PROPOLEOS ANTIOXIDANTE

 

 

1: Life Sci. 2006 Jan 30; [Epub ahead of print]

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Propolis protects human spermatozoa from DNA damage caused by benzo[a]pyrene and exogenous reactive oxygen species.

Russo A, Troncoso N, Sanchez F, Garbarino JA, Vanella A.

Department of Biological Chemistry, Medical Chemistry and Molecular Biology, University of Catania, v.le A. Doria 6, 95125 Catania, Italy.

Many environmental, physiological and genetic factors have been implicated in defective sperm function, the most common cause of infertility. In addition, sperm preparation techniques such as centrifugation, used prior to in vitro fertilization, are associated with the generation of reactive oxygen species (ROS) and an increase in the level of DNA damage. Factors that can offer spermatozoa protection are, therefore, of great importance. This study was designed to examine in vitro the effect of a Chilean propolis ethanolic extract on human spermatozoa treated with benzo[a]pyrene and exogenous reactive oxygen species. Our experimental evidence demonstrated that the natural drug under investigation is able to protect genomic DNA by damage induced by benzo[a]pyrene, hydrogen peroxide (H(2)O(2)) and hydrogen peroxide in combination with adenosine 5'-diphosphate (ADP) and ferrous sulfate (FeSO(4)), determining a significant reduction of the intracellular oxidants. An increase in membrane damage, measured by monitoring the formation of thiobarbituric acid-reactive substances (TBARS) and lactic dehydrogenase (LDH) release, was observed only in sperm treated with H(2)O(2), ADP and FeSO(4). The propolis extract was shown to possess the capacity to protect sperm membrane from the deleterious action of oxidative attack, reducing TBARS formation and LDH release. In summary, our results evidence that the protective effect exhibited by this natural compound in human spermatozoa is correlated, at least in part, to the antioxidant capacity of its active components, and suggest that propolis may have a role in protection against male infertility.

PMID: 16457855 [PubMed - as supplied by publisher]


2: Life Sci. 2005 Dec 20; [Epub ahead of print]

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Therapeutic effect of paclitaxel and propolis on lipid peroxidation and antioxidant system in 7,12 dimethyl benz(a)anthracene-induced breast cancer in female Sprague Dawley rats.

Padmavathi R, Senthilnathan P, Chodon D, Sakthisekaran D.

Department of Medical Biochemistry, University of Madras, Taramani campus, Chennai-600 113, Tamilnadu, India.

Breast cancer is one of the most common cancers in women of developed and developing countries. The optimum management of which requires a multidisciplinary approach including the use of certain biochemical and molecular markers. The effect of propolis along with paclitaxel on 7,12 dimethyl benz(a)anthracene (DMBA) induced experimental breast cancer was investigated in female Sprague Dawley rats. Female Sprague Dawley rats were divided into five groups of six animals each. Group I served as normal control animal. Group II animals received DMBA (20 mg in 0.5 ml sunflower oil and 0.5 ml of saline) i.p. to develop mammary tumor by the end of 90 days. Group III were breast cancer animals treated with 33 mg paclitaxel/kg body weight (bw) weekly once for 4 weeks. Group IV were breast cancer-bearing animals treated with 50 mg propolis/kg bw for 30 days. Group V were breast cancer-bearing animals treated with both paclitaxel and propolis as mentioned above. Administration of paclitaxel and propolis effectively suppressed breast cancer, which is revealed by the decrease in the extent of lipid peroxidation (LPO) with concomitant increase in the activities of enzymic antioxidants (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) and non-enzymic antioxidants (reduced glutathione (GSH), Vitamin C and Vitamin E) levels when compared to breast cancer-bearing animals treated with either paclitaxel or propolis alone. From our results, we conclude that propolis is a potent antioxidant and, when given in combination with paclitaxel, offers maximum protection against DMBA induced mammary carcinogenesis.

PMID: 16375927 [PubMed - as supplied by publisher]


3: J Agric Food Chem. 2005 Dec 28;53(26):10306-9.

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Suppressive effects of ethanolic extracts from propolis and its main botanical origin on dioxin toxicity.

Park YK, Fukuda I, Ashida H, Nishiumi S, Yoshida K, Daugsch A, Sato HH, Pastore GM.

Department of Food Science, College of Food Engineering, State University of Campinas, P.O. Box 6177, Campinas, SP, Brazil. ykpark@fea.unicamp.br

Suppressive effects of ethanolic extracts prepared from propolis group 12 and its main botanical origin (leaf bud of Baccharis dracunculifolia) on transformation of the aryl hydrocarbon receptor (AhR), the initial action of dioxin toxicity, were investigated. It was found that suppressive effects of propolis on AhR transformation were relatively higher than those of resins of its botanical origin in cell-free system and in Hepa-1c1c7 cells. When the composition of chemical ingredients was measured, propolis contained slightly higher amounts of flavonoid aglycones as compared with its botanical origin with the same characteristics. Moreover, antiradical activity, one of the typical biological activities of flavonoids, in propolis was also slightly higher than that in its botanical origin. These results indicate that not only propolis but also its botanical origin contains high amounts of flavonoid aglycones and that both of them are useful dietary sources for flavonoids with a potency to prevent dioxin toxicity.

PMID: 16366731 [PubMed - indexed for MEDLINE]


4: Toxicol Ind Health. 2005 Oct;21(9):223-30.

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Mobile phone-induced myocardial oxidative stress: protection by a novel antioxidant agent caffeic acid phenethyl ester.

Ozguner F, Altinbas A, Ozaydin M, Dogan A, Vural H, Kisioglu AN, Cesur G, Yildirim NG.

Department of Physiology, School of Medicine, Suleyman Demirel University, Isparta, Turkey. drmfehmi@yahoo.com

Electromagnetic radiation (EMR) or radiofrequency fields of cellular mobile phones may affect biological systems by increasing free radicals, which appear mainly to enhance lipid peroxidation, and by changing the antioxidant defense systems of human tissues, thus leading to oxidative stress. Mobile phones are used in close proximity to the heart, therefore 900 MHz EMR emitting mobile phones may be absorbed by the heart. Caffeic acid phenethyl ester (CAPE), one of the major components of honeybee propolis, was recently found to be a potent free radical scavenger and antioxidant, and is used in folk medicine. The aim of this study was to examine 900 MHz mobile phone-induced oxidative stress that promotes production of reactive oxygen species (ROS) and the role of CAPE on myocardial tissue against possible oxidative damage in rats. Thirty rats were used in the study. Animals were randomly grouped as follows: sham-operated control group (N: 10) and experimental groups: (a) group II: 900 MHz EMR exposed group (N: 10); and (b) group III: 900 MHz EMR exposed+CAPE-treated group (N: 10). A 900 MHz EMR radiation was applied to groups II and III 30 min/day, for 10 days using an experimental exposure device. Malondialdehyde (MDA, an index of lipid peroxidation), and nitric oxide (NO, a marker of oxidative stress) were used as markers of oxidative stress-induced heart impairment. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status. In the EMR exposed group, while tissue MDA and NO levels increased, SOD, CAT and GSH-Px activities were reduced. CAPE treatment in group III reversed these effects. In this study, the increased levels of MDA and NO and the decreased levels of myocardial SOD, CAT and GSH-Px activities demonstrate the role of oxidative mechanisms in 900 MHz mobile phone-induced heart tissue damage, and CAPE, via its free radical scavenging and antioxidant properties, ameliorates oxidative heart injury. These results show that CAPE exhibits a protective effect on mobile phone-induced and free radical mediated oxidative heart impairment in rats.

PMID: 16342473 [PubMed - indexed for MEDLINE]


5: Mol Cell Biochem. 2006 Jan;281(1-2):153-61.

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The protective role of topical propolis on experimental keratitis via nitric oxide levels in rabbits.

Duran N, Koc A, Oksuz H, Tamer C, Akaydin Y, Kozlu T, Celik M.

Department of Microbiology, Faculty of Medicine, Mustafa Kemal University, Hatay, Turkey.

The aim of this study was to investigate antioxidant, anti-inflammatory, and antibacterial properties of propolis in the treatment of experimental Staphylococcus aureus keratitis. Twenty young New Zealand white rabbits were used in this experiment. Staphylococcus aureus were given by intrastromal injection to 16 rabbits and 4 rabbits were used as control group (Group 1). Group 2 was treated with phosphate-buffered solution drops; Group 3 was administered ethanolic extract of propolis drops; Group 4 received topical ciprofloxacin drops; Group 5 was treated with topical ciprofloxacin drops along with ethanolic extract of propolis drops. The eyes were examined by slit lamp to assess corneal opacity. And then, corneas were removed to determine nitric oxide (NO) levels and count bacteria. Corneas were also evaluated histologically. Corneal NO concentration in gruop 5, treated with a combination of propolis and ciprofloxacin was determined significantly lower (10.0+/- 1.8 mumol/g wet tissue) than in Group 4, treated with ciprofloxacin (24.0+/- 3.1 mumol/g wet tissue), from Group 3, treated with propolis (15.6+/- 1.8 mumol/g wet tissue), and treated with PBS (44.7+/- 7.8 mumol/g wet tissue). There were significantly fewer bacteria in eyes that received propolis plus ciprofloxacin than in eyes treated with ciprofloxacin (p = 0.0001) or propolis (p = 0.0001) or eyes treated with PBS (p = 0.0001). The light microscopic examination revealed that the control group showed normal corneal morphology. In the nontreated group, sections of the stromal infiltration revealed the presence of inflammatory cells, which were diffusely distributed (p < 0.05). Administrations of ciprofloxacin plus propolis resulted in a significantly reduced histological damage with fewer bacterial inoculation of the corneal stroma in comparison with the other groups (p < 0.05). Based on these findings, we suggest that ethanolic extract of propolis has antioxidant, anti-inflammatory, and antibacterial properties for S. aureus keratitis in rabbits.

PMID: 16328968 [PubMed - in process]


6: Mol Cell Biochem. 2006 Jan;282(1-2):83-8.

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Protective effects of melatonin and caffeic acid phenethyl ester against retinal oxidative stress in long-term use of mobile phone: A comparative study.

Ozguner F, Bardak Y, Comlekci S.

Department of Physiology, School of Medicine, Suleyman Demirel University, P. K. 13, Isparta, 32100, Turkey, drmfehmi@yahoo.com.

There are numerous reports on the effects of electromagnetic radiation (EMR) in various cellular systems. Melatonin and caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, were recently found to be potent free radical scavengers and antioxidants. Mechanisms of adverse effects of EMR indicate that reactive oxygen species may play a role in the biological effects of this radiation. The present study was carried out to compare the efficacy of the protective effects of melatonin and CAPE against retinal oxidative stress due to long-term exposure to 900 MHz EMR emitting mobile phones. Melatonin and CAPE were administered daily for 60 days to the rats prior to their EMR exposure during our study. Nitric oxide (NO, an oxidant product) levels and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of retinal oxidative stress in rats following to use of EMR. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in retinal tissue. Retinal levels of NO and MDA increased in EMR exposed rats while both melatonin and CAPE caused a significant reduction in the levels of NO and MDA. Likewise, retinal SOD, GSH-Px and CAT activities decreased in EMR exposed animals while melatonin and CAPE caused a significant increase in the activities of these antioxidant enzymes. Treatment of EMR exposed rats with melatonin or CAPE increased the activities of SOD, GSH-Px and CAT to higher levels than those of control rats. In conclusion, melatonin and CAPE reduce retinal oxidative stress after long-term exposure to 900 MHz emitting mobile phone. Nevertheless, there was no statistically significant difference between the efficacies of these two antioxidants against to EMR induced oxidative stress in rat retina. The difference was in only GSH-Px activity in rat retina. Melatonin stimulated the retinal GSH-Px activity more efficiently than CAPE did.

PMID: 16317515 [PubMed - in process]


7: Am J Kidney Dis. 2005 Dec;46(6):e125-9.

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Acute renal failure induced by a Brazilian variety of propolis.

Li YJ, Lin JL, Yang CW, Yu CC.

Department of Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan.

Propolis is a resinous substance collected by honeybees and used in hive construction and maintenance. Cumulative evidence suggests that propolis may have anti-inflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties. In addition to topical applications, products containing propolis have been used increasingly as dietary supplements. Although reports of allergic reactions are not uncommon, propolis is reputed to be relatively nontoxic. Its systemic toxicity is rarely reported and hence may be underestimated. This is the first report of propolis-induced acute renal failure. A 59-year-old man required hemodialysis for acute renal failure. The patient had cholangiocarcinoma and had ingested propolis for 2 weeks before presentation. Renal function improved after propolis withdrawal, deteriorated again after reexposure, and then returned to a normal level after the second propolis withdrawal. This case indicates that propolis can induce acute renal failure and emphasizes the need for vigilance and care when propolis is used as a medicine or dietary supplement.

Publication Types:

·       Case Reports


PMID: 16310564 [PubMed - indexed for MEDLINE]


8: Life Sci. 2005 Nov 19; [Epub ahead of print]

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Caffeic acid phenethyl ester ameliorates cerebral infarction in rats subjected to focal cerebral ischemia.

