Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2019 |
| Tipo de documento: | Dissertação |
| Idioma: | por |
| Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFTM |
| Texto Completo: | http://bdtd.uftm.edu.br/handle/tede/857 |
Resumo: | Os protocolos de tratamento de carcinoma epidermoide oral causam numerosos efeitos adversos, podendo dificultar funções importantes como: nutrição, fonação e respiração. Os compostos naturais têm sido estudados para o tratamento do câncer. A Annona muricata é usada com finalidade medicinal por anos, no entanto, sua participação na inibição da tumorigênese ainda não está completamente elucidada. Este estudo visou avaliar o efeito de extratos de Annona muricata sobre citotoxicidade e a proliferação de células SCC-4 de carcinoma epidermoide oral in vitro. Foi realizado screening fitoquímico para detecção de taninos, flavonois/flavonas e alcaloides a 1 mg/mL. O IC50 dos extratos: clorofórmico (EC), etanólico (EE) e metanólico (EM) foi determinado por meio de ensaio de incorporação do Vermelho Neutro por 24 h. Foi quantificado o percentual de células proliferativas por meio de ensaio de incorporação do Brdu em concentrações abaixo do IC50 por 6 h. Foi considerada uma significância de p<0,05. A quantidade de taninos em EC foi menor que em EE e EM (p<0,0001) e o teor de flavonois e flavonas em EC foi maior que EE e EM (p<0,001). No entanto, a quantidade de taninos, flavonois e flavonas foi similar em EE e EM. Não foram detectados alcaloides nos extratos estudados. Os extratos EC, EE e EM foram citotóxicos para células SCC-4, apresentando IC50 de 6,48, 46,52 e 20,38 μg/mL, respectivamente. O percentual de células proliferativas foi significativamente menor em EC, EE e EM que o controle veículo, correspondendo a uma inibição da taxa proliferação celular de: 19%, 38% e 38%, respectivamente. Os resultados sugerem que os extratos clorofórmico, etanólico e metanólico de Annona muricata têm efeito citotóxico e antiproliferativo em células SCC-4 de carcinoma epidermoide oral. |
| id |
UFTM_adcde600e3a5decd99d0c3d75017dffb |
|---|---|
| oai_identifier_str |
oai:bdtd.uftm.edu.br:tede/857 |
| network_acronym_str |
UFTM |
| network_name_str |
Biblioteca Digital de Teses e Dissertações da UFTM |
| repository_id_str |
|
| spelling |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitroAnnona muricata.Carcinoma epidermoide oral.Citotoxicidade.Proliferação celular.Células SCC-4.Annona muricata.Cell proliferation.Cytotoxicity.Oral squamous cell carcinoma.SCC-4 cells.Citologia e Biologia CelularOs protocolos de tratamento de carcinoma epidermoide oral causam numerosos efeitos adversos, podendo dificultar funções importantes como: nutrição, fonação e respiração. Os compostos naturais têm sido estudados para o tratamento do câncer. A Annona muricata é usada com finalidade medicinal por anos, no entanto, sua participação na inibição da tumorigênese ainda não está completamente elucidada. Este estudo visou avaliar o efeito de extratos de Annona muricata sobre citotoxicidade e a proliferação de células SCC-4 de carcinoma epidermoide oral in vitro. Foi realizado screening fitoquímico para detecção de taninos, flavonois/flavonas e alcaloides a 1 mg/mL. O IC50 dos extratos: clorofórmico (EC), etanólico (EE) e metanólico (EM) foi determinado por meio de ensaio de incorporação do Vermelho Neutro por 24 h. Foi quantificado o percentual de células proliferativas por meio de ensaio de incorporação do Brdu em concentrações abaixo do IC50 por 6 h. Foi considerada uma significância de p<0,05. A quantidade de taninos em EC foi menor que em EE e EM (p<0,0001) e o teor de flavonois e flavonas em EC foi maior que EE e EM (p<0,001). No entanto, a quantidade de taninos, flavonois e flavonas foi similar em EE e EM. Não foram detectados alcaloides nos extratos estudados. Os extratos EC, EE e EM foram citotóxicos para células SCC-4, apresentando IC50 de 6,48, 46,52 e 20,38 μg/mL, respectivamente. O percentual de células proliferativas foi significativamente menor em EC, EE e EM que o controle veículo, correspondendo a uma inibição da taxa proliferação celular de: 19%, 38% e 38%, respectivamente. Os resultados sugerem que os extratos clorofórmico, etanólico e metanólico de Annona muricata têm efeito citotóxico e antiproliferativo em células SCC-4 de carcinoma epidermoide oral.Protocols for treatment of oral squamous cell carcinoma cause numerous adverse effects, which may interfere to important functions such as nutrition, phonation and respiration. Natural compounds has been studied for the treatment of cancer. Annona muricata has been used for medicinal purposes for years however its participation in the inhibition of tumorigenesis has not yet been fully elucidated. This study aimed to evaluate the effect of Annona muricata extracts on cytotoxicity and cell proliferation of SCC-4 cells of oral squamous cell carcinoma in vitro. Phytochemical screening was performed