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+Artigo • Hoehnea 49 • 2022 • https://doi.org/10.1590/2236-8906-111/2020 +   + linkCopiar +
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+Open-access Prospecção química, atividade antioxidante, anticolinesterásica e antifúngica de extratos etanólicos de espécies de Senna Mill. (Fabaceae) +

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Chemical prospecting and antioxidant, anticholinesterase and antifungal activity of ethanol extracts from Senna Mill. species. (Fabaceae)

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    RESUMO

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    O objetivo deste trabalho foi avaliar o perfil químico, teor de fenóis totais e as atividades antioxidante, antiacetilcolinesterásica e antifúngica dos extratos etanólicos das folhas (EEF) e do caule (EEC) de cinco espécies de Senna, bem como avaliar a correlação entre o conteúdo de fenóis totais com a atividade sequestradora do radical livre DPPH e com a inibição da enzima acetilcolinesterase AChEI. No teste fitoquímico, evidenciou-se a presença de metabólitos secundários em todos os extratos. Os EEF e EEC de Senna trachypus, destacaram-se por apresentar os maiores valores de fenóis totais. Os EEF e EEC de S. trachypus mostraram a melhor ação sobre a enzima acetilcolinesterase. Todas as espécies apresentaram atividade antioxidante, em especial o EEF de S. trachypus. Foi observado correlação forte para as variáveis fenóis totais e atividade antioxidante (r = -0,71), muito forte para fenóis totais e antiacetilcolinesterase (r = -0,84) e atividade moderada para atividade antioxidante e antiacetilcolinesterase (0,43). Apenas os extratos de S. trachypus apresentaram atividade contra todos os dermatófitos, quando comparado às demais espécies. A espécie S. trachypus foi considerada a planta mais promissora para estudos subsequentes, a fim de encontrar compostos com ações farmacológicas.

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    Palavras-chave:
    acetilcolinesterase; dermatófitos; fitoquímica; produtos naturais; radicais livres

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    ABSTRACT

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    The objective of this work was to evaluate the chemical profile, total phenol content and the antioxidant, antiacetylcholinesterase and antifungal activities of ethanol extracts from leaves (EEF) and stem (EEC) of five species of Senna, as well as to evaluate the correlation between the content of total phenols with the DPPH free radical scavenging activity and with the inhibition of the acetylcholinesterase AChEI enzyme. The phytochemical test showed the presence of secondary metabolites in all extracts. The EEF and EEC of Senna trachypus, stood out for presenting the highest values of total phenols. S. trachypus EEF and EEC showed the best action on the acetylcholinesterase enzyme. All species showed antioxidant activity, especially the EEF from S. trachypus. A strong correlation was observed for the variables total phenols and antioxidant activity (r = -0.71), very strong for total phenols and anti-acetylcholinesterase (r = -0.84) and moderate activity for antioxidant and anti-acetylcholinesterase activity (r = 0.43). Only S. trachypus extracts showed activity against all dermatophytes, when compared to the other species. The species S. trachypus was considered the most promising plant for further studies, in order to find compounds with pharmacological actions.

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    Keywords:
    acetylcholinesterase; dermatophytes; phytochemistry; natural products; free radicals

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    Introdução

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    Senna Mill. é um gênero monofilético com distribuição pantropical e ampla variedade morfológica (Pellerin et al. 2019Pellerin, R.J., Waminal, N.E. & Kim, H.H. 2019. FISH mapping of rDNA and telomeric repeats in 10 Senna species. Horticulture, Environment, and Biotechnology 60: 253-260.). Possuindo aproximadamente 300 espécies, das quais 200 nas Américas, este gênero é o segundo maior da família Fabaceae (Queiroz 2009Queiroz, L.P. 2009. Leguminosas da Caatinga. Universidade Estadual de Feira de Santana, Feira de Santana, 467 p., Kim et al. 2018Kim, M.S., Lee, D.Y., Sung, S.H. & Jeon, W.K. 2018. Anti-cholinesterase activities of hydrolysable tannins and polyhydroxytriterpenoid derivatives from Terminalia chebula Retz. fruit. Fruit Rec Nat Prod 12: 284-289., Souza & Silva 2016Souza, A.O. & Silva, M.J. 2016. Senna (Leguminosae, Caesalpinioideae) na Floresta Nacional de Silvânia, Goiás, Brasil. Rodriguésia 67: 773-784. ). O gênero é representado no Brasil por 79 espécies, onde 29 são endêmicas, sendo a região Nordeste a que apresenta a maior riqueza de espécies com 53 registros (BFG 2018BFG. 2018. Brazilian Flora 2020: Innovation and collaboration to meet Target 1 of the Global Strategy for Plant Conservation (GSPC). Rodriguésia 1513-1527. ).

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    Trata-se de um gênero muito expressivo na flora do semiárido, alcançando destaque no Domínio Fitogeográfico da Caatinga, onde são catalogadas 42 espécies (Souza & Bortoluzzi 2015Souza, V.C.; Bortoluzzi, R.L.C. 2015. Senna in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro. ). As espécies de Senna são geralmente arbustos ou arvoretas, raramente ervas ou subarbustos anuais. Entre as suas características diagnósticas estão os nectários extraflorais convexos, interfoliolares, flores vistosas, com pétalas amarelo-brilhantes, anteras amarelas, rígidas, com deiscência abrindo por poros ou fendas, ausência de bractéolas no pedicelo, frutos deiscentes plano-compressos ou indeiscentes e cilíndricos (Queiroz 2009Queiroz, L.P. 2009. Leguminosas da Caatinga. Universidade Estadual de Feira de Santana, Feira de Santana, 467 p.).

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    As espécies de Senna têm diversas aplicações medicinais e são eficazes no tratamento para uma série de doenças, como malária, micose, dengue, eczema, hepatite e dermatite, sendo também indicadas como anti-hipertensivo, vermífugo, laxante, abortivo e antitussígeno (Macedo et al. 2016Macedo, E.M., Alan, J.G., & Silva, M.G.V. 2016. Quimiodiversidade e propriedades biofarmacológicas de espécies de Senna nativas do Nordeste do Brasil. Revista Virtual de Química 8: 169-195., Bieski et al. 2015Bieski, I.G.C., Leonti, M., Arnason, J.T., Ferrier, J., Rapinski, M., Violante, I.M.P., Balogun,S.O., Pereira, J.F.C.A., Figueiredo, R.D.C.F., Lopes, C.R.A.S., Silva, D.R.D., Pacini, A., Albuquerque, U.P. & Martins, D.T.D.O. 2015. Ethnobotanical study of medicinal plants by population of valley of Juruena region, legal amazon, Mato Grosso, Brazil. Journal of Ethnopharmacology 173: 383-423., Kabir et al. 2014Kabir, M.H., Hasan, N., Rahman, M.M., Rahman, M.A., Khan, J.A., Hoque, N.T., Bhuiyan, M.R.Q., Mou, S.M.; Jahan, R. & Rahmatullah, M. 2014. A survey of medicinal plants used by the Deb barma clan of the Tripura tribe of Moulvibazar district, Bangladesh. Journal of Ethnobiology and Ethnomedicine 10: 1-19.). Além de suas aplicações farmacológicas, estudos têm revelado que espécies pertencentes a este gênero possuem, em sua composição, uma vasta diversidade de princípios bioativos que estão associadas a diferentes atividades biológicas. Neste sentido, podemos citar como exemplo as atividades antioxidantes, antitumoral, antibacterianas, antifúngicas e anti-inflamatórias (Neves et al. 2017Neves, A.M., Costa, O.S., Coutinho, M.G.S., Souza, E.B., Santos, H.S., Silva, M.G.V. & Fontenelle, R.O.S. 2017. Caracterização química e o potencial antimicrobiano de espécies do gênero Senna Mill (Fabaceae). Rev. Virtual Quim 9: 2506-2538.).

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    As plantas são fontes alternativas promissoras de substâncias de interesse biológico e farmacológico, já que podem produzir, a partir de seu metabolismo secundário, uma enorme diversidade de substâncias, dentre estas, os compostos fenólicos. Alguns estudos têm revelado que os compostos fenólicos são responsáveis por várias atividades biológicas, incluindo atividade antifúngica. Esta atividade pode ser direta nos micro-organismos, ou sobre outros fatores necessários para a expressão da virulência ou patogenicidade (Rodrigues et al. 2019Rodrigues, F.C., Dos Santos, A.T.L., Machado, A.J.T., Bezerra, C.F., de Freitas, T.S., Coutinho, H.D.M., Morais-Braga, M.F.B., Bezerra, J.W.A., Duarte, A.E., Kamdem, J.P., Boligon, A.A., Campos, M.M.A., Barros, L.M. 2019. Chemical composition and anti-Candida potencial of the extracts of Tarenaya spinosa (Jacq.) Raf.(Cleomaceae). Comparative immunology, microbiology and infectious diseases 64: 14-19.).

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    Os compostos fenólicos estão entre os metabólitos secundários mais estudados, notadamente por possuírem grande potencial para atividades antioxidantes, atuando na redução do risco de algumas doenças agudas e crônicas relacionadas ao estado redox do corpo humano, ocasionadas pelos radicais livres. Estas moléculas apresentam uma alta capacidade reativa, sendo consideradas perigosas para os organismos vivos, causando doenças prejudiciais, incluindo doenças neurodegenerativas, como o mal de Alzheimer (DA). Atualmente, uma das teorias mais aceitas na abordagem padrão no tratamento sintomático dessa demência é a “hipótese colinérgica”. Portanto, os inibidores da enzima acetilcolinesterase (AChEI) preservam os níveis de acetilcolina, melhorando a eficiência da transmissão colinérgica (Bardakci et al. 2019Bardakci, H., CeleP, E., Gözet, T., Kan, Y. & Kirmizibekmez, H. 2019. Phytochemical characterization and antioxidant activities of the fruit extracts of several Crataegus taxa. South African Journal of Botany 124: 5-13. , Lim et al. 2019Lim, S., Choi, A.H., Kwon, M., Joung, E.J., Shin, T., Lee, S.G., Kim, NG. & Kim, H. R. 2019. Evaluation of antioxidant activities of various solvent extract from Sargassum serratifolium and its major antioxidant components. Food Chemistry 278: 178-184.; Neagu et al. 2016Neagu, E., Radu, G.L., Albu, C., & Paun, G. 2016. Antioxidant activity, acetylcholinesterase and tyrosinase inhibitory potential of Pulmonaria officinalis and Centarium umbellatum extracts. Saudi Journal of Biological Sciences, 3: 578-585.).

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    Por este motivo, a utilização de dietas ricas ou enriquecidas com antioxidantes podem prevenir, ou pelo menos amenizar, a deterioração orgânica por um excessivo estresse oxidativo. Além disso, o crescimento sobre a investigação científica envolvendo os efeitos antioxidantes de extratos brutos, frações purificadas, ou mesmo de compostos isolados, onde estão classificados os compostos fenólicos, são demonstrados em muitos estudos (Penido et al. 2017Penido, A.B., De Morais, S.M., Ribeiro, A.B., Alves, D.R., Rodrigues, A.L.M., dos Santos, L.H. & de Menezes, J.E.S.A. 2017. Medicinal plants from northeastern Brazil against Alzheimer’s disease. Evidence-Based Complementary and Alternative Medicine 2017: 1-7. , Morais et al. 2013Morais, S.M., Lima, K.S.B., Siqueira, S.M.C., Cavalcanti, E.S.B., Souza, M.S.T., Menezes, J.E.S.A., Trevisan, M.T.S. 2013. Correlação entre as atividades antiradical, antiacetilcolinesterase e teor de fenóis totais de extratos de plantas medicinais de farmácias vivas. Revista Brasileira de Plantas Medicinais 15: 575-582. ).

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    Desta forma, investigar a atividade antifúngica e anticolinesterásica de extratos de espécies de Senna, analisando o seu potencial antioxidante, o seu teor de fenóis totais e o seu perfil fitoquímico, são maneiras de promover tanto o conhecimento acerca dessas espécies, como também potencializar o descobrimento de novos fitofármacos para o combate de inúmeras enfermidades. Assim, este trabalho avaliou o perfil fitoquímico, o teor de fenóis totais e as atividades antioxidante, anticolinesterásica e antifúngica dos extratos etanólicos de S. alata (L.) Roxb., S. obtusifolia (L.) H.S.Irwin & Barneby, S. occidentalis (L.) Link, S. siamea (Lam.) H.S.Irwin & Barneby e S. trachypus (Benth.) H.S.Irwin & Barneby, e a correlação entre o teor de fenóis totais e as atividades antioxidante e anticolinesterásica.

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    Materiais e métodos

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    Material vegetal e preparação dos extratos - Foram selecionadas para este estudo cinco espécies de Senna, sendo uma exótica naturalizada e quatro nativas, das quais uma é endêmica do Brasil, ocorrendo no Cerrado e na Caatinga (BFG 2018BFG. 2018. Brazilian Flora 2020: Innovation and collaboration to meet Target 1 of the Global Strategy for Plant Conservation (GSPC). Rodriguésia 1513-1527. ) (Tabela 1). As folhas e caules de Senna spp. foram coletados em diferentes locais da região Noroeste do Ceará. A identificação botânica das espécies foi realizada no Herbário Francisco José de Abreu Matos da Universidade Estadual Vale do Acaraú (HUVA), pelo professor Dr. Elnatan Bezerra de Souza. Para o preparo dos extratos, 200g das folhas e caule secos de cada espécie de um mesmo indivíduo foram triturados e imersos durante 10 dias em 500 mL de etanol e, na sequência o extrato foi filtrado e concentrado em um evaporador rotativo a (60°C) durante 2 h. Após este processo, foi mantido em banho-maria (40°C) até a eliminação total do solvente, obtendo-se o extrato etanólico das folhas (EEF) e extrato etanólico do caule (EEC) (Matos 2009Matos, F.J.A. 2009. Introdução à Fitoquímica Experimental. 3 ed. Fortaleza: UFC. 150p.).

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    +Tabela 1.
    Identificação das espécies de Senna Mill. (Fabaceae) coletadas em diferentes locais da região noroeste do Estado do Ceará. *Exótica, **Endêmica do Brasil. Fonte: Herbário Francisco José de Abreu Matos (HUVA).
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    Triagem fitoquímica - Os extratos etanólicos foram submetidos a triagem fitoquímica, tomando como referência a metodologia descrita por Matos (2009Matos, F.J.A. 2009. Introdução à Fitoquímica Experimental. 3 ed. Fortaleza: UFC. 150p.). Através deste ensaio preliminar, foi possível verificar as principais classes de metabólitos secundários por meio de reações químicas que resultaram no aparecimento de coloração e/ou precipitado, característico para cada classe de substância. Os ensaios foram conduzidos para as seguintes classes de substâncias: fenóis, taninos, flavonoides, saponinas, esteroides, triterpenoides e alcaloides. Todos os testes foram realizados em triplicata procedimentais.

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    Determinação do teor de fenóis totais - O teor de fenóis totais nos extratos etanólicos foi determinado pelo método espectrofotométrico de Folin-Ciocateau, utilizando ácido gálico como padrão de referência (Kim et al. 2006Kim, K.H., Tsao, R., Yang, R. & Cui, S.W. 2006. Phenolic acid profiles and antioxidant activities of wheat bran extracts and the effect of hydrolysis conditions. Food Chemistry 95: 466-473.). Em cada tubo adicionou-se 0,2 mL de cada extrato nas concentrações (0,62; 0,31 e 0,15 mg mL-1) com 1 mL do reagente Folin-Ciocalteau agitado por 2 minutos e adicionado 0,8 mL de carbonato de sódio (Na2CO3) 7,5% (m/v). Para o tubo controle foi utilizado 1 mL do reagente Folin- Ciocalteau com 0,8 mL de Na2CO3 e 0,2 mL de etanol, em triplicata. Os tubos foram deixados em banho-maria a 37 ̊C por 30 minutos na ausência de luz. Logo em seguida, foi realizado a leitura dos tubos em comprimento de onda de 765 nm. O teor de fenóis foi calculado e expresso em mg de equivalente de ácido gálico por grama de extrato (EAG.g-1), com base numa curva padrão preparada com ácido gálico. Todos os testes foram realizados em triplicata.

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    Atividade antioxidante - A atividade antioxidante dos extratos foi determinada pelo método de redução do radical 2,2’-difenil-1-picril-hidrazil (DPPH), segundo a metodologia modificada por Brand-Williams et al. (1995Brand-Williams, W., Cuvelier, M.E. & Berset, C.L.W.T. 1995. Use of a free radical method to evaluate antioxidant activity. LWT-Food Science and Technology 1: 25-30.), Sanchez-Moreno et al. (1998Sánchez‐Moreno, C., Larrauri, J.A. & Saura‐Calixto, F. 1998. A procedure to measure the antiradical efficiency of polyphenols. Journal of the Science of Food and Agriculture 76: 270-276.). Foram preparadas soluções etanólicas das amostras nas concentrações de 5,0; 2,5; 1,25; 0,62; 0,31 e 0,15 mg mL-1. Foram utilizados 100 µL dos extratos com 2,4 mL de DPPH (0,04 mg mL-1). Para o tubo controle foram utilizados 100 µL de etanol com 2,4 mL de DPPH em triplicata. O meio reacional ficou por 30 minutos na ausência da luz, e posteriormente foi realizada a leitura em comprimento de onda 515 nm. A atividade sequestradora do radical DPPH pelos extratos nas diferentes concentrações foi calculada pela expressão do índice de varredura em porcentagem (IV%): IV% = (Abs DPPH - Abs Amostra / Abs DPPH) x 100. A concentração efetiva para inibir 50% do radical livre DPPH (CE50) foi obtida com auxílio do Software Excel 2019, onde, a partir dos valores das concentrações finais da amostra e o índice de varredura (IV%), foram originados gráficos de dispersão cujas equações das retas foram utilizadas para se obter os valores da média e desvio padrão. Para fins de comparação, foi construída uma curva de calibração com diferentes porcentagens do flavonoide quercetina, que apresenta elevada atividade antioxidante em radical livre DPPH.

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    Avaliação da atividade anticolinesterásica in vitro - O ensaio para verificação da inibição da enzima acetilcolinesterase (AChE) dos extratos foi realizado de acordo com a metodologia descrita por Ellman et al. (1961Ellman, G.L., Courtney, K.D., Andres Jr, V. & Featherstone, R.M. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology: 7: 88-95.). Em placas estéreis de 96 poços, foram adicionados 25 µL de iodeto de acetiltiocolina (15 mM), 125 µL de 5,5’-ditiobis-[2-nitrobenzóico] na solução Tris/HCL (50 nM, pH 8, com 0,1 M de NaCL e 0,02 M de MgCL2 .6H2O. (3 mM, DTNB ou reagente de Ellman)), 50 µL da solução Tris/HCL (50 nM, pH 8, com 0,1% de albumina sérica bovina (BSA) e 25 µL dos extratos de Senna spp. na concentraçao de 0,2 mg.mL-1 em tampão Tris/HCL (50 mM, pH 8) de 0,2 mg.mL-1 (Rhee et al. 2001Rhee, I.K., van de Meent, M., Ingkaninan, K. & Verpoorte, R. 2001. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. Journal of Chromatography A 915: 217-223., Trevisan et al. 2003Trevisan, M.T.S., Macedo, F.V.V., Meent, M.V.D., Rhee, I.K. & Verpoorte, R. 2003. Seleção de plantas com atividade anticolinesterase para tratamento da doença de Alzheimer. Química Nova 26: 301-304.).

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    A absorbância foi aferida a 405 nm durante 30 segundos. Em seguida, foram adicionados 25 µL da enzima acetilcolinesterase (0,25 U.mL-1) e a absorbância foi aferida por minuto até o total de 25 minutos de incubação da enzima. Como padrão negativo foram utilizadas todas as soluções, excetuando-se a amostra. O padrão utilizado como controle positivo foi a fisostigmina (0,22 mg.mL-1.) e todas as amostras foram analisadas em triplicata. A atividade anticolinesterásica dos extratos vegetais foi determinada de acordo com os valores de CI50 (Concentração inibitória capaz de inibir 50% da enzima acetilcolinesterase) como: alta potência (CI50 < 20 μg. mL-1); potência moderada (20 < CI50 < 200 μg.mL-1) e baixa potência (200 < CI50 < 1000 μg.mL-1) (Santos et al. 2018Santos, G.H.F., Amaral, A. & Da Silva, E.B. 2018. Antibacterial activity of irradiated extracts of Anacardium occidentale L. on multiresistant strains of Staphylococcus aureus. Applied Radiation and Isotopes 140: 327-332.).

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    Ensaio antifúngico in vitro - No ensaio para verificação da concentração inibitória mínima (CIM) dos EE das espécies de Senna, foram utilizadas cepas de Trichophyton rubrum obtidas a partir da micoteca da Universidade Federal de Pernambuco e do Centro Especializado de Micologia Médica (CEMM) da Universidade Federal do Ceará. Para este ensaio foi utilizado o método de microdiluição em caldo, de acordo com a metodologia descrita por (Neves et al. 2019Neves, A.M., Silva, H.S., Souza, E.B., Fontenelle, R.O.S., Silva, A.C.S., Morais, S.M. 2019. Perfil fitoquímico e avaliação da atividade antifúngica da fração hexânica de Mitracarpus baturitensis (Rubiaceae). Essentia 20: 96-101. ) com as normas do protocolo Clinical Laboratory Standards Insitute do documento M38-A (CLSI M38-A2, 2008Clinical and Laboratory Standards Institute. 2008. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi (Approved Standard Document M38. CLSI), vol. M38-A2, Second ed. Clinical and Laboratory Standards Institute, Wayne, PA.). Em placas de 96 poços estéreis, foram adicionados 100 µL de meio RPMI em todos os poços e 10 mg mL-1 dos extratos de Senna spp. foi acrescentado a todos os poços da primeira coluna e, em sequência foram efetuadas as diluições seriadas. Finalmente, 100 µL do inóculo foi adicionado aos poços da placa. Como controle foi utilizado o Cetoconazol (Sigma, Chemical Co., USA). Para as análises de susceptibilidade, os extratos etanólicos foram testados em concentrações variando de 0,002 a 2,5 mg mL-1. As placas foram cobertas com parafilme e incubadas a 37 °C e a leitura visual foi realizada após cinco dias para T. rubrum. Procedimento realizado em duplicata. A CIM é definida como a menor concentração do extrato capaz de inibir 100% do crescimento fúngico visível (Fontenelle et al. 2007Fontenelle, R.O.S., Morais, S.M., Brito, E.H.S., Kerntopf, M.R., Brilhante, R.S.N., Cordeiro, R.A., Tomé, A.R., Queiroz, M.G.R., Nascimento, N.R.F. & Sidrim, J.J.C. 2007. Chemical composition, toxicological aspects and antifungal activity of essential oil from Lippia sidoides Cham. Journal of Antimicrobial Chemotherapy 59: 934-940. ). A concentração fungicida mínima (CFM) foi determinada por subcultura de 100 μL da solução de poços sem turbidez no meio Ágar Dextrose de Batata, a 28 °C. (Fontenelle et al. 2008Fontenelle, R.O.S., Morais, S.M., Brito, E.H.S., Brilhante, R.S.N., Cordeiro, R.A., Nascimento, N.R.F., Kerntopf, M.R., Sidrim, J.J.C. & Rocha, M.F.G. 2008. Antifungal activity of essential oils of Croton species from the Brazilian caatinga biome. Journal of Applied Microbiology 104: 1383-1390.).

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    Análise estatística - Todas as determinações foram realizadas em triplicata e todos os resultados foram apresentados como média ± desvio-padrão (DP). Foram realizadas análises de variância (ANOVA) com duas repetições e o Teste Tukey, ao nível de significância de 5%, usando programa Graph Pad Prism® v5.01 (GraphPadSoftware, San Diego, CA, E.U.A.). As diferenças entre as médias foram consideradas significativas quando o valor obtido para "p" foi menor que 0,05 (p < 0,05).

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    Para análises da correlação entre os dados, foi utilizado o coeficiente de correlação de Pearson no software Microsoft Excel 2019, a qual mede o grau da correlação linear entre duas variáveis quantitativas. A intensidade dessa correlação é dada pelo “r”, que é um índice adimensional com valores situados entre -1,0 e 1,0. Quando o valor de r estiver entre 0,00-0,19 a correlação é muito fraca; entre 0,20-0,39 é fraca; 0,40-0,59 é uma correlação moderada; entre 0,60-0,79 é forte e finalmente entre 0,80-1,0 diz-se que é uma correlação muito forte (Mukaka 2012Mukaka, M.M. 2012. Statistics corner: A guide to appropriate use of correlation coefficient in medical research. Malawi Med J. 24:69-71.).

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    Resultados e discussãoTabela 3 +

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    Os fito-constituintes ou fitoquímicos são compostos químicos que desempenham importantes funções nas plantas. A triagem fitoquímica em materiais vegetais é geralmente o ponto de partida para o isolamento e purificação de compostos naturais com bioatividade (Omoregie & Oikeh 2015Omoregie, E.S. & Oikeh, E.I. 2015. Comparative studies on the phytochemical composition, phenolic content and antioxidant activities of methanol leaf extracts of Spondias mombin and Polyathia longifolia. Jordan Journal of Biological Sciences 147: 1-5.). A triagem fitoquímica preliminar revelou a presença de fenóis, taninos, flavonoides e esteroides para todos os extratos estudados (Tabela 2). Entretanto, a presença de saponinas foi constatada apenas no EEF e EEC de S. alata e no EEF de S. trachypus. Já os alcaloides foram encontrados exclusivamente no EEF de S. alata e nenhuma das espécies apresentou triterpenoides.

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    Triagem fitoquímica do EEF e do EEC de espécies de Senna Mill. (Fabaceae). Presente: + Ausente: - EEF: Extrato etanólico da folha. EEC: Extrato etanólico do caule.
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    Os metabólitos detectados nas espécies estudadas são consistentes com os metabólitos descritos na literatura para o gênero Senna, conhecido por apresentar flavonoides, alcaloides, taninos, esteroides e saponinas em sua composição (Onyegeme-Okerenta et al. 2017Onyegeme-Okerenta, B.M., Nwosu, T. & Wegwu, M.O. 2017. Proximate and phytochemical composition of leaf extract of Senna alata (L) Roxb. Journal of Pharmacognosy and Phytochemistry 6: 320-326., Ishaku et al. 2016Ishaku, G.A., Arabo, A.A., Bassey, E.E., Uwem, A.A.U.M. & Godwin, E.U. 2016. Physicochemical characterization and antibacterial activity of Senna occidentalis Linn. Journal of Chemistryand Chemical Sciences 6: 9-18. , Silva et al. 2014Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202., Sudi et al. 2011Sudi, I.Y., Ksgbiya, D.M., Muluh, E.K. & Clement, A. 2011. Nutritional and phytochemical screening of Senna obtusifolia indigenous to Mubi, Nigeria. Advances in Applied Science Research 2: 432-437., Bukar et al. 2009Bukar, A., Mukhtar, M. & HASSAN, A. 2009. Phytochemical screening and antibacterial activity of leaf extracts of Senna siamea (Lam) on Pseudomonas aeruginosa. Bayero Journal of Pure and Applied Sciences 1: 139-142. ). É possível perceber que na análise de prospecção química dos extratos houve uma variação de metabólitos secundários. Este fato pode estar atribuído a vários fatores, entre eles estão as diferentes condições ambientais, tais como clima, radiação solar, nutrição mineral, sazonalidade, ritmo circadiano, temperatura, disponibilidade hídrica, e também os tipos de solvente e a metodologia empregada no processo de extração, que podem interferir consideravelmente no conteúdo de praticamente todas as classes de metabólitos secundários (Gomes et al. 2016Gomes, E.M.C., Pena, R.D.C.M. & da Silva, S.S.S.M. 2016. Composição fitoquímica e ação fungicida de extratos brutos de Cinnamomum zeylanicum sobre Quambalaria eucalypti. Biota Amazônia. 6: 54-58., Bezerra et al. 2013Bezerra, A.S., Nörnberg, J.L., Lima, F.O., Rosa, M.B.D. & Carvalho, L.M.D. 2013. Parâmetros climáticos e variação de compostos fenólicos em cevada. Ciência Rural 9: 1546-1552., Gobbo-Neto & Lopes 2007Gobbo-Neto, L. & Lopes, N.P. 2007. Plantas medicinais: Fatores de influência no conteúdo de metabólitos secundários. Química Nova 30: 374-381.).

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    Os teores de fenóis totais apresentaram diferenças significativas entre os extratos etanólicos das diferentes partes e espécies vegetais estudadas (Tabela 3). O conteúdo de fenóis totais para os EEF variou de 32,60 ± 0,53 a 184,8 ± 5,09 EAG/g, enquanto que para o EEC foram de 30,03± 1,00 a 191,3 ± 0,47 EAG/g. Os maiores níveis de fenóis totais foram detectados na espécie S. trachypus. Os dados da literatura sobre o conteúdo de compostos fenólicos obtidos a partir do extrato aquoso, etanólico e acetona da raiz de S. alata, apresentaram uma concentração de fenóis de 46,3, 78,21 e 21,42 mg EAG/g, respectivamente, e de flavonoides de 26,17, 39,29 e 9,65 mg de equivalente de quercetina por grama de extrato (EQ/g), respectivamente (Ita & Ndukwe 2017Ita, B.N., & Ndukwe, G.I. Antioxidant activity of Senna alata root extracts. 2017. J Nat Prod Resour 3: 94-96. ). Já o extrato etanólico preparado a partir das folhas de S. obtusifolia por Ali et al. (2019Ali, I., Yisa, J. & Jacob, J.O. 2019. Corrosion inhibitory potential of ethanol extract of Senna obtusifolia on Mild Steel in 5M HCl. Journal of Chemical Society of Nigeria 44: 187-198. ), apresentou um teor de fenóis e de flavonoides de 14,39 mg/g e 2,85 mg/g, respectivamente, demonstrando possuir teor de compostos fenólicos inferior ao das mostras de S. obtusifolia encontradas no presente estudo. Além disso, o conteúdo de polifenóis encontrado no extrato etanólico e nas frações obtidas a partir das folhas de S. occidentalis por Yakubu et al. (2018Yakubu, O.E., Otitoju, O., Imarenezor, E.P.K., Tatah, S.V. & Habibu, B. 2018. Fractionation and determination of antioxidant activities, of the Leaves of Senna Occidentalis ethanol extract. Pharmacology, 6: 26-30.) variou de 139 mg/mL a 206 mg/mL e de flavonoides de 104 a 142 mg/mL. Já para os extratos preparados a partir das folhas e casca do caule de S. siamea revelaram um teor de fenóis totais de 10,21 ± 0,25 g/g e 24,77 ± 0,15 g/g, respectivamente. Por outro lado, o teor de flavonoides foi de 0,08 ± 0,01 g/g para as folhagens, e de 0,04 ± 0,01 g/g para a casca do caule (Kwada & Tella 2009Kwada, A.D. & Tella, I.O. 2009. Determination of infochemicals and the phytochemical screening of the foliage and stem-bark of Senna siamea (lam.) in Yola, Adamawa State. Journal of Medicinal Plants Research 3: 630-640.). Para os extratos etanólicos das folhas e raízes de S. trachypus o teor de fenóis totais encontrado foi de 322,09 ± 2,83 EAG/g e de 1277,34 ± 79,54 EAG/g, respectivamente (Silva et al. 2014Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202.).Senna.

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    Teor de fenóis totais, atividade antioxidante e inibição da enzima acetilcolinesterase de espécies de Senna Mill. (Fabaceae).
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    Os resultados da atividade antioxidante dos extratos de Senna spp. mostraram que os valores de CE50 para o EEF variaram de 0,63 ± 0,01 a 8,20 ± 0,07 µg/mL, sendo o EEF de S. trachypus o que apresentou menor CE50 com atividade antirradicalar superior ao da quercetina e, portanto, maior potencial antioxidante (Villano et al. 2007Villano, D., Fernandez-Pachón, M.S., Moya, M.L., Troncoso, A.M. & García-Parrilla, M.C. 2007. Radical scavenging ability of polyphenolic compounds towards DPPH free radical. Talanta, 71: 230-235. ). Já para o EEC os valores de CE50 variaram de 0,83 ± 0,01 a 11,19 ± 0,15 µg/mL (Tabela 3). Foi observado que o EEC de S. siamea apresentou capacidade antirradicalar próximo à quercetina. Semelhantes aos nossos resultados, estudos anteriores revelaram que as espécies de S. alata, S. obtusifolia, S. occidentalis, S. siamea e S. trachypus, apresentaram potencial antioxidante e que esta atividade está atribuída à presença de compostos fenólicos (Coelho et al. 2017Coelho, E.M.P., Barbosa, M.C., Mito, M.S., Mantovanelli, G.C., Oliveira, R.S., & Ishii-Iwamoto, E.L. 2017. The activity of the antioxidant defense system of the weed species Senna obtusifolia L. and its resistance to allelochemical stress. Journal of Chemical Ecology 7: 725-738., Ita & Ndukwe 2017Ita, B.N., & Ndukwe, G.I. Antioxidant activity of Senna alata root extracts. 2017. J Nat Prod Resour 3: 94-96. , Barnaby et al. 2016Barnaby, A.G., Reid, R. & Warren, D. 2016. Antioxidant activity, total phenolics and fatty acid profile of Delonix regia, Cassia fistula, Spathodea campanulata, Senna siamea and Tibouchina granulosa. J Anal Pharm Res 3: 00056., Odeja et al. 2015Odeja, O., Obi, G., Ogwuche, C.E., Elemike, E.E. & Oderinlo, Y. 2015. Phytochemical Screening, Antioxidant and Antimicrobial activities of Senna occidentalis (L.) leaves Extract. Clinical Phytoscience 1: 1-6., Silva et al. 2014Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202.).