Tsai SK, Lin MJ, Liao PH, Yang CY, Lin SM, Liu SM, Lin RH, Chih CL, Huang SS.

Department of Anesthesiology, College of Medicine, Buddhist Tzu-Chi University and Hospital, National Taiwan University, Taipei Veterans General Hospital, Taipei, Taiwan.

The effects of caffeic acid phenethyl ester (CAPE), an antioxidant derived from propolis, on the infarct volume elicited by focal cerebral ischemia were studied on Long-Evans rats. Cerebral infarction was induced by microsurgical procedures with ligation of the right middle cerebral artery (MCA) and clipping of bilateral common carotid arteries (CCA) for 60 min. The rats were sacrificed 24 h later and serial brain slices of 2 mm thickness were taken and stained for the measurement of infarct area. CAPE was administered intravenously 15 min before MCA occlusion. Pretreatment of CAPE (0.1, 1 and 10 mug/kg) significantly reduced the total infarct volume from 169.6+/-14.5 mm(3) (control) to 61.0+/-24.1 mm(3) (0.1 mug/kg CAPE), 47.4+/-9.1 mm(3) (1 mug/kg CAPE), and 42.4+/-8.7 mm(3) (10 mug/kg CAPE), respectively. Plasma nitric oxide (NO) content was significantly increased in rats subjected to focal cerebral ischemia. It is concluded that CAPE possesses neuroprotective properties in focal cerebral ischemia injury in rats possibly through its antioxidant effect and/or via the upregulation of NO production.

PMID: 16303144 [PubMed - as supplied by publisher]


9: 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]


10: J Agric Food Chem. 2005 Nov 16;53(23):8957-62.

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Evaluation of the cytotoxicity, genotoxicity, mutagenicity, and antimutagenicity of propolis from Tucuman, Argentina.

Nieva Moreno MI, Zampini IC, Ordonez RM, Jaime GS, Vattuone MA, Isla MI.

Instituto de Estudios Vegetales Dr Antonio Rodolfo Sampietro, Facultad de Bioquimica, Quimica y Farmacia, Universidad Nacional de Tucuman, Ayacucho 461, 4000 San Miguel de Tucuman, Argentina.

This study evaluates the toxic, genotoxic/mutagenic, and antimutagenic effects of propolis extract from Amaicha del Valle, Tucuman, Argentina. The cytotoxicity assays carried out with the lethality test of Artemia salina revealed that the LD50 was around 100 microg/mL. Propolis extracts showed no toxicity to Salmonella typhimurium TA98 and TA100 strains and Allium cepa at concentrations that have antibiotic and antioxidant activities. Otherwise, for the testing doses, neither genotoxicity nor mutagenicity was found in any sample. The propolis extracts were able to inhibit the mutagenesis of isoquinoline (IQ) and 4-nitro o-phenylenediamine (NPD) with ID50 values of 40 and 20 microg/plate, respectively. From this result, the studied propolis may be inferred to contain some chemical compounds capable of inhibiting the mutagenicity of direct-acting and indirect-acting mutagens. A compound isolated from Amaicha del Valle propolis, 2',4'-dihydroxychalcone, showed cytotoxic activity (LC50 values of 0.5 microg/mL) but was not genotoxic or mutagenic. Furthermore, this compound was able to inhibit the mutagenicity of IQ (ID50 values of 1 microg/plate) but was unable to inhibit the mutagenicity of NPD. Our results suggest a potential anticarcinogenic activity of Amaicha del Valle propolis and the chalcone isolated from it.

PMID: 16277388 [PubMed - indexed for MEDLINE]


11: Am J Chin Med. 2005;33(5):779-86.

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Protective effect of propolis ethanol extract on ethanol-induced renal toxicity: an in-vivo study.

Liu CF, Lin CH, Lin CC, Lin YH, Chen CF, Lin SC.

National Taipei College of Nursing, Taipei, 112, Taiwan.

Acute p.o. administration of absolute ethanol (10 ml/kg) to fasted mice would produce extensive renal failure. Pretreatment with p.o. administration of propolis ethanol extract (PEE) could prevent such renal failure effectively and dose dependently. This renal protective effect of PEE may be contributed, at least in part, to its antioxidative activity. The maximal antioxidative effect against absolute ethanol (AE)-induced renal failure could be observed 1 hour after PEE administration. In order to further investigate the renal protective mechanism of PEE, lipid peroxidation and superoxide scavenging activity were conducted in vivo. PEE exhibited dose-dependent antioxidative effects on lipid peroxidation in mice renal homogenate. Results indicated that mice with acute renal failure have higher malonic dialdehyde (MDA) levels compared with those in PEE administered mice. It was concluded that the renal protective mechanism of PEE could be contributed, at least in part, to its prominent superoxide scavenging effect; hence, it could protect, indirectly, the kidney from superoxide-induced renal damages.

PMID: 16265990 [PubMed - indexed for MEDLINE]


12: Ann Clin Lab Sci. 2005 Autumn;35(4):440-8.

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In vivo effects of caffeic acid phenethyl ester on myocardial ischemia-reperfusion injury and apoptotic changes in rats.

Cagli K, Bagci C, Gulec M, Cengiz B, Akyol O, Sari I, Cavdar S, Pence S, Dinckan H.

Division of Cardiovascular Surgery, Yuksek Ihtisas Hospital, Ankara, Turkey.

Ischemia/reperfusion (I/R) has been reported to induce apoptotic cellular death in myocardium. This study tested the hypothesis that caffeic acid phenethyl ester (CAPE), one of the active components of propolis, may ameliorate myocardial apoptosis and oxidative myocardial injury. Wistar rats were divided into 4 groups: (i) sham operated, (ii) I/R, (iii) I/R+CAPE, and (iv) I/R+glutathione (GSH). CAPE (10 micromol/kg) was infused iv 10 min before occlusion of the left anterior descending coronary artery (30 min) followed by reperfusion (120 min). GSH (5 mg/kg) was infused iv after the occlusion and immediately before reperfusion. The TdT-mediated in situ nick end-labeling (TUNEL) method was used to evaluate apoptotic activity. I/R resulted in myocardial apoptosis, alterations of antioxidant status, elevation of serum creatine kinase (CK) and aspartate aminotransferase (AST) activities, evidence of lipid peroxidation, and elevated nitric oxide levels, compared to the sham-operation group. No apoptotic cells were found in the myocardial tissue of sham-operated rats. The TUNEL-positive myocardial cells averaged 60%, 30%, and 40% in the I/R, I/R+CAPE, and I/R+GSH groups, respectively. This study demonstrates that pretreatment with CAPE provides cardio-protection from I/R injury. The I/R+CAPE group showed reduced apoptosis, attenuated NO production, elevated myocardial superoxide dismutase (SOD) activity, and diminished serum CK and AST activities, compared to the I/R group.

PMID: 16254262 [PubMed - in process]


13: Cancer Lett. 2005 Oct 15; [Epub ahead of print]

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Dietary artepillin C suppresses the formation of aberrant crypt foci induced by azoxymethane in mouse colon.

Shimizu K, Das SK, Baba M, Matsuura Y, Kanazawa K.

Department of Life Science, Graduate School of Science and Technology, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501, Japan.

Artepillin C, a prenylated phenylpropanoid found specifically in Brazilian propolis, has been shown to be a bioavailable antioxidant. In this study, artepillin C was tested for colon cancer-preventing activity using azoxymethane-challenged ddY mice. Oral doses of 80 and 160mg/kg body weight of propolis or 10mg/kg of artepillin C (equi-amounts to 160mg propolis) reduced significantly the frequency of colonic aberrant crypt foci (ACF) by 39.2, 43.7 and 43.4%, respectively. In liver of the mice, glutathione S-transferase and NADPH:quinone reductase activity increased with the doses of propolis or artepillin C, and an antioxidant-responsive element (ARE) was found to be activated for binding DNA. Artepillin C is considered to suppress the formation of colonic ACF through the activation of ARE and induction of phase II enzymes in liver.

PMID: 16236434 [PubMed - as supplied by publisher]


14: Mol Carcinog. 2005 Dec;44(4):293-9.

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Artepillin C in Brazilian propolis induces G(0)/G(1) arrest via stimulation of Cip1/p21 expression in human colon cancer cells.

Shimizu K, Das SK, Hashimoto T, Sowa Y, Yoshida T, Sakai T, Matsuura Y, Kanazawa K.

Department of Life Science, Graduate School of Science and Technology, Kobe University, Kobe, Japan.

Potential chemopreventive agents exist in foods. Artepillin C in Brazilian propolis was investigated for its effects on colon carcinogenesis. We had found that artepillin C was a bioavailable antioxidant, which could be incorporated into intestinal Caco-2 and hepatic HepG2 cells without any conjugation and inhibited the oxidation of intracellular DNA. Artepillin C was then added to human colon cancer WiDr cells. It dose-dependently inhibited cell growth, inducing G(0)/G(1) arrest. The events involved a decrease in the kinase activity of a complex of cyclin D/cyclin-dependent kinase 4 and in the levels of retinoblastoma protein phosphorylated at Ser 780 and 807/811. The inhibitors of the complex, Cip1/p21 and Kip1/p27, increased at the protein level. On the other hand, Northern blotting showed that artepillin C did not affect the expression of Kip1/p27 mRNA. According to the experiments using isogenic human colorectal carcinoma cell lines, artepillin C failed to induce G(0)/G(1) arrest in the Cip1/p21-deleted HCT116 cells, but not in the wild-type HCT116 cells. Artepillin C appears to prevent colon cancer through the induction of cell-cycle arrest by stimulating the expression of Cip1/p21 and to be a useful chemopreventing factor in colon carcinogenesis.

PMID: 16224795 [PubMed - indexed for MEDLINE]


15: Biomed Pharmacother. 2005 Dec;59(10):561-70. Epub 2005 Aug 10.

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Antitumor, hematostimulative and radioprotective action of water-soluble derivative of propolis (WSDP).

Orsolic N, Basic I.

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

Several studies suggest that dietary supplementation with antioxidant can influence the response to chemotherapy as well as the development of adverse side effects caused by treatment with chemotherapeutic agents. Using CBA mouse model, we investigated a clinically potential use of a water-soluble derivative of propolis (WSDP) in the treatment of various cytopenias induced by radiation and/or chemotherapy. Also, the antimetastatic efficiency of WSDP given intraperitoneally alone or in combination with chemotherapeutic agents and their effects on the blood leukocytes count as well as on hematopoiesis were studied. Tumor was a transplantable mammary carcinoma (MCa) of CBA mouse. Metastases in the lung were generated by injecting viable tumor cells intravenously (iv). WSDP (50 or 150 mg/kg) exerted a significant antimetastatic effect (P < 0.001) when given either before or after tumor cell inoculation. In combined treatment WSDP and Epirubicin profoundly inhibited metastasis formation; this synergistic effect is maximal when Epirubicin and WSDP were administrated after tumor cell inoculation. Positive outcome of combined treatment with WSDP and Epirubicin was also found regarding the number of red and white blood cells in peripheral blood while in mice treated with Epirubicin alone the significant drop in all hematological parameters was noticed on day 13 after tumor cell inoculation. Furthermore, when WSDP (50 mg/kg) was given perorally (po) for 20 consecutive days an increased number of exogenous CFUs was found in treated mice. WSDP given either for 20 or 40 days increased cellularity of hematopoietic tissue and the number of leucocytes in peripheral blood; prolonged treatment with WSDP also elevated myeloid and megakaryocytic types of CFUs. To conclude, these findings indicate that the combination of WSDP with chemotherapeutics could increase the antimetastatic potential of chemotherapeutic agents; these findings suggest the benefits of potential clinical trials using WSDP combined with chemotherapeutic agents in order to maximize their antitumor activity and minimize postchemotherapeutic or radiotherapeutic deteriorated reactions.

PMID: 16202559 [PubMed - indexed for MEDLINE]


16: Mol Cell Biochem. 2005 Sep;277(1-2):109-15.

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Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester.

Oktem F, Ozguner F, Sulak O, Olgar S, Akturk O, Yilmaz HR, Altuntas I.

Department of Pediatric Nephrology, School of Medicine, Suleyman Demirel University, P.K. 13, 32100, Isparta, Turkey. oktemfaruk@hotmail.com

Lithium carbonate used in the long-term treatment of manic-depressive illness has been reported to lead to progressive renal impairment in rats and humans. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygene species mediated oxidative stress in ischemia-reperfusion and toxic injuries. The beneficial effect CAPE on lithium-induced nephrotoxicity has not been reported yet. The purpose of this study was to examine a possible renoprotective effect of CAPE against lithium-induced nephrotoxicity in a rat model. Twenty-two adult male rats were randomly divided into three experimental groups, as follows: control group, lithium-treated group (Li), and lithium plus CAPE-treated group (Li+CAPE). Li were treated intraperitoneally (i.p.) with 25 mg/kg Li2CO3 solution in 0.9% NaCl twice daily for 4 weeks. CAPE was co-administered i.p. with a dose of 10 microM/kg/day for 4 weeks. Serum Li, blood urea nitrogen and plasma creatinine, urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury), and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in Li-treated rats. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Serum Li levels were found high in the Li and Li+CAPE groups. In Li-administrated rats, urinary NAG and renal MDA levels were increased according to control and Li+CAPE groups (p < 0.05). CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD, CAT and GSH-Px activities were decreased in Li-administrated animals; CAPE caused a significant increase in the activities of these antioxidant enzymes. In conclusion, CAPE treatment has a protective effect against Li-induced renal tubular damage and oxidative stress in a rat model.