for the detection of tannins, flavonol/flavones and alkaloids at 1 mg/mL. The IC50 of extracts: chloroform (EC), ethanolic (EE) e methanolic (EM) was determinate by the Neutral Red incorporation assay for 24 h. The percentage of proliferative cells was quantified by BrdU incorporation assay at concentrations below the IC50 for 6 h. A significance of p<0.05 was considered. The quantity of tannins in EC was lower than in EE and EM (p<0.0001) and the flavonol and flavones content in EC was higher than EE and EM (p<0.001). However, the amount of tannins. However, the amout of tannins, flavonol and flavones was similar in EE and EM. No alkaloids were detected in the extracts studied by using this method. EC, EE and EM extracts were cytotoxic to SCC-4 cells, with IC50 of 6.48, 46.52 and 20.38 μg/mL, respectively. The percentage of proliferative cells was significantly lower in EC, EE and EM than the vehicle control, corresponding to an inhibition of the cell proliferation rate of 19%, 38% and, 38% respectively. These results suggest that chloroform, ethanolic and methanolic extracts of Annona muricata have a cytotoxic and antiproliferative effect on SCC-4 cells of oral squamous cell carcinoma.Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorUniversidade Federal do Triêngulo MineiroUniversidade Federal do Triângulo MineiroInstituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da SaúdeBrasilUFTMPrograma de Pós-Graduação em Ciências da SaúdeCREMA, Virgínia Oliveira66127211620http://lattes.cnpq.br/2599388555203811CARNEIRO, Anna Cecília Dias Maciel08302889610HISS, Lorraine Stephane2019-09-06T13:23:06Z2019-08-06info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfapplication/pdfHISS, Lorraine Stephane. Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro. 2019. 78f. Dissertação (Mestrado em Ciências da Saúde) - Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, 2019.http://bdtd.uftm.edu.br/handle/tede/857porABDUL WAHAB, S. M. et al. Exploring the Leaves of Annona muricata L. as a Source of Potential Anti-inflammatory and Anticancer Agents. Front Pharmacol, v. 9, p. 661, 2018. ABDULLAH, M. et al. The Value of Caspase-3 after the Application of Annona muricata Leaf Extract in COLO-205 Colorectal Cancer Cell Line.. Gastroenterol Res Pract, v. 2017, p. 4357165, 2017. ADAN, A.; KIRAZ, Y.; BARAN, Y. Cell Proliferation and Cytotoxicity Assays. Curr Pharm Biotechnol, v. 17, p. 1213-1221, 2016. ARTANTI, A. N.; ASTIRIN, O. P.; PRAYITNO, A. Cytotoxic Activity Of Non Polar Fraction From Annona Muricata L. Leaves On Hela And Raji Cell Line. J Pharma Sci Clin Res, v. 01, p. 112-118, 2016. ASARE, G. A. et al. Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the prostate, BPH-1 cells, and some target genes. Integr Cancer Ther, v. 14, p. 65-74, 2015. ASTIRIN, O. P. et al. Annonaa muricata linn leaf induce apoptosis in cancer cause virus. J Cancer Ther, v. 4, p. 1244-1250, 2013. AYAZ, M. et al. Neuroprotective and Anti-Aging Potentials of Essential Oils from Aromatic and Medicinal Plants. Front Aging Neurosci, v. 9, p. 168, 2017. BANERJEE A et al. Possible Cytotoxic Activity of Annona muricata Leaves in Huh-7 Human Liver Cancer Cells. Hepatol Pancreat Sci, v. 1, p. 1-6, 2017. BLATT, S. et al. Biomarkers in diagnosis and therapy of oral squamous cell carcinoma: A review of the literature. J Craniomaxillofac Surg, v. 45, p. 722-730, 2017. BORENFREUND, E.; PUERNER, J. A. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol Lett, v. 24, p. 119-124, 1985. BRASILEIRO FILHO, G. Bogliolo Patologia Geral. 4 ed. Rio de Janeiro: GuanabaraKoogan, 2009. 364 p. CHAMCHEU, J. C. et al. Graviola (Annona muricata) Exerts Anti-Proliferative, AntiClonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UWBCC1 and A431 Cells In Vitro: Involvement of Hedgehog Signaling. Int J Mol Sci, v. 19, p. E1791, 2018. CHANG, C. et al. Estimation of Total Flavonoid Content in Propolis by Two Complementary Colorimetric Methods. J Food Drugs Anal, v. 10, p. 178-182, 2002. CHIH, H. W. et al. Bullatacin, a potent antitumor annonaceous acetogenin, inhibits proliferation of human hepatocarcinoma cell line 2.2.15 by apoptosis induction. Life Sci, v. 69, n. 11, p. 1321-1331, 2001. CORIA-TÉLLEZ, A. V. et al. Annona muricata: a comprehensive review on its traditional medicinal uses, phytochemicals, pharmacological activities, mechanisms of action and toxicity. Arabian J Chem, v. 30, p. 662-691, 2016. CORRÊA, M. P. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Rio de Janeiro: Impressa Nacional, v.3, 1978, 486 p. COSTA, A. F. Farmacognosia. v. II, 4. ed. Lisboa: Fundação Calouste Gulbenkian. 1994. 