Leishmania amazonensis induces modulation of costimulatory and surface marker molecules in human macrophages

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQManipulation of costimulatory and surface molecules that shape the extent of immune responses by Leishmania is suggested as one of the mechanisms of evading the host's defences. The experiments reported here were designed to evaluate the expressions of CD40415FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ2013/01536- 1, 2015/23767470724/2013- 7This work was supported by grants from the National Council for Scientific and Technological Development (CNPq) (2013/01536- 1), and the São Paulo Research Foundation (FAPESP) (470724/2013- 7

Multitarget effects of quercetin in leukemia

This study proposes to investigate quercetin antitumor efficacy in vitro and in vivo, using the P39 cell line as a model. The experimental design comprised leukemic cells or xenografts of P39 cells, treated in vitro or in vivo, respectively, with quercetin; apoptosis, cell-cycle and autophagy activation were then evaluated. Quercetin caused pronounced apoptosis in P39 leukemia cells, followed by Bcl-2, Bcl-xL, Mcl-1 downregulation, Bax upregulation, and mitochondrial translocation, triggering cytochrome c release and caspases activation. Quercetin also induced the expression of FasL protein. Furthermore, our results demonstrated an antioxidant activity of quercetin. Quercetin treatment resulted in an increased cell arrest in G1 phase of the cell cycle, with pronounced decrease in CDK2, CDK6, cyclin D, cyclin E, and cyclin A proteins, decreased Rb phosphorylation and increased p21 and p27 expression. Quercetin induced autophagosome formation in the P39 cell line. Autophagy inhibition induced by quercetin with chloroquine triggered apoptosis but did not alter quercetin modulation in the G1 phase. P39 cell treatment with a combination of quercetin and selective inhibitors of ERK1/2 and/or JNK (PD184352 or SP600125, respectively), significantly decreased cells in G1 phase, this treatment, however, did not change the apoptotic cell number. Furthermore, in vivo administration of quercetin significantly reduced tumor volume in P39 xenografts and confirmed in vitro results regarding apoptosis, autophagy, and cell-cycle arrest. The antitumor activity of quercetin both in vitro and in vivo revealed in this study, point to quercetin as an attractive antitumor agent for hematologic malignancies.This study proposes to investigate quercetin antitumor efficacy in vitro and in vivo, using the P39 cell line as a model. The experimental design comprised leukemic cells or xenografts of P39 cells, treated in vitro or in vivo, respectively, with querceti71212401250sem informaçãosem informaçã

Antifungal And Cytotoxic 2-acylcyclohexane-1,3-diones From Peperomia Alata And P. Trineura

