Trypanocidal Activity Of Brazilian Plants Against Epimastigote Forms From Y And Bolivia Strains Of Trypanosoma Cruzi

Chagas disease is one of the main public health problems in Latin America. Since the available treatments for this disease are not effective in providing cure, the screening of potential antiprotozoal agents is essential, mainly of those obtained from natural sources. This study aimed to provide an evaluation of the trypanocidal activity of 92 ethanol extracts from species belonging to the families Annonaceae, Apiaceae, Cucurbitaceae, Lamiaceae, Lauraceae, Moraceae, Nyctaginaceae, and Verbenaceae against the Y and Bolivia strains of Trypanosoma cruzi. Additionally, cytotoxic activity on LLCMK2 fibroblasts was evaluated. Both the trypanocidal activity and cytotoxicity were evaluated using the MTT method, in the following concentrations: 500, 350, 250, and 100 μg/mL. Benznidazole was used for positive control. The best results among the 92 samples evaluated were obtained with ethanol extracts of Ocotea paranapiacabensis (Am93) and Aegiphila lhotzkiana (Am160). Am93 showed trypanocidal activity against epimastigote forms of the Bolivia strain and was moderately toxic to LLCMK2 cells, its Selectivity Index (SI) being 14.56, while Am160 showed moderate trypanocidal activity against the Bolivia strain and moderate toxicicity, its SI being equal to 1.15. The screening of Brazilian plants has indicated the potential effect of ethanol extracts obtained from Ocotea paranapiacabensis and Aegiphila lhotzkiana against Chagas disease.223528533Bastos, J.K., Albuquerque, S., Silva, M.L.A., Evaluation of the trypanocidal activity of lignans isolated from the leaves of Zanthoxylum naranjillo (1999) Planta Med, 65, pp. 1-4Batista Jr., J.M., Lopes, A.A., Ambrósio, D.L., Regasini, L.O., Kato, M.J., Bolzani, V.S., Cicarelli, R.M., Furlan, M., Natural chromenes and chromene derivatives as potencial antitrypanosomal agents (2008) Biol Pharm Bull, 31, pp. 538-540Botsaris, A., Plants used traditionally to treat malaria in Brazil: The archives of Flora Medicinal (2007) J Ethnobiol Ethnomed, 1, p. 18Buainain, A., Giazzi, J.F., Belda Neto, F.M., Martini, A.S., Rosa, J.A., Pozetti, G.L., Estudo da atividade de extratos vegetais sobre o desenvolvimento de Trypanosoma cruzi em meio líquido de Warren (1992) Rev Cien Farm, 14, pp. 93-102Cabral, M.M., Barbosa-Filho, J.M., Maia, G.L., Chaves, M.C., Braga, M.V., de Souza, W., Neolignans from plants in northeastern Brazil (Lauraceae) with activity against (2010) Trypanosoma Cruzi. Exp Parasitol, 124, pp. 319-324Costa-Lotufo, L.V., Silveira, E.R., Barros, M.C., Lima, M.A., de Moraes, M.E., de Moraes, M.O., Pessoa, C., Antiproliferative effects of abietane diterpenes from aegiphilla lhotzkyana (2004) Planta Med, 70, pp. 180-182Cotinguiba, F., Regasini, L.O., Bolzani, V.S., Debonsi, H.M., Passerini, D.O., Cicarelli, R.M.B., Kato, M.J., Furlan, M., Piperamides and their derivatives as potential antitrypanosomal agents (2009) Med Chem Res, 18, pp. 703-711Coura, J.R., Castro, S.L., A critical review on Chagas disease chemotherapy (2002) Mem I Oswaldo Cruz, 97, pp. 3-24Coura, J.R., Present situation and new strategies for Chagas disease chemotherapy: A proposal (2009) Mem I Oswaldo Cruz, 104, pp. 549-554Fernandes, O., Souto, R.P., Castro, J.A., Pereira, J.B., Fernandes, N.C., Junqueira, A.C., Naiff, R.D., Coura, J.R., Brazilian isolates of Trypanosoma cruzi from humans and triatomines classified into two lineages using mini-exon and ribosomal RNA sequences (1998) Am J Trop Med Hyg, 58, pp. 807-811Fournet, A., Ferreira, M.E., Rojas de Arias, A., Guy, I., Guinaudeau, H., Heinzen, H., Phytochemical and antiprotozoal activity of (2007) Ocotea Lancifolia. Fitoterapia, 78, pp. 382-384Lopes, A.A., López, S.N., Regasini, L.O., Batista, J.M., Ambrósio, D.L., Kato, M.J., da Silva, B.V., Furlan, M., In vitro activity of compounds isolated from Piper crassinervium against Trypanosoma cruzi (2008) Nat Prod Res, 22, pp. 1040-1046Macedo, A.M., Oliveira, R.P., Pena, S.D.J., Chagas disease: Role of parasite genetic variation in pathogenesis (2002) Exp Mol Med, 4, pp. 1-16Muelas-Serrano, S., Nogal-Ruiz, J.J., Gómez-Barrio, A., Setting of a colorimetric method to determine the viability of Trypanosoma cruzi epimastigotes (2000) Parasitol Res, 86, pp. 999-1002Nwaka, S., Ridley, R.G., Virtual drug discovery and development for neglected diseases through publicprivate partnerships (2003) Nat Rev Drug Discov, 2, pp. 919-928Osorio, E., Arango, G.J., Jiménez, N., Alzate, F., Ruiz, G., Gutiérrez, D., Paco, M.A., Robledo, S., Antiprotozoal and cytotoxic activities in vitro of Colombian Annonaceae (2007) J Ethnopharmacol, 111, pp. 630-635Regasini, L.O., Cotinguiba, F., Passerini, G.D., Bolzani, V.S., Cicarelli, R.M.B., Kato, M.J., Furlan, M., Trypanocidal activity of Piper arboreum and Piper tuberculatum (Piperaceae) (2009) Rev Bras Farmacog, 19, pp. 199-203Saraiva, J., Vega, C., Rolon, M., da Silva, R., Silva, M.L., Donate, P.M., Bastos, J.K., de Albuquerque, S., In vitro and in vivo activity of lignan lactones derivatives against Trypanosoma cruzi (2007) Parasitol Res, 100, pp. 791-795Tibayrenc, M., Ayala, F.J., The clonal theory of parasitic protozoa: 12 years on (2002) Trends Parasitol, 18, pp. 405-410(2010), http://www.who.int/mediacentre/factsheets/fs340/en/index.html, World Health Organization 2010, accessed in Au