1038 p. DE MORAIS, E. F. et al. Prognostic Factors of Oral Squamous Cell Carcinoma in Young Patients: A Systematic Review. J Oral Maxillofac Surg, v. 75, p. 1555-1566, 2017. ECONOMOPOULOU, P. et al. The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications. Ann Transl Med, v. 4, p. 173, 2016. EGGADI, V. et al. Evaluation of anticancer activity of Annona muricata in 1, 2- dimethyl hydrazine induced colon cancer. World Applied Sciences Journal, v. 32, p. 444–450, 2014. EZIRIM, A. U. et al. Induction of apoptosis in myelogenous leukemic k562 cells by ethanolic leaf extract of Annona muricata L. Global J. Res Med Plants & Indigenous Med, v. 2, p. 142-151, 2013. FAES, S.; DORMOND, O. PI3K and AKT: Unfaithful Partners in Cancer. Int J Mol Sci, v. 16, p. 21138-21152, 2015. FOTAKIS, G.; TIMBRELL, J. A. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett, v. 160, p. 171-177, 2006. FRUMAN, D. A.; ROMMEL, C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov, v. 13, p. 140-156, 2014. GANESH, D. et al. Potentially Malignant Oral Disorders and Cancer Transformation. Anticancer Res, v. 38, p. 3223-3229, 2018. GAVAMUKULYA, Y. et al. Phytochemical screening, anti-oxidant activity and in vitro anticancer potential of ethanolic and water leaves extracts of Annona muricata (Graviola). Asian Pac J Trop Med, v. 7S1, p. S355-5363, 2014. GOMES DE MELO, J. et al. Antiproliferative activity, antioxidant capacity and tannin content in plants of semi-arid northeastern Brazil. Molecules, v. 15, p. 8534-8542, 2010. GRATZNER, H. G. Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: A new reagent for detection of DNA replication. Science, v. 218, p. 474-475, 1982.. GRELA, E.; KOZŁOWSKA, J.; GRABOWIECKA, A. Current methodology of MTT assay in bacteria - A review. Acta Histochem, v. 120, p. 303-311, 2018. HANAHAN, D.; WEINBERG, R. A. Hallmarks of cancer: the next generation. Cell, v. 144, p. 646-674, 2011. INCA. Estimativa 2018: incidência de câncer no Brasil, Coordenação de Prevenção e Vigilância. Rio de Janeiro: INCA, 2018. 128 p. INDRAWATI, L. et al. The effect of an Annona muricata leaf extract on nutritional status and cytotoxicity in colorectal cancer: a randomized controlled trial. Asia Pac J Clin Nutr, v. 26, p. 606-612, 2017. JUNQUEIRA, L. C.; CARNEIRO, J. Histologia Básica. 13 ed. Rio de Janeiro: Guanabara Koogan, 2017. 554 p. KADEMANI, D. Oral cancer. Mayo Clin Proc, v. 82, p. 878-887, 2007. KATCHBURIAN, E.; ARANA, V. Histologia e Embriologia Oral. 2 ed. Rio de Janeiro: Guanabara Koogan, 2004. 388 p. KUMAR, V.; ABBAS, A. K.; ASTER, J. C. Patologia- Bases Patológicas das Doenças. 9. ed. Rio de Janeiro: Elsevier, 2016. 1440 p. LIAW, C. C. et al. Acetogenins from Annonaceae. Prog Chem Org Nat Prod, v. 101, p. 113-230, 2016. LIMA, M. A. C. D.; ELESBÃO, A. R.; FILGUEIRAS, H. A. C. Changes related to softening of soursop during postharvest maturation. Pesq Agro Bras, v. 41, n.12, p.1707-1713, 2006. LIU, N. et al. Functional proteomic analysis revels that the ethanol extract of Annona muricata L. induces liver cancer cell apoptosis through endoplasmic reticulum stress pathway. J Ethnopharmacol, v. 189, p. 210-217, 2016. MACHIELS, J. P. et al. Advances in the management of squamous cell carcinoma of the head and neck. F1000Prime Rep, v. 6, p. 44, 2014. MAGADI, V. P. et al. Evaluation of cytotoxicity of aqueous extract of Graviola leaves on squamous cell carcinoma cell-25 cell lines by 3-(4,5-dimethylthiazol-2-Yl) -2,5- diphenyltetrazolium bromide assay and determination of percentage of cell inhibition at G2M phase of cell cycle by flow cytometry: An in vitro study. Contemp Clin Dent, v. 6, p. 529-33, 2015. MATSON, J. P.; COOK, J. G. Cell cycle proliferation decisions: the impact of single cell analyses. FEBS J, v. 284, p. 362-375, 2017. MEAD, T. J.; LEFEBVRE, V. Proliferation assays (BrdU and EdU) on skeletal tissue sections. Methods Mol Biol, v. 1130, p. 233-243, 2014. MOGHADAMTOUSI, S. Z. et al. Annona muricata (Annonaceae): A Review of Its Traditional Uses, Isolated Acetogenins and Biological Activities. Int J Mol Sci, v. 16, p. 15625-15658, 2015. ______. Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-κB. BMC Complement Altern Med, v. 14, p. 299, 2014. MONTERO, P. H.; PATEL, S. G. Cancer of the oral cavity. Surg Oncol Clin N Am, v. 24, p. 491-508, 2015. MORO, J. D. S. et al. Oral and oropharyngeal cancer: epidemiology and survival analysis. Einstein (Sao Paulo), v. 16, n.2, p. 1-5, 2018. MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, v. 65, p. 55-63, 1983. MÉNAN, H. et al. Antiplasmodial activity and cytotoxicity of plants used in West African traditional medicine for the treatment of malaria. J Ethnopharmacol, v. 105, p. 131-136, 2006. NANCI, A. Ten Cate's Oral Histology Development, Structure and Function. 8 ed., Missouri: Elsevier. 2013. 400 p. NEVILLE, B. W. et al. Patologia Oral e Maxilofacial. 3 ed. Rio de Janeiro: Elsevier. 2009. 