Bioactivity-guided fractionation of the separate CH2Cl 2 extracts from the aerial parts of Peperomia alata and P. trineura yielded seven polyketides: alatanone A [3-hydroxy-2-(5′-phenylpent- 4′E-enoyl)cyclohex-2-en-1-one, 1a] and alatanone B [3-hydroxy-2-(3′- phenyl-6′-methylenedioxypropanoyl)cyclohex-2-en-1-one, 2a] from P. alata and trineurone A [3-hydroxy-2-(11′-phenylundec-10′E-enoyl)cyclohex- 2-en-1-one, 1b], trineurone B [3-hydroxy-2-(15′-phenyl-18′- methylenedioxypentadecanoyl)cyclohex-2-en-1-one, 2b], trineurone C [3-hydroxy-2-(17′-phenyl-20′-methylenedioxyheptadecanoyl) cyclohex-2-en-1-one, 2c], trineurone D [3-hydroxy-2-(hexadec-10′Z-enoyl) cyclohex-2-en-1-one, 3a], and trineurone E [(6R)-(+)-3,6-dihydroxy-2-(hexadec- 10′Z-enoyl)cyclohex-2-en-1-one, 3b] from P. trineura. The isolated compounds were evaluated for antifungal activity against Cladosporium cladosporioides and C. sphaeospermum and for cytotoxicity against the K562 and Nalm-6 leukemia cell lines. © 2014 The American Chemical Society and American Society of Pharmacognosy.77613771382Jaramillo, M.A., Manos, P.S., Zimmer, E.A., (2004) Int. J. Plant Sci., 165, pp. 403-416Wanke, S., Samain, M.S., Vanderschaeve, L., Mathieu, G., Goetghebeur, P., Neinhuis, C., (2006) Plant Biol., 8, pp. 93-102Salazar, K.J.M., Delgado, P.G.E., Luncor, L.R., Young, M.C.M., Kato, M.J., (2005) Phytochemistry, 66, pp. 573-579Seeram, N.P., Jacobs, H., McLean, S., Reynolds, W.F., (1998) Phytochemistry, 49, pp. 1389-1391Tanaka, T., Asai, F., Linuma, M., (1998) Phytochemistry, 49, pp. 229-232Mbah, J.A., Tchuendem, M.H.K., Tane, P., Sterner, O., (2002) Phytochemistry, 60, pp. 799-801Bayma, J.C., Arruda, M.S.P., Müller, A.H., Arruda, A.C., Canto, W.C., (2000) Phytochemistry, 55, pp. 779-782Govindachari, T.R., Kumari, G.N.K., Partho, P.D., (1998) Phytochemistry, 49, pp. 2129-2131Monache, F.D., Compagnone, R.S., (1996) Phytochemistry, 43, pp. 1097-1098Xu, S., Li, N., Ning, M.M., Zhou, C.H., Yang, Q.R., Wang, M.W., (2006) J. Nat. Prod., 69, pp. 247-250Wu, J., Li, N., Hasegawa, T., Sakai, J., Kakuta, S., Tang, W., Oka, S., Ando, M., (2005) J. Nat. Prod., 68, pp. 1656-1660Mahiou, V., Roblot, F., Hocquemiller, R., Cave, A., Rojas Arias, A., Inchausti, A., Yaluff, G., Fournet, A., (1996) J. Nat. Prod., 59, pp. 694-697Soares, M.G., Felippe, A.P.V., Guimarães, E.F., Kato, M.J., Ellena, J., Doriguetto, A.C., (2006) J. Braz. Chem. Soc., 17, pp. 1205-1210Li, N., Wu, J.L., Hasegawa, T., Sakai, J., Bai, L.M., Wang, L.Y., Kakuta, S., Ando, M., (2007) J. Nat. Prod., 70, pp. 998-1001Lago, J.H.G., Oliveira, A., Guimarães, E.F., Kato, M.J., (2007) J. Braz. Chem. Soc., 18, pp. 638-642Kato, M.J., Yoshida, M., Gottlieb, O.R., (1990) Phytochemistry, 29, pp. 1799-1810Nemoto, T., Masao, S., Kuwahara, Y., Takahisa, S., (1987) Agric. Biol. Chem., 51, pp. 1805-1810Mudd, A., (1983) J. Chem. Soc., 1, pp. 2161-2164Kuwahara, Y., Nemoto, T., Shibuya, M., Matsura, H., Shiraiwa, Y., (1983) Agric. Biol. Chem., 47, pp. 1929-1931Li, N., Hasegawa, T., Sakai, J.-I., Kakuta, S., Tang, W., Oka, S., Kiuchi, M., Ando, M., (2005) J. Nat. Prod., 68, pp. 1656-1660Denny, C., Zacharias, M.E., Ruiz, A.L.T.G., Amaral, M.C.E., Bittrich, V., Kohn, L.K., Sousa, I.M.O., Foglio, M.A., (2008) Phytother. Res., 22, pp. 127-130Wang, Q.-W., Yu, D.-H., Lin, M.-G., Zhao, M., Zhu, W.-J., Lu, Q., Li, G.-X., Yang, G.-H., (2012) Molecules, 17, pp. 4474-4483Moreira, D.L., Souza, P.O., Kaplan, M.A.C., Guimarães, E.F., (1999) Acta Hortic., 500, pp. 65-69Haan, J.W.D., Vendeven, L.J., (1973) Org. Magn. Reson., 5, pp. 147-153Azevedo, N.R., Santos, S.C., Miranda, E.G., Ferri, P.H., (1997) Phytochemistry, 46, pp. 1375-1377Cheng, M.J., Lee, S.J., Chang, Y.Y., Wu, S.H., Tsai, I.L., Jayaprakasam, B., Chen, I.S., (2003) Phytochemistry, 63, pp. 603-608Zaitsev, V.G., Mikhal'Chuk, A.L., (2001) Chirality, 13, pp. 488-492Homans, A.L., Fuchs, A., (1970) J. Chromatogr. A, 51, pp. 327-329Koeffler, H.P., Golde, D.W., (1980) Blood, 56, pp. 344-350Hurwitz, R., Hozier, J., Lebien, T., Minowada, J., Gajlpeczalska, K., Kubonishi, I., Kersey, J., (1979) Int. J. Cancer, 23, pp. 174-18

Cytotoxic Non-aromatic B-ring Flavanones From Piper Carniconnectivum C. Dc.