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    Os resultados obtidos na análise de inibição da enzima acetilcolinesterase foram comparados ao do alcaloide fisostigmina que foi o primeiro inibidor descoberto. Os experimentos de inibição da enzima acetilcolinesterase in vitro para as espécies de Senna produziram apenas resultados com potência moderada (Tabela 3). Relatos confirmam a atividade antiacetilcolinesterásica de vários taninos isolados do fruto Terminalia chebula Retz., (Combretaceae) que exibiram um efeito de inibição contra a enzima acetilcolinesterase in vitro (Kim et al. 2018Kim, M.S., Lee, D.Y., Sung, S.H. & Jeon, W.K. 2018. Anti-cholinesterase activities of hydrolysable tannins and polyhydroxytriterpenoid derivatives from Terminalia chebula Retz. fruit. Fruit Rec Nat Prod 12: 284-289.). Outros compostos, como saponinas, alcaloides e compostos fenólicos, também são relatados na literatura como inibidores da enzima acetilcolinesterase (Paiva et al. 2021Paiva, J.R., Queiroz, S.A.S., Pereira, R.D.C.A., Ribeiro, P.R.V., Alves, F.E.G., Silva, L.M.A., Zocolo, G.J., Brito, E.S., Alves, D.R., Morais, S.M., Tavares, J., Pinto, F.C.L., Andrade, G.M., Pessoa, O.D.L., & Canuto, K.M. 2021. Chemical composition and anticholinesterase activity of cultivated bulbs from Hippeastrum elegans, a potential tropical source of bioactive alkaloids. Phytochemistry Letters 43: 27-34., Kozachok et al. 2020Kozachok, S., Pecio, Ł., Orhan, I.E., Deniz, F.S.S., Marchyshyn, S., & Oleszek, W. 2020. Reinvestigation of Herniaria glabra L. saponins and their biological activity. Phytochemistry 169: 112162., Adedayo et al. 2015Adedayo, B.C., Oboh, G., Oyeleye, S.I., Ejakpovi, I.I., Boligon, A.A., & Athayde, M.L. 2015. Blanching alters the phenolic constituents and in vitro antioxidant and anticholinesterases properties of fireweed (Crassocephalum crepidioides). Journal of Taibah University Medical Sciences 10: 419-426.). Estas classes de compostos foram detectadas na triagem fitoquímica, embora provavelmente as concentrações nos extratos eram muito baixas para dar resultados satisfatórios no ensaio. Os extratos foliares e do caule de S. trachypus apresentaram os valores mais satisfatórios de inibição da enzima acetilcolinesterase, indicando que o isolamento de metabólitos pode levar a potenciais agentes antiacetilcolinesterásicos. Na literatura, não foram encontrados estudos do potencial anticolinesterásico paras as espécies de Senna referenciadas, sendo este o primeiro relato de estudo de atividade de inibição para esta enzima.

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    Para os extratos de Senna spp., foi observada forte correlação negativa entre os valores de fenóis totais e CE50 (r = - 0,71), mostrando que quanto maior os teores de fenóis totais, menor a CE50 e, consequentemente, maior o potencial antioxidante, uma vez que a CE50 está inversamente relacionada à capacidade antioxidante de um composto (Villano et al. 2007Villano, D., Fernandez-Pachón, M.S., Moya, M.L., Troncoso, A.M. & García-Parrilla, M.C. 2007. Radical scavenging ability of polyphenolic compounds towards DPPH free radical. Talanta, 71: 230-235. ). Dentre os extratos analisados podemos observar na figura 1 o EEF de S. trachypus.

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    Correlação entre o teor de fenóis totais e CE50 de espécies de Senna Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule.
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    Na correlação da atividade de inibição da enzima acetilcolinesterase, representada pelo CI50 com teor de fenóis totais, observou-se uma correlação muito forte (r = -0,84) entre estas duas variáveis, evidenciando que ambas são inversamente proporcionais entre si, ou seja, à medida que o teor de fenóis totais aumenta o valor de CI50 diminui, como pode ser observado para o EEF de S. occidentalis (Figura 2). Isso demonstra que os compostos fenólicos podem ser determinantes nessa atividade, de modo que alguns estudos evidenciaram que flavonoides e outros compostos fenólicos possuem atividade anticolinesterásica (Amessis-Ouchemoukh et al. 2014Amessis-Ouchemoukh, N., Madani, K., Falé, P.L., Serralheiro, M.L., Araújo, M.E.M. 2014. Antioxidant capacity and phenolic contents of some Mediterranean medicinal plants and their potential role in the inhibition of cyclooxygenase-1 and acetylcholinesterase activities. Industrial Crops and Products, 53: 6-15.).

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    Correlação entre o teor de fenóis totais e CI50 de espécies de Senna Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule.
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    Houve uma correlação moderada (r = 0,43) entre a CI50 e a CE50. Analisando a figura 3, é possível perceber que o EEF e EEC de S. alata e EEF de S. obtusifolia se destacam no gráfico, o que sugere uma grande capacidade dos antioxidantes, como os compostos fenólicos, presentes nos extratos analisados, de atuarem não só através da inibição da acetilcolinesterase (AChEI) mas também por mecanismos de redução de radicais livres.

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    Correlação entre CI50 e a CE50 de espécies de Senna Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule.
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    Os extratos etanólicos das folhas e caule de S. alata, S. obtusifolia, S. occidentalis e S. siamea, apresentaram efeito inibitório contra algumas cepas de T. rubrum. A maioria dos extratos foram eficazes em diferentes concentrações, com CIM que variaram de 0,07 mg/mL à 2,5 mg/mL e CFM de 0,15 a 5,0 mg/mL contra a grande maioria das cepas fúngicas testadas. Dentre os extratos testados, os de S. trachypus foram eficazes contra todas as cepas de T. rubrum com CIM que variaram de 0,31 a 0,62 mg/mL e o CFM de 0,62 a 1,25 mg/mL, para ambos os extratos (Tabela 4). A presença de compostos fitoquímicos tem sido associada às atividades antimicrobianas da maioria dos materiais vegetais. Algumas classes de metabólitos foram identificadas nesse estudo e podem ser associadas à atividade antimicrobiana (Santos et al. 2018Santos, T.C.D., Gomes, T.M., Pinto, B.A.S., Camara, A.L. & Paes, A.M.D.A. 2018. Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer's disease therapy. Frontiers in Pharmacology 9: 1192., Odeja et al. 2015Odeja, O., Obi, G., Ogwuche, C.E., Elemike, E.E. & Oderinlo, Y. 2015. Phytochemical Screening, Antioxidant and Antimicrobial activities of Senna occidentalis (L.) leaves Extract. Clinical Phytoscience 1: 1-6.).

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    Concentração Inibitória Mínima (CIM) e Concentração Fungicida Mínima (CFM) de extratos etanólicos (EEs) de espécies de Senna Mill. (Fabaceae) frente às espécies de Trichophyton rubrum. LABIMIC: Laboratório de Microbiologia; EEF: Extrato etanólico da folha; EEC: Extrato etanólico do caule; NI: Não inibiu.
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    Estudos anteriores realizados com o extrato etanólico da casca do caule de S. alata contra fungos dermatofíticos, entre eles espécies de Trychophyton, revelou um CIM de 5,0 mg/mL para todos os dermatófitos testados (Sule et al. 2011Sule, W.F., Okonko, I.O., Omo-Ogun, S., Nwanze, J.C., Ojezele, M.O., Ojezele, O.J., Alli, J.A., Soyemi, E.T. & Olaonipekun, T.O. 2011. Phytochemical properties and in-vitro antifungal activity of Senna alata Linn. crude stem bark extract. Journal of Medicinal Plants Research, 5: 176-183.). A capacidade antifúngica de extratos de diferentes polaridades preparados a partir das folhas de S. obtusifolia apresentaram um CIM que variou de 500 a 2000 µg/mL contra diferentes espécies de fungos filamentosos (Doughari et al. 2008Doughari, J.H., El-mahmood, A.M. & Tyoyina, I. 2008. Antimicrobial activity of leaf extracts of Senna obtusifolia (L). African Journal of Pharmacy and Pharmacology 2: 7-13.). Os resultados obtidos de extratos foliares de polaridades diferentes de S. occidentalis revelaram que o extrato metanólico mostrou maior atividade antifúngica entre os demais extratos testados, em uma concentração inibitória mínima de 25 mg/mL (Odeja et al. 2015Odeja, O., Obi, G., Ogwuche, C.E., Elemike, E.E. & Oderinlo, Y. 2015. Phytochemical Screening, Antioxidant and Antimicrobial activities of Senna occidentalis (L.) leaves Extract. Clinical Phytoscience 1: 1-6.). Testes utilizando extratos preparados com solventes de diferentes polaridades a partir das folhas de S. siamea apresentaram CIM que variaram de 0,032 a 0,128 mg/mL contra o fungo Cryptococcus gattii (Nnadi et al. 2019Nnadi, N.E., Anukam, N.C., Ayika, P.D., Rotdung, K., Gokum, S.S., Ayanbimpe, G.M., Nvau, J. & Enweani, I. 2019. The in Vitro antifungal activity of some Nigeria medicinal plants against Cryptococcus gattii. IOSR Journal of Pharmacy 9: 16-24. ). Na literatura, não foram encontrados estudos do potencial antifúngico para a espécie de S. trachypus, sendo este o primeiro registro de atividade antifúngica para a referida espécie.

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    Pesquisas têm revelado que o potencial antifúngico de extratos vegetais está intimamente relacionado, entre outros fatores, com as suas variações quantitativas de compostos fenólicos, dentre eles os flavonoides. Nosso estudo confirmou que as espécies estudadas possuem propriedades antifúngicas, e que seus efeitos sobre os dermatófitos fundamentam-se em seus teores de compostos fenólicos encontrados, e os demais outros metabólitos secundários aqui não estudados. Os efeitos antifúngicos atribuídos aos compostos fenólicos podem resultar na ruptura da membrana celular, ou ainda, inibir a divisão celular e o desenvolvimento das hifas por meio de genes específicos, além de interferir nas vias metabólicas e/ou induzir a apoptose por perturbar a homeostase redox (Lagrouh et al. 2017Lagrouh, F., Dakka, N. & Bakri, Y. 2017.The antifungal activity of Moroccan plants and the mechanism of action of secondary metabolites from plants. Journal de Mycologie Medicale 27: 303-311., Mohamed et al. 2017Mohamed, M.S., Saleh, A.M., Abdel-Farid, I.B. & El-Naggar, S.A. 2017. Growth, hydrolases and ultrastructure of Fusarium oxysporum as affected by phenolic rich extracts from several xerophytic plants. Pesticide Biochemistry and Physiology 141: 57-64. ).

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    Foram detectados, nos EEF e EEC das espécies de Senna, a presença de metabólitos secundários, alto teor de fenóis totais e capacidade antioxidante para todas as espécies, em especial S. trachypus. Para a atividade anticolinesterase apenas a espécie de S. trachypus manifestou uma melhor ação inibitória. Nas condições experimentais utilizadas, evidenciou-se atividade antifúngica das espécies frente a maioria dos dermatófitos testados, em especial os extratos de S. trachypus. Foi observada também correlação forte, muito forte e moderada entre as variáveis fenóis totais e atividade antioxidante, fenóis totais e antiacetilcolinesterase e atividade antioxidante e antiacetilcolinesterase, respectivamente. Os resultados apontam que S. trachypus, espécie endêmica da Caatinga, é a mais promissora entre todas as plantas estudadas, representando uma fonte potencial para a obtenção de compostos químicos úteis para estudos clínicos e farmacológicos, visando o desenvolvimento de novos agentes farmacológicos naturais.

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    Agradecimentos

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    Os autores agradecem a Universidade Estadual do Ceará (UECE) e a Universidade Estadual Vale do Acaraú (UVA) pelo apoio técnico, e a Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) pelo apoio financeiro concedido (processos PBI3-0139-00252.01.00/18; BP4-0172-00170.01.00/20).

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    Datas de Publicação

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    • +Publicação nesta coleção
      21 Fev 2022
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    • +Data do Fascículo
      2022
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    Histórico

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    • +Recebido
      14 Out 2020
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    • +Aceito
      03 Dez 2021
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    Creative Common - by 4.0
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    Este é um artigo publicado em acesso aberto sob uma licença Creative Commons
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    + + + + + + + + + + + diff --git a/tests/fixtures/novo-menu-flutuante/2236-8906-hoehnea-49-e1112020/2236-8906-hoehnea-49-e1112020.xml b/tests/fixtures/novo-menu-flutuante/2236-8906-hoehnea-49-e1112020/2236-8906-hoehnea-49-e1112020.xml new file mode 100644 index 000000000..05a6983fa --- /dev/null +++ b/tests/fixtures/novo-menu-flutuante/2236-8906-hoehnea-49-e1112020/2236-8906-hoehnea-49-e1112020.xml @@ -0,0 +1,2597 @@ + + +
    + + + hoehnea + + Hoehnea + Hoehnea + + 0073-2877 + 2236-8906 + + Instituto de Pesquisas Ambientais + + + + 10.1590/2236-8906-111/2020 + 00208 + + + Artigo + + + + Prospecção química, atividade antioxidante, anticolinesterásica e antifúngica de extratos etanólicos de espécies de Senna Mill. (Fabaceae) + + Chemical prospecting and antioxidant, anticholinesterase and antifungal activity of ethanol extracts from Senna Mill. species. (Fabaceae) + + + + + 0000-0002-7388-1844 + + Neves + Andréa Maria + + 1 + 4 + + + 0000-0002-2766-3790 + + Morais + Selene Maia de + + 1 + + + 0000-0001-5527-164X + + Santos + Hélcio Silva dos + + 2 + + + 0000-0003-2503-9772 + + Ferreira + Marcílio Matos + + 3 + + + 0000-0002-2035-0425 + + Cruz + Ricardo Carneiro Vera + + 3 + + + 0000-0002-5222-4378 + + Souza + Elnatan Bezerra de + + 3 + + + 0000-0002-4384-5738 + + Andrade + Lúcia Betânia da Silva + + 3 + + + 0000-0002-8865-5954 + + Fontenelle + Raquel Oliveira dos Santos + + 3 + + + + + Universidade Estadual do Ceará, Centro de Ciências e Tecnologia, Programa de Pós-graduação em Biotecnologia, Avenida Doutor Silas Muguba, 1700, Itaperi, 60740-000 Fortaleza, CE, Brasil + Universidade Estadual do Ceará + Centro de Ciências e Tecnologia + Programa de Pós-graduação em Biotecnologia + + 60740-000 + Fortaleza + CE + + Brasil + + + + Universidade Estadual Vale do Acaraú, Centro de Ciências Exatas e Tecnologia, Curso de Química, Avenida da Universidade, 850, Betânia, 62040-370 Sobral, CE, Brasil + Universidade Estadual Vale do Acaraú + Centro de Ciências Exatas e Tecnologia + Curso de Química + + 62040-370 + Sobral + CE + + Brasil + + + + Universidade Estadual Vale do Acaraú, Centro de Ciências Agrárias e Biológicas, Curso de Ciências Biológicas, Avenida da Universidade, 850, Betânia, 62040-370 Sobral, CE, Brasil + Universidade Estadual Vale do Acaraú + Centro de Ciências Agrárias e Biológicas + Curso de Ciências Biológicas + + 62040-370 + Sobral + CE + + Brasil + + + + Autor para correspondência: andreamarianeves@gmail.com + + + +

    Catarina Carvalho Nievola

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    Andréa Maria Neves: Contribuição substancial em todas as etapas da pesquisa e para a confecção do manuscrito. Selene Maia de Morais: Contribuição na realização do teste de acetilcolinesterase; Contribuição na revisão crítica do manuscrito, agregando conteúdo intelectual. Hélcio Silva dos Santos: Contribuição na preparação dos extratos; Contribuição na revisão crítica do manuscrito, agregando conteúdo intelectual. Marcílio Matos Ferreira: Contribuição para a coleta das espécies e preparação dos extratos. Ricardo Carneiro Vera Cruz: Contribuição na realização dos testes fitoquímicos e quantificação de fenóis totais. Elnatan Bezerra de Souza: Contribuição na coleta e identificação das espécies; Contribuição na revisão crítica do manuscrito, agregando conteúdo intelectual. Lúcia Betânia da Silva Andrade: Contribuição na realização da atividade antioxidante, para a interpretação dos dados, e para revisão crítica, agregando conteúdo intelectual. Raquel Oliveira dos Santos Fontenelle: Contribuição nos testes antifúngicos e para revisão crítica, agregando conteúdo intelectual.

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    Os autores declaram não haver conflitos de interesse a informar.

    +     +     + + 21 + 02 + 2022 + + + 2022 + + 49 + e1112020 + + + 14 + 10 + 2020 + + + 03 + 12 + 2021 + + + + + Este é um artigo publicado em acesso aberto sob uma licença Creative Commons + + + + RESUMO +

    O objetivo deste trabalho foi avaliar o perfil químico, teor de fenóis totais e as atividades antioxidante, antiacetilcolinesterásica e antifúngica dos extratos etanólicos das folhas (EEF) e do caule (EEC) de cinco espécies de Senna, bem como avaliar a correlação entre o conteúdo de fenóis totais com a atividade sequestradora do radical livre DPPH e com a inibição da enzima acetilcolinesterase AChEI. No teste fitoquímico, evidenciou-se a presença de metabólitos secundários em todos os extratos. Os EEF e EEC de Senna trachypus, destacaram-se por apresentar os maiores valores de fenóis totais. Os EEF e EEC de S. trachypus mostraram a melhor ação sobre a enzima acetilcolinesterase. Todas as espécies apresentaram atividade antioxidante, em especial o EEF de S. trachypus. Foi observado correlação forte para as variáveis fenóis totais e atividade antioxidante (r = -0,71), muito forte para fenóis totais e antiacetilcolinesterase (r = -0,84) e atividade moderada para atividade antioxidante e antiacetilcolinesterase (0,43). Apenas os extratos de S. trachypus apresentaram atividade contra todos os dermatófitos, quando comparado às demais espécies. A espécie S. trachypus foi considerada a planta mais promissora para estudos subsequentes, a fim de encontrar compostos com ações farmacológicas.

    +     + + ABSTRACT +

    The objective of this work was to evaluate the chemical profile, total phenol content and the antioxidant, antiacetylcholinesterase and antifungal activities of ethanol extracts from leaves (EEF) and stem (EEC) of five species of Senna, as well as to evaluate the correlation between the content of total phenols with the DPPH free radical scavenging activity and with the inhibition of the acetylcholinesterase AChEI enzyme. The phytochemical test showed the presence of secondary metabolites in all extracts. The EEF and EEC of Senna trachypus, stood out for presenting the highest values of total phenols. S. trachypus EEF and EEC showed the best action on the acetylcholinesterase enzyme. All species showed antioxidant activity, especially the EEF from S. trachypus. A strong correlation was observed for the variables total phenols and antioxidant activity (r = -0.71), very strong for total phenols and anti-acetylcholinesterase (r = -0.84) and moderate activity for antioxidant and anti-acetylcholinesterase activity (r = 0.43). Only S. trachypus extracts showed activity against all dermatophytes, when compared to the other species. The species S. trachypus was considered the most promising plant for further studies, in order to find compounds with pharmacological actions.

    +     + + Palavras-chave: + acetilcolinesterase + dermatófitos + fitoquímica + produtos naturais + radicais livres + + + Keywords: + acetylcholinesterase + dermatophytes + phytochemistry + natural products + free radicals + + + + FUNCAP + PBI3-0139-00252.01.00/18 + BP4-0172-00170.01.00/20 + + + + + + + + +     +     + + + Introdução +

    Senna Mill. é um gênero monofilético com distribuição pantropical e ampla variedade morfológica (Pellerin et al. 2019). Possuindo aproximadamente 300 espécies, das quais 200 nas Américas, este gênero é o segundo maior da família Fabaceae (Queiroz 2009, Kim et al. 2018, Souza & Silva 2016). O gênero é representado no Brasil por 79 espécies, onde 29 são endêmicas, sendo a região Nordeste a que apresenta a maior riqueza de espécies com 53 registros (BFG 2018).

    +

    Trata-se de um gênero muito expressivo na flora do semiárido, alcançando destaque no Domínio Fitogeográfico da Caatinga, onde são catalogadas 42 espécies (Souza & Bortoluzzi 2015). As espécies de Senna são geralmente arbustos ou arvoretas, raramente ervas ou subarbustos anuais. Entre as suas características diagnósticas estão os nectários extraflorais convexos, interfoliolares, flores vistosas, com pétalas amarelo-brilhantes, anteras amarelas, rígidas, com deiscência abrindo por poros ou fendas, ausência de bractéolas no pedicelo, frutos deiscentes plano-compressos ou indeiscentes e cilíndricos (Queiroz 2009).

    +

    As espécies de Senna têm diversas aplicações medicinais e são eficazes no tratamento para uma série de doenças, como malária, micose, dengue, eczema, hepatite e dermatite, sendo também indicadas como anti-hipertensivo, vermífugo, laxante, abortivo e antitussígeno (Macedo et al. 2016, Bieski et al. 2015, Kabir et al. 2014). Além de suas aplicações farmacológicas, estudos têm revelado que espécies pertencentes a este gênero possuem, em sua composição, uma vasta diversidade de princípios bioativos que estão associadas a diferentes atividades biológicas. Neste sentido, podemos citar como exemplo as atividades antioxidantes, antitumoral, antibacterianas, antifúngicas e anti-inflamatórias (Neves et al. 2017).

    +

    As plantas são fontes alternativas promissoras de substâncias de interesse biológico e farmacológico, já que podem produzir, a partir de seu metabolismo secundário, uma enorme diversidade de substâncias, dentre estas, os compostos fenólicos. Alguns estudos têm revelado que os compostos fenólicos são responsáveis por várias atividades biológicas, incluindo atividade antifúngica. Esta atividade pode ser direta nos micro-organismos, ou sobre outros fatores necessários para a expressão da virulência ou patogenicidade (Rodrigues et al. 2019).

    +

    Os compostos fenólicos estão entre os metabólitos secundários mais estudados, notadamente por possuírem grande potencial para atividades antioxidantes, atuando na redução do risco de algumas doenças agudas e crônicas relacionadas ao estado redox do corpo humano, ocasionadas pelos radicais livres. Estas moléculas apresentam uma alta capacidade reativa, sendo consideradas perigosas para os organismos vivos, causando doenças prejudiciais, incluindo doenças neurodegenerativas, como o mal de Alzheimer (DA). Atualmente, uma das teorias mais aceitas na abordagem padrão no tratamento sintomático dessa demência é a “hipótese colinérgica”. Portanto, os inibidores da enzima acetilcolinesterase (AChEI) preservam os níveis de acetilcolina, melhorando a eficiência da transmissão colinérgica (Bardakci et al. 2019, Lim et al. 2019; Neagu et al. 2016).

    +

    Por este motivo, a utilização de dietas ricas ou enriquecidas com antioxidantes podem prevenir, ou pelo menos amenizar, a deterioração orgânica por um excessivo estresse oxidativo. Além disso, o crescimento sobre a investigação científica envolvendo os efeitos antioxidantes de extratos brutos, frações purificadas, ou mesmo de compostos isolados, onde estão classificados os compostos fenólicos, são demonstrados em muitos estudos (Penido et al. 2017, Morais et al. 2013).

    +

    Desta forma, investigar a atividade antifúngica e anticolinesterásica de extratos de espécies de Senna, analisando o seu potencial antioxidante, o seu teor de fenóis totais e o seu perfil fitoquímico, são maneiras de promover tanto o conhecimento acerca dessas espécies, como também potencializar o descobrimento de novos fitofármacos para o combate de inúmeras enfermidades. Assim, este trabalho avaliou o perfil fitoquímico, o teor de fenóis totais e as atividades antioxidante, anticolinesterásica e antifúngica dos extratos etanólicos de S. alata (L.) Roxb., S. obtusifolia (L.) H.S.Irwin & Barneby, S. occidentalis (L.) Link, S. siamea (Lam.) H.S.Irwin & Barneby e S. trachypus (Benth.) H.S.Irwin & Barneby, e a correlação entre o teor de fenóis totais e as atividades antioxidante e anticolinesterásica.

    +     + + Materiais e métodos +

    Material vegetal e preparação dos extratos - Foram selecionadas para este estudo cinco espécies de Senna, sendo uma exótica naturalizada e quatro nativas, das quais uma é endêmica do Brasil, ocorrendo no Cerrado e na Caatinga (BFG 2018) (Tabela 1). As folhas e caules de Senna spp. foram coletados em diferentes locais da região Noroeste do Ceará. A identificação botânica das espécies foi realizada no Herbário Francisco José de Abreu Matos da Universidade Estadual Vale do Acaraú (HUVA), pelo professor Dr. Elnatan Bezerra de Souza. Para o preparo dos extratos, 200g das folhas e caule secos de cada espécie de um mesmo indivíduo foram triturados e imersos durante 10 dias em 500 mL de etanol e, na sequência o extrato foi filtrado e concentrado em um evaporador rotativo a (60°C) durante 2 h. Após este processo, foi mantido em banho-maria (40°C) até a eliminação total do solvente, obtendo-se o extrato etanólico das folhas (EEF) e extrato etanólico do caule (EEC) (Matos 2009).

    +

    + + + + Identificação das espécies de <italic>Senna</italic> Mill. (Fabaceae) coletadas em diferentes locais da região noroeste do Estado do Ceará. <sup>*</sup>Exótica, <sup>**</sup>Endêmica do Brasil. Fonte: Herbário Francisco José de Abreu Matos (HUVA). + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
    EspéciesNome popularLocal de coletaNo. HUVA
    S. alata (L.) Roxb.fedegoso-giganteSobral21547
    S. obtusifolia (L.) H.S.Irwin & Barnebyfedegoso-brandoGraça21775
    S. occidentalis (L.) Linkcafé-negroGraça21774
    S. siamea (Lam.) H.S.Irwin & Barneby*cássia-de-siãoSobral21578
    S. trachypus (Benth.) H.S.Irwin & Barneby**pau-de-besouroGraça21776
    + + +

    Table 1Identification of Senna Senna Mill. (Fabaceae) species collected in different locations in northwestern Ceará State. * Exotic, ** Endemic to Brazil. Source: Herbário Francisco José de Abreu Matos (HUVA).

    + + + +

    +

    Triagem fitoquímica - Os extratos etanólicos foram submetidos a triagem fitoquímica, tomando como referência a metodologia descrita por Matos (2009). Através deste ensaio preliminar, foi possível verificar as principais classes de metabólitos secundários por meio de reações químicas que resultaram no aparecimento de coloração e/ou precipitado, característico para cada classe de substância. Os ensaios foram conduzidos para as seguintes classes de substâncias: fenóis, taninos, flavonoides, saponinas, esteroides, triterpenoides e alcaloides. Todos os testes foram realizados em triplicata procedimentais.

    +

    Determinação do teor de fenóis totais - O teor de fenóis totais nos extratos etanólicos foi determinado pelo método espectrofotométrico de Folin-Ciocateau, utilizando ácido gálico como padrão de referência (Kim et al. 2006). Em cada tubo adicionou-se 0,2 mL de cada extrato nas concentrações (0,62; 0,31 e 0,15 mg mL-1) com 1 mL do reagente Folin-Ciocalteau agitado por 2 minutos e adicionado 0,8 mL de carbonato de sódio (Na2CO3) 7,5% (m/v). Para o tubo controle foi utilizado 1 mL do reagente Folin- Ciocalteau com 0,8 mL de Na2CO3 e 0,2 mL de etanol, em triplicata. Os tubos foram deixados em banho-maria a 37 ̊C por 30 minutos na ausência de luz. Logo em seguida, foi realizado a leitura dos tubos em comprimento de onda de 765 nm. O teor de fenóis foi calculado e expresso em mg de equivalente de ácido gálico por grama de extrato (EAG.g-1), com base numa curva padrão preparada com ácido gálico. Todos os testes foram realizados em triplicata.

    +

    Atividade antioxidante - A atividade antioxidante dos extratos foi determinada pelo método de redução do radical 2,2’-difenil-1-picril-hidrazil (DPPH), segundo a metodologia modificada por Brand-Williams et al. (1995), Sanchez-Moreno et al. (1998). Foram preparadas soluções etanólicas das amostras nas concentrações de 5,0; 2,5; 1,25; 0,62; 0,31 e 0,15 mg mL-1. Foram utilizados 100 µL dos extratos com 2,4 mL de DPPH (0,04 mg mL-1). Para o tubo controle foram utilizados 100 µL de etanol com 2,4 mL de DPPH em triplicata. O meio reacional ficou por 30 minutos na ausência da luz, e posteriormente foi realizada a leitura em comprimento de onda 515 nm. A atividade sequestradora do radical DPPH pelos extratos nas diferentes concentrações foi calculada pela expressão do índice de varredura em porcentagem (IV%): IV% = (Abs DPPH - Abs Amostra / Abs DPPH) x 100. A concentração efetiva para inibir 50% do radical livre DPPH (CE50) foi obtida com auxílio do Software Excel 2019, onde, a partir dos valores das concentrações finais da amostra e o índice de varredura (IV%), foram originados gráficos de dispersão cujas equações das retas foram utilizadas para se obter os valores da média e desvio padrão. Para fins de comparação, foi construída uma curva de calibração com diferentes porcentagens do flavonoide quercetina, que apresenta elevada atividade antioxidante em radical livre DPPH.

    +

    Avaliação da atividade anticolinesterásica in vitro - O ensaio para verificação da inibição da enzima acetilcolinesterase (AChE) dos extratos foi realizado de acordo com a metodologia descrita por Ellman et al. (1961). Em placas estéreis de 96 poços, foram adicionados 25 µL de iodeto de acetiltiocolina (15 mM), 125 µL de 5,5’-ditiobis-[2-nitrobenzóico] na solução Tris/HCL (50 nM, pH 8, com 0,1 M de NaCL e 0,02 M de MgCL2 .6H2O. (3 mM, DTNB ou reagente de Ellman)), 50 µL da solução Tris/HCL (50 nM, pH 8, com 0,1% de albumina sérica bovina (BSA) e 25 µL dos extratos de Senna spp. na concentraçao de 0,2 mg.mL-1 em tampão Tris/HCL (50 mM, pH 8) de 0,2 mg.mL-1 (Rhee et al. 2001, Trevisan et al. 2003).

    +

    A absorbância foi aferida a 405 nm durante 30 segundos. Em seguida, foram adicionados 25 µL da enzima acetilcolinesterase (0,25 U.mL-1) e a absorbância foi aferida por minuto até o total de 25 minutos de incubação da enzima. Como padrão negativo foram utilizadas todas as soluções, excetuando-se a amostra. O padrão utilizado como controle positivo foi a fisostigmina (0,22 mg.mL-1.) e todas as amostras foram analisadas em triplicata. A atividade anticolinesterásica dos extratos vegetais foi determinada de acordo com os valores de CI50 (Concentração inibitória capaz de inibir 50% da enzima acetilcolinesterase) como: alta potência (CI50 < 20 μg. mL-1); potência moderada (20 < CI50 < 200 μg.mL-1) e baixa potência (200 < CI50 < 1000 μg.mL-1) (Santos et al. 2018).