972 p. PADMA, R. et al. The relationship between histological differentiation and disease recurrence of primary oral squamous cell carcinoma. J Oral Maxillofac Pathol, v. 21, p. 461, 2017. PAES, M. M. et al. Potencial citotóxico das Acetogeninas do Gênero Annona. Rev Virtual Quim, v. 8, p. 945-980, 2016. PARÉ, A.; JOLY, A. Oral cancer: Risk factors and management. Presse Med, v. 46, p. 320-330, 2017. PAUL, J. et al. Anti cancer activity on Graviola, an exciting medicinal plant extract vs various cancer cell lines and a detailed computational study on its potent anticancerous leads. Curr Top Med Chem, v. 13, p. 1666-1673, 2013. PEREIRA, M. C. et al. Histologic subtypes of oral squamous cell carcinoma: prognostic relevance. J Can Dent Assoc, v. 73, p. 339-44, 2007. PIEME, C. A. et al. Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) extract on human cancer cells. BMC Complement Altern Med, v. 14, p. 516, 2014. PORTER, S. et al. Risk factors and etiopathogenesis of potentially premalignant oral epithelial lesions. Oral Surg Oral Med Oral Pathol Oral Radiol, v. 125,p. 603-611, 2018. PRABHAKARAN, K. et al. Polyketide Natural Products, Acetogenins from Graviola (Annona muricata L), its Biochemical, Cytotoxic Activity and Various Analyses Through Computational and Bio-Programming Methods. Curr Pharm Des, v. 22, p. 5204-5210, 2016. QAZI, A. K. et al. Emerging therapeutic potential of graviola and its constituents in cancers. Carcinogenesis, v. 39, p. 522-533, 2018. QIN, R.; STEEL, A.; FAZEL, N. Oral mucosa biology and salivary biomarkers. Clin Dermatol, v. 35, p. 477-483, 2017. RADY, I. et al. Anticancer Properties of Graviola. Oxid Med Cell Longev, v. 2018, p. 1-39, 2018. RIVERA, C. et al. Prognostic biomarkers in oral squamous cell carcinoma: A systematic review. Oral Oncol, v. 72, p. 38-47, 2017. ROCHA, J. C. C.; SILVA, S. N. Oncogenética. In: Coelho FRG, Kowalski LP. Bases da Oncologia. 2 ed. São Paulo: TECMEDD. 2003. 700 p. RUBACK, M. J. et al. Clinical and epidemiological characteristics of patients in the head and neck surgery department of a university hospital. Sao Paulo Med J, v. 130, p. 307-313, 2012. SAH, A. K. et al. Application of nanocarrier-based drug delivery system in treatment of oral cancer. Artif Cells Nanomed Biotechnol, v. 46, p. 650-657, 2018. SARASWATHY, M.; GONG, S. Different strategies to overcome multidrug resistance in cancer. Biotechnol Adv, v. 31, p. 1397-407, 2013. SEIGLER, D. S. et al. Tannins from four common Acacia species of Texas and Northeastern Mexico: 220-232 p. 1986. SEO, U. K. et al. Large-scale and effective screening of Korean medicinal plants for inhibitory activity on matrix metalloproteinase-9. J Ethnopharmacol, v. 97, p. 101-6, 2005. SEVER, R.; BRUGGE, J. S. Signal transduction in cancer. Cold Spring Harb Perspect Med, v. 5, p. a006098., 2015. SRIVASTAVA, V. et al. Plant-based anticancer molecules: a chemical and biological profile of some important leads. Bioorg Med Chem, v. 13, p. 5892-5908, 2005. STODDART, M. J. Cell viability assays: introduction. Methods Mol Biol, v. 740, p. 1-6, 2011. STROBER, W. Trypan Blue Exclusion Test of Cell Viability. Curr Protoc Immunol, v. 111, p. A3.B.1-3, 2015. SUN, S. et al. Three new anti-proliferative Annonaceous acetogenins with monotetrahydrofuran ring from graviola fruit (Annona muricata). Bioorg Med Chem Lett, v. 24, p. 2773-2776, 2014. ______. Isolation of three new annonaceous acetogenins from Graviola fruit (Annona muricata) and their anti-proliferation on human prostate cancer cell PC-3. Bioorg Med Chem Lett, v. 26, p. 4382-4385, 2016. SYED NAJMUDDIN, S. U. et al. Anti-cancer effect of Annona Muricata Linn Leaves Crude Extract (AMCE) on breast cancer cell line. BMC Complement Altern Med, v. 16, p. 311, 2016. TANDON, P. et al. The prevalence of squamous cell carcinoma in different sites of oral cavity at our Rural Health Care Centre in Loni, Maharashtra - a retrospective 10- year study. Contemp Oncol (Pozn), v. 21, p. 178-183, 2017. TEIXEIRA, C. K. B.; NEVES, E. C. A.; PENA, R. D. S. Estudo da Pasteurização da Polpa de Graviola. Revista de Alimentos e Nutrição, v. 17, p. 251-257. 2006. TEN CATE, R. Histologia Bucal. 5 ed. Rio de Janeiro: Elsevier, 2001. 439 p. THOMSON, P. J. Perspectives on oral squamous cell carcinoma preventionproliferation, position, progression and prediction. J Oral Pathol Med, v. 47, p. 803- 807, 2018. TORRES, M. P. et al. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett, v. 323, p. 29-40, 2012. TRIGLIA, D. et al. In vitro toxicity of various classes of test agents using the neutral red assay on a human three-dimensional physiologic skin model. In Vitro Cell Dev Biol, v. 27A, p. 239-244, 1991. VEIGA, V. F. Study of the medicinal plants consumption in the Middle-North Region of the Rio de Janeiro State: acceptance by health professionals, way of use of the population: Services on Demand. Rev Bras Farmacognosia. p. 308-313, 2008. WOJTOWICZ, J. M.; KEE, N. BrdU assay for neurogenesis in rodents. Nat Protoc, v. 1, p. 1399-1405, 2006. YAJID, A. I. et al. Potential Benefits of. Malays J Med Sci, v. 25, p. 5-15, 2018. YANG, C. et al. Synergistic interactions among flavonoids and acetogenins in Graviola (Annona muricata) leaves confer protection against prostate