PMID: 16132721 [PubMed - indexed for MEDLINE]


17: Mol Cell Biochem. 2005 Sep;277(1-2):73-80.

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A novel antioxidant agent caffeic acid phenethyl ester prevents long-term mobile phone exposure-induced renal impairment in rat. Prognostic value of malondialdehyde, N-acetyl-beta-D-glucosaminidase and nitric oxide determination.

Ozguner F, Oktem F, Ayata A, Koyu A, Yilmaz HR.

Department of Physiology, School of Medicine, Suleyman Demirel University, P. K. 13, Isparta, 32100, Turkey. drmfehmi@yahoo.com

Caffeic acid phenethyl ester (CAPE), a flavonoid like compound, is one of the major components of honeybee propolis. It has been used in folk medicine for many years in Middle East countries. It was found to be a potent free radical scavenger and antioxidant recently. The aim of this study was to examine long-term applied 900 MHz emitting mobile phone-induced oxidative stress that promotes production of reactive oxygen species (ROS) and, was to investigate the role of CAPE on kidney tissue against the possible electromagnetic radiation (EMR)-induced renal impairment in rats. In particular, the ROS such as superoxide and nitric oxide (NO) may contribute to the pathophysiology of EMR-induced renal impairment. Malondialdehyde (MDA, an index of lipid peroxidation) levels, urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury) and nitric oxide (NO, an oxidant product) levels were used as markers of oxidative stress-induced renal impairment and the success of CAPE treatment. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in renal tissue were determined to evaluate the changes of antioxidant status. The rats used in the study were randomly grouped (10 each) as follows: i) Control group (without stress and EMR), ii) Sham-operated rats stayed without exposure to EMR (exposure device off), iii) Rats exposed to 900 MHz EMR (EMR group), and iv) A 900 MHz EMR exposed + CAPE treated group (EMR + CAPE group). In the EMR exposed group, while tissue MDA, NO levels and urinary NAG levels increased (p < 0.0001), the activities of SOD, CAT, and GSH-Px in renal tissue were reduced (p < 0.001). CAPE treatment reversed these effects as well (p < 0.0001, p < 0.001 respectively). In conclusion, the increase in NO and MDA levels of renal tissue, and in urinary NAG with the decrease in renal SOD, CAT, GSH-Px activities demonstrate the role of oxidative mechanisms in 900 MHz mobile phone-induced renal tissue damage, and CAPE, via its free radical scavenging and antioxidant properties, ameliorates oxidative renal damage. These results strongly suggest that CAPE exhibits a protective effect on mobile phone-induced and free radical mediated oxidative renal impairment in rats.

PMID: 16132717 [PubMed - indexed for MEDLINE]


18: Mol Cell Biochem. 2005 Aug;276(1-2):31-7.

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Comparative analysis of the protective effects of melatonin and caffeic acid phenethyl ester (CAPE) on mobile phone-induced renal impairment in rat.

Ozguner F, Oktem F, Armagan A, Yilmaz R, Koyu A, Demirel R, Vural H, Uz E.

Department of Physiology, School of Medicine, Suleyman Demirel University, P. K. 13 32100 Isparta, Turkey. drmfehmi@yahoo.com

Melatonin and caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, were recently found to be potent free radical scavengers and antioxidants. There are a number of reports on the effects induced by electromagnetic radiation (EMR) in various cellular systems. Mechanisms of adverse effects of EMR indicate that reactive oxygen species may play a role in the biological effects of this radiation. The present study was carried out to compare the protective effects of melatonin and CAPE against 900 MHz EMR emitted mobile phone-induced renal tubular injury. Melatonin was administered whereas CAPE was given for 10 days before the exposure. Urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury) and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in rats exposed to EMR. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Urinary NAG and renal MDA were increased in EMR exposed rats while both melatonin and CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD and GSH-Px activities were decreased in EMR exposed animals while melatonin caused a significant increase in the activities of these antioxidant enzymes but CAPE did not. Melatonin caused a significant decrease in urinary NAG activity and MDA levels which were increased because of EMR exposure. CAPE also reduced elevated MDA levels in EMR exposed renal tissue, but the effect of melatonin was more potent than that of CAPE. Furthermore, treatment of EMR exposed rats with melatonin increased activities of SOD and GSH-Px to higher levels than those of control rats. In conclusion, melatonin and CAPE prevent renal tubular injury by reducing oxidative stress and protect the kidney from oxidative damage induced by 900 MHz mobile phone. Nevertheless, melatonin seems to be a more potent antioxidant compared with CAPE in kidney.
(Mol Cell Biochem 276: 31-37, 2005).

PMID: 16132682 [PubMed - indexed for MEDLINE]


19: Clin Biochem. 2005 Oct;38(10):943-7.

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Antiarrhythmic effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia/reperfusion injury in rats.

Huang SS, Liu SM, Lin SM, Liao PH, Lin RH, Chen YC, Chih CL, Tsai SK.

Department of Pharmacology and Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.

OBJECTIVES: The present study was designed to determine the antiarrhythmic effect of caffeic acid phenethyl ester (CAPE), an active component of propolis, which exhibits antioxidant properties, in rats subjected to myocardial ischemia and ischemia-reperfusion (I/R) injury. DESIGN AND METHODS: Rats were subjected to 30 min coronary artery occlusion for evaluating the effect of CAPE on the myocardial ischemia injury. While in the myocardial I/R injury study, the coronary artery was ligated for a 5-min period of ischemia followed by a 30-min period of reperfusion. Animals were pretreated with or without CAPE before coronary artery ligation and the severity of myocardial ischemia- and I/R-induced arrhythmias and mortality were compared. RESULTS: Pretreatment of CAPE (0.1 and 1 microg/kg) not only reduced both the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) but also decreased the mortality during the myocardial ischemia and I/R injury period. CONCLUSIONS: Our results suggest that CAPE is a potent antiarrhythmic agent with cardioprotective effects in myocardial ischemia and I/R injury rats.

PMID: 16098504 [PubMed - indexed for MEDLINE]


20: Nat Prod Res. 2005 Oct;19(7):673-8.

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Chemical composition of propolis from Canada, its antiradical activity and plant origin.

Christov R, Trusheva B, Popova M, Bankova V, Bertrand M.

Regional Center for Mass Spectrometry, Department of Chemistry, University of Montreal, Quebec, Canada.

The chemical composition of propolis from two regions in Canada was studied: Boreal forest and the Pacific coastal forest that lie outside the area of distribution of Aigeiros poplars, the usual propolis source plants. In the sample from Victoria, p-hydroxyacetophenone, benzyl hydroxybenzoate and cinnamic acid were the major components, accompanied by significant amounts of dihydrochalcones, which allowed the identification of its plant source: Populus trichocarpa of section Tacamahaca. Three dihydrochalcones were new for propolis. The sample from Richmond was characterized by large amounts of p-coumaric and cinnamic acid, typical for poplars of section Leuce, subsection Trepidae, its plant source was identified as P. tremuloides. Both samples showed a good radical scavenging activity against DPPH. Obviously, the Northern type propolis is a promising potential source of biologically active substances and deserves further investigation.

PMID: 16076637 [PubMed - indexed for MEDLINE]


21: 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]


22: Int Immunopharmacol. 2005 Oct;5(11):1652-7.

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Effects of Turkish pollen and propolis extracts on respiratory burst for K-562 cell lines.

Aliyazicioglu Y, Deger O, Ovali E, Barlak Y, Hosver I, Tekelioglu Y, Karahan SC.

Department of Biochemistry, Faculty of Medicine, Ondokuz Mayis University, Samsun, 55139, Turkey.

Bee-collected pollen and propolis are apicultural products which are composed of nutritionally valuable substances and contain considerable amounts of polyphenol substances which may act as potent antioxidants. We wanted to show if respiratory burst within a cancer cell lines could be influenced when incubated with pollen and propolis extracts or not. Pollen and propolis extracts at concentrations of 50, 25, 12.5 and 0 mg/ml were prepared by dimethyl sulfoxide (DMSO). K-562 cell cultures and mononuclear cell (MNC) cultures prepared from a peripheral blood sample to serve as control cells were incubated with extracts for 24 h. Determination of respiratory burst was carried out by intracellular dichlorofluorescein (DCFH) test by using flow-cytometric fluorescence analysis. While about 90% and 66% fluorescence was detected at zero concentrations for both K-562 and MNC cultures, fluorescence positivity decreased (between 3.8% and 11.8%) as concentrations of both propolis and pollen extracts increased for K-562 cell culture, but unchanged (between 20% and 83%) for MNC culture. It was concluded that pollen and propolis extracts inhibit respiratory burst within cancer cell lines probably by their antioxidant potentials.

PMID: 16039555 [PubMed - indexed for MEDLINE]


23: Exp Lung Res. 2005 Jun;31(5):483-96.

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Oleic acid-induced lung injury in rats and effects of caffeic acid phenethyl ester.

Koksel O, Kaplan MB, Ozdulger A, Tamer L, Degirmenci U, Cinel L, Basturk M, Kanik A.

Department of Thoracic Surgery, Mersin University, School of Medicine, 33079 Mersin, Turkey. oguzkoksel@mersin.edu.tr

Caffeic acid phenethyl ester (CAPE) is a phenolic antioxidant and is an active anti-inflammatory component of honeybee propolis. The authors evaluated the effects of CAPE on oxidative stress and lung damage in an oleic acid (OA)-induced lung-injury model. Rats were divided into 5 groups as sham, OA, CAPE, pre-OA-CAPE, and post-OA-CAPE. Acute lung injury was induced by intravenous administration of 100 mg/kg of OA. Pre-OA-CAPE group received CAPE (10 micromol/kg. intravenously) 15 minutes before OA infusion and post-OA-CAPE group received CAPE 2 hours after OA administration. Malondialdehyde (MDA) level of plasma, bronchoalveolar lavage fluid (BALF), and lung tissue; myeloperoxidase activity of BALF and lung tissue; Na(+)-K(+) ATPase activity of lung tissue; and total protein content of BALF were measured. Light microscopic analyses of lung specimens were performed. The increased MDA levels in lung homogenates (47.98+/-13.75 nmol/mL), BALF (31.12+/-3.07 nmol/mL), and plasma (61.84+/-15.34 nmol/mL) decreased significantly to 24.33+/-3.09 nmol/mL (P = 0.000), 23.19+/-4.97 nmol/mL (P = 0.002), and 27.36+/-5.37 nmol/mL (P = 0.000), respectively, following CAPE administration in pre-OA-CAPE group. Another important finding was the restoration of the enzymatic activity of Na(+)-K(+) ATPase from a value of 203.89+/-32.18 nmol Pi/mg Protein/h in OA group, to a value of 302.17+/-51.90 nmol Pi/mg Protein/h (P = 0.012) in pre-OA-CAPE group with CAPE treatment. CAPE has been shown to have a clear attenuating effect on oxidative damage in experimental animal studies. However, further investigations are necessary to suggest CAPE as a treatment agent in critically ill patients with lung injury.

PMID: 16019983 [PubMed - indexed for MEDLINE]


24: Toxicology. 2005 Sep 1;212(2-3):155-64.

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The protective effect of caffeic acid phenethyl ester against cyclosporine A-induced cardiotoxicity in rats.

Rezzani R, Giugno L, Buffoli B, Bonomini F, Bianchi R.

Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, 25123 Brescia, Italy. rezzani@med.unibs.it

Cyclosporine A (CsA) is the immunosuppressor, which is most frequently used in transplant surgery and in the treatment of autoimmune diseases. Oxidative stress has been considered as one of the possible mechanisms of CsA-induced cardiotoxicity. The present investigation examines the ability of caffeic acid phenethyl ester (CAPE), which is an active component of propolis extracts, as a natural antioxidant to protect against CsA-induced oxidative stress and cardiotoxicity. CsA cardiotoxicity was induced by subcutaneous injection of CsA at a dose of 15 mg/kg/body weight daily for 21 days in rats. Cardiotoxicity was evaluated by morphological and biochemical studies. CsA treated rats showed degenerative changes with cardiac fibrosis localized around the fibers. These latters were disorganised and the network was disappeared. The ROS production was increased whereas cytochrome-c-oxidase decreased. The expression and levels of matrix metalloproteinase 2 (MMP2) were increased whereas those of its inhibitor were downregulated. CAPE subcutaneous administration (15 micromol/kg/day) improved cardiac cytoarchitecture, decreased the levels and the expression of MMP2, and increased those of TIMP2 proteins. Moreover, it increased cytochrome-c-oxidase activity and decreased ROS production. These results suggest that CAPE could have protective effect against CsA-induced cardiotoxicity.

