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Artepillin-C

Artepillin C, as a PPARγ ligand, enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells.Toggle title

Choi SS, Cha BY, Iida K, Lee YS, Yonezawa T, Teruya T, Nagai K, Woo JT.

Source

Research Institute for Biological Functions, Chubu University, 1200 Matsumoto, Kasugai, Aichi, Japan.

Abstract

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays an important role in adipocyte differentiation. Its ligands, including thiazolidinediones, improve insulin sensitivity in type 2 diabetes. We investigated the effects of artepillin C, an ingredient of Baccharis dracunculifolia, on adipogenesis and glucose uptake using 3T3-L1 cells. In PPARγ ligand-binding assays, artepillin C exhibited binding affinity toward PPARγ. Artepillin C dose-dependently enhanced adipocyte differentiation of 3T3-L1 cells. As a result of the artepillin C-induced adipocyte differentiation, the gene expression of PPARγ and its target genes, such as aP2, adiponectin and glucose transporter (GLUT) 4, was increased. These increases were abolished by cotreatment with GW9662, a PPARγ antagonist. In mature 3T3-L1 adipocytes, artepillin C significantly enhanced the basal and insulin-stimulated glucose uptake. These effects were decreased by cotreatment with a PI3K inhibitor. Although artepillin C had no effects on the insulin signaling cascade, artepillin C enhanced the expression and plasma membrane translocation of GLUT1 and GLUT4 in mature adipocytes. In conclusion, these findings suggest that artepillin C promotes adipocyte differentiation and glucose uptake in part by direct binding to PPARγ, which could be the basis of the pharmacological benefits of green propolis intake in reducing the risk of type 2 diabetes.

Ethanolic extract of Brazilian green propolis sensitizes prostate cancer cells to TRAIL-induced apoptosis.

Szliszka E, Zydowicz G, Janoszka B, Dobosz C, Kowalczyk-Ziomek G, Krol W.

Source

Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Jordana 19, 41 808 Zabrze, Poland.

Abstract

Prostate cancer represents an ideal disease for chemopreventive intervention. Propolis possesses immuno-modulatory, anti-tumour and chemopreventive properties. The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anti-cancer agent that induces apoptosis selectively in tumour cells. However, some cancer cells are resistant to TRAIL-mediated apoptosis. Naturally occurring phenolic and polyphenolic compounds sensitize TRAIL-resistant cancer cells and augment the apoptotic activity of TRAIL. The ethanolic extract of Brazilian green propolis (EEP) is rich in phenolic components. Our in vitro results indicate the potential targets in the TRAIL-induced apoptotic pathway for the cancer chemopreventive activity of Brazilian propolis. We examined the cytotoxic and apoptotic effects of Brazilian EEP and its bioactive components in combination with TRAIL on LNCaP prostate cancer cells. The chemical composition of Brazilian green propolis was determined by high performance liquid chromatography-diode array detection. The cytotoxicity was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl-tetrazolium and lactate dehydrogenase assays. Apoptosis was detected using annexin V-FITC by flow cytometry and fluorescence microscopy. The mitochondrial membrane potential (∆Ψm) was evaluated using DePsipher staining by fluorescence microscopy. Flow cytometry was used to analyse death receptor (TRAIL-R1 and TRAIL-R2) expression in LNCaP cells. The inhibition of nuclear factor-κB (NF-κB) (p65) activation in cancer cells was confirmed by the ELISA-based TransAM NF-κB kit. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrates that EEP sensitizes TRAIL-resistant prostate cancer cells. The main phenolic components detected in Brazilian green propolis are artepillin C, quercetin, kaempferol and p-coumaric acid. Brazilian propolis and its bioactive components markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Brazilian EEP enhanced the expression of TRAIL-R2 and the activity of NF-κB in LNCaP cells. The co-treatment of prostate cancer cells with 100 ng/ml TRAIL and 50 µg/ml EEP increased the percentage of apoptotic cells to 65.8 ± 1.2% and caused a significant disruption of ∆Ψm in LNCaP cells. We show that Brazilian EEP helped cells overcome TRAIL resistance by engaging both intrinsic and extrinsic apoptotic pathways and regulating NF-κB activity. The data demonstrate the important role of Brazilian green propolis and its bioactive compounds in prostate cancer chemoprevention through the enhancement of TRAIL-mediated apoptosis.