cancer. Carcinogenesis, v. 36, p. 656-665, 2015. ZENG, L. et al. Recent advances in Annonaceous acetogenins. Nat Prod Rep, v. 13, p. 275-306, 1996. ZOROFCHIAN MOGHADAMTOUSI, S. et al. The chemopotential effect of Annona muricata leaves against azoxymethane-induced colonic aberrant crypt foci in rats and the apoptotic effect of Acetogenin Annomuricin E in HT-29 cells: a bioassayguided approach. PLoS One, v. 10, p. e0122288, 2015. ZUANAZZI, J. A. S.; MONTANHA, J. A. Flavonóides. In Simões CMO (org.). Farmacognosia: da planta ao medicamento. Porto Alegre: UFRGS/Ed. UFSC. 2004.p. 577-614.7http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFTMinstname:Universidade Federal do Triangulo Mineiro (UFTM)instacron:UFTM2019-09-07T04:00:17Zoai:bdtd.uftm.edu.br:tede/857Biblioteca Digital de Teses e Dissertaçõeshttp://bdtd.uftm.edu.br/PUBhttp://bdtd.uftm.edu.br/oai/requestbdtd@uftm.edu.br||bdtd@uftm.edu.bropendoar:2019-09-07T04:00:17Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)false |
| dc.title.none.fl_str_mv |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| title |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| spellingShingle |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro HISS, Lorraine Stephane Annona muricata. Carcinoma epidermoide oral. Citotoxicidade. Proliferação celular. Células SCC-4. Annona muricata. Cell proliferation. Cytotoxicity. Oral squamous cell carcinoma. SCC-4 cells. Citologia e Biologia Celular |
| title_short |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| title_full |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| title_fullStr |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| title_full_unstemmed |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| title_sort |
Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro |
| author |
HISS, Lorraine Stephane |
| author_facet |
HISS, Lorraine Stephane |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
CREMA, Virgínia Oliveira 66127211620 http://lattes.cnpq.br/2599388555203811 CARNEIRO, Anna Cecília Dias Maciel 08302889610 |
| dc.contributor.author.fl_str_mv |
HISS, Lorraine Stephane |
| dc.subject.por.fl_str_mv |
Annona muricata. Carcinoma epidermoide oral. Citotoxicidade. Proliferação celular. Células SCC-4. Annona muricata. Cell proliferation. Cytotoxicity. Oral squamous cell carcinoma. SCC-4 cells. Citologia e Biologia Celular |
| topic |
Annona muricata. Carcinoma epidermoide oral. Citotoxicidade. Proliferação celular. Células SCC-4. Annona muricata. Cell proliferation. Cytotoxicity. Oral squamous cell carcinoma. SCC-4 cells. Citologia e Biologia Celular |
| description |
Os protocolos de tratamento de carcinoma epidermoide oral causam numerosos efeitos adversos, podendo dificultar funções importantes como: nutrição, fonação e respiração. Os compostos naturais têm sido estudados para o tratamento do câncer. A Annona muricata é usada com finalidade medicinal por anos, no entanto, sua participação na inibição da tumorigênese ainda não está completamente elucidada. Este estudo visou avaliar o efeito de extratos de Annona muricata sobre citotoxicidade e a proliferação de células SCC-4 de carcinoma epidermoide oral in vitro. Foi realizado screening fitoquímico para detecção de taninos, flavonois/flavonas e alcaloides a 1 mg/mL. O IC50 dos extratos: clorofórmico (EC), etanólico (EE) e metanólico (EM) foi determinado por meio de ensaio de incorporação do Vermelho Neutro por 24 h. Foi quantificado o percentual de células proliferativas por meio de ensaio de incorporação do Brdu em concentrações abaixo do IC50 por 6 h. Foi considerada uma significância de p<0,05. A quantidade de taninos em EC foi menor que em EE e EM (p<0,0001) e o teor de flavonois e flavonas em EC foi maior que EE e EM (p<0,001). No entanto, a quantidade de taninos, flavonois e flavonas foi similar em EE e EM. Não foram detectados alcaloides nos extratos estudados. Os extratos EC, EE e EM foram citotóxicos para células SCC-4, apresentando IC50 de 6,48, 46,52 e 20,38 μg/mL, respectivamente. O percentual de células proliferativas foi significativamente menor em EC, EE e EM que o controle veículo, correspondendo a uma inibição da taxa proliferação celular de: 19%, 38% e 38%, respectivamente. Os resultados sugerem que os extratos clorofórmico, etanólico e metanólico de Annona muricata têm efeito citotóxico e antiproliferativo em células SCC-4 de carcinoma epidermoide oral. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019-09-06T13:23:06Z 2019-08-06 |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| format |
masterThesis |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
HISS, Lorraine Stephane. Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro. 2019. 78f. Dissertação (Mestrado em Ciências da Saúde) - Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, 2019. http://bdtd.uftm.edu.br/handle/tede/857 |
| identifier_str_mv |