PMID: 15967562 [PubMed - indexed for MEDLINE]


25: 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]


26: J Pharm Biomed Anal. 2005 Sep 15;39(3-4):455-62.

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Assessment of the antioxidant activities of Brazilian extracts of propolis alone and in topical pharmaceutical formulations.

Marquele FD, Di Mambro VM, Georgetti SR, Casagrande R, Valim YM, Fonseca MJ.

Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of Ribeirao Preto-USP, Av. do Cafe s/n 14049, 903 Ribeirao Preto, SP, Brazil. frandm@fcfrp.usp.br

The antioxidant activity of extracts of propolis and of formulations added with these extracts were measured by scavenging different radicals in different systems. For the ethanolic extract of propolis (EEP) and the glycolic extract of propolis (GEP) the IC50 observed were respectively of 0.024 and 0.035 microL/mL in scavenging hydroxyl radical, 0.016 and 0.012 microL/mL in inhibiting lipid peroxidation, 0.22 and 0.24 microL/mL in inhibiting chemiluminescence produced in the H2O2/luminol/horseradish peroxide (HRP) system and about 0.005 microL/mL for both extracts in inhibiting chemiluminescence produced in the xanthine/luminol/xanthine oxidase (XOD) system. The antioxidant activity of extracts of propolis in the formulations was not able to be assessed neither using the deoxyribose assay, since the formulation components interfered in the assay measurements, nor using chemiluminescence in the H2O2/luminol/HRP system, since this method did not show to be sensitive for the extract of propolis evaluation. However, the antioxidant activity of extracts of propolis could be successfully evaluated in the formulations using both lipid peroxidation and chemiluminescence generated in the xanthine/luminol/XOD system inhibitions.

PMID: 15908158 [PubMed - indexed for MEDLINE]


27: 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]


28: Biochem Pharmacol. 2005 Jun 15;69(12):1815-27.

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Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase.

Weng MS, Ho YS, Lin JK.

Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 10018, Taiwan.

Flavonoids are a broadly distributed class of plant pigments, universally present in plants. They are strong anti-oxidants that can inhibit carcinogenesis in rodents. Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from many plants, honey, and propolis. It possesses potent anti-inflammatory, anti-oxidant properties, promotes cell death, and perturbing cell cycle progression. However, the mechanism by which chrysin inhibits cancer cell growth remains poorly understood. Therefore, we developed an interest in the relationship between MAPK signaling pathways and cell growth inhibition after chrysin treatment in rat C6 glioma cells. Cell viability assay and flow cytometric analysis suggested that chrysin exhibited a dose-dependent and time-dependent ability to block rat C6 glioma cell line cell cycle progression at the G1 phase. Western blotting analysis showed that the levels of Rb phosphorylation in C6 glioma cells exposed to 30 microM chrysin for 24h decreased significantly. We demonstrated the expression of cyclin-dependent kinase inhibitor, p21(Waf1/Cip1), to be significantly increased, but the p53 protein level did not change in chrysin-treated cells. Both cyclin-dependent kinase 2 (CDK2) and 4 (CDK4) kinase activities were reduced by chrysin in a dose-dependent manner. Furthermore, chrysin also inhibited proteasome activity. We further showed that chrysin induced p38-MAPK activation, and using a specific p38-MAPK inhibitor, SB203580, attenuated chrysin-induced p21(Waf1/Cip1) expression. These results suggest that chrysin exerts its growth-inhibitory effects either through activating p38-MAPK leading to the accumulation of p21(Waf1/Cip1) protein or mediating the inhibition of proteasome activity.

PMID: 15869744 [PubMed - indexed for MEDLINE]


29: 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]


30: Biol Pharm Bull. 2005 Apr;28(4):694-700.

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Synergistic antitumor effect of polyphenolic components of water soluble derivative of propolis against Ehrlich ascites tumour.

Orsolic N, Kosalec I, Basic I.

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

Effect of two preparation (Croatian and Brazilian) of water-soluble derivative of propolis (WSDP), caffeic acid, quercetin, chrysin, naringenin (components present in WSDP) on the development of Ehrlich ascites tumour (EAT) was evaluated. Test components (50 mg/kg) were given perorally or intraperitoneally 2 h prior the intraperitonel injection of EAT (2 x 10(6)) cells. It was observed that all test compounds effectively inhibited tumour growth and the proliferation of EAT. The volume of ascitic fluid induced by EAT cells and total number of cells present in the peritoneal cavity was markedly reduced in EAT-bearing mice treated with test components. In treated mice the number of polymorphonuclear (PMN) cells in the peritoneal cavity was increased while the number of macrophages was decreased. The macrophage spreading activity revealed that WSDP and all test compounds affected the functional state of macrophages increasing their tumorcidal activity; the effect of WSDP was most pronounced indicating synergistic effect of components present in WSDP. Antitumor activity of WSDP may be the result of different specific mechanism(s) of flavonoids present as compared to individual flavonoid given alone. It is likely that the part of antitumor efficacy of test components against EAT cells was the results of increased activity of macrophages.

PMID: 15802812 [PubMed - indexed for MEDLINE]


31: Acta Med Croatica. 2004;58(5):373-6.

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[Antioxidative activity of propolis from Dalmatia (Croatia)]

[Article in Croatian]

Katalinic V, Radic S, Ropac D, Mulic R, Katalinic A.

Odjel sanitarne kemije i toksikologije, Institut pomorske medicine HRM, Split, Hrvatska.

AIM: The aim of this study was to determine the antioxidative activity of propolis from ecologically clean parts of Dalmatia. METHODS: Phenol concentration in ethanolic propolis extracts was determined by Folin-Ciocalteu reagent using gallic acid as the standard. Flavonoid phenolic compounds were analyzed after precipitation with formaldehyde. The residual non-flavonoid phenolics were also determined by Folin-Ciocalteu method. By determining the change of peroxide number (PN), of tiobarbiture acid reactive species (TBARS), and of DPPH-radical activity, antioxidative efficiency of propolis was tested and compared with well known and widely used synthetic antioxidants. Values of PN and TBARS were determined at 60 degrees C in samples of trigyceride substrate (lard) without and with the addition of antioxidants. Compared was the efficiency of three antioxidants: propolis (alcoholic extract), vitamin E, and (+)-catechin in a concentration of 1%. PN was monitored during 50 days. By the method of Sedlacek, TBARS were measured during 30 days. Antioxidative activity of propolis extract was also measured in terms of hydrogen donating ability using stable radical alpha,alpha-diphenyl-beta-picril hidrazyl (DPPH*) and compared with commercial synthetic antioxidants of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and (+)-cathecin. Inhibition degree of DPPH* was calculated by the formula of Yen and Duh. RESULTS: Total phenol content, expressed as gallic acid, in propolis extracts varied from 75.2 to 90.2 g/kg propolis. The proportion of flavonoids in total phenols ranged from 62% to 65%. Values of TBARS were not increased only in samples with added propolis. The inhibition of DPPH-radical by propolis extracts ranged from 93% to 96%, by catechin 95%, by BHT 49%, and by BHA 64%. Compared to BHT and BHA, propolis extracts showed greater reducing activity against DPPH-radical. DISCUSSION: The chemical composition of propolis, and thus its biological activity depend on the plant from which it has been collected, and on the macro- and microclimatic conditions. Many compounds in propolis exert antioxidative activity. A belief was expressed that the biological activity of propolis is very probably based mostly on its antioxidative efficiency. Dalmatian propolis showed high efficiency in the prevention of oxidative processes. This could be explained by the high proportion of polyphenol constituents, especially flavonoids. A very low and equal degree of increase of PN, as a measure of oxidative processes, was noticed in the samples of triglyceride substrate with the addition of propolis and (+)-catechin. The greatest rise of TBARS was measured in the samples of pure lard. There was no increase of TBARS only in the samples with added propolis. Propolis and (+)-catechin showed great efficiency in the inhibition of DPPH-radical, greater than BHT and BHA, which are widely used in food industry. CONCLUSION: The results indicate that Dalmatian propolis could be an efficient protective agent against oxidative processes in food. The high antioxidative activity of propolis, its natural origin, and present knowledge about its biological properties, make it a very promising nutritional additive for human diet.

PMID: 15756802 [PubMed - indexed for MEDLINE]


32: Yakugaku Zasshi. 2005 Mar;125(3):315-21.

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[Xanthine oxidase inhibitory activity and hypouricemia effect of propolis in rats]

[Article in Japanese]

Yoshizumi K, Nishioka N, Tsuji T.

Fancl Corporation Central Research Laboratory, Yokohama 244-0806, Japan. kayoshizu@fancl.co.jp

The xanthine oxidase (XOD) inhibitory activity of propolis from China and Brazil was measured. The propolis from both place were seen to have XOD inhibitory activity. However, a stronger tendency was shown in the propolis from China. The compounds in each the propolis were measured quantitatively. A great deal of chrysin, galangin, and caffeic acid phenetyl ester were found in the propolis from China, an abundance of p-coumaric acid and artepillin C in the propolis from Brazil. Therefore it was revealed that the propolis compounds are very different depending on their place of origin. The XOD inhibitory activity of these five compounds was measured. Caffeic acid phenetyl ester had the strongest activity, with chrysin and galangin next; p-coumaric acid and artepillin C showed weak XOD inhibitory activity. We evaluated the hypouricemic effect of propolis from China on hyperuricemia induced by the uricase inhibitor, oxonic acid (500 mg/kg p.o., 1 h before the test drugs), and measured plasma uric acid values in rats. Oral propolis had a hypouricemic effect 2 h after its administration to oxonate-pretreated rats. These results suggested that a continuous intake of propolis may be effective for the prevention and the treatment of gout and hyperuricemia.

PMID: 15738631 [PubMed - indexed for MEDLINE]


33: J Ethnopharmacol. 2005 Feb 28;97(2):273-80. Epub 2005 Jan 12.

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Caffeic acid phenethyl ester protects kidneys against carbon tetrachloride toxicity in rats.

Ogeturk M, Kus I, Colakoglu N, Zararsiz I, Ilhan N, Sarsilmaz M.

Department of Anatomy, Faculty of Medicine, Firat University, 23119 Elazig, Turkey.

Caffeic acid phenethyl ester (CAPE), an active component of propolis produced by honeybees, exhibits antioxidant and anti-inflammatory properties. The aim of this study was to investigate possible protective effects of CAPE on carbon tetrachloride (CCl4)-induced renal damage in rats. A total of 24 animals were divided into three equal groups: the control rats received pure olive oil subcutaneously, rats in the second group were injected with CCl4 (0.5 ml/kg, s.c. in olive oil) and rats in the third group were injected with CCl4 (0.5 ml/kg) plus CAPE (10 micromol/kg, i.p.) every other day for one month. At the end of the experimental period, the animals were sacrificed and blood samples were collected. Serum urea and creatinine levels and renal malondialdehyde (MDA) contents were determined. Histopathological examination of the kidney was also performed using light microscopic methods. It was found that kidney MDA levels were increased significantly following CCl4 exposure and this increase was significantly inhibited by CAPE treatment, while no significant changes were observed in serum urea and creatinine levels. CCl4 administration alone also caused histopathologically prominent damage in the kidney compared to the control group. Glomerular and tubular degeneration, interstitial mononuclear cell infiltration and fibrosis, and vascular congestion in the peritubular blood vessels were observed in the renal cortex. With exception of rare vascular congestions, these histopathological changes were disappeared in rats treated with CCl4 plus CAPE. In view of the present findings, it is suggested that CAPE protects kidneys against CCl4 toxicity.

PMID: 15707765 [PubMed - indexed for MEDLINE]


34: 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]


35: 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]


36: Fitoterapia. 2004 Dec;75(7-8):683-9.

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New polyisoprenylated benzophenones from Venezuelan propolis.

Trusheva B, Popova M, Naydenski H, Tsvetkova I, Gregorio Rodriguez J, Bankova V.

Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

Two new polyisoprenylated benzophenones, 18-ethyloxy-17-hydroxy-17,18-dihydroscrobiculatone A and 18-ethyloxy-17-hydroxy-17,18-dihydroscrobiculatone B, together with the known scrobiculatones A and B, were isolated from Venezuelan propolis. The scrobiculatones A and B showed significant antibacterial activity and moderate toxicity to Artemia salina nauplii.

PMID: 15567244 [PubMed - indexed for MEDLINE]


37: J Agric Food Chem. 2004 Dec 1;52(24):7286-92.

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Antioxidant activity and constituents of propolis collected in various areas of Korea.

Ahn MR, Kumazawa S, Hamasaka T, Bang KS, Nakayama T.