Brazilian propolis-derived components inhibit TNF-α-mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes.

Ikeda R, Yanagisawa M, Takahashi N, Kawada T, Kumazawa S, Yamaotsu N, Nakagome I, Hirono S, Tsuda T.

Source

College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi 487-8501, Japan.

Abstract

BACKGROUND:

Previous reports suggest that Brazilian propolis has multiple biological functions and may help to restore adiponectin expression and insulin sensitivity. However, little is known about the molecular mechanisms by which these compounds inhibit the downregulation of adiponectin.

METHODS:

The effect of various Brazilian propolis-derived components on inhibition of tumor necrosis factor-α (TNF-α)-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes and molecular mechanism was investigated.

RESULTS AND CONCLUSIONS:

Pretreatment with either artepillin C (C3) or its derivative (C4) significantly inhibited TNF-α-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes. Interestingly, C3 strongly activated peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity. Treatment of adipocytes with C3 resulted in the upregulation of adiponectin and fatty acid-binding protein 4 expression, but C4 did not significantly induce PPARγ transactivation. C4 did, however, inhibit the TNF-α-induced c-Jun-NH(2)-terminal kinase (JNK) signaling that is involved in adiponectin expression. Molecular docking studies based on hPPARγ with C3 and JNK1 with C4 clearly supported our experimental results. These data demonstrate that 1) both C3 and C4 significantly inhibit the TNF-α-mediated downregulation of adiponectin in adipocytes, 2) C3 functions as a PPARγ agonist, and its inhibition of the effect of TNF-α is due to this PPARγ transactivation, and 3) C4 is an effective inhibitor of JNK activation, thus inhibiting the TNF-α-mediated downregulation of adiponectin.

GENERAL SIGNIFICANCE:

Brazilian propolis-derived components (C3 and C4) can significantly inhibit TNF-α-mediated downregulation of adiponectin in adipocytes, although they do so via different mechanisms.

Preferential cytotoxicity to tumor cells of 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated from propolis.

Matsuno T, Jung SK, Matsumoto Y, Saito M, Morikawa J.

Source

National Institute of Health, Tokyo, Japan.

Abstract

A tumoricidal substance was isolated from Brazilian propolis as guided by cytotoxicity assay on HuH 13 (human hepatocellular carcinoma) cell and was characterized to be 3-[4-hydroxy-3,5-bis (3-methyl-2-butenyl) phenyl]-2-propenoic acid (3,5-diprenyl-4-hydroxycinnamic acid (artepillin C)). It exhibited preferential cytotoxicity to tumor cells cultured in vitro. The cytotoxicity observed seemed to be partly attributable to apoptosis-like DNA fragmentation. The compound showed anti-tumor activity more effective than that of 5-fluorouracil to transplantable human tumor cell lines when tested on histoculture drug response assay system.

Apoptosis and suppression of tumor growth by artepillin C extracted from Brazilian propolis.

Kimoto T, Arai S, Kohguchi M, Aga M, Nomura Y, Micallef MJ, Kurimoto M, Mito K.

Source

Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan.

Abstract

Artepillin C was extracted from Brazilian propolis. Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) has a molecular weight of 300.40 and possesses antibacterial activity. When artepillin C was applied to human and murine malignant tumor cells in vitro and in vivo, artepillin C exhibited a cytotoxic effect and the growth of tumor cells was clearly inhibited. The artepillin C was found to cause significant damage to solid tumor and leukemic cells by the MTT assay, DNA synthesis assay, and morphological observation in vitro. When xenografts of human tumor cells were transplanted into nude mice, the cytotoxic effects of artepillin C were most noticeable in carcinoma and malignant melanoma. Apoptosis, abortive mitosis, and massive necrosis combined were identified by histological observation after intratumor injection of 500 microg of artepillin C three times a week. In addition to suppression of tumor growth, there was an increase in the ratio of CD4/CD8 T cells, and in the total number of helper T cells. These findings indicate that artepillin C activates the immune system, and possesses direct antitumor activity.

Renal carcinogenesis induced by ferric nitrilotriacetate in mice, and protection from it by Brazilian propolis and artepillin C.

Kimoto T, Koya S, Hino K, Yamamoto Y, Nomura Y, Micallef MJ, Hanaya T, Arai S, Ikeda M, Kurimoto M.