Structure of a Classical MHC Class I Molecule That Binds “Non-Classical” Ligands

The chicken MHC YF1*7.1 X-ray structures reveal that this protein binds lipids and thus represents a "hybrid" class I complex with features of classical as well as non-classical MHC molecules

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Simulating tumor microenvironment: changes in protein expression in an in vitro co-culture system.

BACKGROUND: The role of the microenvironment during the initiation and progression of carcinogenesis is thought to be of critical importance, both for the enhanced understanding of fundamental cancer biology as well as for improving molecular diagnostics and therapeutics. The aim of this study was to establish an in vitro model based on a co-culture of healthy human fibroblasts (HFs) and human osteosarcoma cells (MG-63s) to simulate the microenvironment including tumor and healthy cells. METHODS: The HFs and MG-63s were in vitro co-cultured for a period of time ranging from 24 h to 7 days. Cell morphology and organization were studied using phase contrast microscopy while the expression of Human Cartilage Glycoprotein 39 (YKL-40), Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloprotease 1 (MMP1) was investigated by Real Time PCR and Western Blotting. RESULTS: The results showed a characteristic disposition of tumor and healthy co-cultured cells in columns which are not visible in tumor and healthy cells grown singularly. The expression of YKL-40, VEGF and MMP1 significantly changed in co-cultured cells compared to HFs and MG-63s separately cultured. CONCLUSIONS: We concluded that the tumor microenvironment has an influence on the protein expression of the healthy surrounding tissues and the process of tumorigenicity