for binding of [3H]17beta-estradiol to the hER with IC(50) values of 9.14 and 9.72 microg/ml, respectively. In yeast estrogen receptor transcription assay, both EEP and REP were found to be estrogenic with EC(50) values of 9.48, and 8.55 microg/ml, respectively. Animals treated with EEP or REP for 4 days (500-1000 mg/kg per day, s.c.) exhibited significant dose-dependent increases in uterine wet weight. However, in the yeast androgen and progesterone receptor transcription assays, either EEP or REP was found not to be active. The results suggest that propolis produces estrogenic effects through activation of estrogen receptors.

PMID: 12241982 [PubMed - indexed for MEDLINE]


21: Arch Pharm Res. 2002 Aug;25(4):500-4.

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Inhibition of angiogenesis by propolis.

Song YS, Park EH, Jung KJ, Jin C.

Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Cheongryang, Seoul.

Propolis, obtained from honeybee hives, has been used in Oriental folk medicine as an anti-inflammatory, anti-carcinogenic, and immunomodulatory agent. There is considerable evidence suggesting that angiogenesis and chronic inflammation are codependent. Blockage of angiogenesis results in an anti-inflammatory effect. Ethanol (EEP) and ether extracts of propolis (REP), and caffeic acid phenethyl ester (CAPE), an active component of propolis, were examined for their anti-angiogenic activities using the chick embryo chorioallantoic membrane (CAM), and the calf pulmonary arterial endothelial (CPAE) cell proliferation, assays. The presence of EEP, REP and CAPE inhibited angiogenesis in the CAM assay and the proliferation of CPAE cells. The results suggest that anti-angiogenic activities of EEP, REP and CAPE are also responsible for their anti-inflammatory effect.

PMID: 12214863 [PubMed - indexed for MEDLINE]


22: J Ethnopharmacol. 2002 May;80(2-3):155-61.

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Ethanol extract of propolis inhibits nitric oxide synthase gene expression and enzyme activity.

Song YS, Park EH, Hur GM, Ryu YS, Kim YM, Jin C.

Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea.

Propolis obtained from honeybee hives has been used in Oriental folk medicine as an anti-inflammatory, anti-carcinogenic, or immunomodulatory agent. However, the molecular basis for anti-inflammatory properties of propolis has not yet been established. Since nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS) has been known to be involved in inflammatory and autoimmune-mediated tissue destruction, modulation of NO synthesis or action represents a new approach to the treatment of inflammatory and autoimmune diseases. The present study, therefore, examined effects of ethanol extract of propolis (EEP) on iNOS expression and activity of iNOS enzyme itself. Treatment of RAW 264.7 cells with EEP significantly inhibited NO production and iNOS protein expression induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). EEP also inhibited iNOS mRNA expression and nuclear factor-kappa B (NF-kappaB) binding activity in a concentration-dependent manner. Furthermore, transfection of RAW 264.7 cells with iNOS promoter linked to a chloramphenicol acetyltransferase (CAT) reporter gene, revealed that EEP inhibited the iNOS promoter activity induced by LPS plus IFN-gamma through the NF-kappaB sites of the iNOS promoter. In addition, EEP directly interfered with the catalytic activity of murine recombinant iNOS enzyme. These results suggest that EEP may exert its anti-inflammatory effect by inhibiting the iNOS gene expression via action on the NF-kappaB sites in the iNOS promoter and by directly inhibiting the catalytic activity of iNOS.

PMID: 12007705 [PubMed - indexed for MEDLINE]


23: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9090-5.

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Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B.

Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB.

Department of Molecular Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have antimitogenic, anticarcinogenic, antiinflammatory, and immunomodulatory properties. The molecular basis for these diverse properties is not known. Since the role of the nuclear factor NF-kappa B in these responses has been documented, we examined the effect of CAPE on this transcription factor. Our results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. The effect of CAPE on inhibition of NF-kappa B binding to the DNA was specific, in as much as binding of other transcription factors including AP-1, Oct-1, and TFIID to their DNA were not affected. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active. Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and antiinflammatory activities.

PMID: 8799159 [PubMed - indexed for MEDLINE]


24: J Ethnopharmacol. 1995 Jul 28;47(3):145-7.

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Immunomodulatory action of propolis. VI. Influence of a water soluble derivative on complement activity in vivo.

Ivanovska ND, Dimov VB, Bankova VS, Popov SS.

Department of Immunology, Bulgarian Academy of Sciences, Sofia.

The water soluble derivative (WSD) of propolis in a dose of 150 mg/kg was administered intravenously (i.v.), intraperitoneally (i.p.) and orally (p.o.) to mice. The alteration of serum alternative pathway (AP) complement level was observed. The WSD also influenced the process of acute inflammation provoked by zymosan in mice. The effect was strongly dependent on the route of WSD administration.

PMID: 8569238 [PubMed - indexed for MEDLINE]


25: J Ethnopharmacol. 1995 Jul 28;47(3):135-43.

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Immunomodulatory action of propolis. V. Anticomplementary activity of a water-soluble derivative.

Ivanovska ND, Dimov VB, Pavlova S, Bankova VS, Popov SS.

Department of Immunology, Bulgarian Academy of Sciences, Sofia.

The effect of a water-soluble derivative (WSD) of propolis on the classical pathway (CP) and the alternative (AP) complement activity has been investigated. The in vitro experiments show that WSD inhibits both pathways and the effect depends on the source of complement. The suppression of complement-mediated haemolysis proves to be time- and temperature-related. High WSD concentrations cause direct damage of the target erythrocytes. The estimation of C3-residual activity indicates that the preparation diminishes C3 functional activity.

PMID: 8569237 [PubMed - indexed for MEDLINE]


26: Vaccine. 1992;10(12):817-23.

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Immunomodulatory action of propolis: IV. Prophylactic activity against gram-negative infections and adjuvant effect of the water-soluble derivative.

Dimov V, Ivanovska N, Bankova V, Popov S.

Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia.

The efficacy of the water-soluble derivative (WSD) of natural propolis (bee glue) was examined for augmentation of host resistance against experimental infections caused by Gram-negative pathogens (Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa). The substance was found to induce significant non-specific protection, but did not inhibit the in vitro growth of the same strains. Pretreatment with WSD prior to the standard scheme for tumour necrosis factor (TNF) induction (BCG and two weeks later lipopolysaccharide (LPS)) provoked an interval-dependent reduction in the lytic capacity of serum against L 929 target cells. The replacement of the triggering or priming signal with WSD markedly increased TNF production. In vivo administration of WSD led to a rapid and route-dependent change in the alternative complement pathway haemolysis.
The alteration in C1q complement component and total protein synthesis, and also in nitroblue tetrazolium reduction, suggests that macrophage activation makes a major contribution to the capacity of WSD to prevent infections.

PMID: 1455907 [PubMed - indexed for MEDLINE]