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Standardized herbal medicines for the treatment of chronic diseases

Grant number: 09/52237-9
Support type:BIOTA-FAPESP Program - Thematic Grants
Duration: April 01, 2011 - March 31, 2016
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Wagner Vilegas
Grantee:Wagner Vilegas
Home Institution: Instituto de Biociências (IB-CLP). Universidade Estadual Paulista (UNESP). Campus Experimental do Litoral Paulista. São Vicente , SP, Brazil
Co-Principal Investigators:Clélia Akiko Hiruma Lima
Associated scholarship(s):15/21479-8 - Standardization of plant extracts of Mimosa spp. development phytomedicines, BP.PD
14/23951-3 - Standardized phytotherapics for the treatment of chronicle diseases: Rhizophora mangle, BP.MS
14/26247-5 - Study of chemical composition of pulp and fiber of Cocos Nucifera fruits, BP.IC
+ associated scholarships 13/06188-1 - Arrabidaea sp: studies to enable the development of phytomedicines, BP.PD
13/10708-0 - Investigation of the mechanisms of action of crude extract of Bauhinia holophylla in liver, SQUELETIC muscle and adipose tissue of streptozotocin diabetic mice, BP.DR
12/18760-9 - Standardized plant extracts for the treatment of chronic diseases: Mimosa spp, BP.DR
12/23605-2 - Investigation of mechanism involved in hypoglycemic action of crude extract of Myrcia bella in liver, skeletal muscle and adipose tissue in model type 1 diabetes by streptozotocin, BP.DR
12/22140-6 - Modulating action of Solanum lycocarpum on the carcinogenesis of colon and liver in Wistar rats, BP.PD
12/50333-3 - Standardized herbal medicines for the treatment of chronic diseases: biomonitoring and standardized chemical studies of Petroselinum crispum (Mill.) Nyman (Apiaceae), BP.PD
12/05305-1 - Determination of the antiulcerogenic activity of Crotalaria pallida Aiden (Fabaceae), BP.IC
12/01996-0 - Standardized phytoterapics for the treatment of chronic diseases: cytotoxic, mutagenic and protective properties and the modulation of gene expression, BP.PD
11/15801-3 - Gastroprotective effect, evaluation of mechanisms of antiulcer action and healing of extract and partitions of leaves and fruits of Solanum paniculatum, BP.MS
11/08880-4 - Standardized extracts for the treatment of chronic diseases, BP.DR
11/09980-2 - Phytotherapics standard for the treatment of chronic diseases: pharmacognostic quality control, microbiological and pharmacological study of medicinal plants of the Brazilian Cerrado, BP.PD
10/12901-4 - Evaluation of hypoglycemic effect of the extract of Bauhinia holophylla in diabetic mice induced by streptozotocin, BP.MS
11/03355-9 - Hypoglycemic effetct of Myrcia bella extract in streptozotocin-induced diabetic mice, BP.MS
11/06529-8 - Phytochemical and pharmacological study of the fruits of Solanum paniculatum (Solanaceae), BP.IC
10/09740-9 - Standardized vegetable extracts for the treatment of chronic diseases: Solanum paniculatum (Solanaceae), BP.PD
09/17877-7 - Standardized herbal medicines for the treatment of chronic diseases: Arrabidaea spp, BP.DR - associated scholarships

Abstract

Increased life expectancy has increased the demand for drugs useful in the treatment of chronic diseases, especially those affecting the digestive tract (gastric and duodenal ulcers, ulcerative colitis and Crohn's disease), diabetes, cancer and other inflammatory diseases. The use of standardized herbal drugs with efficacy and safety has presented some surprising results. In Brazil, there are deficiencies in the correct characterization of chemical raw materials, as well as the evaluation of pharmacological and toxicological activities of these materials, essential steps to ensure efficacy and safety of herbal medicines. Recently, the Ministry of Health released a list of 71 plants for the development of herbal medicines, however, points out that the listed plant species are still not sufficient to meet the needs of government health plans, including within the National Policy on Medicinal Plants and Phytomedicines. As pointed out by external expertise to our previous project, the integrated chemical and pharmacological approach ‘contributes