Source

Hayashibara Biochemical Laboratories Inc., Fujisaki Institute, Fujisaki, Okayama, Japan.

Abstract

The protective effect of Brazilian propolis and its extract Artepillin C against ferric nitrilotriacetate (Fe-NTA)-induced renal lipid peroxidation and carcinogenesis was studied in male ddY mice. Fe-NTA-induced renal lipid peroxidation leads to a high incidence of renal cell carcinoma (RCC) in mice. Administration of propolis by gastric intubation 2 h before or Artepillin C at either the same time, 2 h, or 5 h before the intraperitoneal injection of Fe-NTA (7 mg Fe/kg) effectively inhibited renal lipid peroxidation. This was evaluated from the measurement of renal thiobarbituric acid-reactive substances (TBARS) or histochemical findings of 4-hydroxy-2-nonenal (4-HNE)-modified proteins and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Repeated injection of Fe-NTA (10 mg Fe/kg per day, twice a week for a total of 16 times in 8 weeks) caused subacute nephrotoxicity as revealed by necrosis and pleomorphic large nuclear cells in the renal proximal tubules, and gave rise to RCC 12 months later. A protective effect from carcinogenicity was observed in mice given propolis or Artepillin C. Furthermore, the mice given Fe-NTA only developed multiple cysts composed of precancerous lesions with multilayered and proliferating large atypical cells. Mice treated with propolis and Artepillin C also had cysts, but these were dilated and composed of flat cells. These results suggest that propolis and Artepillin C prevent oxidative renal damage and the carcinogenesis induced by Fe-NTA in mice.

Apoptosis of human leukemia cells induced by Artepillin C, an active ingredient of Brazilian propolis.

Kimoto T, Aga M, Hino K, Koya-Miyata S, Yamamoto Y, Micallef MJ, Hanaya T, Arai S, Ikeda M, Kurimoto M.

Source

Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Fujisaki 675-1, Okayama 702-8006, Japan. fujisaki@hayashibara.co.jp

Abstract

Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) is an active ingredient of Brazilian propolis that possesses anti-tumor activity. When Artepillin C was applied to human leukemia cell lines of different phenotypes, namely, lymphocytic leukemia (7 cell lines of T-cell, 5 cell lines of B-cell), myeloid and monocytic leukemia and non-lymphoid non-myeloid leukemia cell lines in vitro, Artepillin C exhibited potent cytocidal effects and induced marked levels of apoptosis in all the cell lines. The most potent effects were observed in the T-cell lines. Apoptotic bodies and DNA fragmentation were induced in the cell lines after exposure to Artepillin C. DNA synthesis in the leukemia cells was clearly inhibited and disintegration of the cells was confirmed microscopically. Apoptosis of the leukemia cells may be partially associated with enhanced Fas antigen expression and loss of mitochondrial membrane potential. In contrast, although Artepillin C inhibited the growth of pokeweed mitogen (PWM)-stimulated normal blood lymphocytes, it was not cytocidal to normal unstimulated lymphocytes. These results suggested that Artepillin C, an active ingredient of Brazilian propolis, has anti-leukemic effects with limited inhibitory effects on normal lymphocytes.

Pulmonary carcinogenesis induced by ferric nitrilotriacetate in mice and protection from it by Brazilian propolis and artepillin C.

Kimoto T, Koya-Miyata S, Hino K, Micallef MJ, Hanaya T, Arai S, Ikeda M, Kurimoto M.

Source

Hayashibara Biochemical Laboratories Inc., Fujisaki Institute, Fujisaki 675-1, Okayama 702-8006, Japan. fujisaki@hayashibara.co.jp

Abstract

In experiments using the renal carcinogen ferric nitrilotriacetate (Fe-NTA) in male ddY mice, primary pulmonary cancers were also induced in bronchiolar and alveolar tissues. 4-Hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), products of oxidative processes, increased in bronchiolar and alveolar cells after administration of Fe-NTA. These substances disappeared after oral administration of propolis or artepillin C, as shown histochemically, and correlated with an anticancer prophylactic effect of propolis and artepillin C. From our investigation, lipid peroxidation seems to play an important role in pulmonary carcinogenesis. Malignant progression from adenoma of bronchiolar or alveolar origin to malignant tumors has been proposed to involve a stepwise transformation. In our study, adenomas developed into adenocarcinomas and large cell carcinomas after treatment with Fe-NTA. In contrast, after oral administration of propolis or artepillin C, adenomas did not progress to carcinomas. Instead of developing into large cell cancers, as induced by Fe-NTA in control mice, adenomas showed remarkable proliferation of macrophages and local anti-oxidant activity after treatment with either propolis or artepillin C. Propolis and artepillin C therefore appear to inhibit lipid peroxidation and the development of pulmonary cancers.