HISS, Lorraine Stephane. Extratos de folhas de annona muricata são citotóxicos e reduzem a proliferação celular em carcinoma epidermóide oral in vitro. 2019. 78f. Dissertação (Mestrado em Ciências da Saúde) - Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Triângulo Mineiro, Uberaba, 2019. |
| url |
http://bdtd.uftm.edu.br/handle/tede/857 |
| dc.language.iso.fl_str_mv |
por |
| language |
por |
| dc.relation.none.fl_str_mv |
ABDUL WAHAB, S. M. et al. Exploring the Leaves of Annona muricata L. as a Source of Potential Anti-inflammatory and Anticancer Agents. Front Pharmacol, v. 9, p. 661, 2018. ABDULLAH, M. et al. The Value of Caspase-3 after the Application of Annona muricata Leaf Extract in COLO-205 Colorectal Cancer Cell Line.. Gastroenterol Res Pract, v. 2017, p. 4357165, 2017. ADAN, A.; KIRAZ, Y.; BARAN, Y. Cell Proliferation and Cytotoxicity Assays. Curr Pharm Biotechnol, v. 17, p. 1213-1221, 2016. ARTANTI, A. N.; ASTIRIN, O. P.; PRAYITNO, A. Cytotoxic Activity Of Non Polar Fraction From Annona Muricata L. Leaves On Hela And Raji Cell Line. J Pharma Sci Clin Res, v. 01, p. 112-118, 2016. ASARE, G. A. et al. Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the prostate, BPH-1 cells, and some target genes. Integr Cancer Ther, v. 14, p. 65-74, 2015. ASTIRIN, O. P. et al. Annonaa muricata linn leaf induce apoptosis in cancer cause virus. J Cancer Ther, v. 4, p. 1244-1250, 2013. AYAZ, M. et al. Neuroprotective and Anti-Aging Potentials of Essential Oils from Aromatic and Medicinal Plants. Front Aging Neurosci, v. 9, p. 168, 2017. BANERJEE A et al. Possible Cytotoxic Activity of Annona muricata Leaves in Huh-7 Human Liver Cancer Cells. Hepatol Pancreat Sci, v. 1, p. 1-6, 2017. BLATT, S. et al. Biomarkers in diagnosis and therapy of oral squamous cell carcinoma: A review of the literature. J Craniomaxillofac Surg, v. 45, p. 722-730, 2017. BORENFREUND, E.; PUERNER, J. A. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol Lett, v. 24, p. 119-124, 1985. BRASILEIRO FILHO, G. Bogliolo Patologia Geral. 4 ed. Rio de Janeiro: GuanabaraKoogan, 2009. 364 p. CHAMCHEU, J. C. et al. Graviola (Annona muricata) Exerts Anti-Proliferative, AntiClonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UWBCC1 and A431 Cells In Vitro: Involvement of Hedgehog Signaling. Int J Mol Sci, v. 19, p. E1791, 2018. CHANG, C. et al. Estimation of Total Flavonoid Content in Propolis by Two Complementary Colorimetric Methods. J Food Drugs Anal, v. 10, p. 178-182, 2002. CHIH, H. W. et al. Bullatacin, a potent antitumor annonaceous acetogenin, inhibits proliferation of human hepatocarcinoma cell line 2.2.15 by apoptosis induction. Life Sci, v. 69, n. 11, p. 1321-1331, 2001. CORIA-TÉLLEZ, A. V. et al. Annona muricata: a comprehensive review on its traditional medicinal uses, phytochemicals, pharmacological activities, mechanisms of action and toxicity. Arabian J Chem, v. 30, p. 662-691, 2016. CORRÊA, M. P. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Rio de Janeiro: Impressa Nacional, v.3, 1978, 486 p. COSTA, A. F. Farmacognosia. v. II, 4. ed. Lisboa: Fundação Calouste Gulbenkian. 1994. 1038 p. DE MORAIS, E. F. et al. Prognostic Factors of Oral Squamous Cell Carcinoma in Young Patients: A Systematic Review. J Oral Maxillofac Surg, v. 75, p. 1555-1566, 2017. ECONOMOPOULOU, P. et al. The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications. Ann Transl Med, v. 4, p. 173, 2016. EGGADI, V. et al. Evaluation of anticancer activity of Annona muricata in 1, 2- dimethyl hydrazine induced colon cancer. World Applied Sciences Journal, v. 32, p. 444–450, 2014. EZIRIM, A. U. et al. Induction of apoptosis in myelogenous leukemic k562 cells by ethanolic leaf extract of Annona muricata L. Global J. Res Med Plants & Indigenous Med, v. 2, p. 142-151, 2013. FAES, S.; DORMOND, O. PI3K and AKT: Unfaithful Partners in Cancer. Int J Mol Sci, v. 16, p. 21138-21152, 2015. FOTAKIS, G.; TIMBRELL, J. A. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett, v. 160, p. 171-177, 2006. FRUMAN, D. A.; ROMMEL, C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov, v. 13, p. 140-156, 2014. GANESH, D. et al. Potentially Malignant Oral Disorders and Cancer Transformation. Anticancer Res, v. 38, p. 3223-3229, 2018. GAVAMUKULYA, Y. et al. Phytochemical screening, anti-oxidant activity and in vitro anticancer potential of ethanolic and water leaves extracts of Annona muricata (Graviola). Asian Pac J Trop Med, v. 7S1, p. S355-5363, 2014. GOMES DE MELO, J. et al. Antiproliferative activity, antioxidant capacity and tannin content in plants of semi-arid northeastern Brazil. Molecules, v. 15, p. 8534-8542, 2010. GRATZNER, H. G. Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: A new reagent for detection of DNA replication. Science, v. 218, p. 474-475, 1982.. GRELA, E.; KOZŁOWSKA, J.; GRABOWIECKA, A. Current methodology of MTT assay in bacteria - A review. Acta Histochem, v. 120, p. 303-311, 2018. HANAHAN, D.; WEINBERG, R. A. Hallmarks of cancer: the next generation. Cell, v. 144, p. 646-674, 2011. INCA. Estimativa 2018: incidência de câncer no Brasil, Coordenação de Prevenção e Vigilância. Rio de Janeiro: INCA, 2018. 