    +

    Ensaio antifúngico in vitro - No ensaio para verificação da concentração inibitória mínima (CIM) dos EE das espécies de Senna, foram utilizadas cepas de Trichophyton rubrum obtidas a partir da micoteca da Universidade Federal de Pernambuco e do Centro Especializado de Micologia Médica (CEMM) da Universidade Federal do Ceará. Para este ensaio foi utilizado o método de microdiluição em caldo, de acordo com a metodologia descrita por (Neves et al. 2019) com as normas do protocolo Clinical Laboratory Standards Insitute do documento M38-A (CLSI M38-A2, 2008). Em placas de 96 poços estéreis, foram adicionados 100 µL de meio RPMI em todos os poços e 10 mg mL-1 dos extratos de Senna spp. foi acrescentado a todos os poços da primeira coluna e, em sequência foram efetuadas as diluições seriadas. Finalmente, 100 µL do inóculo foi adicionado aos poços da placa. Como controle foi utilizado o Cetoconazol (Sigma, Chemical Co., USA). Para as análises de susceptibilidade, os extratos etanólicos foram testados em concentrações variando de 0,002 a 2,5 mg mL-1. As placas foram cobertas com parafilme e incubadas a 37 °C e a leitura visual foi realizada após cinco dias para T. rubrum. Procedimento realizado em duplicata. A CIM é definida como a menor concentração do extrato capaz de inibir 100% do crescimento fúngico visível (Fontenelle et al. 2007). A concentração fungicida mínima (CFM) foi determinada por subcultura de 100 μL da solução de poços sem turbidez no meio Ágar Dextrose de Batata, a 28 °C. (Fontenelle et al. 2008).

    +

    Análise estatística - Todas as determinações foram realizadas em triplicata e todos os resultados foram apresentados como média ± desvio-padrão (DP). Foram realizadas análises de variância (ANOVA) com duas repetições e o Teste Tukey, ao nível de significância de 5%, usando programa Graph Pad Prism® v5.01 (GraphPadSoftware, San Diego, CA, E.U.A.). As diferenças entre as médias foram consideradas significativas quando o valor obtido para "p" foi menor que 0,05 (p < 0,05).

    +

    Para análises da correlação entre os dados, foi utilizado o coeficiente de correlação de Pearson no software Microsoft Excel 2019, a qual mede o grau da correlação linear entre duas variáveis quantitativas. A intensidade dessa correlação é dada pelo “r”, que é um índice adimensional com valores situados entre -1,0 e 1,0. Quando o valor de r estiver entre 0,00-0,19 a correlação é muito fraca; entre 0,20-0,39 é fraca; 0,40-0,59 é uma correlação moderada; entre 0,60-0,79 é forte e finalmente entre 0,80-1,0 diz-se que é uma correlação muito forte (Mukaka 2012).

    +     + + Resultados e discussão<xref ref-type="table" rid="t3">Tabela 3</xref> +

    Os fito-constituintes ou fitoquímicos são compostos químicos que desempenham importantes funções nas plantas. A triagem fitoquímica em materiais vegetais é geralmente o ponto de partida para o isolamento e purificação de compostos naturais com bioatividade (Omoregie & Oikeh 2015). A triagem fitoquímica preliminar revelou a presença de fenóis, taninos, flavonoides e esteroides para todos os extratos estudados (Tabela 2). Entretanto, a presença de saponinas foi constatada apenas no EEF e EEC de S. alata e no EEF de S. trachypus. Já os alcaloides foram encontrados exclusivamente no EEF de S. alata e nenhuma das espécies apresentou triterpenoides.

    +

    + + + + Triagem fitoquímica do EEF e do EEC de espécies de <italic>Senna</italic> Mill. (Fabaceae)<italic>.</italic> Presente: + Ausente: - EEF: Extrato etanólico da folha. EEC: Extrato etanólico do caule. + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
    Espécies
    MetabólitosS. alataS. obtusifoliaS. occidentalisS. siameaS. trachypus
    ExtratosEEFEECEEFEECEEFEECEEFEECEEFEEC
    Flavonoides++++++++++
    Fenóis++++++++++
    Saponinas++------+-
    Taninos++++++++++
    Esteroides++++++++++
    Alcaloides+---------
    Triterpenoides----------
    + + +

    Table 2. Phytochemical screening of EEF and EEC of Senna Mill. (Fabaceae) species. Present: + Absent: - EEF: Ethanol extract of the leaf. EEC: Ethanol extract from the stem.

    + + + +

    +

    Os metabólitos detectados nas espécies estudadas são consistentes com os metabólitos descritos na literatura para o gênero Senna, conhecido por apresentar flavonoides, alcaloides, taninos, esteroides e saponinas em sua composição (Onyegeme-Okerenta et al. 2017, Ishaku et al. 2016, Silva et al. 2014, Sudi et al. 2011, Bukar et al. 2009). É possível perceber que na análise de prospecção química dos extratos houve uma variação de metabólitos secundários. Este fato pode estar atribuído a vários fatores, entre eles estão as diferentes condições ambientais, tais como clima, radiação solar, nutrição mineral, sazonalidade, ritmo circadiano, temperatura, disponibilidade hídrica, e também os tipos de solvente e a metodologia empregada no processo de extração, que podem interferir consideravelmente no conteúdo de praticamente todas as classes de metabólitos secundários (Gomes et al. 2016, Bezerra et al. 2013, Gobbo-Neto & Lopes 2007).

    +

    Os teores de fenóis totais apresentaram diferenças significativas entre os extratos etanólicos das diferentes partes e espécies vegetais estudadas (Tabela 3). O conteúdo de fenóis totais para os EEF variou de 32,60 ± 0,53 a 184,8 ± 5,09 EAG/g, enquanto que para o EEC foram de 30,03± 1,00 a 191,3 ± 0,47 EAG/g. Os maiores níveis de fenóis totais foram detectados na espécie S. trachypus. Os dados da literatura sobre o conteúdo de compostos fenólicos obtidos a partir do extrato aquoso, etanólico e acetona da raiz de S. alata, apresentaram uma concentração de fenóis de 46,3, 78,21 e 21,42 mg EAG/g, respectivamente, e de flavonoides de 26,17, 39,29 e 9,65 mg de equivalente de quercetina por grama de extrato (EQ/g), respectivamente (Ita & Ndukwe 2017). Já o extrato etanólico preparado a partir das folhas de S. obtusifolia por Ali et al. (2019), apresentou um teor de fenóis e de flavonoides de 14,39 mg/g e 2,85 mg/g, respectivamente, demonstrando possuir teor de compostos fenólicos inferior ao das mostras de S. obtusifolia encontradas no presente estudo. Além disso, o conteúdo de polifenóis encontrado no extrato etanólico e nas frações obtidas a partir das folhas de S. occidentalis por Yakubu et al. (2018) variou de 139 mg/mL a 206 mg/mL e de flavonoides de 104 a 142 mg/mL. Já para os extratos preparados a partir das folhas e casca do caule de S. siamea revelaram um teor de fenóis totais de 10,21 ± 0,25 g/g e 24,77 ± 0,15 g/g, respectivamente. Por outro lado, o teor de flavonoides foi de 0,08 ± 0,01 g/g para as folhagens, e de 0,04 ± 0,01 g/g para a casca do caule (Kwada & Tella 2009). Para os extratos etanólicos das folhas e raízes de S. trachypus o teor de fenóis totais encontrado foi de 322,09 ± 2,83 EAG/g e de 1277,34 ± 79,54 EAG/g, respectivamente (Silva et al. 2014).Senna.

    +

    + + + + Teor de fenóis totais, atividade antioxidante e inibição da enzima acetilcolinesterase de espécies de Senna Mill. (Fabaceae). + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
    EspéciesFenois1 mg EAG.g-1 de extrato DPPH2 CE50 (μg.mL-1) AChEI3 CI50 (μg.mL-1)
    MédiaDespadMédiaDespadMédiaDespad
    S. alata (Folhas)53,76 f± 0,743,70 e± 0,0449,42 f± 0,02
    S. alata (Caule)43,44 g± 0,215,41 c± 0,0653,25 d± 0,02
    S. obtusifolia (Folhas)76,32 e± 0,414,24 d± 0,0650,37 e± 0,32
    S. obtusifolia (Caule)86,20 d± 0,993,00 g± 0,0556,90 c± 0,02
    S. occidentalis (Folhas)32,60 h± 0,538,20 b± 0,0758,76 b± 0,78
    S. occidentalis (Caule)30,03 h± 1,0011,19 a± 0,1557,26 c± 0,02
    S. siamea (Folhas)51,73 f± 0,853,34 f± 0,0559,77 a± 0,26
    S. siamea (Caule)111,7 c± 3,430,83 i± 0,0159,52 ab± 0,15
    S. trachypus (Folhas)184,80 b± 5,090,63 k± 0,0132,40 g± 0,12
    S. trachypus (Caule)191,3 a± 0,472,52 h± 0,0331,44 h± 0,14
    Quercetina--1,03 i± 0,00--
    Fisiostigmina----1,15 i± 0,00
    + + +

    Total phenol content, antioxidant activity and acetylcholinesterase enzyme inhibition of Senna Mill. (Fabaceae) species.

    + + +

    Todas as análises foram realizadas em triplicada e os resultados foram expressos como média ± desvio padrão. As diferenças entre os valores foram examinadas usando análise de variância (ANOVA) e os resultados foram comparados usando o teste de Tukey com 95% nível de confiança. Letras diferentes denotam diferença estatística entre os valores de cada coluna (p < 0,05). 1Miligrama equivalente ao Ácido Gálico por grama de extrato; 2Concentração efetiva para inibir 50% do radical livre DPPH (2,2 -difenil-1-picril-hidrazil); 3Concentração inibitória capaz de inibir 50% da acetilcolinesterase. (-) Testes não realizados.

    +     + +

    All analyzes were performed in triplicate and the results were expressed as mean ± standard deviation. The differences between the values ​​were examined using analysis of variance (ANOVA) and the results were compared using the Tukey test at 95% confidence level. Different letters denote statistical difference between the values ​​of each column (p <0.05). 1 milligram Equivalent to Gallic Acid per gram of extract; 2Effective concentration to inhibit 50% of the free radical DPPH (2,2 - diphenyl - 1 - picryl - hydrazil); 3Inhibitory concentration capable of inhibiting 50% of acetylcholinesterase. (-) Tests not performed.

    +     + + +

    +

    Os resultados da atividade antioxidante dos extratos de Senna spp. mostraram que os valores de CE50 para o EEF variaram de 0,63 ± 0,01 a 8,20 ± 0,07 µg/mL, sendo o EEF de S. trachypus o que apresentou menor CE50 com atividade antirradicalar superior ao da quercetina e, portanto, maior potencial antioxidante (Villano et al. 2007). Já para o EEC os valores de CE50 variaram de 0,83 ± 0,01 a 11,19 ± 0,15 µg/mL (Tabela 3). Foi observado que o EEC de S. siamea apresentou capacidade antirradicalar próximo à quercetina. Semelhantes aos nossos resultados, estudos anteriores revelaram que as espécies de S. alata, S. obtusifolia, S. occidentalis, S. siamea e S. trachypus, apresentaram potencial antioxidante e que esta atividade está atribuída à presença de compostos fenólicos (Coelho et al. 2017, Ita & Ndukwe 2017, Barnaby et al. 2016, Odeja et al. 2015, Silva et al. 2014).

    +

    Os resultados obtidos na análise de inibição da enzima acetilcolinesterase foram comparados ao do alcaloide fisostigmina que foi o primeiro inibidor descoberto. Os experimentos de inibição da enzima acetilcolinesterase in vitro para as espécies de Senna produziram apenas resultados com potência moderada (Tabela 3). Relatos confirmam a atividade antiacetilcolinesterásica de vários taninos isolados do fruto Terminalia chebula Retz., (Combretaceae) que exibiram um efeito de inibição contra a enzima acetilcolinesterase in vitro (Kim et al. 2018). Outros compostos, como saponinas, alcaloides e compostos fenólicos, também são relatados na literatura como inibidores da enzima acetilcolinesterase (Paiva et al. 2021, Kozachok et al. 2020, Adedayo et al. 2015). Estas classes de compostos foram detectadas na triagem fitoquímica, embora provavelmente as concentrações nos extratos eram muito baixas para dar resultados satisfatórios no ensaio. Os extratos foliares e do caule de S. trachypus apresentaram os valores mais satisfatórios de inibição da enzima acetilcolinesterase, indicando que o isolamento de metabólitos pode levar a potenciais agentes antiacetilcolinesterásicos. Na literatura, não foram encontrados estudos do potencial anticolinesterásico paras as espécies de Senna referenciadas, sendo este o primeiro relato de estudo de atividade de inibição para esta enzima.

    +

    Para os extratos de Senna spp., foi observada forte correlação negativa entre os valores de fenóis totais e CE50 (r = - 0,71), mostrando que quanto maior os teores de fenóis totais, menor a CE50 e, consequentemente, maior o potencial antioxidante, uma vez que a CE50 está inversamente relacionada à capacidade antioxidante de um composto (Villano et al. 2007). Dentre os extratos analisados podemos observar na figura 1 o EEF de S. trachypus.

    +

    + + + + Correlação entre o teor de fenóis totais e CE50 de espécies de <italic>Senna</italic> Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule. + + + Figure 1. Correlation between total phenol content and EC50 of Senna Mill species. (Fabaceae). Symbols filled: leaves. Hollow symbols: stem. + +

    +

    Na correlação da atividade de inibição da enzima acetilcolinesterase, representada pelo CI50 com teor de fenóis totais, observou-se uma correlação muito forte (r = -0,84) entre estas duas variáveis, evidenciando que ambas são inversamente proporcionais entre si, ou seja, à medida que o teor de fenóis totais aumenta o valor de CI50 diminui, como pode ser observado para o EEF de S. occidentalis (Figura 2). Isso demonstra que os compostos fenólicos podem ser determinantes nessa atividade, de modo que alguns estudos evidenciaram que flavonoides e outros compostos fenólicos possuem atividade anticolinesterásica (Amessis-Ouchemoukh et al. 2014).

    +

    + + + + Correlação entre o teor de fenóis totais e CI50 de espécies de <italic>Senna</italic> Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule. + + + Figure 2. Correlation between total phenol content and IC50 of Senna Mill species. (Fabaceae). Symbols filled: leaves. Hollow symbols: stem. + +

    +

    Houve uma correlação moderada (r = 0,43) entre a CI50 e a CE50. Analisando a figura 3, é possível perceber que o EEF e EEC de S. alata e EEF de S. obtusifolia se destacam no gráfico, o que sugere uma grande capacidade dos antioxidantes, como os compostos fenólicos, presentes nos extratos analisados, de atuarem não só através da inibição da acetilcolinesterase (AChEI) mas também por mecanismos de redução de radicais livres.

    +

    + + + + Correlação entre CI50 e a CE50 de espécies de <italic>Senna</italic> Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule. + + + Figure 3. Correlation between IC50 and EC50 of Senna Mill species. (Fabaceae). Symbols filled: leaves. Hollow symbols: stem. + +

    +

    Os extratos etanólicos das folhas e caule de S. alata, S. obtusifolia, S. occidentalis e S. siamea, apresentaram efeito inibitório contra algumas cepas de T. rubrum. A maioria dos extratos foram eficazes em diferentes concentrações, com CIM que variaram de 0,07 mg/mL à 2,5 mg/mL e CFM de 0,15 a 5,0 mg/mL contra a grande maioria das cepas fúngicas testadas. Dentre os extratos testados, os de S. trachypus foram eficazes contra todas as cepas de T. rubrum com CIM que variaram de 0,31 a 0,62 mg/mL e o CFM de 0,62 a 1,25 mg/mL, para ambos os extratos (Tabela 4). A presença de compostos fitoquímicos tem sido associada às atividades antimicrobianas da maioria dos materiais vegetais. Algumas classes de metabólitos foram identificadas nesse estudo e podem ser associadas à atividade antimicrobiana (Santos et al. 2018, Odeja et al. 2015).

    +

    + + + + Concentração Inibitória Mínima (CIM) e Concentração Fungicida Mínima (CFM) de extratos etanólicos (EEs) de espécies de <italic>Senna</italic> Mill. (Fabaceae) frente às espécies de <italic>Trichophyton rubrum</italic>. LABIMIC: Laboratório de Microbiologia; EEF: Extrato etanólico da folha; EEC: Extrato etanólico do caule; NI: Não inibiu. + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
    EspéciesExtratoT. rubrumT. rubrumT. rubrumT. rubrum
    LABIMIC 5906 LABIMIC 6213 LABIMIC 6205 LABIMIC 6753
    CIMCFM CIM CFMCIMCFMCIMCFM
    (mg/mL) (mg/mL) (mg/mL) (mg/mL)
    S. alataEEFNI-NI-NI-2,55,0
    EEC0,310,622,55,0NI-NI-
    S. obtusifoliaEEFNI-2,55,0NI-0,621,25
    EECNI-1,252,5NI-0,621,25
    S. occidentalisEEF0,070,150,310,62NI-0,310,62
    EECNI-NI-NI-NI-
    S. siameaEEF0,621,251,252,50,621,251,252,5
    EECNI-2,55,0NI-2,55,0
    S. trachypusEEF0,621,250,310,620,310,620,310,62
    EEC0,621,250,310,620,310,620,310,62
    Cetoconazol 2,0 1,0 1,0 0,5
    + + +

    Table 4. Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) of ethanolic extracts (EEs) from Senna Mill. LABIMIC: Microbiology Laboratory; EEF: Ethanol extract of the leaf; EEC: Ethanol extract from the stem; NI: It didn't inhibit. (Fabaceae) species compared to Trichophyton rubrum species.

    + + + +

    +

    Estudos anteriores realizados com o extrato etanólico da casca do caule de S. alata contra fungos dermatofíticos, entre eles espécies de Trychophyton, revelou um CIM de 5,0 mg/mL para todos os dermatófitos testados (Sule et al. 2011). A capacidade antifúngica de extratos de diferentes polaridades preparados a partir das folhas de S. obtusifolia apresentaram um CIM que variou de 500 a 2000 µg/mL contra diferentes espécies de fungos filamentosos (Doughari et al. 2008). Os resultados obtidos de extratos foliares de polaridades diferentes de S. occidentalis revelaram que o extrato metanólico mostrou maior atividade antifúngica entre os demais extratos testados, em uma concentração inibitória mínima de 25 mg/mL (Odeja et al. 2015). Testes utilizando extratos preparados com solventes de diferentes polaridades a partir das folhas de S. siamea apresentaram CIM que variaram de 0,032 a 0,128 mg/mL contra o fungo Cryptococcus gattii (Nnadi et al. 2019). Na literatura, não foram encontrados estudos do potencial antifúngico para a espécie de S. trachypus, sendo este o primeiro registro de atividade antifúngica para a referida espécie.

    +

    Pesquisas têm revelado que o potencial antifúngico de extratos vegetais está intimamente relacionado, entre outros fatores, com as suas variações quantitativas de compostos fenólicos, dentre eles os flavonoides. Nosso estudo confirmou que as espécies estudadas possuem propriedades antifúngicas, e que seus efeitos sobre os dermatófitos fundamentam-se em seus teores de compostos fenólicos encontrados, e os demais outros metabólitos secundários aqui não estudados. Os efeitos antifúngicos atribuídos aos compostos fenólicos podem resultar na ruptura da membrana celular, ou ainda, inibir a divisão celular e o desenvolvimento das hifas por meio de genes específicos, além de interferir nas vias metabólicas e/ou induzir a apoptose por perturbar a homeostase redox (Lagrouh et al. 2017, Mohamed et al. 2017).

    +

    Foram detectados, nos EEF e EEC das espécies de Senna, a presença de metabólitos secundários, alto teor de fenóis totais e capacidade antioxidante para todas as espécies, em especial S. trachypus. Para a atividade anticolinesterase apenas a espécie de S. trachypus manifestou uma melhor ação inibitória. Nas condições experimentais utilizadas, evidenciou-se atividade antifúngica das espécies frente a maioria dos dermatófitos testados, em especial os extratos de S. trachypus. Foi observada também correlação forte, muito forte e moderada entre as variáveis fenóis totais e atividade antioxidante, fenóis totais e antiacetilcolinesterase e atividade antioxidante e antiacetilcolinesterase, respectivamente. Os resultados apontam que S. trachypus, espécie endêmica da Caatinga, é a mais promissora entre todas as plantas estudadas, representando uma fonte potencial para a obtenção de compostos químicos úteis para estudos clínicos e farmacológicos, visando o desenvolvimento de novos agentes farmacológicos naturais.

    +     + + + + Agradecimentos +

    Os autores agradecem a Universidade Estadual do Ceará (UECE) e a Universidade Estadual Vale do Acaraú (UVA) pelo apoio técnico, e a Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) pelo apoio financeiro concedido (processos PBI3-0139-00252.01.00/18; BP4-0172-00170.01.00/20).

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Universidade Estadual de Feira de Santana, Feira de Santana, 467 p. + + + + Queiroz + L.P. + + + 2009 + Leguminosas da Caatinga + Universidade Estadual de Feira de Santana + Feira de Santana + 467 + + + + Rhee, I.K., van de Meent, M., Ingkaninan, K. & Verpoorte, R. 2001. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. Journal of Chromatography A 915: 217-223. + + + + Rhee + I.K. + + + van de Meent + M. + + + Ingkaninan + K. + + + Verpoorte + R. + + + 2001 + Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining + Journal of Chromatography A + 915 + 217 + 223 + + + + Rodrigues, F.C., Dos Santos, A.T.L., Machado, A.J.T., Bezerra, C.F., de Freitas, T.S., Coutinho, H.D.M., Morais-Braga, M.F.B., Bezerra, J.W.A., Duarte, A.E., Kamdem, J.P., Boligon, A.A., Campos, M.M.A., Barros, L.M. 2019. Chemical composition and anti-Candida potencial of the extracts of Tarenaya spinosa (Jacq.) Raf.(Cleomaceae). Comparative immunology, microbiology and infectious diseases 64: 14-19. + + + + Rodrigues + F.C. + + + Dos Santos + A.T.L. + + + Machado + A.J.T. + + + Bezerra + C.F. + + + de Freitas + T.S. + + + Coutinho + H.D.M. + + + Morais-Braga + M.F.B. + + + Bezerra + J.W.A. + + + Duarte + A.E. + + + Kamdem + J.P. + + + Boligon + A.A. + + + Campos + M.M.A. + + + Barros + L.M. + + + 2019 + Chemical composition and anti-Candida potencial of the extracts of Tarenaya spinosa (Jacq.) Raf.(Cleomaceae) + Comparative immunology, microbiology and infectious diseases + 64 + 14 + 19 + + + + Santos, G.H.F., Amaral, A. & Da Silva, E.B. 2018. Antibacterial activity of irradiated extracts of Anacardium occidentale L. on multiresistant strains of Staphylococcus aureus. Applied Radiation and Isotopes 140: 327-332. + + + + Santos + G.H.F. + + + Amaral + A. + + + Da Silva + E.B. + + + 2018 + Antibacterial activity of irradiated extracts of Anacardium occidentale L. on multiresistant strains of Staphylococcus aureus + Applied Radiation and Isotopes + 140 + 327 + 332 + + + + Santos, T.C.D., Gomes, T.M., Pinto, B.A.S., Camara, A.L. & Paes, A.M.D.A. 2018. Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer's disease therapy. Frontiers in Pharmacology 9: 1192. + + + + Santos + T.C.D. + + + Gomes + T.M. + + + Pinto + B.A.S. + + + Camara + A.L. + + + Paes + A.M.D.A. + + + 2018 + Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer's disease therapy + Frontiers in Pharmacology + 9 + 1192 + + + + Sánchez‐Moreno, C., Larrauri, J.A. & Saura‐Calixto, F. 1998. A procedure to measure the antiradical efficiency of polyphenols. Journal of the Science of Food and Agriculture 76: 270-276. + + + + Sánchez‐Moreno + C. + + + Larrauri + J.A. + + + Saura‐Calixto + F. + + + 1998 + A procedure to measure the antiradical efficiency of polyphenols + Journal of the Science of Food and Agriculture + 76 + 270 + 276 + + + + Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202. + + + + Silva + C. + + + Sampaio + C.G. + + + Silva + M.G.V. + + + 2014 + Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill + From northeast Brazil.Int. J. Pharm. Pharm. Sci + 6 + 199 + 202 + + + + Souza, V.C.; Bortoluzzi, R.L.C. 2015. Senna in Lista de Espécies da Flora do Brasil. 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Pharmacology, 6: 26-30. + + + + Yakubu + O.E. + + + Otitoju + O. + + + Imarenezor + E.P.K. + + + Tatah + S.V. + + + Habibu + B. + + + 2018 + Fractionation and determination of antioxidant activities, of the Leaves of Senna Occidentalis ethanol extract + Pharmacology + 6 + 26 + 30 + + + +     +
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    + Review Article - Position Paper • ABCD, arq. bras. cir. dig. 37 • 2024 • https://doi.org/10.1590/0102-6720202400044e1838 linkcopy +
    +

    + Open-access THE GROWING EVIDENCE + OF THE RELATIONSHIP BETWEEN OBESITY AND CANCER AND THE ROLE OF BARIATRIC SURGERY +

    +

    A CRESCENTE EVIDÊNCIA DA RELAÇÃO ENTRE OBESIDADE E CÂNCER E O PAPEL DA CIRURGIA + BARIÁTRICA

    +
    +
    + AuthorshipSCIMAGO INSTITUTIONS RANKINGS +
    +
    +
      +
      +
      +

      ABSTRACT

      +

      Obesity is recognized as a significant risk factor for various types of cancer. Although the + incidence of some types of cancer across various primary sites is decreasing due to specific + prevention measures (screening programs, smoking cessation), the incidence of neoplasms in the young + population shows a significant increase associated with obesity. There is sufficient evidence to say + that bariatric surgery has been shown to significantly lower the risk of developing obesity-associated + cancers, which are linked to metabolic dysregulation, chronic low-grade systemic inflammation, and + hormonal alterations such as elevated levels of insulin and sex hormones.

      +

      HEADINGS: Obesity; Bariatric surgery; Neoplasms

      +
      +
      +

      RESUMO

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      A obesidade é reconhecida como um fator de risco significativo para vêrios tipos de câncer. Embora a + incidência de alguns tipos de câncer de vêrios locais primêrios esteja diminuindo devido a medidas + específicas de prevenção (programas de triagem, cessação do tabagismo), a incidência de neoplasias na + população jovem mostra um aumento significativo associado à obesidade. Hê evidências suficientes para + dizer que a cirurgia bariêtrica demonstrou reduzir significativamente o risco de desenvolver cânceres + associados à obesidade, que estão ligados à desregulação metabólica, inflamação sistêmica crônica de + baixo grau e alterações hormonais, como níveis elevados de insulina e hormônios sexuais.

      +

      DESCRITORES: Obesidade; Cirurgia bariêtrica; Neoplasias

      +
      +
      +

      SUMMARY OF THE MAIN RECOMMENDATIONS

      +

      • Obesity is recognized as a significant risk factor for various types of cancer.

      +

      • Although the incidence of some types of cancer at different primary sites is decreasing due to + specific prevention measures (screening programs, smoking cessation), the incidence of neoplasms in + the young population shows a significant increase associated with obesity.

      +

      • Bariatric surgery has been shown to significantly lower the risk of developing obesity-associated + cancers, which are linked to metabolic dysregulation, chronic low-grade systemic inflammation, and + hormonal alterations such as elevated insulin and sex hormone levels.

      + +

      INTRODUCTION

      +

      The worldwide increase in obesity has been clearly observed. Kaidar-Person et al., back in 2011, + stated that the 21st century was dealing with 2 major epidemics: obesity and cancer33. + The prevalence of obesity in the United States (U.S.) increased from 30.5 to 41.9% between 2000 and + 2020, while the prevalence of severe obesity increased from 4.7 to 9.2% during the same period64. + Another study found that the incidence of obesity increased by 18% between 2013 and 2017 compared to + 2009 to 201342. + Obesity-related conditions, including heart disease, stroke, type 2 diabetes, and certain types of + cancer, are among the leading causes of premature death and are preventable12. +

      +

      Additionally, projections published in 2019 suggest that by 2030, nearly 1 in 2 adults in the U.S. + will have obesity, with severe obesity becoming increasingly prevalent69,72. + In the young population, the 2023 guidelines from the American Academy of Pediatrics reported that the + percentage of U.S. children and adolescents affected by obesity has more than tripled, rising from 5% + in 1963–1965 to 19% in 2017–201828,69. +

      +

      In Brazil, evidence indicates a significant increase in the prevalence of obesity over recent + decades. A systematic review and meta-analysis by Kodaira et al. found that the pooled prevalence of + obesity in Brazilian adults increased by 15% from 1974–1990 to 2011–2020. This trend was observed in + both men and women across almost all periods34. + Similarly, Estivaleti et al. reported that the prevalence of obesity in Brazilian adults rose from + 11.8% in 2006 to 20.3% in 2019, with projections suggesting that obesity may affect 29.6% of adults by + 2030.This study also highlighted that women, black and other minority ethnicities, and individuals + with lower educational attainment are particularly at risk24. +

      +

      Several medical conditions are associated with obesity, including heart disease, hypertension, + stroke, type 2 diabetes, metabolic syndrome, and certain cancers71. + These are among the leading causes of preventable premature death. The estimated annual medical cost + of obesity in the U.S. was nearly $173 billion (in 2019 dollars), with medical costs for obese adults + being $1,861 higher than for people at a healthy weight60.Other + studies have shown that the cost of inpatient surgical procedures, both oncologic and benign, + abdominal and non-abdominal, is higher in obese patients56. +

      + +

      Evidence of the relationship between obesity and cancer

      +

      Obesity is recognized as a significant risk factor for various types of cancer. According to the + American Cancer Society, excess body fat contributes substantially to cancer risk, with approximately + 10.9% of cancer cases in women and 4.8% in men in the U.S. attributed to overweight or obesity61. + In the United Kingdom (UK), overweight and obesity were the second most common preventable causes of + cancer, accounting for 6.3% of all cases in 2015. The proportion was higher in women (7.5%) than in + men (5.2%), with the highest rates observed in Scotland (6.8%) and the lowest in Wales (5.4%). The + type of cancer most strongly associated with overweight and obesity in women was uterine cancer + (34.0%), while in men, it was esophageal cancer (31.3%)9. +

      +

      The cause-and-effect relationship between obesity and cancer seems to be even more important8. + Although the incidence of certain types of cancer at various primary sites is decreasing due to + specific prevention measures (e.g., screening programs, smoking cessation), the incidence of + neoplasms in younger populations has shown a significant increase associated with obesity.

      +

      A large British population-based study involving 5.24 million individuals with 166,955 new cases + across 22 types of cancer noted a relationship between body mass index (BMI) and certain types of + cancer. Of the more than 5 million individuals, 166,955 developed cancers. BMI was associated with 17 + of the 22 types of cancer, though the effects varied substantially by site. Each 5 kg/m2 + increase in BMI was linearly associated with the incidence of uterine, cervical, thyroid, and leukemia + cancers. High BMI was also associated with liver, colon, ovarian, and postmenopausal breast cancer in + general (all p<0.0001), with these effects varying according to individual characteristics22,36. + It is estimated that 41% of uterine cancers and 10% or more of gallbladder, kidney, liver, and colon + cancers could be attributed to excess weight. A 1 kg/m2 increase in BMI across the + population could result in 3,790 additional cancer cases per year in the UK7. +

      +

      A 2015 study reported the risk of cancer attributable to obesity by gender: in women, around 30% for + breast and uterine cancers, around 10% for colon, rectum, and gallbladder cancers, 8.8% for kidney + cancer, 3.4% for pancreas cancer, and 1.2% for esophageal cancer. In men, obesity was responsible for + over 50% of colon and rectal cancers, 24.8% of kidney cancers, and around 10% for pancreatic and + esophageal cancers4. +

      +

      In addition to these types of cancer, other neoplasms associated with overweight and obesity include + meningiomas, thyroid cancer, multiple myeloma, ovarian cancer, liver cancer, and esophagogastric + junction cancer. From 1995 to 2014, the incidence of obesity-related neoplasms among adults aged 25–49 + years increased significantly in 6 types of cancers: multiple myeloma, colorectal, uterine, + gallbladder, kidney, and pancreatic cancer. This association was more evident in women, as described + in a 17-year study (January 2000 to December 2016), which reported a shift in the age distribution of + obesity-associated cancers, with 70.3% of patients being female. In fact, a BMI greater than or equal + to 30 corresponds to an 86% increase in the relative risk of colorectal cancer in young women, with + the risk increasing by 18% for every 5-unit rise in BMI, even in women with no family history of this + type of cancer41. +

      +

      In an interesting review article, Pati et al. focused on the epidemiology and relationship between + obesity and cancer. They concluded that around 4 to 8% of all cancers can be attributed to obesity, + which is now recognized as a risk factor for several types of cancer, including postmenopausal breast, + liver, gallbladder, pancreas, colon and rectum, endometrial, kidney, and esophageal cancer. They also + noted that excess body fat resulted in an increased risk of approximately 17% in cancer-specific + mortality46. +

      +

      A large cohort study in Spain, involving more than 2.5 million individuals from 2009 to 2018, + analyzed individuals over 45 years of age who were cancer-free in 2009. After 9 years of follow-up, + 225,396 participants were diagnosed with cancer. This analysis demonstrated that longer duration and + higher degrees of obesity, particularly in younger individuals and those who became overweight or + obese during early adulthood, increased the risk of 18 types of cancer, including leukemia and + non-Hodgkin lymphoma. Among never-smokers, head and neck and bladder cancers, not yet recognized as + obesity-related cancers in the literature, were also linked to obesity. The authors emphasized the + importance of including obesity prevention strategies in public health programs49. +

      +

      In summary, according to the literature, increased body weight and obesity are related to at least 13 + types of cancer, 6 of which are located in the digestive system (Table + 1).