Laboratory of Functional Food Science and COE Program in the 21st Century, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

Propolis is a resinous substance collected by honeybees from various plant sources. The composition of propolis depends on time, vegetation, and the area of collection. This study examined the antioxidant activity of propolis from various areas of Korea: Chilgok, Cheongju, Geochang, Muju, Pocheon, and Sangju. Ethanol extracts of propolis (EEP) were prepared and evaluated for their antioxidant activity by beta-carotene bleaching, 1,1-diphenyl-2-picrylhydrazyl free radical scavenging, and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation decolorization assays. Furthermore, the major constituents in EEP were identified by high-performance liquid chromatography analysis with a photodiode array and mass spectrometric detection, and each component was quantitatively analyzed. EEP from Cheongju and Muju had relatively strong antioxidant activity accompanied by high total polyphenol contents. Propolis from Cheongju contained large amounts of antioxidative compounds, such as caffeic acid, kaempferol, and phenethyl caffeate. On the other hand, propolis from Pocheon had compounds not seen in propolis from other areas.

PMID: 15563208 [PubMed - indexed for MEDLINE]


38: Life Sci. 2004 Dec 17;76(5):545-58.

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Chilean propolis: antioxidant activity and antiproliferative action in human tumor cell lines.

Russo A, Cardile V, Sanchez F, Troncoso N, Vanella A, Garbarino JA.

Department of Biological Chemistry, Medical Chemistry and Molecular Biology, University of Catania, v.le A. Doria 6, 95125 Catania-Italy. alrusso@unict.it

Propolis, a natural product derived from plant resins collected by honeybees, has been used for thousands of years in traditional medicine all over the world. The composition of the propolis depends upon the vegetation of the area from where it was collected and on the bee species. In this study, we investigated the antioxidant activity of a propolis sample, provided by NATURANDES-CHILE, collected in a temperate region of central Chile. In addition, this natural compound was tested for its antiproliferative capacity on KB (human mouth epidermoid carcinoma cells), Caco-2 (colon adenocarcinoma cells) and DU-145 (androgen-insensitive prostate cancer cells) human tumor cell lines. Results showed that this Chilean propolis sample exhibits interesting biological properties, correlated with its chemical composition and expressed by its capacity to scavenge free radicals and to inhibit tumor cell growth.

PMID: 15556167 [PubMed - indexed for MEDLINE]


39: Yakugaku Zasshi. 2004 Nov;124(11):847-50.

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[Assessment of antioxidant activity of natural compound by water- and lipid-soluble antioxidant factor]

[Article in Japanese]

Usami E, Kusano G, Katayose T, Wachi H, Seyama Y.

Chigasaki Municipal Hospital, Chigasaki 253-0042, Japan. kusuri@mqi.biglobe.ne.jp

We evaluated the antioxidant activity of natural compounds in water-soluble and lipid-soluble phases and found that ferulic acid, quercetin and caffeic acid showed stronger activity in the water-soluble phase. Various fractions isolated from Bidens pilosa showed this activity mainly in the water-soluble phase. Antioxidant activity in the lipid-soluble phase of propolis depended on the lipophilic extraction.

PMID: 15516812 [PubMed - indexed for MEDLINE]


40: Indian J Exp Biol. 2004 Oct;42(10):993-7.

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Effect of propolis extract on acute carbon tetrachloride induced hepatotoxicity.

Shukla S, Bhadauria M, Jadon A.

School of Studies in Zoology, Jiwaji University, Gwalior, India. dr_sshukla@hotmail.com

Ethanolic extract of propolis was administered to rats intoxicated by carbon tetrachloride. Administration of bolus dose of CCl4 (1.5 ml/kg, ip) resulted in elevation of serum transaminases and serum alkaline phosphatase activities. Levels of hepatic lipid peroxidation were significantly increased. On the contrary, there was significant decrease in hepatic reduced glutathione level. The propolis extract (100 and 200 mg/kg, po) exhibited recoupment in both pre- and post-treatment (prophylactic and curative studies) of biochemical changes induced by CCl4. The post treatment of 200 mg/kg, po extract showed most significant hepatoprotective effect. Histopathological studies showed damage in hepatocytes and disturbed chord arrangement after toxicant administration. Propolis extract (200 mg/kg, po) was found to be more effective in restoring CCl4 induced histopathological alterations.

PMID: 15511003 [PubMed - indexed for MEDLINE]


41: Oncol Res. 2004;14(9):415-26.

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Resveratrol and propolis as necrosis or apoptosis inducers in human prostate carcinoma cells.

Scifo C, Cardile V, Russo A, Consoli R, Vancheri C, Capasso F, Vanella A, Renis M.

Department of Biological Chemistry, Medicinal Chemistry and Molecular Biology, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy.

Vegetables and fruit help the prevention and the therapy of several kinds of cancer because they contain micronutrients, a class of substances that have been shown to exhibit chemopreventive and chemotherapeutic activities. In the present study the effects of resveratrol (100 and 200 microM), a phytoalexin found in grapes, and of the ethanolic extract of propolis (50 and 100 microg/ml), a natural honeybee hive product, were tested in androgen-resistant prostate cancer cells (DU145), a cell line resembling the last stage of prostate carcinoma. A comparison between the activity of these micronutrients and vinorelbine bitartrate (Navelbine), a semi-synthetic drug normally used in the therapy of prostate cancer, was conducted. Several biochemical parameters were tested, such as cell viability (MTT assay), cell membrane integrity (lactate dehydrogenase release), cell redox status (nitric oxide formation, reactive oxygen species production, reduced glutathione levels), genomic DNA fragmentation (COMET assay) with special attention on the presence of apoptotic DNA damage (TUNEL test), and possible mitochondrial transmembrane potential alteration (deltapsi). Our results point out the anticancer activity of resveratrol and propolis extract in human prostate cancer, exerting their cytotoxicity through two different types of cell death: necrosis and apoptosis, respectively. The data obtained suggest the possible use of these micronutrients both in alternative to classic chemotherapy, and in combination with very low dosage of vinorelbine (5 microM).

PMID: 15490973 [PubMed - indexed for MEDLINE]


42: Evid Based Complement Alternat Med. 2004 Sep 1;1(2):175-185.

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Comparison of Radical Scavenging Activity, Cytotoxic Effects and Apoptosis Induction in Human Melanoma Cells by Taiwanese Propolis from Different Sources.

Chen CN, Weng MS, Wu CL, Lin JK.

Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Section 1, Jen-Ai Road, Taipei 100, Taiwan.

Propolis is a sticky substance that is collected from plants by honeybees. We previously demonstrated that propolins A, B, C, D, E and F, isolated from Taiwanese propolis (TP), could effectively induce human melanoma cell apoptosis and were strong antioxidant agents. In this study, we evaluated TP for free radical scavenging activity by DPPH (1,2-diphenyl-2-picrylhydrazyl). The phenolic concentrations were quantified by the Folin-Ciocalteu method. The apoptosis trigger activity in human melanoma cells was evaluated. TP contained a higher level of phenolic compounds and showed strong capability to scavenge free radicals. Additionally, TP1g, TP3, TP4 and TP7 exhibited a cytotoxic effect on human melanoma cells, with an IC(50) of approximately 2.3, 2.0, 3.3 and 3.3 mug/ml, respectively. Flow cytometric analysis for DNA fragmentation indicated that TP1g, TP2, TP3 and TP7 could induce apoptosis in human melanoma cells and there is a marked loss of cells from the G2/M phase of the cell cycle. To address the mechanism of the apoptosis effect of TP, we evaluated its effects on induction of apoptosis-related proteins in human melanoma cells. The levels of procaspase-3 and PARP [poly(ADP-ribose) polymerase] were markedly decreased. Furthermore, propolins A, B, C, D, E and F in TP were determined using HPLC. The results indicate that TP is a rich source of these compounds. The findings suggest that TP induces apoptosis in human melanoma cells due to its high level of propolins.

PMID: 15480443 [PubMed - as supplied by publisher]


43: Cell Biochem Funct. 2004 Sep-Oct;22(5):287-90.

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The effects of the caffeic acid phenethyl ester (CAPE) on erythrocyte membrane damage after hind limb ischaemia-reperfusion.

Tamer L, Sucu N, Ercan B, Unlu A, Calikoglu M, Bilgin R, Degirmenci U, Atik U.

Department of Biochemistry, Medical Faculty, Mersin University, 33079 Mersin, Turkey. lutamer@yahoo.com

Reactive oxygen species have been implicated in pathogenesis injury after ischaemia-reperfusion (I/R). Caffeic Acid Phenethyl Ester (CAPE), an active component of honeybee propolis extract, exhibits antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of CAPE on erythrocyte membrane damage after hind limb I/R. Rats were divided into two groups: I/R and I/R with CAPE pre-treatment. They were anaesthetized with intramuscular ketamine 100 mg kg(-1). A 4-h I/R period was performed on the right hind limb of all animals. In the CAPE-treated group, animals received CAPE 10 microm by intraperitoneal injection 1 h before the reperfusion. At the end of the reperfusion period, a midsternotomy was performed. A 5-ml blood sample was withdrawn from the ascending aorta for biochemical assays. Serum and erythrocyte membrane MDA levels were significantly lower in the CAPE-treated group when compared to the I/R group ( p = 0.001 and p<0.001, respectively). Erythrocyte membrane Na(+)-K(+) ATPases activity in the CAPE-treated group was significantly higher than the I/R group ( p<0.001). In conclusion, CAPE seems to be effective in protecting against oxidative stress. Therefore, we suggest that in order to decrease I/R injury, pre-administration of CAPE may be a promising agent for a variety of conditions associated with I/R.

PMID: 15338467 [PubMed - indexed for MEDLINE]


44: J Chemother. 2004 Aug;16(4):381-7.

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Caffeic acid phenethyl ester ameliorated ototoxicity induced by cisplatin in rats.

Kizilay A, Kalcioglu MT, Ozerol E, Iraz M, Gulec M, Akyol O, Ozturan O.

Department of Otorhinolaryngology, Inonu University Medical School, Malatya, Turkey. akizilay@inonu.edu.tr

Caffeic acid phenethyl ester (CAPE), an active component of propolis, exhibits antioxidant properties. This experimental study was designed to determine the effect of CAPE on ototoxicity induced with cisplatin. Twenty-four adult Wistar albino rats were divided into four groups: cisplatin (n=6), saline (n=6), CAPE (n=6), and cisplatin plus CAPE (n=6). Rats were tested before and 5 days after cisplatin treatment with or without chemo protection. The Distortion Product Otoacoustic Emissions (DPOAEs) were elicited from the control and experimental animals utilizing the standard commercial Otoacoustic Emission (OAEs) apparatus. The animals in all groups were sacrificed under general anesthesia on the fifth day following last OAE measurements. For biochemical investigations, the blood samples were drawn from inferior vena cava. On day 0, the initial baseline DPOAEs measurement results presented similar values while comparing the groups in drug free phase (p>0.05). On day 5, intrasubject measurement parameters of DPgrams and I/O functions of cisplatin group were significantly deteriorated (p<0.05). The second measurements of the other groups revealed no significant differences between their DPgrams and I/O functions in all frequencies (p>0.05). Among the biochemical parameters, plasma xanthine oxidase (XO) activity was found to be more elevated in the cisplatin group than the saline group (p<0.05). CAPE led to more decreased XO activity than cisplatin (p<0.05). The results of this study show that prophylactic administration of CAPE for cisplatin ototoxicity ameliorated hearing deterioration in rats.

PMID: 15332714 [PubMed - indexed for MEDLINE]


45: Clin Biochem. 2004 Aug;37(8):702-5.

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Reduction of ischemia--reperfusion induced myocardial infarct size in rats by caffeic acid phenethyl ester (CAPE).

Ozer MK, Parlakpinar H, Acet A.

Department of Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey. mkozer1971@yahoo.com

Myocardial ischemia--reperfusion (MI/R) represents a clinically relevant problem associated with thrombolysis, angioplasty, and coronary bypass surgery. MI/R injury is known to occur on restoration of coronary flow after a period of myocardial ischemia. Injury of myocardium caused by I/R includes cardiac contractile dysfunction, arrhythmias, as well as irreversible myocyte damage. Prevention of myocardial death in acute coronary syndromes is the immediate goal of therapy. The main factor concerned with the experimental generation of reperfusion damage is oxygen-derived free radicals. This MI/R injury has been shown to be salvaged by supplementing antioxidants to diseased hearts. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has antioxidant and anti-inflammatory properties, and may function in cardiac protection against I/R-induced damage. To test this hypothesis, we randomly assigned 14 male Wistar rats for necrosis experiments. To produce myocardial necrosis, the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion in anesthetized rats. CAPE (50 microM kg-1) was given intravenously 10 min before occlusion and continued during ischemia by infusion pump. The volume of infarct and the risk zone was determined by planimentry of each tracing and multiplying by the slice thickness. Infarct was normalized by expressing it as a percentage of the area at risk. Compared to control group, CAPE administration statistically reduced the myocardial infarct size/area of risk zone (50 +/- 4% and 32 +/- 6%, respectively) and the myocardial infarct size (23 +/- 3% and 9 +/- 4%, respectively) in rat model of ischemia-reperfusion. In conclusion, this result shows that CAPE is important in reducing I/R-induced myocardial damage.