to the development of new drugs, which is important to reducing the national dependency on the import of drugs and medicine’. Thus, this project proposes to standardize new herbal medicines to treat chronic diseases in the Brazilian population: gastrointestinal (ulcers, colitis, inflammatory bowel disease), inflammation, chronic pain, cancer and diabetes. Extracts will be prepared in accordance with pharmacopoeial standards and evaluated by pharmacological aspects (ulcers, cancer, diarrhea, inflammation, diabetes, immunomodulation) and toxicological (acute and chronic toxicity, genotoxicity). The most promising extracts will be standardized according to international standards. The work will be interdisciplinary, with participants from several campi of UNESP (Institute of Chemistry of Araraquara, Faculty of Pharmaceutical Sciences of Araraquara, Biosciences Institute of Botucatu, College of Agricultural Sciences and Veterinary Medicine of Botucatu, Faculty of Sciences of Assis, Faculty of Science of Bauru, University of Campinas, Universidade Estadual de Londrina, Federal University of Santa Catarina and Universidade Federal de Belo Horizonte), consolidating a network of chemical and pharmacological studies of medicinal plants in Brazil. Our research group has always been focused on chemical and pharmacological study of plants with potential biological activity. The studies include the isolation and identification of substances in plant extracts, accompanied by appropriate pharmacological biomonitoring. This approach led to the study of hundreds of plant extracts of various Brazilian plant species, with large volume of results and significant human resources training, all recorded in their Curriculum Lattes. We have isolated and identified sesquiterpene lactones, alkaloids, flavonoids, catechins, tannins, terpenoids, phenolic acids, nafiopironas, glycolipids and saponins, many with proven anti-ulcer activity, anti-venom serum, anti-inflammatory and healing effect. A patent has been applied along with a national pharmaceutical industry (INPI-PI0401592-4). Therefore, the involvement of a multidisciplinary team encourages wide dissemination of knowledge and complete integrated study of medicinal plants and promotes the optimization of financial resources and ultimately contributes to the country to obtain technological and scientific expertise for greater autonomy in the area of drugs. (AU)

Articles published in Agência FAPESP about the research grant
Efficacy and safety of 20 medicinal plants are tested 

Scientific publications (27)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PERICO, LARISSA LUCENA; RODRIGUES, VINICIUS PEIXOTO; OHARA, RIE; ALFIERI NUNES, VANIA VASTI; MACHADO DA ROCHA, LUCIA REGINA; VILEGAS, WAGNER; DOS SANTOS, CATARINA; HIRUMA-LIMA, CLELIA AKIKO. Can the gastric healing effect of Eugenia punicifolia be the same in male and female rats?. Journal of Ethnopharmacology, v. 235, p. 268-278, MAY 10 2019. Web of Science Citations: 0.
DOS SANTOS, RAQUEL DE CASSIA; BONAMIN, FLAVIA; PERICO, LARISSA LUCENA; PEIXOTO RODRIGUES, VINICIUS; ZANATTA, ANA CAROLINE; RODRIGUES, CLENILSON MARTINS; SANNOMIYA, MIRIAM; DOS SANTOS RAMOS, MATHEUS APARECIDO; BONIFACIO, BRUNA VIDAL; BAUAB, THIS MARIA; TAMASHIRO, JORGE; MACHADO DA ROCHA, LUCIA REGINA; VILEGAS, WAGNER; HIRUMA-LIMA, CLELIA AKIKO. Byrsonima intermedia A. Juss partitions promote gastroprotection against peptic ulcers and improve healing through antioxidant and anti-inflammatory activities. BIOMEDICINE & PHARMACOTHERAPY, v. 111, p. 1112-1123, MAR 2019. Web of Science Citations: 0.
DE SOUZA MESQUITA, LEONARDO MENDES; BITTENCOURT RODRIGUES, CAROLINE FABRI; DA ROCHA, CLAUDIA QUINTINO; BIANCHIM, MAYARA SILVEIRA; RODRIGUES, CLENILSON MARTINS; DE OLIVEIRA, VANDA MARIA; GAETA, HENRIQUE HESSEL; BELCHOR, MARIANA NOVO; TOYAMA, MARCOS HIKARI; VILEGAS, WAGNER. LC-ESI-IT-MS/MS and MALDI-TOF Approach: Identification of Natural Polymers from Rhizophora mangle Barks and Determination of Their Analgesic and Anti-inflammatory Properties. NATURAL PRODUCTS AND BIOPROSPECTING, v. 9, n. 1, p. 23-34, FEB 2019. Web of Science Citations: 0.