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      + Thumbnail +
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      +
      + Table 1
      + Evidence of the relationship between high body mass index and types of cancer37. +
      +
      +
      +

      The relationship between BMI and the risk of developing and dying from cancer is so direct that it is + estimated that, in a hypothetical situation where the American population did not exceed a BMI of 25 + kg/m2, 90,000 fewer cancer-related deaths would occur each year in the U.S.7,11,70. +

      +

      The mechanisms linking obesity to cancer are multifactorial. Obesity is associated with metabolic + dysregulation, chronic low-grade systemic inflammation27, + and hormonal changes, including elevated insulin and sex hormones, which can promote carcinogenesis. + Increased circulating estrogens, tumor cell growth and migration, modification of the tumor + microenvironment, and neoangiogenesis have also been implicated. Obesity induces a variety of systemic + changes, including altered levels of insulin, insulin-like growth factor-1 (IGF-1), leptin, + adiponectin, steroid hormones, and cytokines, creating an environment that favors tumor initiation and + progression. Chronic low-grade inflammation, driven by adipose tissue dysfunction and macrophage + infiltration, is a hallmark of obesity and contributes to both cancer risk and progression. Adipose + tissue in obese individuals secretes a large number of biologically active substances termed + adipokines, which include pro-inflammatory cytokines like IL-6 and TNF-α. These adipokines can induce + pathological alterations in insulin pathways and promote a pro-inflammatory state, both of which are + linked to increased cancer risk. Additionally, obesity-related changes in the gut microbiome and + adipokine pathways further contribute to cancer risk30,32,59,62. +

      +

      One hypothesis is that adipose tissue acts as an organ capable of releasing enzymes and other + chemical mediators, such as estrogens, whose increase results from heightened aromatase activity in + adipose tissue50. + Obesity also impacts the tumor microenvironment by modulating immune cell infiltration, influencing + cancer progression and response to therapy15. +

      +

      Therefore, the pathophysiology of the relationship between obesity and cancer is quite complex and + not yet fully understood, as it involves two multifactorial conditions encompassing genetic, + environmental, and social factors in a highly interconnected manner. However, several obesity-related + changes have been shown to influence carcinogenesis, including hyperinsulinemia, elevated leptin + levels, chronic inflammation, oxidative stress, HIF-1α activation, cytokine secretion, DNA + methylation, visceral adipose dysfunction, release of adiponectin, exosome miRNA release, and changes + in the metabolism of sex hormones74. +

      +

      As for weight loss, studies have shown a reduced risk of breast, endometrial, colorectal, and + prostate cancers in patients who lost weight. A large prospective study with postmenopausal women + showed that intentional loss of more than 5% of body weight was associated with a lower risk of + obesity-related neoplasms, though this effect was not observed when weight loss was unintentional39,65. + Lifestyle modifications could prevent a substantial proportion of cancer cases. A study found that + adherence to a healthy lifestyle — defined as non-smoking, moderate alcohol consumption, maintaining a + BMI between 18.5 and 27.5, and engaging in regular physical activity — could prevent 25% of cancer + cases in women and 33% in men9,16,51,63. +

      +

      Obesity negatively impacts all phases of cancer treatment, increasing the incidence of at least 13 + types of cancer and delaying diagnosis due to technical difficulties in the surgical treatment, + difficulties in accessing diagnostic methods, or the stigma that obese patients face, which may + discourage them from seeking medical attention. Obesity also increases therapeutic complications + (surgeries, radiotherapy, chemotherapy, etc.) and adversely affects survival rates in cancer patients. + It compromises quality of life, increases the likelihood of cancer recurrence and progression, and + raises the risk of developing new neoplasms10,11,25,57,66. +

      +

      In conclusion, there seems to be sufficient evidence to link obesity to cancer. The question that + follows is: does bariatric surgery reduce cancer risk?

      + + +

      Does Bariatric Surgery reduce cancer risk?

      +

      Obesity surgery reduces the incidence of cancer. Bariatric surgery has been shown to significantly + lower the risk of developing obesity-associated cancers, which are linked to metabolic dysregulation, + chronic low-grade systemic inflammation, and hormonal alterations such as elevated insulin and sex + hormone levels.

      +

      A systematic review and meta-analysis demonstrated that bariatric surgery is associated with a + reduced overall incidence of cancer (RR 0.62, 95%CI 0.46–0.84) and obesity-related cancer (RR 0.59, + 95%CI 0.39–0.90). Another study found that bariatric surgery was associated with a significantly lower + incidence of obesity-associated cancer (adjusted HR 0.68, 95%CI 0.53–0.87) and cancer-related + mortality (adjusted HR 0.52, 95%CI 0.31–0.88)74. +

      +

      Additionally, a multi-center population-based study reported that the cumulative incidence of cancers + among patients who experienced obesity recurrence was significantly lower in the bariatric surgery + group compared to the nonsurgical control group (HR 0.482, 95%CI 0.459–0.507). This protective effect + extends to specific cancers such as breast, endometrial, and colorectal cancers2,13. +

      +

      Other studies have shown that surgical treatment of obesity is associated with reduced risks of + neoplasms in general, hormone-dependent cancers (breast, endometrium, and prostate), and + obesity-related cancers (postmenopausal breast, endometrium, and colorectal)40,54,68. +

      +

      In summary, bariatric surgery not only aids in weight loss but also significantly reduces the risk of + developing various obesity-associated cancers by mitigating the underlying metabolic and inflammatory + pathways that promote carcinogenesis. The benefits attributed to bariatric surgery in reducing cancer + incidence also extend to other aspects of cancer treatment, including improved outcomes in adjuvant + treatments (chemo and radiotherapy), lower recurrence rates, and increased overall survival. + Therefore, there is substantial evidence that bariatric surgery positively affects the key + pathophysiological mechanisms linking obesity and cancer12. + The mechanisms include reduction in insulin and leptin levels, chronic inflammation, and oxidative + stress, as well as the restoration of sex hormone levels, especially estradiol. Additionally, + bariatric surgery has a significant impact on the intestinal microbiome and serum proteomics60. +

      +

      In 2004, a study involving 1,035 patients who underwent bariatric surgery, compared with a cohort of + more than 5,000 non-operated patients, demonstrated a significant decrease in cancer cases. In those + who underwent surgery, the incidence was 2.03%, while in the non-surgical group, it was 8.49%, + indicating that bariatric surgery reduced cancer incidence fourfold. There was also a large decrease + in the number of hospitalizations for cancer: 54.95/1,000 person-years in the non-operated group + versus only 11.80 in the operated group16. + In the same year, an epidemiological evaluation of 15,850 patients, 7,925 of whom underwent surgery + compared to an equal number of controls, showed a 60% decrease in cancer mortality11. +

      +

      A few years later, a prospective, controlled analysis carried out in Sweden, involving more than + 4,000 patients, about half of whom underwent bariatric surgery compared to controls, revealed the + occurrence of 47 cases of cancer in the non-operated group compared to 29 in the operated group61. + In 2017, another observational study with the impressive number of 18,355 operated patients, compared + to more than 40,000 non-operated controls, revealed a significant decrease in cancer mortality, with + greater weight loss associated with lower mortality55. +

      +

      A recent systematic review and meta-analysis of 32 studies involving patients with obesity who + underwent bariatric surgery compared to controls managed with conventional treatment analysis + suggested that bariatric surgery was associated with a reduced overall incidence of cancer (RR 0.62, + 95%CI 0.46–0.84, p<0.002), obesity-related cancer (RR 0.59, 95%CI 0.39–0.90, p=0.01), and + cancer-associated mortality (RR 0.51, 95%CI 0.42–0.62, p<0.00001). For specific cancers, bariatric + surgery was associated with a reduction in the future incidence of hepatocellular carcinoma (RR 0.35, + 95%CI 0.22–0.55, p<0.00001), colorectal cancer (RR 0.63, 95%CI 0.50–0.81, p=0.0002), pancreatic + cancer (RR 0.52, 95%CI 0.29–0.93, p=0.03), and gallbladder cancer (RR 0.41, 95%CI 0.18–0.96, p=0.04), + as well as female-specific cancers, including breast cancer (RR 0.56, 95%CI 0.44–0.71, p<0.00001), + endometrial cancer (RR 0.38, 95%CI 0.26–0.55, p<0.00001), and ovarian cancer (RR 0.45, 95%CI + 0.31–0.64, p<0.0001). There was no significant reduction in the incidence of esophageal, gastric, + thyroid, kidney, prostate cancer or multiple myeloma after bariatric surgery as compared to patients + with morbid obesity who did not have bariatric surgery. The authors concluded that bariatric surgery + might decrease future overall cancer incidence and mortality, particularly in relation to seven + obesity-related cancers74. +

      +

      Regarding cancers of the upper digestive tract, with the exception of colon cancer, hundreds of + thousands of bariatric surgeries have been performed to date. However, a systematic review analyzing + the relationship between bariatric surgeries and the reduction of digestive cancer specifically + revealed that only a few cases of cancer after the operations were described. Therefore, there is no + conclusive evidence supporting a correlation between obesity surgery and upper gastrointestinal + cancer23. + Åkerström et al. evaluated 748,932 participants diagnosed with obesity, of whom 91,731 underwent + bariatric surgery, predominantly gastric bypass (n=70,176; 76.5%). The adjusted risk of esophageal + cancer decreased over time after gastric bypass, from 2.2 (95%CI 0.9–4.3) after 2 to 5 years to 0.6 + (95%CI <0.1–3.6) after 10 to 40 years. Gastric bypass patients also had a reduced risk of + adenocarcinoma of the cardia compared with non-operated patients with obesity (adjusted HR 0.6, 95%CI + 0.4–1.0 (0.98)), with point estimates decreasing over time. Gastric bypass was followed by a strongly + decreased adjusted risk of esophageal adenocarcinoma (HR 0.3, 95%CI 0.1–0.8) but not of cardia + adenocarcinoma (HR 0.9, 95%CI 0.5–1.6) when analyzed separately29. +

      +

      Lazzati et al. showed that the incidence of esophagogastric cancer in patients undergoing bariatric + surgery is statistically lower when compared with a population that did not undergo the procedure. The + incidence of esophageal-gastric cancer fell from 6.9 to 4.9 per 100,000 population per year, with a + reduction in esophageal cancer from 2.3 to 1.5 and in gastric cancer from 4.6 to 3.3 per 100,000 + population per year38. +

      +

      The association between upper digestive tract cancers after bariatric surgery remains controversial, + as several procedures can increase the incidence of pre-neoplastic conditions in the esophagus58. + A French national study evaluated the incidence of colorectal cancer by comparing nearly 2 million + individuals who did not undergo bariatric surgery with more than 100,000 who did. The incidence of + colorectal cancer has fallen by half in the patients subjected to bariatric surgery5. +

      +

      In the Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death + (SPLENDID) matched cohort study, adult patients with a BMI of 35 or greater who underwent bariatric + surgery at a U.S. health system between 2004 and 2017 were included73. + Patients who underwent bariatric surgery were matched in a 1:5 ratio with patients who did not undergo + surgery for their obesity, resulting in a total of 30,318 patients. Bariatric surgery (n=5053) + included Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). During follow-up, 96 patients in + the bariatric surgery group and 780 patients in the nonsurgical control group had an incident + obesity-associated cancer (incidence rate of 3.0 events vs. 4.6 events, respectively, per 1,000 + person-years). The cumulative incidence of the primary endpoint at 10 years was 2.9% (95%CI 2.2–3.6%) + in the bariatric surgery group and 4.9% (95%CI 4.5–5.3%) in the nonsurgical control group (absolute + risk difference, 2.0% [95%CI 1.2–2.7%]; adjusted HR 0.68 [95%CI 0.53–0.87], p=0.002, p<0.05). + Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in + the nonsurgical control group (incidence rate of 0.6 events vs. 1.2 events, respectively, per + 1,000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95%CI + 0.4–1.2%) in the bariatric surgery group and 1.4% (95%CI 1.1–1.6%) in the nonsurgical control group + (absolute risk difference, 0.6% [95%CI 0.1–1.0%]; adjusted HR 0.52 [95%CI 0.31–0.88], p=0.01, + p<0.05). The authors concluded that, among adults with obesity, bariatric surgery compared with no + surgery was associated with a significantly lower incidence of obesity-associated cancer and + cancer-related mortality2. +

      + + +

      Does the bariatric surgery technique — Roux-en-Y gastric bypass, sleeve gastrectomy, or single + anastomosis mini gastric bypass — influence the risk of cancer after the operation?

      +

      Bariatric surgery has become a widely performed procedure globally, with approximately 1 million + surgeries estimated to occur each year. Among the procedures performed, SG and RYGB account for + approximately 80% of surgeries performed in the U.S. Mini gastric bypass (OAGB) is another technique + that has been gaining a lot of attention and has a growing number of followers, becoming the most + performed procedure in some countries17,43. +

      +

      These three procedures raise some concerns regarding potential carcinogenic characteristics. + Specifically, SG is associated with a higher incidence of reflux, esophagitis, and Barrett’s + esophagus. RYGB raises concerns due to the exclusion of the stomach, while OAGB is linked to alkaline + reflux. The major concern among these issues would be the development of esophageal cancer in this + population47. +

      + + +

      Sleeve gastrectomy

      +

      The incidence of cancer after SG has been a subject of investigation in several studies. According to + a systematic review and meta-analysis, bariatric surgery, including SG, is associated with a + significant reduction in overall cancer incidence compared to nonsurgical treatment. Specifically, the + odds ratio (OR) for cancer incidence in patients undergoing SG was 0.44 (95%CI 0.27–0.70)14. +

      +

      However, there are specific concerns regarding the risk of esophageal cancer post SG due to the + potential for increased gastroesophageal reflux disease (GERD) and consequently esophagitis and risk + of Barrett’s esophagus. One study found that the crude incidence rate of esophageal cancer in patients + undergoing reflux-prone procedures like SG was higher than in nonsurgical controls, but this + difference was not significant after adjusting for confounders3. +

      +

      Some case studies reported an incidence of approximately 18% for Barrett’s esophagus, 52% for the + need for stomach-protective medication, and 41% for esophagitis within 5 years of evolution58. + The shape of the gastric tube appears to influence the incidence of reflux, especially when it is made + in a twisted manner26. + However, the incidence of Barrett’s in patients undergoing SG varies widely in the literature. Dantas + et al., in an endoscopic evaluation with more than 5 years of follow-up, did not identify any cases of + Barrett’s esophagus in their case study18. + In summary, while sleeve gastrectomy is associated with a reduced overall cancer incidence, there is a + notable concern for esophageal cancer due to increased GERD and Barrett’s esophagus. Therefore, SG is + generally lower for most cancer types, vigilance for esophageal cancer remains necessary.

      + + +

      Roux-en-Y gastric bypass

      +

      The creation of an excluded gastric chamber in this type of surgery raises concerns mainly due to the + difficulty in accessing the excluded stomach. Some studies, in which the excluded chamber was accessed + through double-balloon endoscopy, showed an incidence of atrophic gastritis of 14.3%, metaplasia in + 11.4%, and H. pylori presence in 20% of cases. In addition to the changes mentioned, there + appear to be changes in the microenvironment that may predispose to oncogenic molecular mutations48,52,53. +

      +

      The incidence of gastric cancer after RYGB is rare but has been documented in the medical literature. + According to a systematic review by Chemaly et al., the occurrence of gastroesophageal cancer + post-RYGB is primarily reported through case studies, with 27 out of 44 cases of gastroesophageal + cancer occurring in the gastric tube after RYGB13. + Another systematic review by Dong et al. identified 21 cases of remnant gastric cancer after RYGB, + with a median time to diagnosis of 11 years postoperatively20. + Additionally, Doukas et al.21 + reported an increasing trend of gastric cancer cases in the excluded stomach post-RYGB, with 77% of + these cancers diagnosed at an advanced stage13,20,21. +

      +

      In summary, while the exact incidence rate is not well-defined due to the rarity and the nature of + case reports, available data suggest that gastric cancer can occur in the remnant stomach or gastric + tube after RYGB, typically many years postoperatively. Although rare, this warrants awareness and + long-term surveillance in high-risk patients.

      + + +

      Mini gastric bypass

      +

      Despite being a relatively recent procedure in the arsenal of surgical treatment for obesity, OAGB + brings with it a problem already faced in gastrectomy surgery with B-II reconstruction, which is + alkaline reflux. Alkaline reflux can cause changes in the gastric mucosa and esophageal mucosa, with + some studies reporting its presence in 21% of cases, potentially increasing cancer incidence35. + Gastroesophageal cancer appears to be the most commonly reported type of cancer following mini gastric + bypass (OAGB), although the incidence is not significantly higher compared to RYGB. According to a + systematic review and meta-analysis by Chemaly et al., 37.5% of gastroesophageal cancers after OAGB + were located in the gastric tube, compared to 61% after RYGB, with an odds ratio of 0.38, indicating + no significant increase in cancer occurrence in the gastric tube after OAGB compared to RYGB13. +

      +

      The arguments that bile reaches the terminal ileum diluted are unfounded, since physiology studies + show that 90% of bile reaches that location intact, where it is later reabsorbed. This technique + should be used with great caution, since the potential harmful effects, such as the development of + cancer in the gastric remnant and esophagus, may only become apparent 30 to 40 years + postoperatively1,6,19,35. +

      +

      In conclusion, the incidence of cancer in patients undergoing bariatric surgery is low. Large + systematic reviews and meta-analyses list a small number of cases relative to the total number of + surgeries performed worldwide, demonstrating that the benefits of surgery, in terms of cancer + incidence reduction, outweigh the risks, regardless of the surgical technique employed43,44,45. + Therefore, while the incidence of cancer in patients undergoing bariatric surgery remains numerically + low, it is a concern, and surgeons must remain vigilant to avoid understanding symptoms and delaying + diagnosis. On the other hand, there is sufficient evidence to suggest that bariatric surgery reduces + the incidence of many types of cancer. However, indications for surgery should be thoroughly discussed + with multidisciplinary teams, avoiding exaggeration and sensationalism, especially regarding + procedures that increase the incidence of gastroesophageal reflux.

      + +
      +
      +

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        » https://doi.org/10.3390/ijms24076192 +
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      +Prospecção química, atividade antioxidante, anticolinesterásica e antifúngica de extratos etanólicos de espécies de Senna Mill. (Fabaceae) +

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      Chemical prospecting and antioxidant, anticholinesterase and antifungal activity of ethanol extracts from Senna Mill. species. (Fabaceae)

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      + Andréa Maria Neves Selene Maia de Morais Hélcio Silva dos Santos Marcílio Matos Ferreira Ricardo Carneiro Vera Cruz Elnatan Bezerra de Souza Lúcia Betânia da Silva Andrade Raquel Oliveira dos Santos Fontenelle Sobre os autores +
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      RESUMO

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      O objetivo deste trabalho foi avaliar o perfil químico, teor de fenóis totais e as atividades antioxidante, antiacetilcolinesterásica e antifúngica dos extratos etanólicos das folhas (EEF) e do caule (EEC) de cinco espécies de Senna, bem como avaliar a correlação entre o conteúdo de fenóis totais com a atividade sequestradora do radical livre DPPH e com a inibição da enzima acetilcolinesterase AChEI. No teste fitoquímico, evidenciou-se a presença de metabólitos secundários em todos os extratos. Os EEF e EEC de Senna trachypus, destacaram-se por apresentar os maiores valores de fenóis totais. Os EEF e EEC de S. trachypus mostraram a melhor ação sobre a enzima acetilcolinesterase. Todas as espécies apresentaram atividade antioxidante, em especial o EEF de S. trachypus. Foi observado correlação forte para as variáveis fenóis totais e atividade antioxidante (r = -0,71), muito forte para fenóis totais e antiacetilcolinesterase (r = -0,84) e atividade moderada para atividade antioxidante e antiacetilcolinesterase (0,43). Apenas os extratos de S. trachypus apresentaram atividade contra todos os dermatófitos, quando comparado às demais espécies. A espécie S. trachypus foi considerada a planta mais promissora para estudos subsequentes, a fim de encontrar compostos com ações farmacológicas.

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      Palavras-chave:
      acetilcolinesterase; dermatófitos; fitoquímica; produtos naturais; radicais livres

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      ABSTRACT

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      The objective of this work was to evaluate the chemical profile, total phenol content and the antioxidant, antiacetylcholinesterase and antifungal activities of ethanol extracts from leaves (EEF) and stem (EEC) of five species of Senna, as well as to evaluate the correlation between the content of total phenols with the DPPH free radical scavenging activity and with the inhibition of the acetylcholinesterase AChEI enzyme. The phytochemical test showed the presence of secondary metabolites in all extracts. The EEF and EEC of Senna trachypus, stood out for presenting the highest values of total phenols. S. trachypus EEF and EEC showed the best action on the acetylcholinesterase enzyme. All species showed antioxidant activity, especially the EEF from S. trachypus. A strong correlation was observed for the variables total phenols and antioxidant activity (r = -0.71), very strong for total phenols and anti-acetylcholinesterase (r = -0.84) and moderate activity for antioxidant and anti-acetylcholinesterase activity (r = 0.43). Only S. trachypus extracts showed activity against all dermatophytes, when compared to the other species. The species S. trachypus was considered the most promising plant for further studies, in order to find compounds with pharmacological actions.

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      Keywords:
      acetylcholinesterase; dermatophytes; phytochemistry; natural products; free radicals

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      Introdução

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      Senna Mill. é um gênero monofilético com distribuição pantropical e ampla variedade morfológica (Pellerin et al. 2019Pellerin, R.J., Waminal, N.E. & Kim, H.H. 2019. FISH mapping of rDNA and telomeric repeats in 10 Senna species. Horticulture, Environment, and Biotechnology 60: 253-260.). Possuindo aproximadamente 300 espécies, das quais 200 nas Américas, este gênero é o segundo maior da família Fabaceae (Queiroz 2009Queiroz, L.P. 2009. Leguminosas da Caatinga. Universidade Estadual de Feira de Santana, Feira de Santana, 467 p., Kim et al. 2018Kim, M.S., Lee, D.Y., Sung, S.H. & Jeon, W.K. 2018. Anti-cholinesterase activities of hydrolysable tannins and polyhydroxytriterpenoid derivatives from Terminalia chebula Retz. fruit. Fruit Rec Nat Prod 12: 284-289., Souza & Silva 2016Souza, A.O. & Silva, M.J. 2016. Senna (Leguminosae, Caesalpinioideae) na Floresta Nacional de Silvânia, Goiás, Brasil. Rodriguésia 67: 773-784. ). O gênero é representado no Brasil por 79 espécies, onde 29 são endêmicas, sendo a região Nordeste a que apresenta a maior riqueza de espécies com 53 registros (BFG 2018BFG. 2018. Brazilian Flora 2020: Innovation and collaboration to meet Target 1 of the Global Strategy for Plant Conservation (GSPC). Rodriguésia 1513-1527. ).

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      Trata-se de um gênero muito expressivo na flora do semiárido, alcançando destaque no Domínio Fitogeográfico da Caatinga, onde são catalogadas 42 espécies (Souza & Bortoluzzi 2015Souza, V.C.; Bortoluzzi, R.L.C. 2015. Senna in Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro. ). As espécies de Senna são geralmente arbustos ou arvoretas, raramente ervas ou subarbustos anuais. Entre as suas características diagnósticas estão os nectários extraflorais convexos, interfoliolares, flores vistosas, com pétalas amarelo-brilhantes, anteras amarelas, rígidas, com deiscência abrindo por poros ou fendas, ausência de bractéolas no pedicelo, frutos deiscentes plano-compressos ou indeiscentes e cilíndricos (Queiroz 2009Queiroz, L.P. 2009. Leguminosas da Caatinga. Universidade Estadual de Feira de Santana, Feira de Santana, 467 p.).

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      As espécies de Senna têm diversas aplicações medicinais e são eficazes no tratamento para uma série de doenças, como malária, micose, dengue, eczema, hepatite e dermatite, sendo também indicadas como anti-hipertensivo, vermífugo, laxante, abortivo e antitussígeno (Macedo et al. 2016Macedo, E.M., Alan, J.G., & Silva, M.G.V. 2016. Quimiodiversidade e propriedades biofarmacológicas de espécies de Senna nativas do Nordeste do Brasil. Revista Virtual de Química 8: 169-195., Bieski et al. 2015Bieski, I.G.C., Leonti, M., Arnason, J.T., Ferrier, J., Rapinski, M., Violante, I.M.P., Balogun,S.O., Pereira, J.F.C.A., Figueiredo, R.D.C.F., Lopes, C.R.A.S., Silva, D.R.D., Pacini, A., Albuquerque, U.P. & Martins, D.T.D.O. 2015. Ethnobotanical study of medicinal plants by population of valley of Juruena region, legal amazon, Mato Grosso, Brazil. Journal of Ethnopharmacology 173: 383-423., Kabir et al. 2014Kabir, M.H., Hasan, N., Rahman, M.M., Rahman, M.A., Khan, J.A., Hoque, N.T., Bhuiyan, M.R.Q., Mou, S.M.; Jahan, R. & Rahmatullah, M. 2014. A survey of medicinal plants used by the Deb barma clan of the Tripura tribe of Moulvibazar district, Bangladesh. Journal of Ethnobiology and Ethnomedicine 10: 1-19.). Além de suas aplicações farmacológicas, estudos têm revelado que espécies pertencentes a este gênero possuem, em sua composição, uma vasta diversidade de princípios bioativos que estão associadas a diferentes atividades biológicas. Neste sentido, podemos citar como exemplo as atividades antioxidantes, antitumoral, antibacterianas, antifúngicas e anti-inflamatórias (Neves et al. 2017Neves, A.M., Costa, O.S., Coutinho, M.G.S., Souza, E.B., Santos, H.S., Silva, M.G.V. & Fontenelle, R.O.S. 2017. Caracterização química e o potencial antimicrobiano de espécies do gênero Senna Mill (Fabaceae). Rev. Virtual Quim 9: 2506-2538.).

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      As plantas são fontes alternativas promissoras de substâncias de interesse biológico e farmacológico, já que podem produzir, a partir de seu metabolismo secundário, uma enorme diversidade de substâncias, dentre estas, os compostos fenólicos. Alguns estudos têm revelado que os compostos fenólicos são responsáveis por várias atividades biológicas, incluindo atividade antifúngica. Esta atividade pode ser direta nos micro-organismos, ou sobre outros fatores necessários para a expressão da virulência ou patogenicidade (Rodrigues et al. 2019Rodrigues, F.C., Dos Santos, A.T.L., Machado, A.J.T., Bezerra, C.F., de Freitas, T.S., Coutinho, H.D.M., Morais-Braga, M.F.B., Bezerra, J.W.A., Duarte, A.E., Kamdem, J.P., Boligon, A.A., Campos, M.M.A., Barros, L.M. 2019. Chemical composition and anti-Candida potencial of the extracts of Tarenaya spinosa (Jacq.) Raf.(Cleomaceae). Comparative immunology, microbiology and infectious diseases 64: 14-19.).

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      Os compostos fenólicos estão entre os metabólitos secundários mais estudados, notadamente por possuírem grande potencial para atividades antioxidantes, atuando na redução do risco de algumas doenças agudas e crônicas relacionadas ao estado redox do corpo humano, ocasionadas pelos radicais livres. Estas moléculas apresentam uma alta capacidade reativa, sendo consideradas perigosas para os organismos vivos, causando doenças prejudiciais, incluindo doenças neurodegenerativas, como o mal de Alzheimer (DA). Atualmente, uma das teorias mais aceitas na abordagem padrão no tratamento sintomático dessa demência é a “hipótese colinérgica”. Portanto, os inibidores da enzima acetilcolinesterase (AChEI) preservam os níveis de acetilcolina, melhorando a eficiência da transmissão colinérgica (Bardakci et al. 2019Bardakci, H., CeleP, E., Gözet, T., Kan, Y. & Kirmizibekmez, H. 2019. Phytochemical characterization and antioxidant activities of the fruit extracts of several Crataegus taxa. South African Journal of Botany 124: 5-13. , Lim et al. 2019Lim, S., Choi, A.H., Kwon, M., Joung, E.J., Shin, T., Lee, S.G., Kim, NG. & Kim, H. R. 2019. Evaluation of antioxidant activities of various solvent extract from Sargassum serratifolium and its major antioxidant components. Food Chemistry 278: 178-184.; Neagu et al. 2016Neagu, E., Radu, G.L., Albu, C., & Paun, G. 2016. Antioxidant activity, acetylcholinesterase and tyrosinase inhibitory potential of Pulmonaria officinalis and Centarium umbellatum extracts. Saudi Journal of Biological Sciences, 3: 578-585.).

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      Por este motivo, a utilização de dietas ricas ou enriquecidas com antioxidantes podem prevenir, ou pelo menos amenizar, a deterioração orgânica por um excessivo estresse oxidativo. Além disso, o crescimento sobre a investigação científica envolvendo os efeitos antioxidantes de extratos brutos, frações purificadas, ou mesmo de compostos isolados, onde estão classificados os compostos fenólicos, são demonstrados em muitos estudos (Penido et al. 2017Penido, A.B., De Morais, S.M., Ribeiro, A.B., Alves, D.R., Rodrigues, A.L.M., dos Santos, L.H. & de Menezes, J.E.S.A. 2017. Medicinal plants from northeastern Brazil against Alzheimer’s disease. Evidence-Based Complementary and Alternative Medicine 2017: 1-7. , Morais et al. 2013Morais, S.M., Lima, K.S.B., Siqueira, S.M.C., Cavalcanti, E.S.B., Souza, M.S.T., Menezes, J.E.S.A., Trevisan, M.T.S. 2013. Correlação entre as atividades antiradical, antiacetilcolinesterase e teor de fenóis totais de extratos de plantas medicinais de farmácias vivas. Revista Brasileira de Plantas Medicinais 15: 575-582. ).

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      Desta forma, investigar a atividade antifúngica e anticolinesterásica de extratos de espécies de Senna, analisando o seu potencial antioxidante, o seu teor de fenóis totais e o seu perfil fitoquímico, são maneiras de promover tanto o conhecimento acerca dessas espécies, como também potencializar o descobrimento de novos fitofármacos para o combate de inúmeras enfermidades. Assim, este trabalho avaliou o perfil fitoquímico, o teor de fenóis totais e as atividades antioxidante, anticolinesterásica e antifúngica dos extratos etanólicos de S. alata (L.) Roxb., S. obtusifolia (L.) H.S.Irwin & Barneby, S. occidentalis (L.) Link, S. siamea (Lam.) H.S.Irwin & Barneby e S. trachypus (Benth.) H.S.Irwin & Barneby, e a correlação entre o teor de fenóis totais e as atividades antioxidante e anticolinesterásica.

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      Materiais e métodos

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      Material vegetal e preparação dos extratos - Foram selecionadas para este estudo cinco espécies de Senna, sendo uma exótica naturalizada e quatro nativas, das quais uma é endêmica do Brasil, ocorrendo no Cerrado e na Caatinga (BFG 2018BFG. 2018. Brazilian Flora 2020: Innovation and collaboration to meet Target 1 of the Global Strategy for Plant Conservation (GSPC). Rodriguésia 1513-1527. ) (Tabela 1). As folhas e caules de Senna spp. foram coletados em diferentes locais da região Noroeste do Ceará. A identificação botânica das espécies foi realizada no Herbário Francisco José de Abreu Matos da Universidade Estadual Vale do Acaraú (HUVA), pelo professor Dr. Elnatan Bezerra de Souza. Para o preparo dos extratos, 200g das folhas e caule secos de cada espécie de um mesmo indivíduo foram triturados e imersos durante 10 dias em 500 mL de etanol e, na sequência o extrato foi filtrado e concentrado em um evaporador rotativo a (60°C) durante 2 h. Após este processo, foi mantido em banho-maria (40°C) até a eliminação total do solvente, obtendo-se o extrato etanólico das folhas (EEF) e extrato etanólico do caule (EEC) (Matos 2009Matos, F.J.A. 2009. Introdução à Fitoquímica Experimental. 3 ed. Fortaleza: UFC. 150p.).