Cell growth inhibitory effect of cinnamic acid derivatives from propolis on human tumor cell lines.

Akao Y, Maruyama H, Matsumoto K, Ohguchi K, Nishizawa K, Sakamoto T, Araki Y, Mishima S, Nozawa Y.

Source

Gifu International Institute of Biotechnology, Kakamigahara, Japan. yakao@giib.or.jp

Abstract

A cell growth inhibitory effect of drupanin and baccharin, ingredients of propolis, was found in human cancer cell lines. These compounds induced apoptosis in the cells characterized by morphological and nucleosomal DNA fragmentation analysis. Their effects were less potent compared with that of artepillin C, which is a known anticancer compound from propolis. Importantly, HL60 cells were more sensitive to drupanin than were Con A-stimulated peripheral blood lymphocytes, whereas the potency of artepillin C was the opposite of that of drupanin.

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.

Source

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

Abstract

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.

Antioxidative bioavailability of artepillin C in Brazilian propolis.

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

Source

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

Abstract

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.

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.

Source

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

Abstract

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.

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.

Source

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

Abstract

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 160 mg/kg body weight of propolis or 10mg/kg of artepillin C (equi-amounts to 160 mg 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.

Water extract of propolis and its main constituents, caffeoylquinic acid derivatives, exert neuroprotective effects via antioxidant actions.

Nakajima Y, Shimazawa M, Mishima S, Hara H.

Source

Department of Biofunctional Molecules, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.

Abstract

We investigated whether water extract of Brazilian green propolis (WEP) and its main constituents [caffeoylquinic acid derivatives (3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, chlorogenic acid) and cinnamic acid derivatives (p-coumaric acid, artepillin C, drupanin, baccharin)] exert neuroprotective effects against the retinal damage induced by oxidative stress. Additionally, their neuroprotective effects were compared with their antioxidant effects. WEP, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, chlorogenic acid, and p-coumaric acid (but not artepillin C, baccharin, or drupanin) concentration-dependently inhibited oxidative stress-induced neurotoxicity [achieved using L-buthionine-(S,R)-sulfoximine (BSO) to deplete glutathione in combination with glutamate to inhibit cystine uptake] in cultured retinal ganglion cells (RGC-5, a rat ganglion cell line transformed using E1A virus). At their effective concentrations against oxidative stress-induced retinal damage, WEP, 3,4-di-caffeoylquinic acid, 3,5-di-caffeoylquinic acid, and chlorogenic acid (but not cinnamic acid derivatives) inhibited lipid peroxidation (LPO) in mouse forebrain homogenates. Thus, the neuroprotective effects of WEP and caffeoylquinic acid derivatives paralleled those against LPO. These findings indicate that WEP and caffeoylquinic acid derivatives have neuroprotective effects against retinal damage in vitro, and that these effects may be partly mediated via antioxidant effects.

Suppression of tumor-induced angiogenesis by Brazilian propolis: major component artepillin C inhibits in vitro tube formation and endothelial cell proliferation.

Ahn MR, Kunimasa K, Ohta T, Kumazawa S, Kamihira M, Kaji K, Uto Y, Hori H, Nagasawa H, Nakayama T.

Source

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

Abstract

Propolis, a resinous substance collected by honeybees from various plant sources, possesses various physiological activities such as antitumor effects. We have previously shown that propolis of Brazilian origin was composed mainly of artepillin C and that its constituents were quite different from those of propolis of European origin. In this report, we examined an antiangiogenic effects of Brazilian propolis and investigated whether artepillin C was responsible for such effects. In an in vivo angiogenesis assay using ICR mice, we found that the ethanol extract of Brazilian propolis (EEBP) significantly reduced the number of newly formed vessels. EEBP also showed antiangiogenic effects in an in vitro tube formation assay. When compared with other constituents of EEBP, only artepillin C was found to significantly inhibit the tube formation of HUVECs in a concentration-dependent manner (3.13-50microg/ml). In addition, artepillin C significantly suppressed the proliferation of HUVECs in a concentration-dependent manner (3.13-50microg/ml). Furthermore, artepillin C significantly reduced the number of newly formed vessels in an in vivo angiogenesis assay. Judging from its antiangiogenic activity in vitro and in vivo, we concluded that artepillin C at least in part is responsible for the antiangiogenic activity of EEBP in vivo. Artepillin C may prove useful in the development of agents and foods with therapeutic or preventive activity against tumor angiogenesis.