128 p. INDRAWATI, L. et al. The effect of an Annona muricata leaf extract on nutritional status and cytotoxicity in colorectal cancer: a randomized controlled trial. Asia Pac J Clin Nutr, v. 26, p. 606-612, 2017. JUNQUEIRA, L. C.; CARNEIRO, J. Histologia Básica. 13 ed. Rio de Janeiro: Guanabara Koogan, 2017. 554 p. KADEMANI, D. Oral cancer. Mayo Clin Proc, v. 82, p. 878-887, 2007. KATCHBURIAN, E.; ARANA, V. Histologia e Embriologia Oral. 2 ed. Rio de Janeiro: Guanabara Koogan, 2004. 388 p. KUMAR, V.; ABBAS, A. K.; ASTER, J. C. Patologia- Bases Patológicas das Doenças. 9. ed. Rio de Janeiro: Elsevier, 2016. 1440 p. LIAW, C. C. et al. Acetogenins from Annonaceae. Prog Chem Org Nat Prod, v. 101, p. 113-230, 2016. LIMA, M. A. C. D.; ELESBÃO, A. R.; FILGUEIRAS, H. A. C. Changes related to softening of soursop during postharvest maturation. Pesq Agro Bras, v. 41, n.12, p.1707-1713, 2006. LIU, N. et al. Functional proteomic analysis revels that the ethanol extract of Annona muricata L. induces liver cancer cell apoptosis through endoplasmic reticulum stress pathway. J Ethnopharmacol, v. 189, p. 210-217, 2016. MACHIELS, J. P. et al. Advances in the management of squamous cell carcinoma of the head and neck. F1000Prime Rep, v. 6, p. 44, 2014. MAGADI, V. P. et al. Evaluation of cytotoxicity of aqueous extract of Graviola leaves on squamous cell carcinoma cell-25 cell lines by 3-(4,5-dimethylthiazol-2-Yl) -2,5- diphenyltetrazolium bromide assay and determination of percentage of cell inhibition at G2M phase of cell cycle by flow cytometry: An in vitro study. Contemp Clin Dent, v. 6, p. 529-33, 2015. MATSON, J. P.; COOK, J. G. Cell cycle proliferation decisions: the impact of single cell analyses. FEBS J, v. 284, p. 362-375, 2017. MEAD, T. J.; LEFEBVRE, V. Proliferation assays (BrdU and EdU) on skeletal tissue sections. Methods Mol Biol, v. 1130, p. 233-243, 2014. MOGHADAMTOUSI, S. Z. et al. Annona muricata (Annonaceae): A Review of Its Traditional Uses, Isolated Acetogenins and Biological Activities. Int J Mol Sci, v. 16, p. 15625-15658, 2015. ______. Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-κB. BMC Complement Altern Med, v. 14, p. 299, 2014. MONTERO, P. H.; PATEL, S. G. Cancer of the oral cavity. Surg Oncol Clin N Am, v. 24, p. 491-508, 2015. MORO, J. D. S. et al. Oral and oropharyngeal cancer: epidemiology and survival analysis. Einstein (Sao Paulo), v. 16, n.2, p. 1-5, 2018. MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, v. 65, p. 55-63, 1983. MÉNAN, H. et al. Antiplasmodial activity and cytotoxicity of plants used in West African traditional medicine for the treatment of malaria. J Ethnopharmacol, v. 105, p. 131-136, 2006. NANCI, A. Ten Cate's Oral Histology Development, Structure and Function. 8 ed., Missouri: Elsevier. 2013. 400 p. NEVILLE, B. W. et al. Patologia Oral e Maxilofacial. 3 ed. Rio de Janeiro: Elsevier. 2009. 972 p. PADMA, R. et al. The relationship between histological differentiation and disease recurrence of primary oral squamous cell carcinoma. J Oral Maxillofac Pathol, v. 21, p. 461, 2017. PAES, M. M. et al. Potencial citotóxico das Acetogeninas do Gênero Annona. Rev Virtual Quim, v. 8, p. 945-980, 2016. PARÉ, A.; JOLY, A. Oral cancer: Risk factors and management. Presse Med, v. 46, p. 320-330, 2017. PAUL, J. et al. Anti cancer activity on Graviola, an exciting medicinal plant extract vs various cancer cell lines and a detailed computational study on its potent anticancerous leads. Curr Top Med Chem, v. 13, p. 1666-1673, 2013. PEREIRA, M. C. et al. Histologic subtypes of oral squamous cell carcinoma: prognostic relevance. J Can Dent Assoc, v. 73, p. 339-44, 2007. PIEME, C. A. et al. Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) extract on human cancer cells. BMC Complement Altern Med, v. 14, p. 516, 2014. PORTER, S. et al. Risk factors and etiopathogenesis of potentially premalignant oral epithelial lesions. Oral Surg Oral Med Oral Pathol Oral Radiol, v. 125,p. 603-611, 2018. PRABHAKARAN, K. et al. Polyketide Natural Products, Acetogenins from Graviola (Annona muricata L), its Biochemical, Cytotoxic Activity and Various Analyses Through Computational and Bio-Programming Methods. Curr Pharm Des, v. 22, p. 5204-5210, 2016. QAZI, A. K. et al. Emerging therapeutic potential of graviola and its constituents in cancers. Carcinogenesis, v. 39, p. 522-533, 2018. QIN, R.; STEEL, A.; FAZEL, N. Oral mucosa biology and salivary biomarkers. Clin Dermatol, v. 35, p. 477-483, 2017. RADY, I. et al. Anticancer Properties of Graviola. Oxid Med Cell Longev, v. 2018, p. 1-39, 2018. RIVERA, C. et al. Prognostic biomarkers in oral squamous cell carcinoma: A systematic review. Oral Oncol, v. 72, p. 38-47, 2017. ROCHA, J. C. C.; SILVA, S. N. Oncogenética. In: Coelho FRG, Kowalski LP. Bases da Oncologia. 