DE PAULA CAMAFORTE, NATHALIA AP; SALDANHA, LUIZ LEONARDO; PONCE VAREDA, PRISCILLA MARIA; REZENDE-NETO, JOAO M.; SENGER, MARIO R.; DELGADO, AISLAN Q.; MORGAN, HENRIQUE J. N.; VIOLATO, NATALIA MORETTI; PIERONI, LAIS GOYOS; DOKKEDAL, ANNE LIGIA; SILVA, FLORIANO P.; BOSQUEIRO, JOSE ROBERTO. Hypoglycaemic activity of Bauhinia holophylla through GSK3-beta inhibition and glycogenesis activation. Pharmaceutical Biology, v. 57, n. 1, p. 269-279, JAN 1 2019. Web of Science Citations: 0.
PERICO, LARISSA LUCENA; RODRIGUES, VINICIUS PEIXOTO; OHARA, RIE; BUENO, GABRIELA; ALFIERI NUNES, VANIA VASTI; DOS SANTOS, RAQUEL DE CASSIA; LIMA CAMARGO, ANA CAROLINA; JUSTULIN JUNIOR, LUIS ANTONIO; DE ANDRADE, SERGIO FALONI; BISPO STEIMBACH, VIVIANE MIRANDA; DA SILVA, LUISA MOTA; MACHADO DA ROCHA, LUCIA REGINA; VILEGAS, WAGNER; DOS SANTOS, CATARINA; HIRUMA-LIMA, CLELIA AKIKO. Sex-specific effects of Eugenia punicifolla extract on gastric ulcer healing in rats. WORLD JOURNAL OF GASTROENTEROLOGY, v. 24, n. 38, p. 4369-4383, OCT 14 2018. Web of Science Citations: 0.
DE SOUZA MESQUITA, LEONARDO MENDES; RABELO E PAIVA CARIA, CINTIA; SANTOS, PAOLA SOUZA; RUY, CAIO CESAR; LIMA, NATALIA DA SILVA; TAKETA MOREIRA, DEBORA KONO; DA ROCHA, CLAUDIA QUINTINO; MURADOR, DANIELLA CARISA; DE ROSSO, VERIDIANA VERA; GAMBERO, ALESSANDRA; VILEGAS, WAGNER. Modulatory Effect of Polyphenolic Compounds from the Mangrove Tree Rhizophora mangle L. on Non-Alcoholic Fatty Liver Disease and Insulin Resistance in High-Fat Diet Obese Mice. Molecules, v. 23, n. 9 SEP 2018. Web of Science Citations: 2.
VALERINO-DIAZ, ALEXANDER B.; GAMIOTEA-TURRO, DAYLIN; ZANATTA, ANA C.; VILEGAS, WAGNER; GOMES MARTINS, CARLOS HENRIQUE; SILVA, THAYNA DE SOUZA; RASTRELLI, LUCA; DOS SANTOS, LOURDES CAMPANER. New Polyhydroxylated Steroidal Saponins from Solanum paniculatum L. Leaf Alcohol Tincture with Antibacterial Activity against Oral Pathogens. Journal of Agricultural and Food Chemistry, v. 66, n. 33, p. 8703-8713, AUG 22 2018. Web of Science Citations: 1.
DE ANDRADE, CAROLINA GOMES; DE SOUZA MESQUITA, LEONARDO MENDES; MURADOR, DANIELLA CARISA; CAVALCANTE BRAGA, ANNA RAFAELA; DE ROSSO, VERIDIANA VERA; GARCIA DE ALMEIDA, ODAIR JOSE; VILEGAS, WAGNER. Application of electrospray ionization mass spectrometry fingerprinting associated with macroscopic and histological analysis for Plantago major herbal infusions quality control. Food Research International, v. 107, p. 314-324, MAY 2018. Web of Science Citations: 0.