Enhanced radical-scavenging activity of naturally-oriented artepillin C derivatives.

Manda S, Nakanishi I, Ohkubo K, Uto Y, Kawashima T, Hori H, Fukuhara K, Okuda H, Ozawa T, Ikota N, Fukuzumi S, Anzai K.

Source

Radiation Modifier Team, Heavy-Ion Radiobiology Research Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences (NIRS), Inage-ku, Chiba 263-8555, Japan.

Abstract

More than two-fold augmentation in the radical-scavenging activity of artepillin C could be achieved via altering the O-H bond dissociation enthalpy of artepillin C by means of structural modifications.

Artepillin C derived from propolis induces neurite outgrowth in PC12m3 cells via ERK and p38 MAPK pathways.

Kano Y, Horie N, Doi S, Aramaki F, Maeda H, Hiragami F, Kawamura K, Motoda H, Koike Y, Akiyama J, Eguchi S, Hashimoto K.

Source

Department of Occupational Therapy, School of Health Science, Kibi International University, 8 Iga-machi, Takahashi-city, Okayama, 716-8508, Japan. yoshio@kiui.ac.jp

Abstract

We investigated whether artepillin C, a major component of Brazilian propolis, acts as a neurotrophic-like factor in rat PC12m3 cells, in which nerve growth factor (NGF)-induced neurite outgrowth is impaired. When cultures of PC12m3 cells were treated with artepillin C at a concentration of 20 microM, the frequency of neurite outgrowth induced by artepillin C was approximately 7-fold greater than that induced by NGF alone. Artepillin C induced-neurite outgrowth of PC12m3 cells was inhibited by the ERK inhibitor U0126 and by the p38 MAPK inhibitor SB203580. Although artepillin C-induced p38 MAPK activity was detected in PC12m3 cells, phosphorylation of ERK induced by artepillin C was not observed. On the other hand, artepillin C caused rapid activation of ERK and the time course of the activation was similar to that induced by NGF treatment in PC12 parental cells. However, NGF-induced neurite outgrowth was inhibited by artepillin C treatment. Interestingly, inhibition of ERK by U0126 completely prevented artepillin C-induced p38 MAPK phosphorylation of PC12m3 cells. These findings suggest that artepillin C-induced activation of p38 MAPK through the ERK signaling pathway is responsible for the neurite outgrowth of PC12m3 cells.

In vitro and in vivo antileishmanial activities of a Brazilian green propolis extract.

Pontin K, Da Silva Filho AA, Santos FF, Silva ML, Cunha WR, Nanayakkara NP, Bastos JK, de Albuquerque S.

Source

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Ribeirão Preto, SP, Brazil.

Abstract

The in vitro antileishmanial activity of Brazilian green propolis hydroalcoholic extract (BPE) were carried out on Leishmania (Viannia) braziliensis against both promastigote (doses ranging from 1 to 750 microg mL(-1)) and amastigote (10, 100, and 250 microg mL(-1)) assays in comparison with the positive (amphotericin B) and negative (dimethyl sulfoxide at 1% in physiologic solution) control groups. BPE displayed in vitro antileishmanial activities against promastigote forms of the parasite (p < 0.05). However, it was inactive against its amastigote ones. In the in vitro cytotoxicity assay against Vero cells, BPE showed no cytotoxicity in the maximum doses tested. The high-performance liquid chromatography analysis allowed the identification of caffeic acid, p-coumaric acid, aromadendrine-4′-methyl-ether, 3-prenyl-p-coumaric acid (drupanin), and 3,5-diprenil-p-cumárico acid (artepillin C) as major compounds of BPE. In the in vivo assay, using a Balb/C lineage of Mus musculus male mice, groups of ten animals each were treated (1.5 mg kg day(-1)) with BPE orally (group 1), BPE topically (group 2), BPE orally and topically (group 3), and glucantime (group 4), using NaCl 0.9% (group 5) as the negative control group. Groups 1, 2, and 3 displayed a decrease on lesion development, after 90 days of treatment, by 78.6%, 84.3%, and 90.0%, respectively, while the glucantime-treated group showed 57.7% of decrease, all in comparison with the negative control group. It is the first time that the in vivo antileishmanial activity has been reported for Brazilian green propolis.