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      +Tabela 1.
      Identificação das espécies de Senna Mill. (Fabaceae) coletadas em diferentes locais da região noroeste do Estado do Ceará. *Exótica, **Endêmica do Brasil. Fonte: Herbário Francisco José de Abreu Matos (HUVA).
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      Triagem fitoquímica - Os extratos etanólicos foram submetidos a triagem fitoquímica, tomando como referência a metodologia descrita por Matos (2009Matos, F.J.A. 2009. Introdução à Fitoquímica Experimental. 3 ed. Fortaleza: UFC. 150p.). Através deste ensaio preliminar, foi possível verificar as principais classes de metabólitos secundários por meio de reações químicas que resultaram no aparecimento de coloração e/ou precipitado, característico para cada classe de substância. Os ensaios foram conduzidos para as seguintes classes de substâncias: fenóis, taninos, flavonoides, saponinas, esteroides, triterpenoides e alcaloides. Todos os testes foram realizados em triplicata procedimentais.

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      Determinação do teor de fenóis totais - O teor de fenóis totais nos extratos etanólicos foi determinado pelo método espectrofotométrico de Folin-Ciocateau, utilizando ácido gálico como padrão de referência (Kim et al. 2006Kim, K.H., Tsao, R., Yang, R. & Cui, S.W. 2006. Phenolic acid profiles and antioxidant activities of wheat bran extracts and the effect of hydrolysis conditions. Food Chemistry 95: 466-473.). Em cada tubo adicionou-se 0,2 mL de cada extrato nas concentrações (0,62; 0,31 e 0,15 mg mL-1) com 1 mL do reagente Folin-Ciocalteau agitado por 2 minutos e adicionado 0,8 mL de carbonato de sódio (Na2CO3) 7,5% (m/v). Para o tubo controle foi utilizado 1 mL do reagente Folin- Ciocalteau com 0,8 mL de Na2CO3 e 0,2 mL de etanol, em triplicata. Os tubos foram deixados em banho-maria a 37 ̊C por 30 minutos na ausência de luz. Logo em seguida, foi realizado a leitura dos tubos em comprimento de onda de 765 nm. O teor de fenóis foi calculado e expresso em mg de equivalente de ácido gálico por grama de extrato (EAG.g-1), com base numa curva padrão preparada com ácido gálico. Todos os testes foram realizados em triplicata.

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      Atividade antioxidante - A atividade antioxidante dos extratos foi determinada pelo método de redução do radical 2,2’-difenil-1-picril-hidrazil (DPPH), segundo a metodologia modificada por Brand-Williams et al. (1995Brand-Williams, W., Cuvelier, M.E. & Berset, C.L.W.T. 1995. Use of a free radical method to evaluate antioxidant activity. LWT-Food Science and Technology 1: 25-30.), Sanchez-Moreno et al. (1998Sánchez‐Moreno, C., Larrauri, J.A. & Saura‐Calixto, F. 1998. A procedure to measure the antiradical efficiency of polyphenols. Journal of the Science of Food and Agriculture 76: 270-276.). Foram preparadas soluções etanólicas das amostras nas concentrações de 5,0; 2,5; 1,25; 0,62; 0,31 e 0,15 mg mL-1. Foram utilizados 100 µL dos extratos com 2,4 mL de DPPH (0,04 mg mL-1). Para o tubo controle foram utilizados 100 µL de etanol com 2,4 mL de DPPH em triplicata. O meio reacional ficou por 30 minutos na ausência da luz, e posteriormente foi realizada a leitura em comprimento de onda 515 nm. A atividade sequestradora do radical DPPH pelos extratos nas diferentes concentrações foi calculada pela expressão do índice de varredura em porcentagem (IV%): IV% = (Abs DPPH - Abs Amostra / Abs DPPH) x 100. A concentração efetiva para inibir 50% do radical livre DPPH (CE50) foi obtida com auxílio do Software Excel 2019, onde, a partir dos valores das concentrações finais da amostra e o índice de varredura (IV%), foram originados gráficos de dispersão cujas equações das retas foram utilizadas para se obter os valores da média e desvio padrão. Para fins de comparação, foi construída uma curva de calibração com diferentes porcentagens do flavonoide quercetina, que apresenta elevada atividade antioxidante em radical livre DPPH.

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      Avaliação da atividade anticolinesterásica in vitro - O ensaio para verificação da inibição da enzima acetilcolinesterase (AChE) dos extratos foi realizado de acordo com a metodologia descrita por Ellman et al. (1961Ellman, G.L., Courtney, K.D., Andres Jr, V. & Featherstone, R.M. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology: 7: 88-95.). Em placas estéreis de 96 poços, foram adicionados 25 µL de iodeto de acetiltiocolina (15 mM), 125 µL de 5,5’-ditiobis-[2-nitrobenzóico] na solução Tris/HCL (50 nM, pH 8, com 0,1 M de NaCL e 0,02 M de MgCL2 .6H2O. (3 mM, DTNB ou reagente de Ellman)), 50 µL da solução Tris/HCL (50 nM, pH 8, com 0,1% de albumina sérica bovina (BSA) e 25 µL dos extratos de Senna spp. na concentraçao de 0,2 mg.mL-1 em tampão Tris/HCL (50 mM, pH 8) de 0,2 mg.mL-1 (Rhee et al. 2001Rhee, I.K., van de Meent, M., Ingkaninan, K. & Verpoorte, R. 2001. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. Journal of Chromatography A 915: 217-223., Trevisan et al. 2003Trevisan, M.T.S., Macedo, F.V.V., Meent, M.V.D., Rhee, I.K. & Verpoorte, R. 2003. Seleção de plantas com atividade anticolinesterase para tratamento da doença de Alzheimer. Química Nova 26: 301-304.).

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      A absorbância foi aferida a 405 nm durante 30 segundos. Em seguida, foram adicionados 25 µL da enzima acetilcolinesterase (0,25 U.mL-1) e a absorbância foi aferida por minuto até o total de 25 minutos de incubação da enzima. Como padrão negativo foram utilizadas todas as soluções, excetuando-se a amostra. O padrão utilizado como controle positivo foi a fisostigmina (0,22 mg.mL-1.) e todas as amostras foram analisadas em triplicata. A atividade anticolinesterásica dos extratos vegetais foi determinada de acordo com os valores de CI50 (Concentração inibitória capaz de inibir 50% da enzima acetilcolinesterase) como: alta potência (CI50 < 20 μg. mL-1); potência moderada (20 < CI50 < 200 μg.mL-1) e baixa potência (200 < CI50 < 1000 μg.mL-1) (Santos et al. 2018Santos, G.H.F., Amaral, A. & Da Silva, E.B. 2018. Antibacterial activity of irradiated extracts of Anacardium occidentale L. on multiresistant strains of Staphylococcus aureus. Applied Radiation and Isotopes 140: 327-332.).

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      Ensaio antifúngico in vitro - No ensaio para verificação da concentração inibitória mínima (CIM) dos EE das espécies de Senna, foram utilizadas cepas de Trichophyton rubrum obtidas a partir da micoteca da Universidade Federal de Pernambuco e do Centro Especializado de Micologia Médica (CEMM) da Universidade Federal do Ceará. Para este ensaio foi utilizado o método de microdiluição em caldo, de acordo com a metodologia descrita por (Neves et al. 2019Neves, A.M., Silva, H.S., Souza, E.B., Fontenelle, R.O.S., Silva, A.C.S., Morais, S.M. 2019. Perfil fitoquímico e avaliação da atividade antifúngica da fração hexânica de Mitracarpus baturitensis (Rubiaceae). Essentia 20: 96-101. ) com as normas do protocolo Clinical Laboratory Standards Insitute do documento M38-A (CLSI M38-A2, 2008Clinical and Laboratory Standards Institute. 2008. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi (Approved Standard Document M38. CLSI), vol. M38-A2, Second ed. Clinical and Laboratory Standards Institute, Wayne, PA.). Em placas de 96 poços estéreis, foram adicionados 100 µL de meio RPMI em todos os poços e 10 mg mL-1 dos extratos de Senna spp. foi acrescentado a todos os poços da primeira coluna e, em sequência foram efetuadas as diluições seriadas. Finalmente, 100 µL do inóculo foi adicionado aos poços da placa. Como controle foi utilizado o Cetoconazol (Sigma, Chemical Co., USA). Para as análises de susceptibilidade, os extratos etanólicos foram testados em concentrações variando de 0,002 a 2,5 mg mL-1. As placas foram cobertas com parafilme e incubadas a 37 °C e a leitura visual foi realizada após cinco dias para T. rubrum. Procedimento realizado em duplicata. A CIM é definida como a menor concentração do extrato capaz de inibir 100% do crescimento fúngico visível (Fontenelle et al. 2007Fontenelle, R.O.S., Morais, S.M., Brito, E.H.S., Kerntopf, M.R., Brilhante, R.S.N., Cordeiro, R.A., Tomé, A.R., Queiroz, M.G.R., Nascimento, N.R.F. & Sidrim, J.J.C. 2007. Chemical composition, toxicological aspects and antifungal activity of essential oil from Lippia sidoides Cham. Journal of Antimicrobial Chemotherapy 59: 934-940. ). A concentração fungicida mínima (CFM) foi determinada por subcultura de 100 μL da solução de poços sem turbidez no meio Ágar Dextrose de Batata, a 28 °C. (Fontenelle et al. 2008Fontenelle, R.O.S., Morais, S.M., Brito, E.H.S., Brilhante, R.S.N., Cordeiro, R.A., Nascimento, N.R.F., Kerntopf, M.R., Sidrim, J.J.C. & Rocha, M.F.G. 2008. Antifungal activity of essential oils of Croton species from the Brazilian caatinga biome. Journal of Applied Microbiology 104: 1383-1390.).

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      Análise estatística - Todas as determinações foram realizadas em triplicata e todos os resultados foram apresentados como média ± desvio-padrão (DP). Foram realizadas análises de variância (ANOVA) com duas repetições e o Teste Tukey, ao nível de significância de 5%, usando programa Graph Pad Prism® v5.01 (GraphPadSoftware, San Diego, CA, E.U.A.). As diferenças entre as médias foram consideradas significativas quando o valor obtido para "p" foi menor que 0,05 (p < 0,05).

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      Para análises da correlação entre os dados, foi utilizado o coeficiente de correlação de Pearson no software Microsoft Excel 2019, a qual mede o grau da correlação linear entre duas variáveis quantitativas. A intensidade dessa correlação é dada pelo “r”, que é um índice adimensional com valores situados entre -1,0 e 1,0. Quando o valor de r estiver entre 0,00-0,19 a correlação é muito fraca; entre 0,20-0,39 é fraca; 0,40-0,59 é uma correlação moderada; entre 0,60-0,79 é forte e finalmente entre 0,80-1,0 diz-se que é uma correlação muito forte (Mukaka 2012Mukaka, M.M. 2012. Statistics corner: A guide to appropriate use of correlation coefficient in medical research. Malawi Med J. 24:69-71.).

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      Resultados e discussãoTabela 3 +

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      Os fito-constituintes ou fitoquímicos são compostos químicos que desempenham importantes funções nas plantas. A triagem fitoquímica em materiais vegetais é geralmente o ponto de partida para o isolamento e purificação de compostos naturais com bioatividade (Omoregie & Oikeh 2015Omoregie, E.S. & Oikeh, E.I. 2015. Comparative studies on the phytochemical composition, phenolic content and antioxidant activities of methanol leaf extracts of Spondias mombin and Polyathia longifolia. Jordan Journal of Biological Sciences 147: 1-5.). A triagem fitoquímica preliminar revelou a presença de fenóis, taninos, flavonoides e esteroides para todos os extratos estudados (Tabela 2). Entretanto, a presença de saponinas foi constatada apenas no EEF e EEC de S. alata e no EEF de S. trachypus. Já os alcaloides foram encontrados exclusivamente no EEF de S. alata e nenhuma das espécies apresentou triterpenoides.

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      +Tablela 2
      Triagem fitoquímica do EEF e do EEC de espécies de Senna Mill. (Fabaceae). Presente: + Ausente: - EEF: Extrato etanólico da folha. EEC: Extrato etanólico do caule.
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      Os metabólitos detectados nas espécies estudadas são consistentes com os metabólitos descritos na literatura para o gênero Senna, conhecido por apresentar flavonoides, alcaloides, taninos, esteroides e saponinas em sua composição (Onyegeme-Okerenta et al. 2017Onyegeme-Okerenta, B.M., Nwosu, T. & Wegwu, M.O. 2017. Proximate and phytochemical composition of leaf extract of Senna alata (L) Roxb. Journal of Pharmacognosy and Phytochemistry 6: 320-326., Ishaku et al. 2016Ishaku, G.A., Arabo, A.A., Bassey, E.E., Uwem, A.A.U.M. & Godwin, E.U. 2016. Physicochemical characterization and antibacterial activity of Senna occidentalis Linn. Journal of Chemistryand Chemical Sciences 6: 9-18. , Silva et al. 2014Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202., Sudi et al. 2011Sudi, I.Y., Ksgbiya, D.M., Muluh, E.K. & Clement, A. 2011. Nutritional and phytochemical screening of Senna obtusifolia indigenous to Mubi, Nigeria. Advances in Applied Science Research 2: 432-437., Bukar et al. 2009Bukar, A., Mukhtar, M. & HASSAN, A. 2009. Phytochemical screening and antibacterial activity of leaf extracts of Senna siamea (Lam) on Pseudomonas aeruginosa. Bayero Journal of Pure and Applied Sciences 1: 139-142. ). É possível perceber que na análise de prospecção química dos extratos houve uma variação de metabólitos secundários. Este fato pode estar atribuído a vários fatores, entre eles estão as diferentes condições ambientais, tais como clima, radiação solar, nutrição mineral, sazonalidade, ritmo circadiano, temperatura, disponibilidade hídrica, e também os tipos de solvente e a metodologia empregada no processo de extração, que podem interferir consideravelmente no conteúdo de praticamente todas as classes de metabólitos secundários (Gomes et al. 2016Gomes, E.M.C., Pena, R.D.C.M. & da Silva, S.S.S.M. 2016. Composição fitoquímica e ação fungicida de extratos brutos de Cinnamomum zeylanicum sobre Quambalaria eucalypti. Biota Amazônia. 6: 54-58., Bezerra et al. 2013Bezerra, A.S., Nörnberg, J.L., Lima, F.O., Rosa, M.B.D. & Carvalho, L.M.D. 2013. Parâmetros climáticos e variação de compostos fenólicos em cevada. Ciência Rural 9: 1546-1552., Gobbo-Neto & Lopes 2007Gobbo-Neto, L. & Lopes, N.P. 2007. Plantas medicinais: Fatores de influência no conteúdo de metabólitos secundários. Química Nova 30: 374-381.).

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      Os teores de fenóis totais apresentaram diferenças significativas entre os extratos etanólicos das diferentes partes e espécies vegetais estudadas (Tabela 3). O conteúdo de fenóis totais para os EEF variou de 32,60 ± 0,53 a 184,8 ± 5,09 EAG/g, enquanto que para o EEC foram de 30,03± 1,00 a 191,3 ± 0,47 EAG/g. Os maiores níveis de fenóis totais foram detectados na espécie S. trachypus. Os dados da literatura sobre o conteúdo de compostos fenólicos obtidos a partir do extrato aquoso, etanólico e acetona da raiz de S. alata, apresentaram uma concentração de fenóis de 46,3, 78,21 e 21,42 mg EAG/g, respectivamente, e de flavonoides de 26,17, 39,29 e 9,65 mg de equivalente de quercetina por grama de extrato (EQ/g), respectivamente (Ita & Ndukwe 2017Ita, B.N., & Ndukwe, G.I. Antioxidant activity of Senna alata root extracts. 2017. J Nat Prod Resour 3: 94-96. ). Já o extrato etanólico preparado a partir das folhas de S. obtusifolia por Ali et al. (2019Ali, I., Yisa, J. & Jacob, J.O. 2019. Corrosion inhibitory potential of ethanol extract of Senna obtusifolia on Mild Steel in 5M HCl. Journal of Chemical Society of Nigeria 44: 187-198. ), apresentou um teor de fenóis e de flavonoides de 14,39 mg/g e 2,85 mg/g, respectivamente, demonstrando possuir teor de compostos fenólicos inferior ao das mostras de S. obtusifolia encontradas no presente estudo. Além disso, o conteúdo de polifenóis encontrado no extrato etanólico e nas frações obtidas a partir das folhas de S. occidentalis por Yakubu et al. (2018Yakubu, O.E., Otitoju, O., Imarenezor, E.P.K., Tatah, S.V. & Habibu, B. 2018. Fractionation and determination of antioxidant activities, of the Leaves of Senna Occidentalis ethanol extract. Pharmacology, 6: 26-30.) variou de 139 mg/mL a 206 mg/mL e de flavonoides de 104 a 142 mg/mL. Já para os extratos preparados a partir das folhas e casca do caule de S. siamea revelaram um teor de fenóis totais de 10,21 ± 0,25 g/g e 24,77 ± 0,15 g/g, respectivamente. Por outro lado, o teor de flavonoides foi de 0,08 ± 0,01 g/g para as folhagens, e de 0,04 ± 0,01 g/g para a casca do caule (Kwada & Tella 2009Kwada, A.D. & Tella, I.O. 2009. Determination of infochemicals and the phytochemical screening of the foliage and stem-bark of Senna siamea (lam.) in Yola, Adamawa State. Journal of Medicinal Plants Research 3: 630-640.). Para os extratos etanólicos das folhas e raízes de S. trachypus o teor de fenóis totais encontrado foi de 322,09 ± 2,83 EAG/g e de 1277,34 ± 79,54 EAG/g, respectivamente (Silva et al. 2014Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202.).Senna.

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      Teor de fenóis totais, atividade antioxidante e inibição da enzima acetilcolinesterase de espécies de Senna Mill. (Fabaceae).
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      Os resultados da atividade antioxidante dos extratos de Senna spp. mostraram que os valores de CE50 para o EEF variaram de 0,63 ± 0,01 a 8,20 ± 0,07 µg/mL, sendo o EEF de S. trachypus o que apresentou menor CE50 com atividade antirradicalar superior ao da quercetina e, portanto, maior potencial antioxidante (Villano et al. 2007Villano, D., Fernandez-Pachón, M.S., Moya, M.L., Troncoso, A.M. & García-Parrilla, M.C. 2007. Radical scavenging ability of polyphenolic compounds towards DPPH free radical. Talanta, 71: 230-235. ). Já para o EEC os valores de CE50 variaram de 0,83 ± 0,01 a 11,19 ± 0,15 µg/mL (Tabela 3). Foi observado que o EEC de S. siamea apresentou capacidade antirradicalar próximo à quercetina. Semelhantes aos nossos resultados, estudos anteriores revelaram que as espécies de S. alata, S. obtusifolia, S. occidentalis, S. siamea e S. trachypus, apresentaram potencial antioxidante e que esta atividade está atribuída à presença de compostos fenólicos (Coelho et al. 2017Coelho, E.M.P., Barbosa, M.C., Mito, M.S., Mantovanelli, G.C., Oliveira, R.S., & Ishii-Iwamoto, E.L. 2017. The activity of the antioxidant defense system of the weed species Senna obtusifolia L. and its resistance to allelochemical stress. Journal of Chemical Ecology 7: 725-738., Ita & Ndukwe 2017Ita, B.N., & Ndukwe, G.I. Antioxidant activity of Senna alata root extracts. 2017. J Nat Prod Resour 3: 94-96. , Barnaby et al. 2016Barnaby, A.G., Reid, R. & Warren, D. 2016. Antioxidant activity, total phenolics and fatty acid profile of Delonix regia, Cassia fistula, Spathodea campanulata, Senna siamea and Tibouchina granulosa. J Anal Pharm Res 3: 00056., Odeja et al. 2015Odeja, O., Obi, G., Ogwuche, C.E., Elemike, E.E. & Oderinlo, Y. 2015. Phytochemical Screening, Antioxidant and Antimicrobial activities of Senna occidentalis (L.) leaves Extract. Clinical Phytoscience 1: 1-6., Silva et al. 2014Silva, G.A., Monteiro, J.A., Ferreira, E.B., Fernandes, M.I.B., Pessoa, C.; Sampaio, C.G. & Silva, M.G.V. 2014. Total phenolic content, antioxidant and anticancer activities of four species of Senna Mill. From northeast Brazil. Int. J. Pharm. Pharm. Sci 6: 199-202.).

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      Os resultados obtidos na análise de inibição da enzima acetilcolinesterase foram comparados ao do alcaloide fisostigmina que foi o primeiro inibidor descoberto. Os experimentos de inibição da enzima acetilcolinesterase in vitro para as espécies de Senna produziram apenas resultados com potência moderada (Tabela 3). Relatos confirmam a atividade antiacetilcolinesterásica de vários taninos isolados do fruto Terminalia chebula Retz., (Combretaceae) que exibiram um efeito de inibição contra a enzima acetilcolinesterase in vitro (Kim et al. 2018Kim, M.S., Lee, D.Y., Sung, S.H. & Jeon, W.K. 2018. Anti-cholinesterase activities of hydrolysable tannins and polyhydroxytriterpenoid derivatives from Terminalia chebula Retz. fruit. Fruit Rec Nat Prod 12: 284-289.). Outros compostos, como saponinas, alcaloides e compostos fenólicos, também são relatados na literatura como inibidores da enzima acetilcolinesterase (Paiva et al. 2021Paiva, J.R., Queiroz, S.A.S., Pereira, R.D.C.A., Ribeiro, P.R.V., Alves, F.E.G., Silva, L.M.A., Zocolo, G.J., Brito, E.S., Alves, D.R., Morais, S.M., Tavares, J., Pinto, F.C.L., Andrade, G.M., Pessoa, O.D.L., & Canuto, K.M. 2021. Chemical composition and anticholinesterase activity of cultivated bulbs from Hippeastrum elegans, a potential tropical source of bioactive alkaloids. Phytochemistry Letters 43: 27-34., Kozachok et al. 2020Kozachok, S., Pecio, Ł., Orhan, I.E., Deniz, F.S.S., Marchyshyn, S., & Oleszek, W. 2020. Reinvestigation of Herniaria glabra L. saponins and their biological activity. Phytochemistry 169: 112162., Adedayo et al. 2015Adedayo, B.C., Oboh, G., Oyeleye, S.I., Ejakpovi, I.I., Boligon, A.A., & Athayde, M.L. 2015. Blanching alters the phenolic constituents and in vitro antioxidant and anticholinesterases properties of fireweed (Crassocephalum crepidioides). Journal of Taibah University Medical Sciences 10: 419-426.). Estas classes de compostos foram detectadas na triagem fitoquímica, embora provavelmente as concentrações nos extratos eram muito baixas para dar resultados satisfatórios no ensaio. Os extratos foliares e do caule de S. trachypus apresentaram os valores mais satisfatórios de inibição da enzima acetilcolinesterase, indicando que o isolamento de metabólitos pode levar a potenciais agentes antiacetilcolinesterásicos. Na literatura, não foram encontrados estudos do potencial anticolinesterásico paras as espécies de Senna referenciadas, sendo este o primeiro relato de estudo de atividade de inibição para esta enzima.

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      Para os extratos de Senna spp., foi observada forte correlação negativa entre os valores de fenóis totais e CE50 (r = - 0,71), mostrando que quanto maior os teores de fenóis totais, menor a CE50 e, consequentemente, maior o potencial antioxidante, uma vez que a CE50 está inversamente relacionada à capacidade antioxidante de um composto (Villano et al. 2007Villano, D., Fernandez-Pachón, M.S., Moya, M.L., Troncoso, A.M. & García-Parrilla, M.C. 2007. Radical scavenging ability of polyphenolic compounds towards DPPH free radical. Talanta, 71: 230-235. ). Dentre os extratos analisados podemos observar na figura 1 o EEF de S. trachypus.

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      Correlação entre o teor de fenóis totais e CE50 de espécies de Senna Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule.
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      Na correlação da atividade de inibição da enzima acetilcolinesterase, representada pelo CI50 com teor de fenóis totais, observou-se uma correlação muito forte (r = -0,84) entre estas duas variáveis, evidenciando que ambas são inversamente proporcionais entre si, ou seja, à medida que o teor de fenóis totais aumenta o valor de CI50 diminui, como pode ser observado para o EEF de S. occidentalis (Figura 2). Isso demonstra que os compostos fenólicos podem ser determinantes nessa atividade, de modo que alguns estudos evidenciaram que flavonoides e outros compostos fenólicos possuem atividade anticolinesterásica (Amessis-Ouchemoukh et al. 2014Amessis-Ouchemoukh, N., Madani, K., Falé, P.L., Serralheiro, M.L., Araújo, M.E.M. 2014. Antioxidant capacity and phenolic contents of some Mediterranean medicinal plants and their potential role in the inhibition of cyclooxygenase-1 and acetylcholinesterase activities. Industrial Crops and Products, 53: 6-15.).

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      +Figura 2.
      Correlação entre o teor de fenóis totais e CI50 de espécies de Senna Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule.
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      Houve uma correlação moderada (r = 0,43) entre a CI50 e a CE50. Analisando a figura 3, é possível perceber que o EEF e EEC de S. alata e EEF de S. obtusifolia se destacam no gráfico, o que sugere uma grande capacidade dos antioxidantes, como os compostos fenólicos, presentes nos extratos analisados, de atuarem não só através da inibição da acetilcolinesterase (AChEI) mas também por mecanismos de redução de radicais livres.

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      Correlação entre CI50 e a CE50 de espécies de Senna Mill. (Fabaceae). Símbolos cheios: folhas. Símbolos vazados: caule.
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      Os extratos etanólicos das folhas e caule de S. alata, S. obtusifolia, S. occidentalis e S. siamea, apresentaram efeito inibitório contra algumas cepas de T. rubrum. A maioria dos extratos foram eficazes em diferentes concentrações, com CIM que variaram de 0,07 mg/mL à 2,5 mg/mL e CFM de 0,15 a 5,0 mg/mL contra a grande maioria das cepas fúngicas testadas. Dentre os extratos testados, os de S. trachypus foram eficazes contra todas as cepas de T. rubrum com CIM que variaram de 0,31 a 0,62 mg/mL e o CFM de 0,62 a 1,25 mg/mL, para ambos os extratos (Tabela 4). A presença de compostos fitoquímicos tem sido associada às atividades antimicrobianas da maioria dos materiais vegetais. Algumas classes de metabólitos foram identificadas nesse estudo e podem ser associadas à atividade antimicrobiana (Santos et al. 2018Santos, T.C.D., Gomes, T.M., Pinto, B.A.S., Camara, A.L. & Paes, A.M.D.A. 2018. Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer's disease therapy. Frontiers in Pharmacology 9: 1192., Odeja et al. 2015Odeja, O., Obi, G., Ogwuche, C.E., Elemike, E.E. & Oderinlo, Y. 2015. Phytochemical Screening, Antioxidant and Antimicrobial activities of Senna occidentalis (L.) leaves Extract. Clinical Phytoscience 1: 1-6.).

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      +Tabela 4.
      Concentração Inibitória Mínima (CIM) e Concentração Fungicida Mínima (CFM) de extratos etanólicos (EEs) de espécies de Senna Mill. (Fabaceae) frente às espécies de Trichophyton rubrum. LABIMIC: Laboratório de Microbiologia; EEF: Extrato etanólico da folha; EEC: Extrato etanólico do caule; NI: Não inibiu.
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      Estudos anteriores realizados com o extrato etanólico da casca do caule de S. alata contra fungos dermatofíticos, entre eles espécies de Trychophyton, revelou um CIM de 5,0 mg/mL para todos os dermatófitos testados (Sule et al. 2011Sule, W.F., Okonko, I.O., Omo-Ogun, S., Nwanze, J.C., Ojezele, M.O., Ojezele, O.J., Alli, J.A., Soyemi, E.T. & Olaonipekun, T.O. 2011. Phytochemical properties and in-vitro antifungal activity of Senna alata Linn. crude stem bark extract. Journal of Medicinal Plants Research, 5: 176-183.). A capacidade antifúngica de extratos de diferentes polaridades preparados a partir das folhas de S. obtusifolia apresentaram um CIM que variou de 500 a 2000 µg/mL contra diferentes espécies de fungos filamentosos (Doughari et al. 2008Doughari, J.H., El-mahmood, A.M. & Tyoyina, I. 2008. Antimicrobial activity of leaf extracts of Senna obtusifolia (L). African Journal of Pharmacy and Pharmacology 2: 7-13.). Os resultados obtidos de extratos foliares de polaridades diferentes de S. occidentalis revelaram que o extrato metanólico mostrou maior atividade antifúngica entre os demais extratos testados, em uma concentração inibitória mínima de 25 mg/mL (Odeja et al. 2015Odeja, O., Obi, G., Ogwuche, C.E., Elemike, E.E. & Oderinlo, Y. 2015. Phytochemical Screening, Antioxidant and Antimicrobial activities of Senna occidentalis (L.) leaves Extract. Clinical Phytoscience 1: 1-6.). Testes utilizando extratos preparados com solventes de diferentes polaridades a partir das folhas de S. siamea apresentaram CIM que variaram de 0,032 a 0,128 mg/mL contra o fungo Cryptococcus gattii (Nnadi et al. 2019Nnadi, N.E., Anukam, N.C., Ayika, P.D., Rotdung, K., Gokum, S.S., Ayanbimpe, G.M., Nvau, J. & Enweani, I. 2019. The in Vitro antifungal activity of some Nigeria medicinal plants against Cryptococcus gattii. IOSR Journal of Pharmacy 9: 16-24. ). Na literatura, não foram encontrados estudos do potencial antifúngico para a espécie de S. trachypus, sendo este o primeiro registro de atividade antifúngica para a referida espécie.

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      Pesquisas têm revelado que o potencial antifúngico de extratos vegetais está intimamente relacionado, entre outros fatores, com as suas variações quantitativas de compostos fenólicos, dentre eles os flavonoides. Nosso estudo confirmou que as espécies estudadas possuem propriedades antifúngicas, e que seus efeitos sobre os dermatófitos fundamentam-se em seus teores de compostos fenólicos encontrados, e os demais outros metabólitos secundários aqui não estudados. Os efeitos antifúngicos atribuídos aos compostos fenólicos podem resultar na ruptura da membrana celular, ou ainda, inibir a divisão celular e o desenvolvimento das hifas por meio de genes específicos, além de interferir nas vias metabólicas e/ou induzir a apoptose por perturbar a homeostase redox (Lagrouh et al. 2017Lagrouh, F., Dakka, N. & Bakri, Y. 2017.The antifungal activity of Moroccan plants and the mechanism of action of secondary metabolites from plants. Journal de Mycologie Medicale 27: 303-311., Mohamed et al. 2017Mohamed, M.S., Saleh, A.M., Abdel-Farid, I.B. & El-Naggar, S.A. 2017. Growth, hydrolases and ultrastructure of Fusarium oxysporum as affected by phenolic rich extracts from several xerophytic plants. Pesticide Biochemistry and Physiology 141: 57-64. ).

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      Foram detectados, nos EEF e EEC das espécies de Senna, a presença de metabólitos secundários, alto teor de fenóis totais e capacidade antioxidante para todas as espécies, em especial S. trachypus. Para a atividade anticolinesterase apenas a espécie de S. trachypus manifestou uma melhor ação inibitória. Nas condições experimentais utilizadas, evidenciou-se atividade antifúngica das espécies frente a maioria dos dermatófitos testados, em especial os extratos de S. trachypus. Foi observada também correlação forte, muito forte e moderada entre as variáveis fenóis totais e atividade antioxidante, fenóis totais e antiacetilcolinesterase e atividade antioxidante e antiacetilcolinesterase, respectivamente. Os resultados apontam que S. trachypus, espécie endêmica da Caatinga, é a mais promissora entre todas as plantas estudadas, representando uma fonte potencial para a obtenção de compostos químicos úteis para estudos clínicos e farmacológicos, visando o desenvolvimento de novos agentes farmacológicos naturais.

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      Agradecimentos

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      Os autores agradecem a Universidade Estadual do Ceará (UECE) e a Universidade Estadual Vale do Acaraú (UVA) pelo apoio técnico, e a Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) pelo apoio financeiro concedido (processos PBI3-0139-00252.01.00/18; BP4-0172-00170.01.00/20).