The EtOAc extract from the leaves of Piper carniconnectivum C. DC. was subjected to chromatographic separation to afford two non-aromatic B-ring flavanone compounds: 5-hydroxy-2-(1′-hydroxy-4′-oxo-cyclohex- 2′-en-1′-yl)-6,7-dimethoxy-2,3-dihydro-4H-chromen-4-one (1) and 5-hydroxy-2-(1′,2′-dihydroxy-4′-oxo-cyclohexyl)-6, 7-dimethoxy-2,3-dihydro-4H-chromen-4-one (2). The absolute configuration of (+)-1 was unambiguously determined as 2S,1′R by electronic circular dichroism (ECD) spectroscopy and comparison to simulated spectra that were calculated using time-dependent density functional theory (TDDFT). This methodology allowed the assignment of the absolute configuration of (+)-2 also as 2S,1′R, except for the stereogenic center at C-2′, which was assigned as R because of the evidence drawn from high resolution NMR experiments. The cytotoxic activity of both compounds and 3 (hydrogenated B-ring derivative of 1) was evaluated on twelve human leukemia cell lines, and the IC50 values (<10 μM) indicated the activity of 1 against seven cell lines. © 2013 Elsevier Ltd. All rights reserved.978187Batista, Jr.J.M., Batista, A.N.L., Rinaldo, D., Vilegas, W., Ambrósio, D.L., Cicarelli, R.M.B., Bolzani, V.S., Furlan, M., Absolute configuration and selective trypanocidal activity of gaudichaudianic acid enantiomers (2011) J. Nat. Prod., 74 (1154), p. 1160Chang, H.-L., Wu, Y.-C., Su, J.-H., Yeh, Y.-T., Yuan, S.-S.F., Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2 (2008) J. Pharmacol. Exp. 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Seasonal Influence And Cytotoxicity Of Extracts, Fractions And Major Compounds From Allamanda Schottii

The aim of this research was to evaluate the fractions obtained from the leaf, stem and roots of Allamanda schottii, Pohl, Apocynaceae, responsible for the cytotoxicity, using several cell lines. Cytotoxicity was correlated with the season the part of the plant, and the major compounds were assessed. The ethanol extracts of leaves, stems and roots obtained at different seasons were evaluated in the human erythromyeloblastoid leukemia cell line (K562). Subsequently the ethanol extracts and dichloromethane fractions collected in winter were evaluated in mouse fibroblast cell line (Mus musculus) (L929), cervix adenocarcinoma (HeLa), human pre-B leukemia (Nalm6), as well as K562 cell line. The compounds plumericin, plumieride and ursolic acid isolated from ethanol extracts of the stems were evaluated in the same cell lines, as well as on breast adenocarcinoma cell line (MCF-7), and Mus musculus skin melanoma cell line (B16F10). The chromatographic profiles of the dichloromethane fractions were obtained by high performance liquid chromatography. The results revealed that the season during which A. schottii was collected, and the part of the plant analyzed, influence the cytotoxicity on the K562 cells tested. On the other hand the dichloromethane fractions, mainly from the stems and roots, are responsible for the cytoxicity on the cells tested. These results may be associated with the seasonal variation of plumericin in these parts of the plant. This information is in accordance with the HPLC analysis. The results clearly show the potential for the phytotherapeutic use of this species, and suggest that the cytotoxic activity observed may be due to the presence of plumericin, or to minor compounds not yet identified. 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Ankhd1 Silencing Inhibits Stathmin 1 Activity, Cell Proliferation And Migration Of Leukemia Cells

ANKHD1 is highly expressed in human acute leukemia cells and potentially regulates multiple cellular functions through its ankyrin-repeat domains. In order to identify interaction partners of the ANKHD1 protein and its role in leukemia cells, we performed a yeast two-hybrid system screen and identified SIVA, a cellular protein known to be involved in proapoptotic signaling pathways. The interaction between ANKHD1 and SIVA was confirmed by co-imunoprecipitation assays. Using human leukemia cell models and lentivirus-mediated shRNA approaches, we showed that ANKHD1 and SIVA proteins have opposing effects. While it is known that SIVA silencing promotes Stathmin 1 activation, increased cell migration and xenograft tumor growth, we showed that ANKHD1 silencing leads to Stathmin 1 inactivation, reduced cell migration and xenograft tumor growth, likely through the inhibition of SIVA/Stathmin 1 association. In addition, we observed that ANKHD1 knockdown decreases cell proliferation, without modulating apoptosis of leukemia cells, while SIVA has a proapoptotic function in U937 cells, but does not modulate proliferation in vitro. Results indicate that ANKHD1 binds to SIVA and has an important role in inducing leukemia cell proliferation and migration via the Stathmin 1 pathway. ANKHD1 may be an oncogene and participate in the leukemia cell phenotype.18533583593Stone, R.M., O'Donnell, M.R., Sekeres, M.A., Acute myeloid leukemia, Hematology (2004) Am. Soc. Hematol. Educ. 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