RIBEIRO, DIEGO LUIS; CILIAO, HELOISA LIZOTTI; LEAL SPECIAN, ANA FLAVIA; SERPELONI, JULIANA MARA; DE OLIVEIRA, MARCELO TEMPESTA; VARANDA, ELIANA APARECIDA; VILEGAS, WAGNER; SALDANHA, LUIZ LEONARDO; MARTINEZ-LOPEZ, WILNER; DOKKEDAL, ANNE LIGIA; SYLLOS COLUS, ILCE MARA. Phytochemical study and evaluation of cytotoxicity, mutagenicity, cell cycle kinetics and gene expression of Bauhinia holophylla (Bong.) Steud. in HepG2 cells in vitro. Cytotechnology, v. 70, n. 2, p. 713-728, APR 2018. Web of Science Citations: 1.
TUTTIS, KATIUSKA; GOMES DA COSTA, DARYNE LU MALDONADO; NUNES, HIGOR LOPES; LEAL SPECIAN, ANA FLAVIA; SERPELONI, JULIANA MARA; DOS SANTOS, LOURDES CAMPANER; VARANDA, ELIANA APARECIDA; VILEGAS, WAGNER; MARTINEZ-LOPEZ, WILNER; DE SYLLOS COLUS, ILCE MARA. Pouteria ramiflora (Mart.) Radlk. extract: Flavonoids quantification and chemopreventive effect on HepG2 cells. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES, v. 81, n. 16, p. 792-804, 2018. Web of Science Citations: 2.
RESENDE, FLAVIA APARECIDA; NOGUEIRA, CATARINE HAIDE; ESPANHA, LIVIA GREGHI; BOLDRIN, PAULA KARINA; OLIVEIRA-HOHNE, ANA PAULA; DE CAMARGO, MARIANA SANTORO; DA ROCHA, CLAUDIA QUINTINO; VILEGAS, WAGNER; VARANDA, ELIANA APARECIDA. In vitro toxicological assessment of Arrabidaea brachypoda (DC.) Bureau: Mutagenicity and estrogenicity studies. REGULATORY TOXICOLOGY AND PHARMACOLOGY, v. 90, p. 29-35, NOV 2017. Web of Science Citations: 0.
RODRIGUES, VINICIUS PEIXOTO; DA ROCHA, CLAUDIA QUINTINO; PERICO, LARISSA LUCENA; DOS SANTOS, RAQUEL DE CASSIA; OHARA, RIE; NISHIJIMA, CATARINE MASSUCATO; QUEIROZ, EMERSON FERREIRA; WOLFENDER, JEAN-LUC; MACHADO DA ROCHA, LUCIA REGINA; SOARES SANTOS, ADAIR ROBERTO; VILEGAS, WAGNER; HIRUMA-LIMA, CLELIA AKIKO. Involvement of Opioid System, TRPM8, and ASIC Receptors in Antinociceptive Effect of Arrabidaea brachypoda (DC) Bureau. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 11 NOV 2017. Web of Science Citations: 0.
DE SOUZA MESQUITA, LEONARDO MENDES; DELEVATI COLPO, KARINE; DA ROCHA, CLAUDIA QUINTINO; GATTE-PICCHI, DOUGLAS; PEREIRA TANGERINA, MARCELO MARUCCI; ZACHELLO-NUNES, BEATRIZ; GONCALVES MARTINS, MARIA BERNADETE; VILEGAS, WAGNER. Anatomical differentiation and metabolomic profiling: a tool in the diagnostic characterization of some medicinal Plantago species. BRAZILIAN JOURNAL OF BOTANY, v. 40, n. 3, p. 801-810, SEP 2017. Web of Science Citations: 2.
DA ROCHA, CLAUDIA QUINTINO; DE-FARIA, FELIPE MEIRA; MARCOURT, LAURENCE; EBRAHIMI, SAMAD NEJAD; KITANO, BRUNA TIEMI; GHILARDI, AMANDA FRANCESCHINI; FERREIRA, ANDERSON LUIZ; DE ALMEIDA, ANA CRISTINA ALVES; DUNDER, RICARDO JOSE; MONTEIRO SOUZA-BRITO, ALBA REGINA; HAMBURGER, MATTHIAS; VILEGAS, WAGNER; QUEIROZ, EMERSON FERREIRA; WOLFENDER, JEAN-LUC. Gastroprotective effects of hydroethanolic root extract of Arrabidaea brachypoda: Evidences of cytoprotection and isolation of unusual glycosylated polyphenols. Phytochemistry, v. 135, p. 93-105, MAR 2017. Web of Science Citations: 7.