PMID: 15302615 [PubMed - indexed for MEDLINE]


46: Nahrung. 2004 Jun;48(3):226-9.

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Preparation and functional properties of extracts from bee bread.

Nagai T, Nagashima T, Myoda T, Inoue R.

Department of Food Science and Technology, Tokyo University of Agriculture, Hokkaido 0992493, Japan. t1nagai@seibutu.bioindustry.nodai.ac.jp

Three extracts, namely hot-water fraction (HWF), water-soluble fraction (WSF), and ethanol-soluble fraction (ESF), were prepared from fresh bee bread imported from Lithuania. The protein and total phenolic contents of these samples were very high. Among them, WSF at 100% concentration showed the highest antioxidative ability and scavenging ability. On the other hand, ESF at 10% concentration possessed the highest ability against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radicals. Bee bread will apply more and more as health food and medicine due to its functional properties such as antioxidative ability and scavenging activities of reactive oxygen species.

PMID: 15285117 [PubMed - indexed for MEDLINE]


47: Free Radic Biol Med. 2004 Aug 1;37(3):386-94.

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Protective effects of caffeic acid phenethyl ester against experimental allergic encephalomyelitis-induced oxidative stress in rats.

Ilhan A, Akyol O, Gurel A, Armutcu F, Iraz M, Oztas E.

Department of Neurology, Inonu University, Turgut Ozal Medical Center, Malatya, Turkey. ailhan@inonu.edu.tr

Because oxidative damage has been known to be involved in inflammatory and autoimmune-mediated tissue destruction, modulation of oxygen free radical production represents a new approach to the treatment of inflammatory and autoimmune diseases. Central nervous system tissue is particularly vulnerable to oxidative damage, suggesting that oxidation plays an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Caffeic acid phenethyl ester (CAPE), an active component of honeybee propolis, has been determined to have antioxidant, anti-inflammatory, antiviral, and anticancer activities. We have previously reported that CAPE inhibits ischemia-reperfusion injury and oxidative stress in rabbit spinal cord tissue. The present study, therefore, examined effects of CAPE on oxidative tissue damage in EAE in rats. Treatment with CAPE significantly inhibited reactive oxygen species (ROS) production induced by EAE, and ameliorated clinical symptoms in rats. These results suggest that CAPE may exert its anti-inflammatory effect by inhibiting ROS production at the transcriptional level through the suppression of nuclear factor kappaB activation, and by directly inhibiting the catalytic activity of inducible nitric oxide synthase.

PMID: 15223072 [PubMed - indexed for MEDLINE]


48: Arch Biochem Biophys. 2004 Apr 15;424(2):181-8.

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Antioxidative bioavailability of artepillin C in Brazilian propolis.

Shimizu K, Ashida H, Matsuura Y, Kanazawa K.

Department of Life Science, Graduate School of Science and Technology, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501, Japan.

Propolis has strong antioxidative activity. We investigated here whether this activity was available in intestinal Caco-2 and hepatic HepG2 cells. Phenolics in Brazilian propolis, extracted with ethyl acetate after the removal of resin and wax with 90% methanol, included artepillin C at 21 mmol/100 g, p-coumaric acid and cinnamic acid relatives 24mmol, kaempferol and its derivatives 9.4 mmol, naringenin 2.8 mmol, isosakuranetin 0.9 mmol, chrysin at 0.8 mmol/100 g, and several minor components. When the extract was added to the apical side of Caco-2 monolayers, artepillin C was specifically incorporated into the cells and released to the basolateral side mostly without conjugation. Then, artepillin C was added to HepG2 cells and exposed to reactive oxygens. Artepillin C prevented oxidative damage dose-dependently, and suppressed lipid peroxidation evaluated with thiobarbituric acid reactive substances by 16% and the formation of 8-hydroxy-2'-deoxyguanosine in DNA by 36% at a concentration of 20microM. Artepillin C is a bioavailable antioxidant.

PMID: 15047190 [PubMed - indexed for MEDLINE]


49: J Biol Chem. 2004 Jun 25;279(26):26885-92. Epub 2004 Mar 23.

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Stimulatory actions of caffeic acid phenethyl ester, a known inhibitor of NF-kappaB activation, on Ca2+-activated K+ current in pituitary GH3 cells.

Lin MW, Yang SR, Huang MH, Wu SN.

Institute of Basic Medical Sciences, National Cheng-Kung University Medical College, Tainan 701, Taiwan.

Caffeic acid phenethyl ester (CAPE), a phenolic antioxidant derived from the propolis of honeybee hives, is known to be an inhibitor of activation of nuclear transcript factor NF-kappaB. Its effects on ion currents have been investigated in pituitary GH(3) cells. This compound increased Ca(2+)-activated K(+) current (I(K(Ca))) in a concentration-dependent manner with an EC(50) value of 14 +/- 2 microm. However, the magnitude of CAPE-induced stimulation of I(K(Ca)) was attenuated in GH(3) cells preincubated with 2,2'-azo-bis-(2-amidinopropane) hydrochloride (100 microm) or t-butyl hydroperoxide (1 mm). CAPE (50 microm) slightly suppressed voltage-dependent L-type Ca(2+) current. In inside-out configuration, CAPE (20 microm) applied to the intracellular face of the detached patch enhanced the activity of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels with no modification in single-channel conductance. After BK(Ca) channel activity was increased by CAPE (20 microm), subsequent application of nordihydroguaiaretic acid (20 microm) did not further increase the channel activity. CAPE-stimulated channel activity was dependent on membrane potential. CAPE could also increase Ca(2+) sensitivity of BK(Ca) channels in these cells. Its increase in the open probability could primarily involve a decrease in the mean closed time. In current-clamp conditions, CAPE hyperpolarized the membrane potential and reduced the firing of action potentials. The stimulatory effects on these channels may partly contribute to the underlying mechanisms through which this compound influences the functional activities of neurons or neuroendocrine cells. Caution has to be used in attributing its response in the activation of NF-kappaB.

PMID: 15039450 [PubMed - indexed for MEDLINE]


50: Toxicology. 2004 Mar 1;196(1-2):87-93.

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Antioxidative natural product protect against econazole-induced liver injuries.

Liu CF, Lin CH, Lin CC, Lin YH, Chen CF, Lin CK, Lin SC.

National Taipei College of Nursing, Taipei 112, Taiwan.

The study objective of this research is in order to investigate the hepatoprotective and therapeutic effects of propolis ethanol extract (PEE) on acute econazole-induced liver injury. Positive control of various concentrations of PEE on liver function and the dose-response relationship of liver injury induced by various doses of econazole were firstly observed from biochemical assay of serum level of aspartate transaminase (SGOT) and serum alanine transaminase (SGPT) and histopathological microscopic examination. The hepatoprotective effects of various concentration of PEE on liver damage induced by hepatotoxic dose (300 mg/kg) of econazole were observed by the obvious decrement of SGOT and SGPT level and further confirmed by hepatohistological microscopic examination. The inhibitory effects of PEE on FeCl(2)-induced (in vitro) or econazole-induced (in vivo) lipid peroxidation were investigated from the measurement of the formed malonic dialdehyde (MDA) level in the rat liver homogenate. The IC(50) (microM) of various concentrations of PEE in the superoxide scavenging activity in econazole (300 mg/kg)-damaged rat liver homogenate were assessed by cytochrome c reduction method and compared with that of (+)-alpha-tocopherol. It could be postulated that the hepatoprotective effect of PEE may be, at least in part, due to their inhibitory ability on membrane lipid peroxidation and free radical formation or due to their free radical scavenging ability.

PMID: 15036759 [PubMed - indexed for MEDLINE]


51: Burns. 2004 Mar;30(2):121-5.

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The effect of CAPE on lipid peroxidation and nitric oxide levels in the plasma of rats following thermal injury.

Hosnuter M, Gurel A, Babuccu O, Armutcu F, Kargi E, Isikdemir A.

Department of Plastic and Reconstructive Surgery, Zonguldak Karaelmas University School of Medicine, Kozlu-Zonguldak 67600, Turkey. hosnuter@karaelmas.edu.tr

Both experimental and clinical studies have shown that oxygen-derived free radicals rise in the plasma after thermal injury and participate in the pathogenesis of tissue damage. Hence, various antioxidant molecules have been used in treatment of burn injury both experimentally and clinically. Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have potent antioxidant property. The purpose of the present study was to investigate the effects of CAPE on oxidative stress in plasma of burned rats. Experiment was designed in three groups of rats with 20% full-thickness burn: (a) sham burn (n = 7); (b) burn only (n = 22); (c) burn + treatment with CAPE (n = 22). Plasma levels of malondialdehyde (MDA), nitric oxide (NO) and the activities of xanthine oxidase (XO), and superoxide dismutase (SOD) were used as both bio-indicators of oxidant status and determinant of antioxidant effect of CAPE. They were assessed by biochemical methods at 1st, 3rd, 7th, and 14th post-burn days. In conclusion, CAPE was shown to possess antioxidant activity by saving SOD activity, preventing XO activity and decreasing the levels of MDA, and NO. Our study showed that CAPE may be beneficial in burn injury.

PMID: 15019118 [PubMed - indexed for MEDLINE]


52: Arch Pediatr Adolesc Med. 2004 Mar;158(3):222-4.

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Comment on:

·       Arch Pediatr Adolesc Med. 2004 Mar;158(3):217-21.


Can an herbal preparation of echinacea, propolis, and vitamin C reduce respiratory illnesses in children?

Sangvai S, Chianese J, Morone N, Bogen DL, Voigt L, Shaikh N.

General Academic Pediatrics, Children's Hospital of Pittsburgh, PA 15213, USA. shilpa.sangvai@chp.edu

Publication Types:

·       Comment


PMID: 14993079 [PubMed - indexed for MEDLINE]


53: Arch Pediatr Adolesc Med. 2004 Mar;158(3):217-21.

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Comment in:

·       Arch Pediatr Adolesc Med. 2004 Mar;158(3):222-4.


Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.

Cohen HA, Varsano I, Kahan E, Sarrell EM, Uziel Y.

Pediatric and Adolescent Ambulatory Community Clinic, Petach Tikva, Israel. hermanc@post.tau.ac.il

OBJECTIVE: To evaluate the effectiveness and safety of a preparation containing echinacea, propolis, and vitamin C in the prevention of respiratory tract infections in children during a 12-week winter period. DESIGN: Randomized, double-blind, placebo-controlled study. SUBJECTS: Four hundred thirty children, aged 1 to 5 years, were randomized to an herbal extract preparation (n = 215) or a placebo elixir (n = 215). INTERVENTION: Administration of an herbal preparation (Chizukit) containing 50 mg/mL of echinacea, 50 mg/mL of propolis, and 10 mg/mL of vitamin C, or placebo (5.0 mL and 7.5 mL twice daily for ages 1 to 3 years and 4 to 5 years, respectively) for 12 weeks. RESULTS: Significant mean +/- SD reductions of illnesses were seen in the Chizukit group in the number of illness episodes, 138 vs 308 (55% reduction); number of episodes per child, 0.9 +/- 1.1 vs 1.8 +/- 1.3 (50% reduction, P<.001); and number of days with fever per child, 2.1 +/- 2.9 vs 5.4 +/- 4.4) (62% reduction, P<.001). The total number of illness days and duration of individual episodes were also significantly lower in the Chizukit group. Adverse drug reactions were rare, mild, and transient. CONCLUSION: A preventive effect of a product containing echinacea, propolis, and vitamin C on the incidence of respiratory tract infections was observed.

Publication Types:

·       Clinical Trial

·       Multicenter Study

·       Randomized Controlled Trial


PMID: 14993078 [PubMed - indexed for MEDLINE]


54: Bioresour Technol. 2004 May;93(1):43-8.

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Screening of poplar biomass for bio-active compounds: a simple method to assess antioxidant activity.

Warnant P, Mertens P, Marche C.

ISI, rue St. Victor 3, B-4500 Huy, Belgium. paul.warnant@infonie.be

Poplar bud resinoids are a potential source of natural antioxidants. As poplar culture today involves many hybrids, a simple screening test to assess antioxidant properties was proposed. This method used the second derivative of the UV spectra at 233 nm of the iron induced peroxidienes resulting from linoleic acid peroxidation. Kinetic data showed a lag period followed by a quadratic increase in peroxidienes. These two phases were more clearly separated using the square root of the data. An acceptable linear fitting of the length of the lag phase with antioxidant concentration was observed. Calibrating the experimental test with BHA therefore allowed an antioxidant assessment as "BHA equivalent". First results clustered well with taxonomic data, with typically 0.5, 0.15 and 0.08 "BHA equivalent" for P. nigra, P. X euramericana and P. X interamericana, respectively.

PMID: 14987719 [PubMed - indexed for MEDLINE]


55: J Med Food. 2003 Winter;6(4):387-90.

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Effects of chrysin on urinary testosterone levels in human males.

Gambelunghe C, Rossi R, Sommavilla M, Ferranti C, Rossi R, Ciculi C, Gizzi S, Micheletti A, Rufini S.