Neuroprotective effects of Brazilian green propolis and its main constituents against oxygen-glucose deprivation stress, with a gene-expression analysis.

Nakajima Y, Shimazawa M, Mishima S, Hara H.

Source

Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.

Abstract

Our purpose was to investigate the neuroprotective effects (and the underlying mechanism) exerted by water extract of Brazilian green propolis (WEP) and its main constituents against the neuronal damage induced by oxygen-glucose deprivation (OGD)/reoxygenation in retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus). Cell damage was induced by OGD 4 h plus reoxygenation 18 h exposure. In RGC-5, and also in PC12 (rat pheochromocytoma, neuronal cells), WEP and some of its main constituents attenuated the cell damage. At the end of the period of OGD/reoxygenation, RNA was extracted and DNA microarray analysis was performed to examine the gene-expression profile in RGC-5. Expression of casein kinase 2 (CK2) was down-regulated and that of Bcl-2-related ovarian killer protein (Bok) was up-regulated following OGD stress, results that were confirmed by quantitative reverse transcriptase-PCR (qRT-PCR). These effects were normalized by WEP. Our findings indicate that WEP has neuroprotective effects against OGD/reoxygenation-induced cell damage and that certain constituents of WEP (caffeoylquinic acid derivatives, artepillin C, and p-coumaric acid) may be partly responsible for its neuroprotective effects. Furthermore, the protective mechanism may involve normalization of the expressions of antioxidant- and apoptosis-related genes (such as CK2 and Bok, respectively).

Inhibitory activity of Brazilian green propolis components and their derivatives on the release of cys-leukotrienes.

Tani H, Hasumi K, Tatefuji T, Hashimoto K, Koshino H, Takahashi S.

Source

Institute for Bee Products and Health Science, Yamada Apiculture Center, Inc, 194 Ichiba, Kagamino 708-0393, Japan. ht0807@yamada-bee.com

Abstract

The effects of Brazilian green propolis ethanol extract on Cry j1-induced cys-leukotrienes and histamine release from peripheral leukocytes of patients with allergic rhinitis were investigated. One of the key mechanisms for the anti-allergic properties of the extract was revealed to be the suppression of cys-LTs release. Furthermore, a series of propolis components and their phenethyl esters were synthesized and evaluated as inhibitors of cys-LTs release. Artepillin C, baccharin, and kaempferide were the major active components of the ethanol extract. The inhibitory activity of artepillin C phenethyl ester was comparable to that of existing LT synthesis inhibitors.

Green propolis phenolic compounds act as vaccine adjuvants, improving humoral and cellular responses in mice inoculated with inactivated vaccines.

Fischer G, Paulino N, Marcucci MC, Siedler BS, Munhoz LS, Finger PF, Vargas GD, Hübner SO, Vidor T, Roehe PM.

Source

Centro de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil. geferson.fischer@gmail.com

Abstract

Adjuvants play an important role in vaccine formulations by increasing their immunogenicity. In this study, the phenolic compound-rich J fraction (JFR) of a Brazilian green propolis methanolic extract stimulated cellular and humoral immune responses when co-administered with an inactivated vaccine against swine herpesvirus type 1 (SuHV-1). When compared to control vaccines that used aluminium hydroxide as an adjuvant, the use of 10 mg/dose of JFR significantly increased (p < 0.05) neutralizing antibody titres against SuHV-1, as well as the percentage of protected animals following SuHV-1 challenge (p < 0.01). Furthermore, addition of phenolic compounds potentiated the performance of the control vaccine, leading to increased cellular and humoral immune responses and enhanced protection of animals after SuHV-1 challenge (p < 0.05). Prenylated compounds such as Artepillin C that are found in large quantities in JFR are likely to be the substances that are responsible for the adjuvant activity.

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