DE SOUZA MESQUITA, LEONARDO MENDES; DA ROCHA, CLAUDIA QUINTINO; LIMA AFFONSO, LUIZ HENRIQUE; CERULLI, ANTONIETTA; PIACENTE, SONIA; PEREIRA TANGERINA, MARCELO MARUCCI; GONCALVES MARTINS, MARIA BERNADETE; VILEGAS, WAGNER. Phenolic Isomers from Plantago catharinea Leaves: Isolation, Identification, Quantification and in vitro Antioxidant Activity. NATURAL PRODUCT COMMUNICATIONS, v. 12, n. 3, p. 409-412, MAR 2017. Web of Science Citations: 1.
SPECIAN, ANA FLAVIA L.; SERPELONI, JULIANA M.; TUTTIS, KATIUSKA; RIBEIRO, DIEGO L.; CILIAO, HELOISA L.; VARANDA, ELIANA A.; SANNOMIYA, MIRIAM; MARTINEZ-LOPEZ, WILNER; VILEGAS, WAGNER; COLUS, ILCE M. S. LDH, proliferation curves and cell cycle analysis are the most suitable assays to identify and characterize new phytotherapeutic compounds. Cytotechnology, v. 68, n. 6, p. 2729-2744, DEC 2016. Web of Science Citations: 6.
RIBEIRO, DIEGO LUIS; CILIAO, HELOISA LIZOTTI; LEAL SPECIAN, ANA FLAVIA; SERPELONI, JULIANA MARA; DE SOUZA, MARILESIA FERREIRA; PEREIRA TANGERINA, MARCELO MARUCCI; VILEGAS, WAGNER; BOLDRIN, PAULA KARINA; RESENDE, FLAVIA APARECIDA; VARANDA, ELIANA APARECIDA; MARTINEZ-LOPEZ, WILNER; SANNOMIYA, MIRIAM; SYLLOS COLUS, ILCE MARA. Chemical and biological characterisation of Machaerium hirtum (Vell.) Stellfeld: absence of cytotoxicity and mutagenicity and possible chemopreventive potential. MUTAGENESIS, v. 31, n. 2, p. 147-160, MAR 2016. Web of Science Citations: 3.
SERPELONI, JULIANA MARA; LEAL SPECIAN, ANA FLAVIA; RIBEIRO, DIEGO LUIS; TUTTIS, KATIUSKA; VILEGAS, WAGNER; MARTINEZ-LOPEZ, WILNER; DOKKEDAL, ANNE LIGIA; SALDANHA, LUIZ LEONARDO; DE SYLLOS COLUS, ILCE MARA; VARANDA, ELIANA APARECIDA. Antimutagenicity and induction of antioxidant defense by flavonoid rich extract of Myrcia bella Cambess. in normal and tumor gastric cells. Journal of Ethnopharmacology, v. 176, p. 345-355, DEC 24 2015. Web of Science Citations: 6.
FRANCO, D. M.; SALDANHA, L. L.; SILVA, E. M.; NOGUEIRA, F. T. S.; DOKKEDAL, A. L.; SANTOS, C.; ROLIM DE ALMEIDA, L. F. Effects of leaf extracts of Myrcia guianensis (Aubl.) DC. on growth and gene expression during root development of Sorghum bicolor (L.) Moench. ALLELOPATHY JOURNAL, v. 35, n. 2, p. 237-248, APR 2015. Web of Science Citations: 4.
HEREDIA-VIEIRA, SILVIA C.; SIMONET, ANA M.; VILEGAS, WAGNER; MACIAS, FRANCISCO A. Unusual C,O-Fused Glycosylapigenins from Serjania marginata Leaves. Journal of Natural Products, v. 78, n. 1, p. 77-84, JAN 2015. Web of Science Citations: 6.