Department of Clinical and Experimental Medicine, Division of Sports Medicine-Laboratorio delle Attivita Motorie e Sportive, University of Perugia, Perugia, Italy. labsport@unipg.it

The equilibrium of sexual hormones in both sexes is controlled in vertebrates by the enzyme aromatase, a member of the cytochrome P450 superfamily, which catalyzes the conversion of androstenedione and testosterone into estrone and estradiol, respectively. Flavonoids are diphenolic compounds present in whole grains, legumes, fruits, and vegetables that are strongly implicated as protective in coronary heart disease, stroke, and cancer. One flavonoid, chrysin, found in high concentrations in honey and propolis, has been shown to be an inhibitor of aromatase enzyme activity. These foods are often used as supplements, particulary by sportsmen for their energetic and antioxidant properties. The aim of this study was to verify if daily treatment for 21 days with propolis and honey, containing chrysin, would modify urinary concentrations of testosterone in volunteer male subjects. In fact, aromatase inhibition by chrysin could block the conversion of androgens into estrogens with a consequent increase of testosterone, eventually measurable in urine samples. The obtained data did not show alterations of the levels of testosterone in the volunteers after 7, 14, and 21 days of treatment in comparison with baseline values and compared with measurements on the control subjects at the same time. In conclusion, the use of these foods for 21 days at the doses usually taken as oral supplementation does not have effects on the equilibrium of testosterone in human males.

PMID: 14977449 [PubMed - indexed for MEDLINE]


56: Mol Divers. 2004;8(1):21-33.

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Creating molecular diversity from antioxidants in Brazilian propolis. Combination of TOPS-MODE QSAR and virtual structure generation.

Estrada E, Quincoces JA, Patlewicz G.

Safety, and Environmental Assurance Centre (SEAC), Unilever Colworth, Sharnbrook, Bedford, UK. estrada66@yahoo.com

A QSAR model for antioxidative activity based on the Sub-Structural Molecular Design (TOPS-MODE) approach is developed for a series of compounds present in Brazilian propolis. This approach permitted the structural interpretation of the antioxidative activity of these compounds in terms of bond contributions. By these means we have identified the structural groups and regions that contribute to the antioxidative activity of the cinnamic acid and flavonoid derivatives present in the propolis. These results were then used to identify the positions and substituents to be used in a virtual compound generation experiment. Using this approach a total of 327 compounds were generated from which more than 70 are predicted to be more active than the most powerful antioxidants in the Brazilian propolis. From these 70 compounds less than 20 have been reported in the literature. Consequently, a high proportion of novel compounds with potential antioxidative activity has been identified by the current approach. This contributes to enhance the molecular diversity of the analogues of Brazilian propolis compounds with antioxidative properties.

PMID: 14964785 [PubMed - indexed for MEDLINE]


57: Acta Pharm. 2003 Dec;53(4):275-85.

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Analysis of propolis from the continental and Adriatic regions of Croatia.

Kosalec I, Bakmaz M, Pepeljnjak S.

Institute of Microbiology, Faculty of Pharmacy and Biochemistry, University of Zagreb, HR-10000 Zagreb, Croatia. ivan.kosalec@zg.htnet.hr

Thin-layer chromatography of ethanolic extract of propolis (EEP) from the continental and Adriatic regions of Croatia showed that 72.2% of propolis samples contain galangin, 88.8% of samples contain kaempferol, naringenin and apigenin and 66.6% of samples contain caffeic acid. Caffeic acid, pinocembrin, galangin, chrysin and naringenin were analyzed by HPLC. In all samples, pinocembrin was the dominant flavonoid. In samples from the Adriatic region, concentration of pinocembrin ranged from 0.03 to 6.14% (x = 2.87%) and in the continental region samples from 0 to 4.74% (x = 2.84%). Chrysin was found in all propolis samples in a concentration ranging from 0.22 to 5.32% (x = 1.86%) in the continental region samples and from 0.03 to 3.64% (x = 1.96%) in samples from the Adriatic region. Chrysin was followed by naringenin, ranging from 0 to 1.14% (x = 0.42%) in samples from the Adriatic region and from 0.22 to 2.41% (x = 0.60%) in the continental region samples. Concentration of caffeic acid ranged from 0 to 10.11% (x = 2.69%) in the Adriatic region samples and from 0.27 to 2.67% (x = 1.37%) in samples from the continental region of Croatia. Results of HPLC analyses suggest that propolis samples collected from various parts of Croatia do not differ markedly in contents of chrysin, pinocembrin, naringenin and galangin but differ in the concentration of caffeic acid. All EEPs significantly inhibited the growth of Bacillus subtilis in comparison with the control (80% ethanol) (p < 0.05), showing inhibition zones of 16 +/- 2 mm for samples from the continental region, and of 18 +/- 3 mm for samples from the Adriatic region. There was no significant difference in antimicrobial activity of EEPs from the continental and Adriatic regions of Croatia, suggesting that bactericidal activity depends on synergism of all phenolic compounds.

PMID: 14769234 [PubMed - indexed for MEDLINE]


58: J Appl Toxicol. 2004 Jan-Feb;24(1):27-35.

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Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin-induced nephrotoxicity in rats.

Ozen S, Akyol O, Iraz M, Sogut S, Ozugurlu F, Ozyurt H, Odaci E, Yildirim Z.

Department of Pathology, Yuzuncu Yil University Medical School, Van, Turkey.

We have investigated the effect of caffeic acid phenethyl ester (CAPE) on cisplatin-induced nephrotoxicity in rats. Administration of a single dose of cisplatin resulted in the elevation of blood urea nitrogen and creatinine in serum, as well as nitric oxide in kidney tissue of rats. Cisplatin also caused reduction of catalase (P < 0.0001), superoxide dismutase (P = 0.149) and glutathrone peroxidase (P < 0.0001) activities in kidney tissue. Although cisplatin caused elevation in malondialdehyde levels and myeloperoxidase activities in kidney tissue, they were not statistically significant. Caffeic acid phenethyl ester was found to be protective against cisplatin-induced antioxidant enzyme reductions. Treatment with free-radical scavenger CAPE attenuated the increase in plasma blood urea nitrogen and kidney nitric oxide levels, and showed histopathological protection against cisplatin-induced acute renal failure. Extensive epithelial cell vacuolization, swelling, desquamation and necrosis were observed in the kidney of the cisplatin-treated rat. There were also larger tubular lumens in cisplatin-treated rats than those of the control and the CAPE groups. Caffeic acid phenethyl ester caused a marked reduction in the extent of tubular damage. It is concluded that administration of cisplatin imposes an oxidative stress to renal tissue and CAPE confers protection against the oxidative damage associated with cisplatin. This mechanism may be attributed to its free-oxygen-radical scavenging activity.
Copyright 2004 John Wiley & Sons, Ltd.

PMID: 14745844 [PubMed - indexed for MEDLINE]


59: Biosci Biotechnol Biochem. 2004 Jan;68(1):260-2.

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A new prenylated flavonoid from propolis collected in Okinawa, Japan.

Kumazawa S, Goto H, Hamasaka T, Fukumoto S, Fujimoto T, Nakayama T.

Laboratory of Functional Food Science and COE Program in the 21st Century, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan. kumazawa@smail.u-shizuoka-ken.ac.jp

The new prenylflavonoid, isonymphaeol-B (1), together with three known compounds, nymphaeol-A (2), nymphaeol-B (3), and nymphaeol-C (4), were isolated from propolis collected in Okinawa, the southern-most prefecture of Japan. The structure of each compound was determined by spectral methods, including mass spectrometry and 2D NMR. Each compound had 1,1-diphenyl-2-picryl-hydrazyl radical-scavenging activity.

PMID: 14745198 [PubMed - indexed for MEDLINE]


60: Neurosci Lett. 2004 Jan 30;355(3):231-5.

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Antioxidant propolis attenuates kainate-induced neurotoxicity via adenosine A1 receptor modulation in the rat.

Kwon YS, Park DH, Shin EJ, Kwon MS, Ko KH, Kim WK, Jhoo JH, Jhoo WK, Wie MB, Jung BD, Kim HC.

Neurotoxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.

We examined the effects of the antioxidant propolis on seizures induced by kainic acid (KA). Sprague-Dawley rats received propolis (75 and 150 mg/kg, p.o.) five times at 12 h intervals. KA (10 mg/kg, i.p.) was injected 1 h after the last propolis treatment. Pretreatment with propolis significantly attenuated KA-induced seizures and KA-induced increases in hippocampal AP-1 DNA binding activity in a dose-dependent manner. KA induced increases in the levels of malondialdehyde and protein carbonyl, and a decrease in the ratio of GSH/GSSG. These oxidative stresses and neuronal degenerations were significantly attenuated by pretreatment with propolis. The neuroprotective effects of propolis appeared to be counteracted by adenosine receptor antagonists [A1 antagonist, 8-cyclopentyl-1,3-dimethylxanthine (25 or 50 microg/kg); A2A antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1 mg/kg); and A2B antagonist, alloxazine (1.5 or 3.0 mg/kg)]. However, this counteraction was most pronounced in the presence of the A1 antagonist. Our results suggest that the protective effect of propolis against KA-induced neurotoxic oxidative damage is, at least in part, via adenosine A1 receptor modulation.

PMID: 14732473 [PubMed - indexed for MEDLINE]


61: Biochem Pharmacol. 2004 Jan 1;67(1):53-66.

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Propolin C from propolis induces apoptosis through activating caspases, Bid and cytochrome c release in human melanoma cells.

Chen CN, Wu CL, Lin JK.

Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Section 1, Jen-Ai Road, 100, ROC, Taipei, Taiwan.

We had demonstrated that two prenylflavanones, propolin A and propolin B, isolated and characterized from Taiwanese propolis, induced apoptosis in human melanoma cells and significantly inhibited xanthine oxidase activity. Here, we have isolated a third compound called propolin C. The chemical structure of propolin C has been characterized by NMR and HRMS spectra, and was identical to nymphaeol-A. However, no biological activities of this compound have ever been reported. In the present study, propolin C effectively induced a cytotoxic effect on human melanoma cells, with an IC(50) of about 8.5 microM. DNA flow cytometric analysis indicated that propolin C actively induced apoptosis in human melanoma cells and there is a marked loss of cells from the G2/M phase of the cell cycle. To address the mechanism of the apoptosis effect of propolin C, we evaluated the effect of propolin C on induction of apoptosis-related proteins in human melanoma cells. The levels of procaspase-8, Bid, procaspase-3, and poly(ADP-ribose) polymerase were decreased in dose- or time course-dependent manners. Moreover, propolin C was capable of releasing cytochrome c from mitochondria to cytosol. The findings suggest that propolin C may activate a mitochondria-mediated apoptosis pathway. On other hand, propolin C is a potential antioxidant agent and shows a strong capability to scavenge free radicals and inhibit on xanthine oxidase activity with IC(50) of about 17.0microM. In conclusion, the isolation and characterization of propolin C from bee propolis are described for the first time, and this compound is a powerful inducer of apoptosis in human melanoma cells.

PMID: 14667928 [PubMed - indexed for MEDLINE]


62: Biochem Pharmacol. 2003 Dec 15;66(12):2281-9.

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Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells.

Lee YJ, Kuo HC, Chu CY, Wang CJ, Lin WC, Tseng TH.

Department of Chemistry, National Changhua University of Education, Changhua, Taiwan, ROC.

Caffeic acid phenethyl ester (CAPE), an active component of propolis, has many biological and pharmacological activities including antioxidant, anti-inflammation, antiviral action, and anticancer effect. Our previous studies showed that CAPE exhibited significant cytotoxicity in oral cancer cells. Herein we further investigated the cytotoxicity potential of CAPE and the mechanism of its action in C6 glioma cells. The data exhibited that C6 glioma cells underwent internucleosomal DNA fragmentation 24 hr after the treatment of CAPE (50 microM). The proportion of C6 glioma cells with hypodiploid nuclei was increased to 24% at 36 hr after the exposure. Further results showed that CAPE induced the release of cytochrome c from mitochondria into cytosol, and the activation of CPP32. CAPE application also enhanced the expression of p53, Bax, and Bak. Finally, the potential signaling components underlying CAPE induction of apoptosis were elucidated. We found that CAPE activated extracellular signal-regulated kinase (ERKs) and p38 mitogen-activated protein kinase (p38 MAPK) in C6 glioma cells. More importantly, p38 kinase formed a complex with p53 after the treatment of CAPE for 0.5 hr. The expression of p53, phospho-serine 15 of p53, and Bax, and inactivate form of CPP32 was suppressed by a pretreatment of a specific p38 MAPK inhibitor, SB203580. The resultant data suggest that p38 MAPK mediated the CAPE-induced p53-dependent apoptosis in C6 glioma cells.

PMID: 14637186 [PubMed - indexed for MEDLINE]


63: Org Biomol Chem. 2003 May 7;1(9):1452-4.

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Efficient radical scavenging ability of artepillin C, a major component of Brazilian propolis, and the mechanism.