2 ed. São Paulo: TECMEDD. 2003. 700 p. RUBACK, M. J. et al. Clinical and epidemiological characteristics of patients in the head and neck surgery department of a university hospital. Sao Paulo Med J, v. 130, p. 307-313, 2012. SAH, A. K. et al. Application of nanocarrier-based drug delivery system in treatment of oral cancer. Artif Cells Nanomed Biotechnol, v. 46, p. 650-657, 2018. SARASWATHY, M.; GONG, S. Different strategies to overcome multidrug resistance in cancer. Biotechnol Adv, v. 31, p. 1397-407, 2013. SEIGLER, D. S. et al. Tannins from four common Acacia species of Texas and Northeastern Mexico: 220-232 p. 1986. SEO, U. K. et al. Large-scale and effective screening of Korean medicinal plants for inhibitory activity on matrix metalloproteinase-9. J Ethnopharmacol, v. 97, p. 101-6, 2005. SEVER, R.; BRUGGE, J. S. Signal transduction in cancer. Cold Spring Harb Perspect Med, v. 5, p. a006098., 2015. SRIVASTAVA, V. et al. Plant-based anticancer molecules: a chemical and biological profile of some important leads. Bioorg Med Chem, v. 13, p. 5892-5908, 2005. STODDART, M. J. Cell viability assays: introduction. Methods Mol Biol, v. 740, p. 1-6, 2011. STROBER, W. Trypan Blue Exclusion Test of Cell Viability. Curr Protoc Immunol, v. 111, p. A3.B.1-3, 2015. SUN, S. et al. Three new anti-proliferative Annonaceous acetogenins with monotetrahydrofuran ring from graviola fruit (Annona muricata). Bioorg Med Chem Lett, v. 24, p. 2773-2776, 2014. ______. Isolation of three new annonaceous acetogenins from Graviola fruit (Annona muricata) and their anti-proliferation on human prostate cancer cell PC-3. Bioorg Med Chem Lett, v. 26, p. 4382-4385, 2016. SYED NAJMUDDIN, S. U. et al. Anti-cancer effect of Annona Muricata Linn Leaves Crude Extract (AMCE) on breast cancer cell line. BMC Complement Altern Med, v. 16, p. 311, 2016. TANDON, P. et al. The prevalence of squamous cell carcinoma in different sites of oral cavity at our Rural Health Care Centre in Loni, Maharashtra - a retrospective 10- year study. Contemp Oncol (Pozn), v. 21, p. 178-183, 2017. TEIXEIRA, C. K. B.; NEVES, E. C. A.; PENA, R. D. S. Estudo da Pasteurização da Polpa de Graviola. Revista de Alimentos e Nutrição, v. 17, p. 251-257. 2006. TEN CATE, R. Histologia Bucal. 5 ed. Rio de Janeiro: Elsevier, 2001. 439 p. THOMSON, P. J. Perspectives on oral squamous cell carcinoma preventionproliferation, position, progression and prediction. J Oral Pathol Med, v. 47, p. 803- 807, 2018. TORRES, M. P. et al. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett, v. 323, p. 29-40, 2012. TRIGLIA, D. et al. In vitro toxicity of various classes of test agents using the neutral red assay on a human three-dimensional physiologic skin model. In Vitro Cell Dev Biol, v. 27A, p. 239-244, 1991. VEIGA, V. F. Study of the medicinal plants consumption in the Middle-North Region of the Rio de Janeiro State: acceptance by health professionals, way of use of the population: Services on Demand. Rev Bras Farmacognosia. p. 308-313, 2008. WOJTOWICZ, J. M.; KEE, N. BrdU assay for neurogenesis in rodents. Nat Protoc, v. 1, p. 1399-1405, 2006. YAJID, A. I. et al. Potential Benefits of. Malays J Med Sci, v. 25, p. 5-15, 2018. YANG, C. et al. Synergistic interactions among flavonoids and acetogenins in Graviola (Annona muricata) leaves confer protection against prostate cancer. Carcinogenesis, v. 36, p. 656-665, 2015. ZENG, L. et al. Recent advances in Annonaceous acetogenins. Nat Prod Rep, v. 13, p. 275-306, 1996. ZOROFCHIAN MOGHADAMTOUSI, S. et al. The chemopotential effect of Annona muricata leaves against azoxymethane-induced colonic aberrant crypt foci in rats and the apoptotic effect of Acetogenin Annomuricin E in HT-29 cells: a bioassayguided approach. PLoS One, v. 10, p. e0122288, 2015. ZUANAZZI, J. A. S.; MONTANHA, J. A. Flavonóides. In Simões CMO (org.). Farmacognosia: da planta ao medicamento. Porto Alegre: UFRGS/Ed. UFSC. 2004.p. 577-614.7 |
| dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Universidade Federal do Triângulo Mineiro Instituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da Saúde Brasil UFTM Programa de Pós-Graduação em Ciências da Saúde |
| publisher.none.fl_str_mv |
Universidade Federal do Triângulo Mineiro Instituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da Saúde Brasil UFTM Programa de Pós-Graduação em Ciências da Saúde |
| dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFTM instname:Universidade Federal do Triangulo Mineiro (UFTM) instacron:UFTM |
| instname_str |
Universidade Federal do Triangulo Mineiro (UFTM) |
| instacron_str |
UFTM |
| institution |
UFTM |
| reponame_str |
Biblioteca Digital de Teses e Dissertações da UFTM |
| collection |
Biblioteca Digital de Teses e Dissertações da UFTM |
| repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM) |
| repository.mail.fl_str_mv |
bdtd@uftm.edu.br||bdtd@uftm.edu.br |
| _version_ |
1813013335838294016 |