BONIFACIO, BRUNA VIDAL; DOS SANTOS RAMOS, MATHEUS APARECIDO; DA SILVA, PATRICIA BENTO; SILVEIRA NEGRI, KAMILA MARIA; LOPES, ERICA DE OLIVEIRA; DE SOUZA, LEONARDO PEREZ; VILEGAS, WAGNER; PAVAN, FERNANDO ROGERIO; CHORILLI, MARLUS; BAUAB, TAIS MARIA. Nanostructured lipid system as a strategy to improve the anti-Candida albicans activity of Astronium sp.. INTERNATIONAL JOURNAL OF NANOMEDICINE, v. 10, p. 5081-5092, 2015. Web of Science Citations: 13.
M.E. GALLON; B.S.P. BARROS; M.A. SILVA; S.H.M. DIAS; G. ALVES-DA-SILVA. Determinação dos parâmetros anatômicos, físico-químico e fitoquímicos das folhas de Solanum lycocarpum A. St.- Hill. Revista Brasileira de Plantas Medicinais, v. 17, n. 4, p. 937-944, 2015.
ROZZA, A. L.; CESAR, D. A. S.; PIERONI, L. G.; SALDANHA, L. L.; DOKKEDAL, A. L.; DE-FARIA, F. M.; SOUZA-BRITO, A. R. M.; VILEGAS, W.; TAKAHIRA, R. K.; PELLIZZON, C. H. Antiulcerogenic Activity and Toxicity of Bauhinia holophylla Hydroalcoholic Extract. Evidence-based Complementary and Alternative Medicine, 2015. Web of Science Citations: 5.
BASTING, ROSANNA T.; NISHIJIMA, CATARINE M.; LOPES, JULIANA A.; SANTOS, RAQUEL C.; PERICO, LARISSA LUCENA; LAUFER, STEFAN; BAUER, SILKE; COSTA, MIRIAM F.; SANTOS, LOURDES C.; ROCHA, LUCIA R. M.; VILEGAS, WAGNER; SANTOS, ADAIR R. S.; DOS SANTOS, CATARINA; HIRUMA-LIMA, CLELIA A. Antinociceptive, anti-inflammatory and gastroprotective effects of a hydroalcoholic extract from the leaves of Eugenia punicifolia (Kunth) DC. in rodents. Journal of Ethnopharmacology, v. 157, p. 257-267, NOV 18 2014. Web of Science Citations: 6.
DA ROCHA, CLAUDIA QUINTINO; QUEIROZ, EMERSON FERREIRA; MEIRA, CASSIO SANTANA; MAGALHAES MOREIRA, DIOGO RODRIGO; PEREIRA SOARES, MILENA BOTELHO; MARCOURT, LAURENCE; VILEGAS, WAGNER; WOLFENDER, JEAN-LUC. Dimeric Flavonoids from Arrabidaea brachypoda and Assessment of Their Anti-Trypanosoma cruzi Activity. Journal of Natural Products, v. 77, n. 6, p. 1345-1350, JUN 2014. Web of Science Citations: 16.
MININEL, FRANCISCO JOSE; LEONARDO JUNIOR, CARLOS SERGIO; ESPANHA, LIVIA GREGHI; RESENDE, FLAVIA APARECIDA; VARANDA, ELIANA APARECIDA; FUJIMURA LEITE, CLARICE QUEICO; VILEGAS, WAGNER; DOS SANTOS, LOURDES CAMPANER. Characterization and Quantification of Compounds in the Hydroalcoholic Extract of the Leaves from Terminalia catappa Linn. (Combretaceae) and Their Mutagenic Activity. Evidence-based Complementary and Alternative Medicine, 2014. Web of Science Citations: 3.
SALDANHA, LUIZ L.; VILEGAS, WAGNER; DOKKEDAL, ANNE L. Characterization of Flavonoids and Phenolic Acids in Myrcia bella Cambess. Using FIA-ESI-IT-MSn and HPLC-PAD-ESI-IT-MS Combined with NMR. Molecules, v. 18, n. 7, p. 8402-8416, JUL 2013. Web of Science Citations: 60.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.
Filed patent(s) as a result of this research project

Solicitação em análise e dentro do prazo legal de sigilo previsto na legislação PCT/BR2016/050148 - Universidade Estadual Paulista (UNESP) ; Université de Genève . Solicitação em análise e dentro do prazo legal de sigilo previsto na legislação - June 2016, 28

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