Nakanishi I, Uto Y, Ohkubo K, Miyazaki K, Yakumaru H, Urano S, Okuda H, Ueda J, Ozawa T, Fukuhara K, Fukuzumi S, Nagasawa H, Hori H, Ikota N.

Redox Regulation Research Group, Research Center for Radiation Safety, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan. nakanis@nirs.go.jp

Hydrogen transfer from artepillin C to cumylperoxyl radical proceeds via one-step hydrogen atom transfer rather than via electron transfer, the rate constant of which is comparable to that of (+)-catechin, indicating that artepillin C can act as an efficient antioxidant.

PMID: 12926271 [PubMed - indexed for MEDLINE]


64: Cell Biochem Funct. 2003 Sep;21(3):283-9.

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Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain.

Irmak MK, Fadillioglu E, Sogut S, Erdogan H, Gulec M, Ozer M, Yagmurca M, Gozukara ME.

Department of Histology and Embryology, Gulhane Military Medical Academy, Ankara, Turkey. mkirmak@gata.edu.tr

Oxygen-derived free radicals have been implicated in the pathogenesis of cerebral injury after ischaemia-reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant properties. The purpose of the present study was to investigate the effects of ischaemia and subsequent reperfusion on rat brain and to investigate the effects of two free radical scavengers, CAPE and alpha-tocopherol, on this in vivo model of cerebral injury. Ischaemia was induced by bilateral occlusion of the carotid arteries for 20 min and reperfusion was achieved by releasing the occlusion to restore the circulation for 20 min. Control rats underwent a sham operation. CAPE at 10 micromol kg(-1) or alpha-tocopherol at 25 micromol kg(-1) was administered intraperitoneally before reperfusion. Reperfusion led to significant increase in the activity of xanthine oxidase and higher malondialdehyde levels in the brain. Acute administration of both CAPE and alpha-tocopherol suppressed ischaemia-reperfusion-induced cerebral lipid peroxidation and injury, but CAPE seems to offer a better therapeutic advantage over alpha-tocopherol. Copyright 2003 John Wiley & Sons, Ltd.

PMID: 12910483 [PubMed - indexed for MEDLINE]


65: Brain Res Mol Brain Res. 2003 Jul 23;115(2):111-20.

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Caffeic acid phenethyl ester (CAPE) prevents inflammatory stress in organotypic hippocampal slice cultures.

Montpied P, de Bock F, Rondouin G, Niel G, Briant L, Courseau AS, Lerner-Natoli M, Bockaert J.

Faculte de Pharmacie, CNRS-UMR 5094, 15 Avenue Charles Flahault, 34060 Montpellier Cedex 2, France. pascale.montpied@ibph.pharma.univ-montp1.fr

Caffeic acid phenethyl ester (CAPE) is an antioxidant component of propolis, a natural product secreted by honeybee. Recent literature shows that CAPE inhibits nuclear factor kappa B (NFkappaB) activation in cell lines. Since NFkappaB was shown to be a crucial factor in neuroinflammation and to be associated with some neuropathologies, CAPE might reduce these disorders in brain too and have therapeutic applications. To test this hypothesis we used a model of endotoxic insult (interferon-gamma, followed by lipopolysaccharide) on rat organotypic hippocampal cultures. Cerebral inflammatory responses were strongly inhibited by CAPE (100 microM): reductions of NFkappaB nuclear activity, tumor necrosis factor alpha and nitric oxide productions were observed. At the dose of maximal effects (100 microM), an increase of cAMP-responsive element binding protein (CREB) activity, which anti-inflammatory role is well known, was seen. We compared CAPE effects with those of other drugs: anti-inflammatory as acetyl-salicylate and dexamethasone (glucocorticoid), antioxidant as pyrrolidine dithiocarbamate, or selective permeant inhibitor of NFkappaB as SN 50 peptide. These studies lead us to conclude that CAPE presents an interesting and original neuropharmacological profile compared to these drugs and might be helpful in the prevention of neurotoxic events due to excessive inflammatory reaction in brain. CAPE interferes with several effectors of neuroinflammation that might have complementary and synergic effects and allows a rather durable control since an acute treatment at the time of endotoxin exposure allows to control inflammatory factors for over 48 h.

PMID: 12877982 [PubMed - indexed for MEDLINE]


66: J Nat Prod. 2003 Apr;66(4):503-6.

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Cytotoxic prenylflavanones from Taiwanese propolis.

Chen CN, Wu CL, Shy HS, Lin JK.

Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-ai Road, Taipei, Taiwan 100, Republic of China.

Two new prenylflavanones, propolin A (2) and propolin B (3), were isolated and characterized from Taiwanese propolis. Both compounds were found to have cytotoxic properties against three cancer cell lines. DNA content analyses and DNA fragmentation indicated that propolin A (2) efficiently induced apoptosis in cancer cell lines, but had no effect on the cell cycle program. Furthermore, both propolin A (2) and B (3) are potential antioxidant agents and show strong scavenging effects against most types of free radicals.

PMID: 12713401 [PubMed - indexed for MEDLINE]


67: Redox Rep. 2002;7(5):347-50.

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Free radical scavenging activity of propolis.

Ichikawa H, Satoh K, Tobe T, Yasuda I, Ushio F, Matsumoto K, Endo K, Ookubo C.

Tokyo Metropolitan Research Laboratory of Public Health, Tokyo, Japan. ichikawa@tokyo-eiken.go.jp

We investigated the radical scavenging activity of propolis by ESR spectroscopy using spin trapping method. In addition, we examined the influence of a diet of 2% propolis on mice under oxidative stress. At low concentrations, the methanolic extract of propolis exhibited strong scavenging activity in vitro towards both the superoxide anion radical, generated by the hypoxanthine-xanthine oxidase reaction, and the NO radical, generated from the mixture of NOC-7 (NO generator) and carboxy-PTIO (spin trapping agent). An inhibitory effect of propolis on lipid peroxidation in vivo was observed, as determined by measurement of thiobarbituric acid-reactive substances in mouse liver homogenate. The level of vitamin C in the brain of mice under oxidative stress significantly increased compared with control mice under atmosphere, which was not observed in the mice given 2% propolis. The level of alpha-tocopherol in the brain of mice given 2% propolis significantly increased compared with control mice under atmosphere, which was not observed in mice under oxidative stress. SOD activity in the brain and plasma of mice given 2% propolis significantly decreased under atmosphere and oxidative stress compared with control mice. These results suggest that propolis possesses potent antioxidant activity in vitro and in vivo.

PMID: 12688527 [PubMed - indexed for MEDLINE]


68: Arch Pharm Res. 2003 Jan;26(1):43-6.

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In vivo anti-oxidant activities of tectochrysin.

Lee S, Kim KS, Park Y, Shin KH, Kim BK.

College of Pharmacy, Seoul National University, Seoul 151-742, Korea.

The anti-oxidant activities of tectochrysin, a major compound of propolis, were investigated. Tectochrysin exhibited a significant decrease in serum transaminase activities elevated by hepatic damage induced by CCl4-intoxication in rats. Tectochrysin tested exhibited a lipid peroxidation causing a significant decrease in MDA production in TBA-reactant assay. Tectochrysin was strong in the increase in the anti-oxidant enzymes such as hepatic cytosolic superoxide dismutase, catalase and glutathione peroxidase activities in CCl4-intoxicated rats. These results suggest that tectochrysin possess not only the anti-oxidant, but also the activities in CCl4-intoxicated rats. Especially, tectochrysin was found to cause significant increases in the rat liver cytosolic SOD, catalase, GSH-px activities as well as a significant decrease in the MDA production.

PMID: 12568357 [PubMed - indexed for MEDLINE]


69: Fitoterapia. 2002 Nov;73 Suppl 1:S21-9.

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Antioxidant activity of propolis: role of caffeic acid phenethyl ester and galangin.

Russo A, Longo R, Vanella A.

Department of Biochemistry, Medical Chemistry and Molecular Biology, University of Catania, V.le A. Doria 6, 95125, Catania, Italy. alrusso@mbow.unict.it

Propolis, a natural product produced by the honeybee, has been used for thousands of years in folk medicine for several purposes. The extract contains amino acids, phenolic acids, phenolic acid esters, flavonoids, cinnamic acid, terpenes and caffeic acid. It possesses several biological activities such as antiinflammatory, immunostimulatory, antiviral and antibacterial. The exact mode of physiological or biochemical mechanisms responsible for the medical effects, however, is yet to be determined. In this work, we have investigated the antioxidant activity of a propolis extract deprived of caffeic acid phenethyl ester (CAPE). In addition, the activity of CAPE and galangin was also examined. Propolis extract (with and without CAPE) and its active components showed a dose-dependent free radical scavenging effect, a significant inhibition of xanthine oxidase activity, and an antilipoperoxidative capacity. Propolis extract with CAPE was more active than propolis extract without CAPE. CAPE, used alone, exhibited a strong antioxidant activity, higher than galangin. The experimental evidence, therefore, suggests that CAPE plays an important role in the antioxidant activity of propolis.

PMID: 12495706 [PubMed - indexed for MEDLINE]


70: Pharmacol Ther. 2002 Nov-Dec;96(2-3):67-202.

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The biochemistry and medical significance of the flavonoids.

Havsteen BH.

Department of Biochemistry, University of Kiel, Olshausenstrasse 40, D-24098, Kiel, Germany. benthavs@worldonline.dk

Flavonoids are plant pigments that are synthesised from phenylalanine, generally display marvelous colors known from flower petals, mostly emit brilliant fluorescence when they are excited by UV light, and are ubiquitous to green plant cells. The flavonoids are used by botanists for taxonomical classification. They regulate plant growth by inhibition of the exocytosis of the auxin indolyl acetic acid, as well as by induction of gene expression, and they influence other biological cells in numerous ways. Flavonoids inhibit or kill many bacterial strains, inhibit important viral enzymes, such as reverse transcriptase and protease, and destroy some pathogenic protozoans. Yet, their toxicity to animal cells is low. Flavonoids are major functional components of many herbal and insect preparations for medical use, e.g., propolis (bee's glue) and honey, which have been used since ancient times. The daily intake of flavonoids with normal food, especially fruit and vegetables, is 1-2 g. Modern authorised physicians are increasing their use of pure flavonoids to treat many important common diseases, due to their proven ability to inhibit specific enzymes, to simulate some hormones and neurotransmitters, and to scavenge free radicals.

Publication Types:

·       Review


PMID: 12453566 [PubMed - indexed for MEDLINE]


71: Am J Chin Med. 2002;30(2-3):245-54.

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Cytoprotection by propolis ethanol extract of acute absolute ethanol-induced gastric mucosal lesions.

Liu CF, Lin CC, Lin MH, Lin YS, Lin SC.

National Taipei College of Nursing, Taiwan, ROC.

Acute p.o. administration of absolute ethanol (1.0 ml/kg) to fasted rats produced extensive necrosis of gastric mucosa. Pretreatment with p.o. administration of propolis ethanol extract (PEE) could effectively and dose-dependently prevent such necrosis. This protective effect is called "cytoprotection. "The maximal cytoprotective effect against absolute ethanol (AE)-induced gastric mucosal lesion was observed 1 hour after PEE administration. A gross examination of the gastric mucosa showed a marked improvement in groups receiving PEE. In order to further investigate the gastric protective mechanism of PEE, lipid peroxidation (LPO) levels in vivo and in vitro were estimated. PEE exhibited dose-dependent superoxide scavenging activity and antioxidant effects on AE-induced LPO in rat gastric mucosal homogenates. It was concluded that the gastric protective mechanism of PEE was due, at least in part, to its ability to inhibit LPO, and hence indirectly protect the gastric mucosa from oxidative stress.

PMID: 12230013 [PubMed - indexed for MEDLINE]


72: Free Radic Res. 2002 Jun;36(6):711-6.

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In vitro antioxidant profile of phenolic acid derivatives.

Cos P, Rajan P, Vedernikova I, Calomme M, Pieters L, Vlietinck AJ, Augustyns K, Haemers A, Vanden Berghe D.

Laboratory of Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Several caffeic acid esters isolated from propolis exhibit interesting antioxidant properties, but their in vivo use is compromised by hydrolysis of the ester bond in the gastrointestinal tract. Therefore, a series of caffeic acid amides were synthesized and their in vitro antioxidant profile was determined. A series of hydroxybenzoic acids, hydroxycinnamic acids, and the synthesized caffeic acid amides were tested for both their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and microsomal lipid peroxidation-inhibiting activity. Some of the highly active antioxidants were further tested by means of electron paramagnetic resonance for their hydroxyl radical scavenging activity. Since a promising antioxidant compound should show a lipid peroxidation-inhibiting activity at micromolar level and a low cytotoxicity, the cytotoxicity of the phenolic compounds was also studied. In all the assays used, the caffeic acid anilides and the caffeic acid dopamine amide showed an interesting antioxidant activity.

PMID: 12180197 [PubMed - indexed for MEDLINE]


73: Phytother Res. 2002 Jun;16(4):340-7.

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