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      Literatura citada

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        • +
      • Amessis-Ouchemoukh, N., Madani, K., Falé, P.L., Serralheiro, M.L., Araújo, M.E.M. 2014. Antioxidant capacity and phenolic contents of some Mediterranean medicinal plants and their potential role in the inhibition of cyclooxygenase-1 and acetylcholinesterase activities. Industrial Crops and Products, 53: 6-15.
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      Datas de Publicação

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      • +Publicação nesta coleção
        21 Fev 2022
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      • +Data do Fascículo
        2022
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      Histórico

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      • +Recebido
        14 Out 2020
        • +
      • +Aceito
        03 Dez 2021
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      +
      +
      Creative Common - by 4.0
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* Article\n */\n@import \"../../common/scss/itcssImports/vars\";\n@import \"../../common/scss/itcssImports/mixins\";\n\n\n\n \n\n .article {\n\t.zindexFix {\n\t\tz-index: 98 !important;\n\t}\n\n\n\n /*\n\t.copyLink{\n\t\tposition: relative;\n\n\t\t[class^=\"sci-ico-\"] {\n\t\t\tfont-size: 24px;\n\t\t\t//color: $Blue;\n\t\t}\n\n\t\t&:after {\n\t\t\tposition: absolute;\n\t\t\tbackground: #34ad65;\n\t\t\ttop: 100%;\n\t\t\tleft: 0;\n\t\t\tright: 0;\n\t\t\tbottom: 0;\n\t\t\tz-index: 2;\n\t\t\ttext-align: center;\n\t\t\tfont-family: 'scielo-glyphs' !important;\n\t\t\tcontent: \"\\e924\";\n\t\t\tcolor: #fff;\n\t\t\tfont-size: 20px;\n\t\t\tvisibility: hidden;\n\t\t\tvertical-align: middle;\n\n\t\t\tdisplay: flex;\n\t\t\tjustify-content: center;\n\t\t\talign-items: center;\n\t\t\t//.cssAnimations @include animated(.3s,all);\n\t\t}\n\n\t\t&.copyFeedback:after {\n\t\t\ttop: 0;\n\t\t\tvisibility: visible;\n\t\t}\n\t}\n */\n\n\ta.goto {\n\t\twhite-space: nowrap;\n\t\ttext-decoration: none;\n\n\t\t.glyphBtn {\n\t\t\tmargin-right: -5px;\n\t\t}\n\t}\n\n\t.levelMenu {\n\t\tpadding: 18px 0;\n\t\tmargin: 0;\n\t\theight: 100px;\n\t\tbackground: #efeeec;\n\n\t\ta.selected:after {\n\t\t\tborder-bottom-color: #fff;\n\t\t\tdisplay: none;\n\t\t}\n\t}\n\n\t.levelMenu .downloadOptions {\n\t\tul,li {\n\t\t\tdisplay: inline;\n\t\t\tmargin: 0;\n\t\t\tpadding: 0;\n\t\t}\n\t\tli {\n\t\t\tlist-style: none;\n\t\t}\n\t\tul.dropdown-menu {\n\t\t\tdisplay: none;\n\t\t\tmin-width: inherit;\n\t\t\twidth: 100%;\n\t\t\tborder-color: #dedddb;\n\t\t\tfont-size: .9em;\n\t\t\tborder-top-left-radius: 0;\n\t\t\tborder-top-right-radius: 0;\n\t\t\tborder-top: 0;\n\t\t}\n\t\t.group:hover {\n\t\t\tul.dropdown-menu {\n\t\t\t\tdisplay: block;\n\t\t\t}\n\t\t\ta.btn {\n\t\t\t\t//background: $Blue !important;\n\t\t\t\tcolor: #fff;\n\n\t\t\t\t.glyphBtn.pdfDownload {\n\t\t\t\t\tbackground-position: center -2800px;\n\t\t\t\t}\n\t\t\t\t.glyphBtn.xmlDownload {\n\t\t\t\t\tbackground-position: center -2845px;\n\t\t\t\t}\n\t\t\t\t.glyphBtn.epubDownload {\n\t\t\t\t\tbackground-position: center -3700px;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t\t.btn-group .group:not(:first-child):not(:last-child) .btn {\n\t\t\tborder-radius: 0;\n\t\t}\n\t\t.btn-group .group:first-child:not(:last-child) .btn { \n\t\t\tborder-bottom-right-radius: 0;\n\t\t\tborder-top-right-radius: 0;\n\t\t}\n\t\t.btn-group .group:first-child:not(:last-child) .btn {\n\t\t\tborder-bottom-right-radius: 0;\n\t\t\tborder-top-right-radius: 0;\n\t\t}\n\t\t.btn-group .group:last-child:not(:first-child) .btn {\n\t\t\tborder-bottom-left-radius: 0;\n\t\t\tborder-top-left-radius: 0;\n\t\t}\n\t\t.group {\n\t\t\t/*width: 25%;*/\n\t\t\tdisplay: block;\n\t\t\tfloat: left;\n\t\t\tposition: relative;\n\n\t\t\ta.btn {\n\t\t\t\twidth: 100%;\n\t\t\t}\n\t\t}\n\t\t.group + .group {\n\t\t\tmargin-left: -1px;\n\t\t}\n\t\t.btn {\n\t\t\ttext-align: left;\n\t\t}\n\t}\n\n\t.share {\n\t\tdisplay: flex;\n\t\tjustify-content: flex-end;\n\t\talign-items: center;\n\t\theight: 36px;\n\n\t\ta {\n\t\t\tmargin: 0 3px;\n\t\t}\n\n\t\t.sendViaMail {\n\t\t\tmargin-left: 4px;\n\t\t}\n\t}\n\n\t.journalMenu {\n\t\t.language {\n\t\t\ttop: 10px;\n\t\t}\n\t}\n\n\t.alternativeHeader {\n\t\ttop: 0 !important;\n\n\t\t.mainNav {\n\t\t\theight: 55px;\n\t\t}\n\t}\n\n\t.mainNav {\n\t\theight: 55px;\n\t}\n\n\t.mainMenu {\n\t\ttop: -7px;\n\t}\n\n\t.xref {\n\t\tdisplay: inline-block;\n\t\tfont-weight: bold;\n\t\ttext-align: center;\n\t\t//color: $Blue;\n\t\tcursor: pointer;\n\n\t\t&::selection {\n\t\t\t//background: $BlueHover;\n\t\t}\n\t\t&.big {\n\t\t\tmargin-top: 0px;\n\t\t\tvertical-align: middle;\n\t\t\tfont-size: 12px;\n\t\t}\n\n \n\t}\n\n\tsup.xref {\n\t\tpadding: 4px 0 3px;\n\t\tfont-size: 11px;\n\n /*\n\t\t@media $maxTablet2 {\n\t\t\tpadding: 10px;\n\t\t}\n */\n\t}\n\n\t.ref {\n\t\tposition: relative;\n\t\tdisplay: inline;\n\t\t//font-size: 13px;\n\n\t\t@include __breakpoint--xsmall-only() {\n\t\t\tposition: static;\n\t\t}\n\n /*\n\t\t@media $maxTablet {\n\t\t\tposition: static;\n\t\t}\n */\n\n\t\t.refCtt {\n\t\t\t//.cssAnimations @include slideInUp(.3s);\n\t\t\t-webkit-box-shadow: 2px 2px 7px 0px rgba(0,0,0,0.2);\n\t\t\t-moz-box-shadow: 2px 2px 7px 0px rgba(0,0,0,0.2);\n\t\t\tbox-shadow: 2px 2px 7px 0px rgba(0,0,0,0.2);\n\t\t}\n\n\t\t.closed {\n\t\t\tdisplay: none;\n\t\t}\n\n\t\t.opened {\n\t\t\tmargin-top: 1.4em;\n\t\t\tpadding: 14px;\n\t\t\tposition: absolute;\n\t\t\twidth: 350px;\n\t\t\theight: auto !important;\n\t\t\toverflow-y: inherit !important;\n\t\t\toverflow-x: hidden;\n\t\t\ttext-overflow: ellipsis;\n border-radius: 4px;\n\t\t\t//color: #fff;\n\t\t\t//background: $Blue;\n\t\t\t//@include radius(4px);\n\t\t\t////@include border-box;\n\t\t\tz-index: 99;\n\n background: $__interaction--light;\n color: $__white;\n\n\t\t\t@include __breakpoint--xsmall-only() {\n\t\t\t\twidth: 90%;\n\t\t\t}\n\n @include __on-theme--dark {\n background: $__interaction--dark;\n color: $__bg--dark;\n outline: 2px solid red !important;\n }\n @include __on-theme--light {\n background: $__interaction--light;\n color: $__white;\n }\n\n /*\n\t\t\t@media $maxTablet {\n\t\t\t\twidth: 100%;\n\t\t\t\tdisplay: inline-block;\n\t\t\t\tleft:0 !important;\n\t\t\t}\n */\n\n\t\t\t&:before {\n\t\t\t\tcontent: '';\n\t\t\t\tdisplay: block;\n\t\t\t\twidth: 100%;\n\t\t\t\tposition: absolute;\n\t\t\t\theight: 0.6em;\n\t\t\t\tmargin-top: -1.6em;\n\t\t\t\tbackground: transparent;\n\t\t\t\tleft: 0;\n\t\t\t}\n\n\t\t\ta {\n\t\t\t\tcolor: #fff !important;\n\n\t\t\t\t&:hover {\n\t\t\t\t\ttext-decoration: underline;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\tstrong {\n\t\t\t\tdisplay: block;\n\t\t\t\tmargin: 0 0 5px;\n\t\t\t}\n\n\t\t\t.source {\n\t\t\t\tdisplay: block;\n\t\t\t\tmargin-top: 5px;\n\t\t\t}\n\n\t\t\t.refOverflow {\n\t\t\t\toverflow-x: hidden;\n\t\t\t\ttext-overflow: ellipsis;\n\t\t\t}\n\t\t}\n\n\t\t&.footnote {\n\t\t\tletter-spacing: 0;\n\n\t\t\t.xref {\n\t\t\t\tcolor: darken(#fef5e8,40%);\n\n\t\t\t\t&.xrefblue {\n\t\t\t\t\t//color: $Blue;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t.refCtt {\n\t\t\t\tpadding: 0;\n\n\t\t\t\t.refCttPadding {\n\t\t\t\t\tdisplay: block;\n\t\t\t\t\tpadding: 14px;\n\t\t\t\t}\n\n\t\t\t\t&.opened {\n\t\t\t\t\tbackground: #fef5e8;\n\t\t\t\t\tborder: 1px solid darken(#fef5e8,10%);\n\t\t\t\t\t//color: $Gray;\n\n\t\t\t\t\ta {\n\t\t\t\t\t\t//color: $Blue !important;\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t.fn-title {\n\t\t\t\tdisplay: block;\n\t\t\t\ttext-transform: uppercase;\n\t\t\t\tcolor: darken(#fef5e8,40%);\n\t\t\t}\n\t\t\t.footref {\n\t\t\t\t//color: $Blue;\n\t\t\t\tcursor: default;\n\t\t\t}\n\n\t\t\t.smallRef {\n\t\t\t\tfont-size: 1em;\n\t\t\t\tposition: relative;\n\t\t\t\tdisplay: block;\n\t\t\t\tpadding: 14px;\n\t\t\t\twidth: 100%;\n\t\t\t\tcolor: #fff;\n\t\t\t\t//background: $Blue;\n\t\t\t\tborder: 0;\n\t\t\t\tborder-radius: 0;\n\t\t\t\t//@include border-box;\n\n\t\t\t\t&:last-child {\n\t\t\t\t\t//border-top: 1px solid $BlueHover;\n\t\t\t\t}\n\n\t\t\t\t.xref {\n\t\t\t\t\tposition: absolute;\n\t\t\t\t\ttop: 12px;\n\t\t\t\t\t//color: $White;\n\t\t\t\t\tcursor: default;\n\n\t\t\t\t\t&:first-child {\n\t\t\t\t\t\tfont-size: 11px !important;\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\t.footrefCtt {\n\t\t\t\t\tdisplay: block;\n\t\t\t\t\tpadding-left: 14px;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t}\n\n\t.refList {\n\t\tmargin: 0;\n\t\tpadding: 0;\n\t\tfont-size: .8em;\n\t\t//color: $Gray;\n\t\tmargin-top: -10px;\n\t\twidth: 100%;\n\n\t\t* {\n line-height: 130%;\n\t\t\t\n\t\t}\n \n [class^=\"material-icons\"], [class*=\" material-icons\"] {\n line-height: 1;\n }\n\t\ta {\n\t\t\tdisplay: block;\n\t\t\t//color: $Gray;\n\t\t\toverflow-x: hidden; \n\t\t\ttext-overflow: ellipsis;\n\n\t\t\t&:hover {\n\t\t\t\t//color: $Blue;\n\t\t\t}\n\t\t}\n\t\t&.outer {\n\t\t\tpadding-bottom: 10px;\n\t\t\toverflow: hidden;\n\t\t\t-webkit-box-shadow: inset 0px -7px 7px -7px rgba(0, 0, 0, 0.2);\n\t\t\tbox-shadow: inset 0px -7px 7px -7px rgba(0, 0, 0, 0.2);\n\t\t}\n\t\t&.full {\n\t\t\tposition: absolute;\n\t\t\theight: auto !important;\n\t\t\toverflow: inherit !important;\n\t\t\tbackground: #fff;\n\t\t\tz-index: 99;\n\t\t\t//@include border-box;\n\t\t\tpadding-bottom: 0;\n\n\t\t\t-webkit-box-shadow: 0px 0px 10px 0px rgba(0, 0, 0, 0.2);\n\t\t\tbox-shadow: 0px 0px 10px 0px rgba(0, 0, 0, 0.2);\n\t\t}\n\t\tli {\n\t\t\tlist-style: none;\n\t\t\t//background: url(../img/dashline.png) bottom left repeat-x;\n\t\t\tpadding: 14px 7px;\n\t\t\tmargin: 0;\n\t\t\twidth: 100%;\n\n\t\t\tborder-bottom: 1px dotted $__border--light;\n\n\t\t\t@include __on-theme--dark {\n\t\t\t\tborder-bottom: 1px dotted $__border--dark;\n\t\t\t}\n\n\t\t\t@include __on-theme--light {\n\t\t\t\tborder-bottom: 1px dotted $__border--light;\n\t\t\t} \n\n\t\t\t&:last-child {\n\t\t\t\tbackground: none;\n\t\t\t\tborder: none;\n\t\t\t}\n\n\t\t\t&:after {\n\t\t\t\tcontent: '';\n\t\t\t\tclear: both;\n\t\t\t\tdisplay: block;\n\t\t\t\theight: 1px;\n\t\t\t\tfloat: none;\n\t\t\t\twidth: 100%;\n\t\t\t}\n\n\t\t\t/*.opened {\n\t\t\t\tdisplay: none;\n\t\t\t}*/\n\t\t\t&.highlight {\n\t\t\t\tbackground-color: #f0f3fb;\n\n\t\t\t\t.closed {\n\t\t\t\t\tdisplay: none;\n\t\t\t\t}\n\t\t\t\t.opened {\n\t\t\t\t\tdisplay: inline-block;\n\t\t\t\t}\n\t\t\t}\n\t\t\tstrong {\n\t\t\t\tdisplay: block;\n\t\t\t\tmargin: 0 0 10px;\n\t\t\t}\n\t\t}\n\t\tsup {\n\t\t\tborder-radius: 30px;\n\t\t}\n\t\t.source {\n\t\t\tfont-style: italic;\n\t\t}\n\t\t/*.closed, .opened {\n\t\t\tmargin-left: 2%;\n\t\t\twidth: 85%;\n\t\t\tdisplay: inline-block;\n\t\t\tvertical-align: top;\n\t\t}\n\t\t.closed {\n\t\t\tfont-weight: bold;\n\n\t\t\t.source {\n\t\t\t\tfont-weight: normal;\n\t\t\t\tmargin-top: 3px;\n\t\t\t\ttext-align: right;\n\t\t\t}\n\t\t}\n\t\t.opened {\n\t\t\t.source {\n\t\t\t\tmargin-top: 10px;\n\t\t\t}\n\t\t}*/\n\n\t\t&.footnote {\n\t\t\t.xref.big {\n\t\t\t\tcolor: darken(#fef5e8,40%);\n\n\t\t\t\t&.xrefblue {\n\t\t\t\t\t//color: $Blue;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t}\n\n\t.ref-list {\n\n\t\t.refList {\n\n\t\t\t.xref.big {\n\t\t\t\twidth: 33px;\n\t\t\t\tpadding: 5px 10px;\n\t\t\t\tcursor: default;\n\t\t\t\tposition: absolute;\n\t\t\t\tleft: 0;\n\t\t\t\ttop: 0;\n\t\t\t\tmargin-top: 1%;\n\t\t\t}\n\n\t\t\t.refCtt.opened {\n\t\t\t\tmargin-top: 1.4em;\n\t\t\t}\n\n\t\t\tli {\n\t\t\t\tposition: relative;\n\t\t\t\tpadding-left: 30px;\n\t\t\t\ttext-overflow: ellipsis;\n\t\t\t\tz-index: 1;\n\n\t\t\t}\n\n\t\t\tdiv {\n\t\t\t\tdisplay: block;\n\t\t\t\tmargin: -2px 0 0 1%;\n\t\t\t\tfont-size: 1.2em;\n\n\t\t\t\t//quebra linha de link\n\t\t\t\toverflow-wrap: break-word;\n\t\t\t\tword-wrap: break-word;\n\t\t\t\t-ms-word-break: break-all;\n\t\t\t\tword-break: break-all;\n\t\t\t\tword-break: break-word;\n\t\t\t\t-ms-hyphens: auto;\n\t\t\t\t-moz-hyphens: auto;\n\t\t\t\t-webkit-hyphens: auto;\n\n\t\t\t\tstrong {\n\t\t\t\t\tdisplay: inline;\n\t\t\t\t}\n\t\t\t}\n\t\t\ta {\n\t\t\t\t//color: #00e;\n\n /*\n color: $__interaction--light;\n\n @include __on-theme--dark {\n color: $__interaction--dark;\n }\n\n @include __on-theme--light {\n color: $__interaction--light;\n } \n */\n\t\t\t}\n\t\t}\n\n\t\t.refList.footnote{\n\t\t\tli{\n\t\t\t\tpadding: 0 7px 0 0;\n\n\t\t\t\t.xref.big{\n\t\t\t\t\tposition: static;\n\t\t\t\t\twidth: auto;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t}\n}\n\n.articleCtt {\n\t//background: #f7f6f5;\n \n\n background: $__bg__gray--1;\n\n @include __on-theme--dark {\n background: $__bg__white--1;\n }\n\n @include __on-theme--light {\n background: $__bg__gray--1;\n }\n \n\n\thr {\n\t\tborder: 0;\n\t\tbackground: url(../img/dashline.png) bottom left repeat-x;\n\t\theight: 1px;\n\t\tmargin: 50px 0;\n\t}\n\n\t.sci-ico-fileFigure, .sci-ico-fileTable, .sci-ico-fileFormula {\n\t\tfont-size: 22px;\n\n\t\t&:before {\n\t\t\tmargin-left: -2px;\n\t\t\tmargin-right: -4px;\n\t\t}\n\t}\n\n\t.open-asset-modal {\n\t\twhite-space: nowrap;\n\t}\n\n\t.container {\n\t\tposition: relative;\n\t}\n\n\t.articleBlock {\n\t\th1 {\n\t\t\tmargin: 0;\n\t\t\tfont-size: 1.9em;\n\t\t\t//color: $DarkBlue;\n\t\t}\n\t\ta {\n\t\t\t//color: #0000ee;\n\n\n\n\t\t\t&:active, &:focus, &:visited {\n\t\t\t\ttext-decoration: none;\n\t\t\t}\n\t\t}\n\t}\n\n\t.editionMeta, .articleMeta {\n\t\ttext-align: center;\n\t\tfont-size: .85em;\n\n\t\tspan {\n\t\t\tfont-size: 1em;\n\t\t\tmargin: 0;\n\t\t\tfont-weight: normal;\n\t\t\tcolor: #a7a49e;\n\t\t}\n\n\t\t.atricleLink {\n\t\t\twidth: 18px;\n\t\t\tbackground-position: center -2576px;\n\t\t}\n\t}\n\n\t.articleMeta {\n\t\tline-height: 24px;\n\n\t\t.sci-ico-public-domain,\n\t\t.sci-ico-cr {\n\t\t\tfont-size: 21px;\n\t\t\t//color: $Gray;\n\t\t}\n\n\t\tlabel {\n\t\t\tmargin-left: 8px;\n\t\t\twidth: 10%;\n\t\t\tborder: 1px solid #e0e0df;\n\t\t\t//@include radius(4px);\n\t\t\tcursor: pointer;\n\t\t}\n\n\t\tdiv {\n\t\t\tdisplay: inline;\n\n\t\t\t&:first-child {\n\t\t\t\tmargin-right: 60px;\n\t\t\t}\n\t\t}\n\n\t\t.doi {\n\t\t\tcolor: #1b92e4;\n\t\t}\n\t}\n\n\t.license {\n\t\t$size: 44px;\n\t\t$letterSpacing: $size*0.37;\n\t\t$nLetterSpacing: ($letterSpacing - (2*$letterSpacing));\n\n\n\t\tletter-spacing: $nLetterSpacing;\n\t\tvertical-align: middle;\n\t\tline-height: $size;\n\t\twhite-space: nowrap;\n\t\tdisplay: inline-block;\n\t\tmargin-bottom: 5px;\n\t\tcursor: pointer;\n\n\t\t[class^=\"sci-ico-\"], [class*=\" sci-ico-\"] {\n\t\t\t//color: $Blue;\n\t\t\t//.cssAnimations .animated (.5s,all);\n\t\t\tcursor: pointer;\n\t\t\tfont-size: $size;\n\n\t\t\t&.sci-ico-cc {\n\t\t\t\tmargin-right: 4px;\n\t\t\t}\n\t\t}\n\n\t\t&:hover {\n\t\t\t[class^=\"sci-ico-\"], [class*=\" sci-ico-\"] {\n\t\t\t\t//color: $Blue;\n\t\t\t}\n\t\t}\n\t}\n\n /*\n\t.copyLink {\n\t\tpadding: 5px 10px 5px 5px;\n\t\tcolor: #1b92e4;\n\t\tfont-weight: normal;\n\t\ttext-transform: uppercase;\n \t\tfont-size: 10px;\n \t\tcursor: pointer;\n\t\tborder: 1px solid #e0e0df;\n\t\tmargin-right: 15px;\n\t\t//@include radius(4px);\n\n\t\t&:focus {\n\t\t\ttext-decoration: none;\n\t\t}\n\t}\n */\n\n \n\t.contribGroup {\n\t\tcolor: #403d39;\n\t\tmargin: 15px 10%;\n\t\tfont-size: 1.1em;\n\t\ttext-align: center;\n\n\t\ta.btn-fechar{\n\t\t\tdisplay: inline-block;\n\t\t\t//border: 1px solid $Blue;\n\t\t\tborder-radius: 100%;\n\t\t\tcursor: pointer;\n\t\t width: 30px;\n\t\t height: 30px;\n\t\t font-size: 86%;\n\t\t padding: 5px 0;\n\t\t text-align: center;\n\t\t margin-top: 10px;\n\n\t\t &:hover{\n\t\t \t//background: $Blue;\n\t\t \tcolor: #fff;\n\t\t }\n\t\t}\n\n\t\t.sci-ico-emailOutlined {\n\t\t\tfont-size: 20px;\n\t\t\tvertical-align: baseline;\n\t\t}\n\n\t\t.dropdown {\n\t\t\tdisplay: inline-block;\n\t\t\tpadding: 0 10px;\n\n\t\t\t.dropdown-toggle {\n\t\t\t\twhite-space: nowrap;\n\t\t\t}\n\n\t\t\t.dropdown-menu {\n\t\t\t\tpadding: 0 20px 10px 20px;\n\t\t\t\tcolor: #fff;\n\t\t\t\ttext-align: left;\n\t\t\t\t//background: $Blue;\n\t\t\t\t//@include radius(4px);\n\t\t\t\t////@include border-box;\n\t\t\t\tbox-shadow: none;\n\t\t\t\tborder: none;\n\n /*\n\t\t\t\t@media $minDesktop {\n\t\t\t\t\twidth: 340px;\n\t\t\t\t}\n */\n\n\t\t\t\tstrong {\n\t\t\t\t\tdisplay: block;\n\t\t\t\t\tmargin: 20px 0 8px 0;\n\t\t\t\t\tfont-size: 11px;\n\t\t\t\t\tcolor: #00314c;\n\t\t\t\t\ttext-transform: uppercase;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\ta {\n\t\t\t\tcursor: pointer;\n\n\t\t\t\tspan {\n\t\t\t\t\tdisplay: inline-block;\n\t\t\t\t\tpadding: 5px 0;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t&.open {\n\t\t\t\t//background: $Blue;\n\t\t\t\t//@include radius(4px);\n\n\t\t\t\t a {\n\t\t\t\t \tcolor: #fff;\n\t\t\t\t }\n\t\t\t}\n\t\t}\n\n /*\n\t\t.btnContribLinks {\n\t\t\tpadding: 5px 10px;\n\t\t\ttext-align: left;\n\t\t\tborder: 1px solid #859ed9;\n\t\t\t//@include radius(4px);\n\t\t\tdisplay: block;\n\t\t\toverflow: hidden;\n\t\t\twhite-space: nowrap;\n\t\t\ttext-overflow: ellipsis;\n\t\t\tmargin-bottom: 7px;\n\t\t\t//.cssAnimations .animated (.3s,all);\n\n \n\t\t\t@media $onlyTablet {\n\t\t\t\tdisplay: block;\n\t\t\t\tmargin-bottom: 10px;\n\n\t\t\t\t&:last-child {\n\t\t\t\t\tmargin-bottom: 0;\n\t\t\t\t}\n\t\t\t}\n \n\n\t\t\t&:hover {\n\t\t\t\tborder-color: #fff;\n\t\t\t}\n\t\t}\n */\n\n\t\t&.contribGroupAlignLeft {\n\t\t\ttext-align: left;\n\t\t\tmargin-left: 0;\n\t\t\tmargin-top: 0;\n\n\t\t\t.dropdown:first-child {\n\t\t\t\tmargin-left: -10px;\n\t\t\t}\n\t\t}\n\t}\n\n\t.linkGroup {\n\t\tposition: relative;\n\t\tfont-size: .85em;\n\n\t\ta.selected {\n\t\t\tposition: relative;\n\n\t\t\t&:after {\n\t\t\t\tcontent: '';\n\t\t\t\tdisplay: block;\n\t\t\t\tposition: absolute;\n\t\t\t\tbottom: -16px;\n\t\t\t\tleft: 4px;\n\t\t\t\twidth: 16px;\n\t\t\t\theight: 7px;\n\t\t\t\tbackground: url(../img/articleContent-arrow.png) bottom center no-repeat;\n\t\t\t\tz-index: 999;\n\t\t\t}\n\t\t}\n\t}\n\n\t.floatInformation {\n\t\tmargin-top: 9px;\n\t\tborder: 1px solid #ddd;\n\t\t//background: $LightGray;\n\t\t//@include radius;\n\t\tpadding: 15px;\n\t\t//@include shadow(0 0 3px rgba(0,0,0,.2));\n\t\tposition: absolute;\n\t\tdisplay: none;\n\t\tz-index: 99;\n\t\twidth: 100%;\n\n background: $__bg__gray--1;\n\n @include __on-theme--dark {\n background: $__bg__white--1;\n }\n \n @include __on-theme--light {\n background: $__bg__gray--1;\n } \n\n\t\t.close {\n\t\t\tmargin-top: -7px;\n\t\t}\n\t\tul {\n\t\t\tmargin: 0;\n\t\t\tpadding: 0;\n\t\t}\n\t\tli {\n\t\t\tlist-style: none;\n\t\t\tmargin-bottom: 7px;\n\t\t\tpadding-left: 20px;\n\n\t\t\t.xref:first-child {\n\t\t\t\tmargin-left: -22px;\n\t\t\t}\n\t\t}\n\t\t.rowBlock {\n\t\t\tpadding: 7px 15px;\n\t\t\tbackground: url(../img/dashline.png) bottom left repeat-x;\n\n\t\t\t&:last-child {\n\t\t\t\tbackground: none;\n\t\t\t}\n\t\t}\n\t\th3 {\n\t\t\tmargin: 0 0 10px;\n\t\t}\n\t}\n\n\t.articleTxt {\n\t\tposition: relative;\n\t\tpadding: 0px 50px 100px;\n\t\tmargin-top: -30px;\n\t\tmargin-bottom: 60px;\n\t\t//background: #fff;\n\t\t//@include radius(4px);\n\t\t//@include shadow();\n\t\toverflow-x: hidden;\n\n background: $__bg--light;\n\n @include __on-theme--dark {\n background: $__bg--dark;\n }\n\n @include __on-theme--light {\n background: $__bg--light;\n }\n\n\t\t\n\t\t.articleSectionTitle,\n\t\t.article-title {\n\t\t\tmargin: 25px 0 12px;\n\t\t\t//color: $DarkBlue;\n\t\t\t//font-size: 1.5em;\n\n\t\t\t@include __breakpoint--xsmall-only() {\n\t\t\t\t@include __text__title--3;\n\t\t\t}\n\t\t}\n\t\t\n\n\n\t\t.articleBadge-editionMeta-doi-copyLink{\n\t\t font-size: .85em;\n\t\t margin: 0;\n\t\t font-weight: normal;\n\t\t //color: #a7a49e;\n\t\t padding: 10px 0 0px;\n\t\t text-align: center;\n\t\t min-height: 35px;\n\t\t line-height: 110%;\n\n color: $__text__subtle--light;\n\n @include __on-theme--dark {\n color: $__text__subtle--dark;\n }\n \n @include __on-theme--light {\n color: $__text__subtle--light;\n }\n\n\t\t\t._articleBadge{\n\t\t\t\tfont-weight: bold;\n\t\t\t\topacity: .88;\n\t\t\t}\n\t\t\t.group-doi{\n\t\t\t\twhite-space: nowrap;\n\t\t\t\tdisplay:inline-block;\n\t\t\t}\n\t\t\t._doi{\n\t\t\t\t//color: #6789d3;\n color: $__interaction--light;\n\n\t\t\t\t//@include media-breakpoint-only(xs) {\n\t\t\t\t@include __breakpoint--xsmall-only() {\n\t\t\t\t\tdisplay: table;\n\t\t\t\t\twhite-space: pre-wrap;\n \t\t\t\tmargin: 12px 0;\n\t\t\t\t}\n\n @include __on-theme--dark {\n color: $__interaction--dark;\n }\n \n @include __on-theme--light {\n color: $__interaction--light;\n }\n\t\t\t}\n\t\t\t.copyLink{\n\t\t\t\twhite-space:nowrap;\n margin: 0 0 8px 8px;\n\t\t\t}\n\t\t}\n\n\n\t\t.article-title {\n\t\t\t/*\n\t\t\tfont-size: 2.571em; //36px (body 14px)\n\t\t\ttext-align: center;\n\t\t\tmargin-top: 0;\n\t\t\tletter-spacing: -0.025em;\n\t\t\t*/\n\t\t\t\n\t\t\ttext-align: center;\n\n\t\t\t@include __breakpoint--xsmall-only() {\n\t\t\t\t@include __text__title--3;\n\t\t\t}\n\n\t\t\t.sci-ico-openAccess{\n\t\t\t\tmargin-bottom: 7px;\n\t\t\t}\n\n\n\t\t\t.short-link {\n\t\t\t\tposition: relative;\n\t\t\t\tvisibility: hidden;\n\t\t\t\tcursor: pointer;\n\t\t\t\ttext-decoration: none;\n\n\t\t\t\t[class^=\"sci-ico-\"] {\n\t\t\t\t\t//color: $Blue;\n\t\t\t\t}\n\n\t\t\t\t&:after {\n\t\t\t\t\tposition: absolute;\n\t\t\t\t\tbackground: #34ad65;\n\t\t\t\t\ttop: 100%;\n\t\t\t\t\tleft: 0;\n\t\t\t\t\tright: 0;\n\t\t\t\t\tbottom: 0;\n\t\t\t\t\tz-index: 2;\n\t\t\t\t\ttext-align: center;\n\t\t\t\t\tfont-family: 'scielo-glyphs' !important;\n\t\t\t\t\tcontent: \"\\e924\";\n\t\t\t\t\tcolor: #fff;\n\t\t\t\t\tfont-size: 20px;\n\t\t\t\t\tvisibility: hidden;\n\t\t\t\t\tvertical-align: middle;\n\t\t\t\t\tdisplay: flex;\n\t\t\t\t\tjustify-content: center;\n\t\t\t\t\talign-items: center;\n\t\t\t\t\tborder-radius: 4px;\n\t\t\t\t\t//.cssAnimations @include animated(.3s,all);\n\t\t\t\t}\n\n\t\t\t\t&.copyFeedback:after {\n\t\t\t\t\ttop: 0;\n\t\t\t\t\tvisibility: visible;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t.ref {\n\t\t\t\t.opened {\n\t\t\t\t\tmargin-top: 2.4em;\n\n /*\n\t\t\t\t\t@media $onlyMobile {\n\t\t\t\t\t\tmargin: 0;\n\t\t\t\t\t}\n */\n\t\t\t\t}\n\n\t\t\t\t&.footnote {\n\t\t\t\t\t.xref:first-child {\n\t\t\t\t\t\tfont-size: 1.5em;\n\t\t\t\t\t}\n\n\t\t\t\t\t.refCtt {\n\t\t\t\t\t\t&.opened {\n\t\t\t\t\t\t\ttext-align: left;\n\t\t\t\t\t\t\tfont-weight: normal;\n\t\t\t\t\t\t\tfont-size: 13px;\n\t\t\t\t\t\t\tletter-spacing: inherit;\n\t\t\t\t\t\t}\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t&:hover{\n\t\t\t\t.short-link{\n\t\t\t\t\tvisibility: visible;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\t\th2.article-title {\n\t\t\t//font-size: 1.8em;\n\t\t\tfont-weight: normal;\n\t\t\t//padding: 10px 0;\n\t\t\t//margin-bottom: 0;\n\t\t}\n\n\t\th2 {\n\t\t\t//color: $DarkBlue;\n\t\t\t//font-size: 1.2em;\n\t\t}\n\n\t\t.article-correction-title {\n\t\t\tmargin: 10px 15% 20px;\n\t\t\tborder: 2px solid #f5d431;\n\t\t\tpadding: 20px;\n\n\t\t\t.panel-heading {\n\t\t\t\tfont-size: 13px;\n\t\t\t\tfont-weight: bold;\n\t\t\t\ttext-align: left;\n\t\t\t\tpadding: 3px;\n\t\t\t\tpadding: 5px;\n\t\t\t}\n\n\t\t\t.panel-body {\n\t\t\t\tpadding: 0;\n\t\t\t}\n\n\t\t\tul {\n\t\t\t\tmargin: 0;\n\t\t\t\tpadding: 0;\n\t\t\t\ttext-align: left;\n\t\t\t\tfont-size: 14px;\n\t\t\t}\n\n\t\t\tli {\n\t\t\t\tlist-style: none;\n\t\t\t\tpadding-left: 15px;\n\t\t\t\tposition: relative;\n\n\t\t\t\t&:before {\n\t\t\t\t\tcontent: '\\00bb';\n\t\t\t\t\tfont-weight: bold;\n\t\t\t\t\t//color: $Blue;\n\t\t\t\t\tposition: absolute;\n\t\t\t\t\tleft: 0;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\ta {\n\t\t\t\t//color: $Blue;\n\t\t\t\tfont-weight: bold;\n\n\t\t\t\t&:hover {\n\t\t\t\t\ttext-decoration: underline;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\t\t.articleSection {\n\t\t\tpadding: 0 0 1px;\n\t\t\tbackground: url(../img/dashline.png) bottom left repeat-x;\n\n\t\t\t.article-title {\n\t\t\t\ttext-align: left;\n\t\t\t\t//margin: 14px 0 20px;\n\t\t\t\t//font-size: 2em;\n\n\t\t\t\t@include __breakpoint--xsmall-only() {\n\t\t\t\t\t@include __text__title--3;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t&:last-child {\n\t\t\t\tbackground: none;\n\t\t\t}\n\n\t\t\t.articleSignature {\n\t\t\t\tfont-size: 15px;\n\t\t\t\tfont-style: italic;\n\n\t\t\t\tsmall {\n\t\t\t\t\tdisplay: block;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t\t.paragraph {\n\t\t\tposition: relative;\n\t\t\tmargin-bottom: 25px;\n\t\t\tfont-size: 1em;\n\t\t\tline-height: 1.7em;\n\t\t}\n\t\t.btn.primary {\n\t\t\tbackground: #fff;\n\t\t\t//border: 1px solid lighten($Blue,20%);\n\t\t\t//color: $Blue;\n\t\t\tfont-size: 1.1em;\n\t\t\tpadding: 10px 15px;\n\n\t\t\t&:hover {\n\t\t\t\t//background: $Blue;\n\t\t\t\tcolor: #fff;\n\t\t\t}\n\t\t}\n\n\t\tspan.formula {\n\t\t\tdisplay: block;\n\t\t\tmargin: 20px 0;\n\t\t\tpadding: 7px;\n\t\t\ttext-align: center;\n\t\t\tfont-size: 2em;\n\t\t\tborder-radius: 3px;\n\n\t\t\timg {\n\t\t\t\tmax-width: 95%;\n\t\t\t}\n\t\t}\n\n\t\tp {\n\t\t\tmargin: 0 0 15px;\n\t\t\tpadding: 0;\n\n\t\t\t//quebra linha de link\n\t\t\toverflow-wrap: break-word;\n\t\t\tword-wrap: break-word;\n\t\t\t-ms-word-break: break-all;\n\t\t\tword-break: break-all;\n\t\t\tword-break: break-word;\n\t\t\t-ms-hyphens: auto;\n\t\t\t-moz-hyphens: auto;\n\t\t\t-webkit-hyphens: auto;\n\t\t\t//hyphens: auto;\n\t\t}\n\n\t\t.articleReferral {\n\t\t\tdisplay: flex;\n\t\t\talign-items: center;\n\t\t\tposition: relative;\n\t\t\tmargin-bottom: 20px;\n\t\t\tpadding: 15px 50px 15px 140px;\n\t\t\tborder: 1px solid #f3f2e4;\n\t\t\tvertical-align: middle;\n\t\t\tmin-height: 168px;\n\t\t\t//@include border-box;\n\n\t\t\t.arText {\n\t\t\t\tpadding-left: 25px;\n\n\t\t\t\th2 {\n\t\t\t\t\tmargin-top: 0;\n\t\t\t\t}\n\n\t\t\t\tp {\n\t\t\t\t\tmargin-bottom: 0;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t.arPicture {\n\t\t\t\tposition: relative;\n\t\t\t\twidth: 98px;\n\t\t\t\tmargin-left: -120px;\n\n\t\t\t\tsmall {\n\t\t\t\t\tfont-size: 62%;\n\t\t\t\t\twhite-space: nowrap;\n\n\t\t\t\t\tspan {\n\t\t\t\t\t\tdisplay: block;\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t&.noPicture {\n\t\t\t\tpadding: 15px 40px;\n\t\t\t\tmin-height: 100%;\n\n\t\t\t\t.arText {\n\t\t\t\t\tpadding-left: 0;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t&.biography {\n\t\t\t\t.arPicture {\n\t\t\t\t\tmargin-top: -40px;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t}\n\n /*\n\t.floatingMenuCtt{\n\t\toverflow: hidden;\n\t\theight: 130px;\n\t\tmargin-top: -190px;\n\t\tmargin-bottom:150px;\n\t\tmargin-left: -150px;\n\t\tdisplay:inline-block;\n\n\t\tposition: absolute;\n\t\tz-index: 1010;\n\n\t\tmargin-left: 0;\n\t\tdisplay: block;\n\t\twidth:100%;\n\t\tleft:0;\n\n\t\t\n\t &.smallerViewPort{\n\t \tmargin-left: 0;\n\t }\n\t \n\n\t}\n */\n\n\t.articleMenu {\n\t\tposition: absolute;\n\t\tmargin: 25px 0 90px 0;\n\t\tpadding: 0 15px 0 0;\n\t\tfont-size: .85em;\n //display: none;\n\n /*\n @include media-breakpoint-up(md) {\n display: block; \n }\n */\n\n\t\t&.fixed {\n\t\t\tposition: fixed;\n\t\t\ttop: 50px;\n\t\t}\n\n\t\t&.fixedBottom {\n\t\t\tposition: absolute;\n\t\t\ttop: initial;\n\t\t\tbottom: 50px;\n\t\t}\n\n\t\tli {\n\t\t\tlist-style: none;\n\t\t\tpadding-left: 17px;\n\n\t\t\t&:before {\n\t\t\t\tcontent: '\\00bb';\n\t\t\t\tdisplay: inline-block;\n\t\t\t\twidth: 12px;\n\t\t\t\ttext-align: center;\n\t\t\t\tmargin-left: -17px;\n\t\t\t\t//color: #aba8a3;\n\t\t\t\tvertical-align: middle;\n\t\t\t\tmargin-bottom: 5px;\n\n color: $__text__subtle--light;\n\n @include __on-theme--dark {\n color: $__text__subtle--dark;\n }\n\n @include __on-theme--light {\n color: $__text__subtle--light;\n }\n\t\t\t}\n\n\t\t\t&.link-to-top{\n\n\t\t\t\tmargin-top: 20px;\n\n\t\t\t\t&:before{\n\t\t\t\t\tcontent: '';\n\t\t\t\t\tdisplay: inline;\n\t\t\t\t\twidth:auto;\n\t\t\t\t}\n\n\t\t\t\ta{\n\t\t\t\t\t//color: $Blue;\n\t\t\t\t\t.circle{\n\t\t\t\t\t\twidth: 20px;\n\t\t\t\t\t\theight: 20px;\n\t\t\t\t\t\t//background: $Blue;\n\t\t\t\t\t\tdisplay: inline-block;\n\t\t\t\t\t\tcolor: #fff;\n\t\t\t\t\t\tborder-radius:100px;\n\t\t\t\t\t\tpadding: 0px 0 0 3px;\n \t\t\t\t\tfont-size: 125%;\n\t\t\t\t\t}\n\n\t\t\t\t}\n\t\t\t}\n\n\t\t}\n\t\ta {\n\t\t\t//color: #aba8a3;\n\t\t\tdisplay: inline-block;\n\t\t\twidth: 100%;\n\t\t\twhite-space: nowrap;\n\t\t\toverflow: hidden;\n\t\t\ttext-overflow: ellipsis;\n\t\t\tvertical-align: middle;\n\t\t\tmargin-bottom: 5px;\n text-decoration: none;\n\n color: $__text__subtle--light;\n\n @include __on-theme--dark {\n color: $__text__subtle--dark;\n }\n \n @include __on-theme--light {\n color: $__text__subtle--light;\n } \n\t\t}\n\n\t\tul {\n\t\t\tmargin: 0 0 0 0px;\n\t\t\tpadding: 0;\n\t\t}\n\t\tli li {\n\t\t\tpadding-left: 7px;\n\n\t\t\t&:before {\n\t\t\t\tdisplay: none;\n\t\t\t}\n\t\t}\n\n\t\tli.selected {\n\t\t\t&:before, & > a {\n\t\t\t\t//color: #738390;\n\t\t\t\tfont-weight: bold;\n\n //color: red;\n\n color: $__text__emphasis--light;\n\n @include __on-theme--dark {\n color: $__text__emphasis--dark;\n }\n\n @include __on-theme--light {\n color: $__text__emphasis--light;\n } \n\t\t\t}\n\n\t\t\tli:before, li a {\n\t\t\t\t//color: #aba8a3;\n //color: blue;\n color: $__text__emphasis--light;\n\n @include __on-theme--dark {\n color: $__text__emphasis--dark;\n }\n\n @include __on-theme--light {\n color: $__text__emphasis--light;\n } \n\t\t\t}\n\t\t}\n\t\ta:active, a:focus, a:visited {\n\t\t\ttext-decoration: none;\n\t\t}\n\t}\n\n\t.articleFigure {\n\t\tposition: absolute;\n\t\tborder: 4px solid #efeeec;\n\t}\n\n\t.table-notes a {\n\t\tdisplay: block;\n\t\tpadding: 5px 0;\n\t}\n\n\t.nav-tabs {\n\t\tli:first-child {\n\t\t\tmargin-left: 15px;\n\t\t}\n\t\ta {\n\t\t\tborder: 1px solid #ddd;\n\t\t\tbackground: #fff;\n\t\t\t//color: $DarkBlue;\n\n\t\t\t&:hover {\n\t\t\t\t//color: $Blue;\n\t\t\t\t//background: $LightGray;\n\n background: $__bg__gray--1;\n\n @include __on-theme--dark {\n background: $__bg__white--1;\n }\n \n @include __on-theme--light {\n background: $__bg__gray--1;\n } \n\t\t\t}\n\t\t}\n\t}\n\n\t.articleTimeline {\n\t\tmargin: 0 0 25px;\n\t\tpadding: 0;\n\t\tfont-size: .9em;\n\n\t\tli {\n\t\t\tdisplay: inline-block;\n\t\t\twidth: 33%;\n\t\t\theight: 40px;\n\t\t\tpadding-left: 25px;\n\t\t\tlist-style: none;\n\n\t\t\t&:before {\n\t\t\t\tcontent: '\\00bb';\n\t\t\t\tmargin-left: -25px;\n\t\t\t\tdisplay: inline-block;\n\t\t\t\twidth: 22px;\n\t\t\t\ttext-align: center;\n\t\t\t}\n\t\t}\n\t}\n\n\t.documentLicense {\n\t\tmargin: 20px 0;\n\n\t\t.container-license {\n\t\t\t//background: #f2f1ee;\n\t\t\tfont-size: .8em;\n\t\t\t//color: #6d6d6b;\n\t\t\tpadding: 25px;\n\t\t\twidth:100%;\n\n background: $__bg__gray--2;\n\n @include __on-theme--dark {\n background: $__bg__white--2;\n }\n \n @include __on-theme--light {\n background: $__bg__gray--2;\n } \n\n\t\t\t.row{\n\t\t\t\tdiv{\n\t\t\t\t\t&:first-child{\n\t\t\t\t\t\ttext-align: center;\n\t\t\t\t\t}\n\t\t\t\t\t&:last-child{\n\t\t\t\t\t\tpadding-left: 0;\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t}\n\t\t\ta{\n\t\t\t\t//color: $Gray;\n\t\t\t\tcursor: pointer;\n\t\t\t\tdisplay: inline-block;\n\t\t\t}\n\t\t}\n\t\timg {\n\t\t\tmargin: 0 auto;\n\t\t\twidth:100%;\n\t\t}\n\t}\n\n\t.journalLicense .row {\n\t\tpadding-bottom: 25px;\n\t\tfont-size: .9em;\n\t}\n\n\t.share {\n\t\ttext-align: center;\n\t\tmargin-top: -3px;\n\t\tbackground: url(../img/dashline.png) bottom left repeat-x;\n\t\tpadding-bottom: 5px;\n\t}\n\n\t.collapseBlock {\n\t\tfont-size: .9em;\n\n\t\t.collapseTitle {\n\t\t\tposition: relative;\n\t\t\tdisplay: block;\n\t\t\tbackground: url(../img/dashline.png) bottom left repeat-x;\n\t\t\t//color: $DarkBlue;\n\t\t\tpadding: 7px 2px;\n\n\t\t\t.collapseIcon {\n\t\t\t\tposition: absolute;\n\t\t\t\tright: 0;\n\t\t\t}\n\t\t\t&:active, &:focus {\n\t\t\t\ttext-decoration: none;\n\t\t\t\t//color: $Blue;\n\t\t\t}\n\t\t}\n\t}\n\n\t.collapseContent {\n\t\tbackground: #f7f6f5;\n\t\tfont-size: .9em;\n\t\tpadding: 15px;\n\t\t//color: #00e;\n\n /*\n color: $__interaction--light;\n\n @include __on-theme--dark {\n color: $__interaction--dark;\n }\n \n @include __on-theme--light {\n color: $__interaction--light;\n } \n */\n\n\n\t\tul {\n\t\t\tmargin: 0 0 0 0;\n\t\t\tpadding: 0;\n\t\t}\n\t\tli {\n\t\t\tlist-style: none;\n\t\t\tpadding-left: 15px;\n\t\t\tmargin-bottom: 5px;\n\n\t\t\t&:before {\n\t\t\t\tcontent: '\\00bb';\n\t\t\t\tdisplay: inline-block;\n\t\t\t\twidth: 13px;\n\t\t\t\ttext-align: center;\n\t\t\t\tmargin-left: -15px;\n\t\t\t}\n\n\t\t}\n\t\t.logos {\n\t\t\t&:before {\n\t\t\t\twidth: 22px;\n\t\t\t\theight: 12px;\n\t\t\t\tdisplay: inline-block;\n\t\t\t\tcontent: '';\n\t\t\t\tbackground: url(../img/button.glyphs.png) no-repeat;\n\t\t\t}\n\t\t\t&.scielo:before {\n\t\t\t\tbackground-position: center -4556px;\n\t\t\t}\n\t\t\t&.fapesp:before {\n\t\t\t\tbackground-position: center -4506px;\n\t\t\t}\n\t\t\t&.google:before {\n\t\t\t\tbackground-position: center -4531px;\n\t\t\t}\n\t\t}\n\n\n\t\ta {\n\t\t\t//color: #00e;\n\n /*\n color: $__interaction--light;\n\n @include __on-theme--dark {\n color: $__interaction--dark;\n }\n\n @include __on-theme--light {\n color: $__interaction--light;\n } \n */\n\t\t}\n\t}\n\n\t.functionsBlock {\n\t\tposition: absolute;\n\t\tright: 0;\n\t\tz-index: 99;\n\t}\n\n\t.articleBadge {\n\t\ttext-align: center;\n\n\t\tspan {\n\t\t\tdisplay: inline-block;\n\t\t\tpadding: 5px 10px;\n\t\t\t//color: $Gray;\n\t\t\tmargin: 0 0 15px 0;\n\t\t\tborder-radius: 4px;\n\t\t\tposition: relative;\n\t\t\tfont-size: 20px;\n\n\t\t\t&:after {\n\t\t\t\tcontent: '';\n\t\t\t\tposition: absolute;\n\t\t\t\tleft: 0;\n\t\t\t\tright: 0;\n\t\t\t\tbottom: 0;\n\t\t\t\t//border-bottom: 2px solid $Gray;\n\t\t\t}\n\n\t\t}\n\t}\n\n\t.articleCttLeft {\n\t\t.editionMeta,\n\t\t.articleMeta,\n\t\t.article-title,\n\t\t.articleBadge {\n\t\t\ttext-align: left !important;\n\t\t}\n\n\t\t.contribGroup {\n\t\t\tmargin-left: 0;\n\t\t\tmargin-right: 0;\n\t\t\ttext-align: left;\n\n\t\t\t.dropdown:first-child {\n\t\t\t\tmargin-left: -10px;\n\t\t\t}\n\t\t}\n\t}\n}\n\n#translateArticleModal {\n\t.modal-body {\n\t\t//background: $LightGray;\n\t\tfont-size: .9em;\n\n background: $__bg__gray--1;\n\n @include __on-theme--dark {\n background: $__bg__white--1;\n }\n \n @include __on-theme--light {\n background: $__bg__gray--1;\n } \n\t}\n\t.modal-footer {\n\t\tmargin-top: 0;\n\t}\n\t.dashline {\n\t\tpadding-bottom: 5px;\n\t\tbackground: url(../img/dashline.png) bottom left repeat-x;\n\t}\n\tth {\n\t\tpadding: 12px;\n\t\tborder: 1px solid #ddd;\n\t\tborder-radius: 4px;\n\t\tbackground: #fdfcf9;\n\t}\n\ttable {\n\t\twidth: 100%;\n\t}\n\ttd {\n\t\tpadding: 8px 10px;\n\t\tborder-bottom: 1px solid #dee5f5;\n\t\ttext-align: center;\n\t}\n\tth {\n\t\tvertical-align: top;\n\t}\n}\n\n.articleCtt,\n.ModalDefault {\n\t.tab-pane {\n\t\tfont-size: .9em;\n\n\t\tp {\n\t\t\tmargin: 10px 0;\n\t\t}\n\t\t.center {\n\t\t\ttext-align: center;\n\t\t}\n\t\tlabel {\n\t\t\tfont-weight: normal;\n\t\t\tcolor: #888;\n\t\t}\n\t\t.big {\n\t\t\tfont-size: 2em;\n\t\t\tfont-weight: normal;\n\t\t\t//color: $Blue;\n\t\t}\n\t\ttable {\n\t\t\tth,td {\n\t\t\t\tpadding: 7px 10px;\n\t\t\t}\n\t\t\tth {\n\t\t\t\tfont-weight: normal;\n\t\t\t\tcolor: #b7b7b7;\n\t\t\t}\n\t\t}\n\t\ta.midGlyph {\n\t\t\tdisplay: block;\n\t\t\ttext-align: center;\n\t\t}\n\t}\n\n\t.fig, .table {\n\t\t//font-size: 13px;\n\t\tmargin-top: 10px;\n\t\tmargin-bottom: 40px;\n\t\tposition: relative;\n\t\twidth: initial;\n\n\t\t.col-md-8 {\n\t\t\tpadding-top: 10px;\n\t\t}\n\n\t\tstrong {\n\t\t\t//color: $Blue;\n padding: 0;\n\t\t}\n\n\t\t.thumb,\n\t\t.thumbOff {\n\t\t\t//@include border-box;\n\t\t\t//border: 4px solid #e5e4e3;\n\t\t\theight: 160px;\n\t\t\tbackground-size: 100% auto;\n\t\t\ttext-indent: -5000px;\n\t\t\tbackground-color: #e5e4e3;\n\t\t\tcursor: pointer;\n\t\t\tborder-radius: 3px;\n\t\t\tposition: relative;\n\n border: 4px solid $__border--light;\n\n @include __on-theme--dark {\n border: 4px solid $__border--dark;\n }\n \n @include __on-theme--light {\n border: 4px solid $__border--light;\n }\n\n\t\t\timg {\n\t\t\t\twidth: 100%;\n\t\t\t}\n\n\t\t\t.zoom {\n\t\t\t\tposition: absolute;\n\t\t\t\tbottom: 10px;\n\t\t\t\tright: 10px;\n\t\t\t\t//background-color: $Blue;\n\t\t\t\t//@include radius(4px);\n \n border-radius: 4px;\n\t\t\t\t//color: #fff;\n\t\t\t\tfont-size: 24px;\n\t\t\t\ttext-align: center;\n\t\t\t\twidth: 30px;\n\t\t\t\theight: 30px;\n\t\t\t\tline-height: 30px;\n\n\t\t\t\ttext-indent: 0;\n\n background-color: $__interaction--light;\n color: $__white;\n\n @include __on-theme--dark {\n background-color: $__interaction--dark;\n color: $__text--light;\n }\n \n @include __on-theme--light {\n background-color: $__interaction--light;\n color: $__white;\n }\n\n\n\t\t\t}\n\t\t}\n\n\t\t.thumbOff {\n\t\t\t//font-family: 'scielo-glyphs' !important;\n font-family: 'Material Icons Outlined' !important;\n\t\t\ttext-align: center;\n\t\t\tline-height: 140px;\n\t\t\tfont-size: 100px;\n\t\t\tcolor: #b7b4af;\n\t\t\t//background: #fff;\n\t\t\ttext-indent: 0;\n\t\t\toverflow: hidden;\n\n background: $__bg--light;\n \n @include __on-theme--dark {\n background: $__bg--dark;\n }\n \n @include __on-theme--light {\n background: $__bg--light;\n }\n\n\t\t\t&:before {\n\t\t\t\t//content: \"\\e918\";\n content: \"table_chart\";\n\t\t\t}\n\t\t}\n\n\t\t.thumbImg{\n\t\t\tposition: relative;\n\t\t\toverflow: hidden;\n\t\t\tbox-sizing: border-box;\n\t\t\theight: 140px;\n\t\t\tborder: 4px solid #e5e4e3;\n\t\t\tborder-radius: 3px;\n\t\t\tbackground-color: #e5e4e3;\n\t\t\tcursor: pointer;\n\n\t\t\timg{\n\t\t\t\twidth: 100%;\n\t\t\t\theight: auto;\n\t\t\t\tmin-height: 131px;\n\t\t\t\tdisplay: block;\n\t\t\t}\n\n\t\t\t.zoom{\n\t\t\t\tposition: absolute;\n\t\t\t\tbottom: 10px;\n\t\t\t\tright: 10px;\n\t\t\t\twidth: 30px;\n\t\t\t\theight: 30px;\n\t\t\t\tborder-radius: 4px;\n\t\t\t\t//background-color: #6789d3;\n\t\t\t\tpadding: 5px;\n\t\t\t\tdisplay: inline-block;\n\t\t\t\tfont-size: 24px;\n\t\t\t\t//color: white;\n\t\t\t\tline-height: 50%;\n\n background-color: $__interaction--light;\n color: $__white;\n\n @include __on-theme--dark {\n background-color: $__interaction--dark;\n color: $__text--light;\n }\n \n @include __on-theme--light {\n background-color: $__interaction--light;\n color: $__white;\n }\n\t\t\t }\n\t\t}\n\n\t\t.preview {\n\t\t\tposition: absolute;\n\t\t\tborder-radius: 3px;\n\t\t\tborder: 4px solid #e5e4e3;\n\t\t\tbackground-color: #fff;\n\t\t\ttop: 0;\n\t\t\tright: 0;\n\t\t\tz-index: 99;\n\t\t\tpadding: 10px;\n\n\t\t\timg {\n\t\t\t\twidth: 100%;\n\t\t\t}\n\t\t}\n\n\t\t.figInfo {\n\t\t\tpadding: 10px 10px 10px 45px;\n\t\t\tline-height: 1.4em;\n\t\t\tcolor: #8a8987;\n\t\t\tposition: relative;\n\n\t\t\t.glyphBtn {\n\t\t\t\tposition: absolute;\n\t\t\t\ttop: 10px;\n\t\t\t\tmargin-left: -34px;\n\t\t\t}\n\t\t}\n\t}\n\n\t.formula {\n\t\ttext-align: center;\n\t\tfont-family: \"Times New Roman\", Times, serif;\n\t\tmargin-bottom: 15px;\n\n\t\tspan {\n\t\t\tfont-family: Arial;\n\t\t\tfont-weight: bold;\n\t\t\tfont-size: 16px;\n\t\t\tdisplay: block;\n\t\t\twidth: 100%;\n\t\t}\n\n\t\t.formula-container {\n\t\t\twidth: 100%;\n\t\t\tdisplay: flex;\n\t\t\talign-content: center;\n\t\t\talign-items: center;\n\t\t\tposition: relative;\n\t\t\tflex-direction: column;\n\n\t\t\t.formula-body,\n\t\t\t.MathJax_SVG_Display,\n\t\t\t.MathJax_Display,\n\t\t\t.MathJax_SVG {\n\t\t\t\tflex: 99;\n\t\t\t\tfont-size: 1.4rem !important;\n\t\t\t}\n\n\t\t\t& > span {\n\t\t\t\tflex: 1\n\t\t\t}\n\n\t\t\t.label {\n\t\t\t\tflex: 1;\n\t\t\t\tcolor: #000;\n\t\t\t\tfont-size: 1.4rem;\n\t\t\t\tdisplay: block;\n\t\t\t\t// position: absolute;\n\t\t\t\twidth: auto;\n\t\t\t}\n\n\t\t\t.label:first-child {\n\t\t\t\tleft: 0;\n\t\t\t}\n\n\t\t\t.label:last-child {\n\t\t\t\tright: 0;\n\t\t\t}\n\t\t}\n\n\n\t\tsvg {\n\t\t\tdisplay: block;\n\t\t\twidth: 100%;\n\t\t}\n\t}\n\n /*\n\t.outlineFadeLink {\n\t\tdisplay: inline-block;\n\t\tpadding: 5px 10px;\n\t\tmargin-left: 8px;\n\t\tmin-width: 10%;\n\t\tcolor: #1b92e4;\n\t\tfont-weight: normal;\n\t\ttext-transform: uppercase;\n\t\ttext-decoration: none !important;\n\t\tfont-size: 10px;\n\t\tborder: 1px solid #e0e0df;\n\t\t//@include radius(4px);\n\t}\n */\n}\n\n.ModalDefault {\n /*\n\t.modal-header {\n\t\t//background: #f5f3f1;\n\t\t//@include radius(4px);\n\n\t\t.modal-title {\n\t\t\ttext-transform: uppercase;\n\t\t}\n\t}\n */\n\n\t.modal-center {\n\t\ttext-align: center;\n\t}\n\n\t.md-list {\n\t\tmargin: 0;\n\t\tpadding: 0;\n\t\tlist-style: none;\n\n\t\tli {\n\t\t\tmargin-bottom: 4px;\n\t\t\t////@include border-box;\n\n /*\n\t\t\ta {\n\t\t\t\tdisplay: block;\n\t\t\t\tpadding: 5px;\n\t\t\t\tborder: 1px solid #e1e7f6;\n\t\t\t\t//@include radius(4px);\n\t\t\t\tfont-size: 0.929em;\n\t\t\t\t//color: #6789d3;\n\t\t\t\tclear: both;\n\t\t\t\twhite-space: nowrap;\n\t\t\t\t//.cssAnimations .animated (.3s,all);\n\t\t\t\t////@include border-box;\n\t\t\t\twidth: 100%;\n\n\t\t\t\t&:hover {\n\t\t\t\t\t//border-color: #6789d3;\n\n border-color: $__interaction--light;\n\n @include __on-theme--dark {\n border-color: $__interaction--dark;\n }\n\n @include __on-theme--light {\n border-color: $__interaction--light;\n }\n\t\t\t\t}\n\t\t\t}\n */\n\n\t\t\t&:last-child {\n\t\t\t\tmargin-bottom: 0;\n\t\t\t}\n\n\t\t\t&.colspan3 {\n\t\t\t\tmargin-bottom: 10px;\n\n\t\t\t\ta {\n\t\t\t\t\tdisplay: flex;\n\t\t\t\t\tvertical-align: middle;\n\t\t\t\t\tjustify-content: center;\n\t\t\t\t\talign-items: center;\n\t\t\t\t\theight: 63px;\n\t\t\t\t\twhite-space: normal;\n\t\t\t\t\toverflow: hidden;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\t\t&.inline {\n\t\t\tli {\n\t\t\t\tfloat: left;\n\t\t\t\tmin-width: 18%;\n\t\t\t\tmargin-right: 10px;\n\t\t\t}\n\t\t}\n\t}\n\n\t.md-tabs {\n\t\tmargin: 0;\n\t\tpadding: 0;\n\n\t\t&>li {\n\t\t\tdisplay: flex;\n\t\t\talign-items: center;\n\t\t\tjustify-content: center;\n\t\t\ttext-align: center;\n\t\t\tpadding: 0;\n\n\t\t\ta {\n\t\t\t\t//padding: 5px 0;\n\t\t\t\tpadding: 5px;\n\t\t\t\tdisplay: inline-block;\n\t\t\t\tmargin: 0;\n\t\t\t\tborder: none;\n\t\t\t\tcolor: #7f7a71;\n\n\t\t\t\t&:hover,\n\t\t\t\t&:focus {\n\t\t\t\t\tbackground: none;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t&.active {\n\t\t\t\t//border-bottom: 2px solid $Blue;\n\n\t\t\t\ta {\n\t\t\t\t\t//color: $Blue;\n\n\t\t\t\t\t&:hover,\n\t\t\t\t\t&:focus {\n\t\t\t\t\t\t//color: $Blue;\n\t\t\t\t\t\tborder: none;\n\t\t\t\t\t\tbackground: none;\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\t.figureIconGray {\n\t\t\t\t\tbackground-position: center -4414px;\n\t\t\t\t}\n\n\t\t\t\t.tableIconGray {\n\t\t\t\t\tbackground-position: center -4368px;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t.glyphBtn {\n\t\t\t\twidth: 40px;\n\t\t\t\theight: 40px;\n\t\t\t}\n\t\t}\n\t}\n\n\t.fig, .table {\n\t\tmargin-top: 20px;\n\t\tmargin-bottom: 20px;\n\t}\n}\n\n.ModalTutors {\n\t.info {\n\t\tpadding: 28px 0;\n\t\t//background: url(../img/dashline.png) bottom left repeat-x;\n\n border-bottom: 1px dotted $__border--light;\n \n @include __on-theme--dark {\n border-bottom: 1px dotted $__border--dark;\n }\n \n @include __on-theme--light {\n border-bottom: 1px dotted $__border--light;\n } \n\n\t\t&:last-child {\n\t\t\t//background: none;\n border-bottom: 0;\n\t\t}\n\n\t\t&:first-child {\n\t\t\tpadding-top: 0;\n\t\t}\n\n\t\th3 {\n\t\t\tmargin: 0 0 15px;\n\t\t\tfont-size: 1.429em;\n\t\t\tfont-weight: normal;\n\t\t}\n\n\t\t.tutors {\n\t\t\tmargin-bottom: 25px;\n\n\t\t\tstrong:first-child {\n\t\t\t\tfont-size: 1.071em;\n\t\t\t}\n\n\t\t\t&:last-child {\n\t\t\t\tmargin-bottom: 0;\n\t\t\t}\n\t\t}\n\t}\n\n\tul li {\n\t\tmargin-top: 10px;\n\t\tborder-color: #e0e0df;\n\n\t\t&.inline li {\n\t\t\tdisplay: inline;\n\t\t}\n\t}\n}\n\n#ModalDownloads {\n\tstrong {\n\t\tdisplay: inline-block;\n\t\tpadding: 15px 0;\n\t}\n\n\t.glyphBtn {\n\t\twidth: 40px;\n\t\theight: 40px;\n\t}\n\n\t[class^=\"sci-ico-file\"] {\n\t\tline-height: 40px !important;\n\t\t//color: $Blue;\n\t\tfont-size: 40px;\n\t}\n}\n\n#ModalArticles,\n#ModalMetrics {\n\t.md-tabs {\n\t\tmargin: 0 0 25px;\n\n\t\t&>li {\n\t\t\tmin-height: 50px;\n\t\t}\n\t}\n}\n\n#ModalMetrics {\n\t.outlineFadeLink {\n\t\tmargin: 0 0 20px;\n\t\tpadding: 12px;\n\t\tfont-size: 15px;\n\t\tdisplay: block;\n\t\ttext-align: center;\n\t}\n}\n\n#ModalArticles {\n\t#how2cite-export {\n\t\tmargin: 20px 0 2px;\n\t\tbackground: url(../img/dashline.png) top left repeat-x;\n\n\t\t.col-md-2.col-sm-2 {\n\t\t\twidth: 20%;\n\t\t}\n\t}\n\n\t.outlineFadeLink {\n\t\tmargin-left: 0;\n\t}\n\n\t.download {\n\t\tdisplay: block;\n\t}\n\n\t#citation-ctt {\n\t\tposition: absolute;\n\t\ttop: -5000px;\n\t}\n\n\t#citationCut {\n\t\tposition: absolute;\n\t\ttop: -5000px;\n\t}\n}\n\n.ModalFigs,\n.ModalTables {\n\t.modal-title {\n\t\t.sci-ico-fileFigure, .sci-ico-fileTable {\n\t\t\tfont-size: 24px;\n\t\t}\n\t}\n\t.link-newWindow {\n /*\n\t\tposition: absolute;\n\t\tright: 55px;\n\t\tfont-size: 20px;\n\t\ttop: 9px;\n\t\topacity: .2;\n\t\tcolor: #000;\n\t\t//.cssAnimations @include animated(.3s,all);\n */\n\n text-decoration: none;\n\n\t\t&:hover {\n\t\t\topacity: 1;\n\t\t}\n\t}\n\n\t.modal-footer {\n\t\t//background: $LightGray;\n\t\tmargin-top: 0;\n\t\ttext-align: left;\n\n background: $__bg__gray--1;\n\n @include __on-theme--dark {\n background: $__bg__white--1;\n }\n \n @include __on-theme--light {\n background: $__bg__gray--1;\n } \n\t}\n}\n\n.ModalFigs {\n\t.modal-title{\n\t\twidth: #{\"calc(100% - 70px)\"};\n\t}\n\timg {\n\t\t// width: 100%;\n\t\tfloat: left;\n\t}\n\n\t.modal-body {\n\t\tpadding: 3px;\n\t}\n}\n\n.ModalTables {\n\t.modal-body {\n\t\toverflow: auto;\n\n\t\t&:after {\n\t\t\tcontent: '';\n\t\t\tposition: absolute;\n\t\t\ttop: 0;\n\t\t\tbottom: 0;\n\t\t\tleft: 0;\n\t\t\tright: 0;\n\t\t\tbackground: #fff url(../img/list.loading.gif) center center no-repeat;\n\n @include __on-theme--dark {\n background: $__bg--dark url(../img/list.loading.gif) center center no-repeat;\n }\n \n @include __on-theme--light {\n background: $__bg--light url(../img/list.loading.gif) center center no-repeat;\n } \n\t\t}\n\n\t\t&.cached:after {\n\t\t\tdisplay: none;\n\t\t}\n\t}\n\n\t.table {\n\t\tmargin-top: 0;\n\t\tfont-size: 14px;\n\n position: relative;\n z-index: 1;\n\n\t\t.autoWidth {\n\t\t\twidth: auto;\n\t\t}\n\n\t\t.striped {\n\t\t\tbackground-color: #f8f8f8;\n\t\t}\n\n\t\t.inline-graphic {\n\t\t\twidth: 100%;\n\t\t}\n\t}\n\n\t.table-hover .table > tbody > tr:hover > td,\n\t.table-hover .table > tbody > tr:hover > th {\n\t\tbackground-color: #f0f3fb;\n\n\t\t&.striped {\n\t\t\tbackground-color: #e8eaf2;\n\t\t}\n\t}\n\n\t.ref-list {\n\n\t\th2 {\n\t\t\tfont-size: 14px;\n\t\t}\n\n\t\t.refList .xref.big {\n\t\t\tpadding: 5px 10px;\n\t\t}\n\t}\n\n\t.refList {\n\t\tli {\n\t\t\tpadding-bottom: 0;\n\t\t}\n\t}\n\n\t.xref {\n\t\tcursor: text;\n\t}\n}\n\n#ModalRelatedArticles {\n\t.inline li {\n\t\tmin-width: 48%;\n\n\t\t&:nth-child(2),\n\t\t&:nth-child(4) {\n\t\t\tmargin-right: 0;\n\t\t}\n\t}\n}\n\n#ModalVersionsTranslations {\n\t.modal-body {\n\t\t.md-body-dashVertical {\n\t\t\tdisplay: inline-block;\n\t\t\tmin-height: 150px;\n\t\t\tbackground: url(../img/dashline.v.png) top center repeat-y;\n\t\t}\n\t}\n\n\tstrong {\n\t\tdisplay: inline-block;\n\t\tpadding: 15px 0;\n\t}\n}\n\n.articleCtt .contribGroup .btnContribLinks,\n.ModalDefault .md-list li a {\n\t//&.orcid,\n\t&.lattes,\n\t&.researcherid, \n\t&.scopus {\n\t\tpadding-left: 30px;\n\t}\n\n\t&.scopus {\n\t\tbackground: url(../img/authorIcon-scopus.png) 10px center no-repeat;\n\t}\n\t&.orcid {\n\t\t//background: url(../img/authorIcon-orcid.png) 10px center no-repeat;\n\t}\n\t&.lattes {\n\t\tbackground: url(../img/authorIcon-lattes.png) 10px center no-repeat;\n\t}\n\t&.researcherid {\n\t\tbackground: url(../img/authorIcon-researcherid.png) 10px center no-repeat;\n\t}\n\t&.lattes-matteWhite {\n\t\tbackground: url(../img/authorIcon-lattes-matteWhite.png) 10px center no-repeat;\n\t}\n}\n\n\n\n\n\n\n/*\nAjustes para mobile\n*/\n/*\n@media $onlyMobile {\n\n\t.article{\n\n\t\t.no-gutter{\n\t\t\tmargin-left:0;\n\t\t\tmargin-right:0;\n\t\t}\n\n\t\t.bugherd,\n\t\t.articleMenu{\n\t\t\tdisplay:none;\n\t\t}\n\t\t#flDebugToolbarHandle{\n\t\t\tdisplay:none !important;\n\t\t}\n\n\t\t.container{\n\t\t\tmin-width:auto !important;\n\t\t}\n\t\t.articleCtt{\n\t\t\t//padding-top: 100px;\n\t\t}\n\n\t\t.levelMenu{\n\n\t\t\t&.levelMenu-xs{\n\t\t\t\tdisplay: block !important;\n\t\t\t}\n\n\t\t\tmargin-top: 50px !important;\n\t\t\theight: 135px !important;\n\n\t\t\t.btn-group{\n\t\t\t\tpadding-left:2px;\n\n\t\t\t\ta{\n\t\t\t\t\twidth:25%;\n\t\t\t\t}\n\t\t\t}\n\n\t\t\t.btn-group{\n\t\t\t\t&.levelMenuMobileTop{\n\t\t\t\t\tpadding-left:2px;\n\n\t\t\t\t\ta{\n\t\t\t\t\t\twidth:25%;\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t\t&.levelMenuMobileBottom{\n\t\t\t\t\tpadding-left:2px;\n\t\t\t\t\tmargin-top: -1px;\n\n\t\t\t\t\ta{\n\t\t\t\t\t\twidth:50%;\n\t\t\t\t\t\theight:38px;\n\n\t\t\t\t\t\t&:first-child{\n\t\t\t\t\t\t\twidth:25%;\n\t\t\t\t\t\t}\n\t\t\t\t\t\t&:last-child{\n\t\t\t\t\t\t\twidth:25%;\n\t\t\t\t\t\t\tmargin-left:-2px;\n\t\t\t\t\t\t}\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t}\n\t\t}\n\n\t\t.articleCtt .articleTxt .articleBadge-editionMeta-doi-copyLink .group-doi{\n\t\t\twhite-space: normal;\n\t\t\tmargin-top: 10px;\n\t\t\tdisplay:block;\n\t\t}\n\t\t.articleCtt .copyLink{\n\t\t\tdisplay: block;\n\t \tmargin: 10px auto;\n\t \tmax-width: 90px;\n\t\t}\n\t\t.articleCtt .contribGroup .dropdown .dropdown-toggle{\n\t\t\twhite-space: normal;\n\t\t}\n\t\t.articleCtt .articleTxt .articleSectionTitle,\n\t\t.articleCtt .articleTxt h2,\n\t\t.articleCtt .contribGroup\n\t\t{\n\t\t\tfont-size: auto;\n\t\t}\n\t\t.articleCtt .contribGroup {\n\t\t\tfont-size: 1em !important;\n\n\t\t\t.dropdown{\n\t\t\t\tdisplay: block;\n\t\t\t}\n\t\t}\n\t\t.articleCtt .articleTimeline li{\n\t\t\twidth: auto;\n\t\t\tdisplay: block;\n\t\t}\n\t\t.floatingBtnError{\n\t\t\tdisplay:none;\n\t\t}\n\n\t\t.floatingMenuMobile{\n\t\t\tleft: 5px;\n\t\t\tmargin: 0;\n\t\t\tbottom: 40px;\n\n\t\t\t&.isCookiebarActive{\n\t\t\t\tbottom: 120px;\n\t\t\t}\n\n\t\t\t@media (orientation : landscape) {\n\t\t\t\tbottom: 5px;\n\n\t\t\t\t&.isCookiebarActive{\n\t\t\t\t\tbottom: 70px;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\t\t.partners img{\n\t\t\tmargin: 10px;\n\t\t}\n\t\t.collectionSignature{\n\n\t\t\tdiv{\n\t\t\t\twidth: 100%;\n\t\t\t\ttext-align: center;\n\t\t\t}\n\n\t\t}\n\t\t.collectionSignature{\n\t\t\tpadding: 0 30px;\n\t\t\ttext-align: center;\n\n\t\t\t.logo-svg-footer{\n\t\t\t\tdisplay: inline-block;\n\t\t\t}\n\t\t}\n\t\t.articleCtt .articleTxt{\n\t\t\tpadding: 0 50px 10px;\n\t\t}\n\t\t.articleCtt .documentLicense .container-license{\n\t\t\ttext-align: center;\n\t\t\tpadding: 25px 25px 10px;\n\n\t\t\ta{\n\t\t\t\tmargin: 0 0 15px;\n\t\t\t}\n\t\t}\n\n\t\th1.article-title{\n\t\t\tfont-size:1.8em !important;\n\t\t}\n\t\th2.article-title{\n\t\t\tfont-size:1.5em !important;\n\t\t}\n\n\t\t.journalAddress{\n\t\t\ttext-align: center;\n\t\t\twidth: 100%;\n\n\t\t\tdiv{\n\t\t\t\twidth:100%;\n\t\t\t}\n\t\t\t.pin{\n\t\t\t\tmargin-bottom: 15px;\n\t\t\t}\n\t\t}\n\n\t\t.journalLinks{\n\t\t\ttext-align: center;\n\t\t\twidth: 100%;\n\n\t\t\ta {\n\t\t\t\tdisplay: block;\n\t\t\t\tmargin: 25px 0 0 0;\n\t\t\t}\n\t\t}\n\n\t\t.articleCtt .articleTxt .article-title .short-link{\n\t\t\tvisibility: visible;\n\t\t}\n\t\t.article .refList li{\n\t\t\tpadding: 8px 7px 14px;\n\t\t}\n\t\t.article .ref {\n\t\t\tposition: static;\n\n\t\t\t.opened{\n\t\t\t\twidth: auto;\n\t\t\t\tpadding: 10px;\n\t\t\t\tmax-width:350px;\n\n\t\t\t\t@media (orientation : landscape) {\n\t\t\t\t\tleft: auto !important;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t\t.article .ref-list .refList div{\n\t\t\tword-break: break-word;\n\t\t}\n\n\t\th2.logo-svg-mini {\n\n\t\t\tmargin-top: 10px;\n\t\t\tmargin-left: -25px;\n\n\t\t\ta {\n\t\t\t width: 58px;\n\t\t\t height: 50px;\n\t\t\t display: block;\n\t\t\t background: url(../img/logo-scielo-svg.svg) center center no-repeat;\n\t\t\t background-size: 95%;\n\t\t\t background-position-y: -5px;\n\t\t\t}\n\t\t}\n\n\t\t.language{\n\n\t\t\t@media (orientation : landscape) {\n\t\t\t\tposition: absolute;\n\t\t\t\tright: -85px;\n\t\t\t}\n\n\t\t\ta {\n\t\t\t\tdisplay: block;\n\t\t\t\tposition: static !important;\n\t\t\t\tdisplay: block;\n\t\t\t\twidth:auto;\n\n\n\t\t\t\t&:nth-child(1){\n\t\t\t\t\tmargin: 18px 0 0 15px !important;\n\t\t\t\t}\n\t\t\t\t&:nth-child(2){\n\t\t\t\t\tmargin: 10px 0 0 15px !important;\n\t\t\t\t\tbackground-position-x: 0px;\n\t\t\t\t}\n\n\t\t\t\t&.lang-es{\n\t\t\t\t\t//background-position: 1px -2px;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\n\t\t.journalNameMobile{\n\t\t\tpadding: 1rem;\n\t\t\tbackground: rgba(0,0,0,0.05);\n\n\t\t\ttext-align: center;\n\n\t\t\t&.open{\n\t\t\t\tul{\n\t\t\t\t\t.JournalMenuMobile{\n\t\t\t\t\t\tpadding: 0;\n\t\t\t\t\t\tmargin-top: 1rem;\n\n\t\t\t\t\t\tli{\n\t\t\t\t\t\t\ta{\n\t\t\t\t\t\t\t\tdisplay: block;\n\t\t\t\t\t\t\t\tpadding: @include 5rem;\n\t\t\t\t\t\t\t\ttext-align: left;\n\t\t\t\t\t\t\t}\n\t\t\t\t\t\t}\n\t\t\t\t\t}\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\t\t@media (orientation : landscape) {\n\t\t\t.alternativeHeader{\n\t\t\t\t.mainMenu{\n\t\t\t\t\tmax-height: 360px;\n\t\t\t\t\toverflow-y: auto;\n\t\t\t\t}\n\t\t\t}\n\t\t}\n\n\t\t.alternativeHeader{\n\t\t\t&.alternativeHeader-xs{\n\t\t\t\tdisplay: block !important;\n\t\t\t}\n\t\t\t.truncate{\n\t\t\t\twhite-space: nowrap;\n\t\t\t\toverflow: hidden;\n\t\t\t\ttext-overflow: ellipsis;\n\t\t\t\tmax-width: 315px;\n\t\t\t\tdisplay: inline-block;\n\t\t\t}\n\t\t\t.sci-ico-arrowDown{\n\t\t\t\tdisplay: inline-block;\n \t\t\tmargin: -10px 0 0 0;\n\t\t\t}\n\t\t}\n\n\t\t.alternativeHeader .dropdown-menu{\n\t\t\tmargin: -5px 10px 0 10px;\n\t \tborder-color: rgba(0,0,0,.15);\n\t \twidth: auto;\n\n\t \t@media (orientation : landscape) {\n\n\t\t\t\twidth: 300px;\n\t\t\t\tleft: 50%;\n\t\t\t\tmargin-left:-150px;\n\n\t\t\t}\n\n\t \ta{\n\t \t\timg{\n\n\t \t\t\t@media (orientation : landscape) {\n\n\t\t\t\t\t\twidth: auto;\n\t\t\t\t\t\tmax-height: 50px;\n\n\t\t\t\t\t}\n\t \t\t}\n\t \t}\n\t\t}\n\n\t\t.menu-share-mobile{\n\t\t\tright: 3px;\n\t \tleft: auto;\n\t \ttop: 35px;\n\n\t \t@media (orientation : landscape) {\n\t \t\tz-index: 998;\n\t \t}\n\t\t}\n\n\t\t.tooltip-mobile-on{\n\t\t\t&:after{\n\t\t\t\tcontent:\"\";\n\t\t\t}\n\t\t}\n\n\n\t}\n\n\n}\n\n*/\n\n/** Article container\n*************************************/\n.articleCtt {\n\t.article-title.page-header-title,\n\t.only-renditions-available p {\n\t\ttext-align: center;\n\t}\n\n\t/** Graphical information container\n\t*************************************/\n\t.only-renditions-available .jumbotron {\n\t\tbackground-color: #f6f8fa;\n\t\tmargin-top: 35px;\n\t}\n}\n\n\n.levelMenu{\n\n\t.btn{\n\t\tmin-height: 38px;\n\n\t\t&.group{\n\t\t\twidth: auto;\n\t\t\tpadding-left: 16px !important;\n\t\t\tpadding-right: 16px !important;\n\n /*\n\t\t\t@media $minDesktop {\n\t\t\t\tpadding-left: 32px !important;\n\t\t\t\tpadding-right: 32px !important;\n\t\t\t}\n */\n\t\t}\n\n\t\t&:hover{\n\t\t\t//background: $Blue !important;\n\t\t\tcolor: #fff;\n\n\t\t\t[class^=\"sci-ico-\"] {\n\t\t\t\tcolor: #fff;\n\t\t\t}\n\t\t}\n\t}\n\t.dropdown-menu{\n\t\ta.current{\n\t\t\tposition: relative;\n\t\t\twidth: 100%;\n\t\t\tfont-weight: bold;\n\n\t\t\t&:after{\n\t\t\t\tcontent:\"✓\";\n\t\t\t\tdisplay: inline-block;\n\t\t\t\tposition: absolute;\n\t\t\t\tright: 5px;\n\t\t\t}\n\t\t}\n\n\t\t&.menu-share-mobile{\n /*\n\t\t\t@media $onlyTablet {\n\t\t\t\tleft: auto;\n\t\t\t}\n */\n\t\t}\n\n\n\t}\n}\n\n.levelMenu-xs{\n\n\t/* Btn Group nav mobile*/\n\t.btn-group{\n\n\t\t&.btn-group-nav-mobile{\n\t\t\twidth: 100%;\n\t\t\tdisplay: table;\n\n\t\t\t>.btn{\n\t\t\t\tdisplay: table-cell;\n\t\t\t\twidth: 60%;\n\n\t\t\t\t&:first-of-type{\n\t\t\t\t\twidth: 20%;\n\t\t\t\t}\n\n\t\t\t\t&:last-of-type{\n\t\t\t\t\twidth: 20%;\n\t\t\t\t}\n\n\t\t\t\t.sci-ico-socialOther{\n\t\t\t\t\tdisplay: inline-block;\n\t\t\t\t\twidth: 70%;\n\t\t\t\t}\n\n /*\n\t\t\t\t@media $onlyMobile {\n\t\t\t\t\t.caret{\n\t\t\t\t\t\tposition: absolute;\n\t\t\t\t\t\tright: 10px;\n\t\t\t\t\t\ttop: 17px;\n\t\t\t\t\t}\n\t\t\t\t}\n */\n\n\t\t\t}\n\t\t}\n\t\t&.btn-group-nav-mobile-content{\n\t\t\twidth: 100%;\n\t\t\tdisplay: table;\n\t\t\tpadding: 5px 2px;\n\n\t\t\t>.dropdown{\n\t\t\t\tdisplay: table-cell;\n\t\t\t\twidth: 33%;\n\t\t\t\tpadding-right:4px;\n\n\t\t\t\t&:last-child{\n\t\t\t\t\tpadding-right: 0;\n\n\t\t\t\t\t.btn{\n\t\t\t\t\t\tspan{\n\t\t\t\t\t\t\twidth: auto;\n\n\t\t\t\t\t\t\t&:nth-child(2){\n\t\t\t\t\t\t\t\twidth: 55%;\n\t\t\t\t\t\t\t}\n\t\t\t\t\t\t}\n\t\t\t\t\t}\n\t\t\t\t}\n\n\t\t\t\t.btn{\n\t\t\t\t\twidth: 100%;\n\t\t\t\t\tposition: relative;\n\n\t\t\t\t\tspan{\n\n\t\t\t\t\t\twidth: 90%;\n\t\t\t\t\t\tdisplay: inline-block;\n\n\t\t\t\t\t\t&:last-child{\n\t\t\t\t\t\t\twidth: auto;\n\t\t\t\t\t\t}\n\n\t\t\t\t\t\t&.caret{\n\t\t\t\t\t\t\tposition: absolute; \n\t\t\t\t\t\t\tright: 10px;\n\t\t\t\t\t\t\ttop: 17px; \n\t\t\t\t\t\t}\n\n\t\t\t\t\t} \n\t\t\t\t}\n\t\t\t}\n\t\t}\n\t}\n}\n \n\n.xref.xrefblue{\n color: $__interaction--light;\n // outline: 2px solid green; \n\n @include __on-theme--dark {\n color: $__interaction--dark; \n // outline: 2px solid red;\n }\n\n @include __on-theme--light {\n color: $__interaction--light;\n // outline: 2px solid brown;\n } \n}\n\n\n\n\n\n/*\nApenas para teste fora do opac\n*/\n\n.ref {\n\n\t@include __breakpoint--xsmall-only() {\n\t\tposition: static;\n\t}\n \n .opened {\n\n background: $__interaction--light;\n color: $__white;\n\n\t\t@include __breakpoint--xsmall-only() {\n\t\t\twidth: 90%;\n\t\t\tmargin-left: 5%;\n\t\t} \n\n @include __on-theme--dark {\n background: $__interaction--dark;\n color: $__bg--dark;\n }\n @include __on-theme--light {\n background: $__interaction--light;\n color: $__white;\n }\n }\n}\n/*\n*/","@mixin __on-theme--dark {\n @at-root .#{$__classPrefix}__theme--dark & {\n @content;\n }\n}\n\n@mixin __on-theme--light {\n @at-root .#{$__classPrefix}__theme--light & {\n @content;\n }\n}\n\n\n@mixin animated($time: .5s, $prop: background, $prop2: text-indent){\n -webkit-animation-fill-mode: both;\n -moz-animation-fill-mode: both;\n -ms-animation-fill-mode: both;\n -o-animation-fill-mode: both;\n animation-fill-mode: both;\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time;\n\n -o-transition: $prop $time ease-out, $prop2 $time ease-out;\n -ms-transition: $prop $time ease-out, $prop2 $time ease-out;\n -moz-transition: $prop $time ease-out, $prop2 $time ease-out;\n -webkit-transition: $prop $time ease-out, $prop2 $time ease-out;\n transition: $prop $time ease-out, $prop2 $time ease-out;\n}\n\n@-webkit-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-webkit-transform: translateY(0);}\n 40% {-webkit-transform: translateY(30px);}\n 60% {-webkit-transform: translateY(15px);}\n}\n\n@-moz-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-moz-transform: translateY(0);}\n 40% {-moz-transform: translateY(30px);}\n 60% {-moz-transform: translateY(15px);}\n}\n\n@-ms-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-ms-transform: translateY(0);}\n 40% {-ms-transform: translateY(30px);}\n 60% {-ms-transform: translateY(15px);}\n}\n\n@-o-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-o-transform: translateY(0);}\n 40% {-o-transform: translateY(30px);}\n 60% {-o-transform: translateY(15px);}\n}\n@keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {transform: translateY(0);}\n 40% {transform: translateY(30px);}\n 60% {transform: translateY(15px);}\n}\n\n@mixin bounce($time: .5s){\n -webkit-animation-name: bounce;\n -moz-animation-name: bounce;\n -ms-animation-name: bounce;\n -o-animation-name: bounce;\n animation-name: bounce;\n\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time; \n}\n\n@mixin slideInUp($time: .5s){\n -webkit-animation-name: slideInUp;\n animation-name: slideInUp;\n\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time;\n}\n\n@-webkit-keyframes slideInUp {\n from {\n -webkit-transform: translate3d(0, 30%, 0);\n transform: translate3d(0, 30%, 0);\n visibility: visible;\n opacity: 0;\n }\n\n to {\n -webkit-transform: translate3d(0, 0, 0);\n transform: translate3d(0, 0, 0);\n opacity: 1;\n }\n}\n","@mixin __breakpoint--xsmall() {\n @media screen and (min-width: #{$__breakpoints--xsmall}) {\n @content;\n }\n}\n\n@mixin __breakpoint--xsmall-only() {\n @media screen and (max-width: #{$__breakpoints--small - 1px}) {\n @content;\n }\n}\n\n@mixin __breakpoint--small() {\n @media screen and (min-width: #{$__breakpoints--small}) {\n @content;\n }\n}\n\n@mixin __breakpoint--small-only() {\n @media screen and (min-width: #{$__breakpoints--small}) and (max-width: #{$__breakpoints--medium - 1px}) {\n @content;\n }\n}\n\n@mixin __breakpoint--medium() {\n @media screen and (min-width: #{$__breakpoints--medium}) {\n @content;\n }\n}\n\n@mixin __breakpoint--medium-only() {\n @media screen and (min-width: #{$__breakpoints--medium}) and (max-width: #{$__breakpoints--large - 1px}) {\n @content;\n }\n}\n\n@mixin __breakpoint--large() {\n @media screen and (min-width: #{$__breakpoints--large}) {\n @content;\n }\n}\n\n@mixin __breakpoint--large-only() {\n @media screen and (min-width: #{$__breakpoints--large}) and (max-width: #{$__breakpoints--xlarge - 1px}) {\n @content;\n }\n}\n\n@mixin __breakpoint--xlarge() {\n @media screen and (min-width: #{$__breakpoints--xlarge}) {\n @content;\n }\n}","$__white: #fff;\n$__black: #000;\n\n$__brand__main: #DA202C;\n// $__brand__gradient: linear-gradient(71.13deg, #27396E 0%, #4AB0E6 100%);\n\n$__bg--light: $__white;\n$__bg--dark: #333;\n\n$__text--light: #333;\n$__text__emphasis--light: #00314C;\n$__text__subtle--light: #6C6B6B;\n\n$__text--dark: #C4C4C4;\n$__text__emphasis--dark: #EEE;\n$__text__subtle--dark: #ADADAD;\n\n$__interaction--light: #3867CE;\n$__interaction--dark: #86ACFF;\n\n//$__hover--light: rgba(0, 176, 230, 0.2);\n$__hover--light: rgba(0, 176, 230, 0.2);\n$__hover--light40: rgba(0, 176, 230, 0.08);\n$__hover--dark: rgba(0, 176, 230, 0.6);\n$__hover--dark40: rgba(0, 176, 230, 0.24);\n\n$__positive--light: #2C9D45;\n$__positive--dark: #2C9D45;\n\n$__negative--light: #C63800;\n$__negative--dark: #FF7E4A;\n\n$__warning--light: #B67F00;\n$__warning--dark: #B67F00;\n\n$__info--light: #2195A9;\n$__info--dark: #2299AD;\n\n$__support__green--light: #30A47F;\n$__support__green--dark: #30A47F;\n\n$__support__purple--light: #6628EE;\n$__support__purple--dark: #8D5DF8;\n\n$__support__yellow--light: #C38900;\n$__support__yellow--dark: #C38900;\n\n$__support__blue--light: #25A2B7;\n$__support__blue--dark: #25A2B7;\n\n$__disabled: rgba($__black,.1);\n$__disabled--light: rgba($__black,.1);\n$__disabled__text--light: rgba($__black,.1);\n$__disabled--dark: rgba($__white,.2);\n$__disabled__text--dark: rgba($__white,.2);\n\n$__bg__gray--1: #F7F6F4;\n$__bg__gray--2: #EFEEEC;\n$__bg__white--1: #393939;\n$__bg__white--2: #414141;\n\n//$__border--light: #ccc;\n//$__border--dark: #ccc;\n\n//$__border--light: $__bg__gray--2;\n$__border--light: #ccc;\n$__border--dark: rgba($__white,.3);\n\n$__border--light--focus: rgba($__interaction--light,0.6);\n$__border--dark--focus: rgba($__interaction--dark,0.6);\n\n\n// verificar utilização \n$__menu--light: $__white;\n$__menu--dark: $__text__emphasis--dark;\n\n// Text marker\n$__selection: #F8F567;\n$__selection--dark: #070a98;\n\n//private\n$_bg__backdrop: rgba($__black,.8);\n\n//hover secondary\n$__hover__secondary--light: $__bg__gray--1;\n$__hover__secondary--dark: $__bg__white--2;\n\n\n//focus\n$__focus: rgba($__interaction--light, .25);\n\n\n$__focus--primary: rgba($__interaction--light, .25);\n$__focus--secondary: rgba($__border--light, .25);\n$__focus--success: rgba($__positive--light, .25);\n$__focus--warning: rgba($__warning--light, .25);\n$__focus--info: rgba($__info--light, .25);\n$__focus--alert: rgba($__negative--light, .25);","@mixin __text__overline {\n font-weight: bold;\n font-size: .75rem;\n line-height: $__font__line-height;\n letter-spacing: 0.06px;\n}\n\n@mixin __text__caption {\n font-weight: normal;\n font-size: 1rem;\n line-height: 1.2em;\n}\n\n@mixin __text__caption--large {\n font-weight: 700;\n font-size: 1;\n line-height: 1.2em;\n letter-spacing: 0;\n}\n\n@mixin __text__button {\n font-weight: 400 !important;\n font-size: 1rem;\n letter-spacing: 0.1px !important;\n white-space: nowrap;\n}\n\n@mixin __text__button--large {\n font-size: 1.25rem;\n}\n\n@mixin __text__body {\n font-weight: normal;\n font-size: 1rem;\n line-height: 1.6em;\n letter-spacing: 0.1px;\n}\n\n@mixin __text__body--large {\n font-size: __remcalc(18);\n}\n\n@mixin __text__body--small {\n font-size: .75rem;\n letter-spacing: 0.06;\n}\n\n@mixin __text__body--micro {\n font-size: .75rem;\n}\n\n@mixin __text__body--link {\n //font-weight: bold;\n}\n\n@mixin __text__subhead {\n font-weight: bold;\n font-size: __remcalc(21);\n line-height: 1.25em;\n letter-spacing: 0;\n}\n\n@mixin __text__subhead--small {\n font-size: __remcalc(16.5);\n letter-spacing: 0;\n}\n\n@mixin __text__title--1 {\n font-weight: 700;\n font-size: 2.5rem; \n line-height: $__font__line-height;\n letter-spacing: -0.2px;\n}\n\n@mixin __text__title--2 {\n font-weight: 700;\n font-size: 2rem;\n line-height: $__font__line-height;\n letter-spacing: -0.16px;\n}\n\n@mixin __text__title--3 {\n font-weight: 700;\n font-size: 1.75rem;\n line-height: $__font__line-height;\n letter-spacing: -0.14px;\n}\n\n@mixin __text__title--4 {\n font-weight: 700;\n font-size: 1.5rem;\n line-height: $__font__line-height;\n letter-spacing: -.12px;\n}\n\n@mixin __text__title--5 {\n font-weight: 700;\n font-size: 1.25rem;\n line-height: $__font__line-height;\n letter-spacing: -.1px;\n}\n\n@mixin __text__title--6 {\n font-weight: 700;\n font-size: 1rem;\n line-height: $__font__line-height;\n letter-spacing: .08px;\n}\n\n@mixin __text__brand {\n font-family: $__font__family--brand;\n font-weight: 400;\n font-size: 1rem;\n line-height: $__font__line-height;\n}\n\n@mixin __material-icons{\n\n .material-icons,\n .material-icons-outlined{\n \n vertical-align: text-bottom;\n font-size: inherit;\n line-height: inherit;\n display: inline-block;\n\n /*\n correção da largura máxima dos ícones para titulo de modal\n .modal-title &{\n max-width: 30px;\n outline: 1px solid red;\n }\n */\n\n }\n}","$__font__family: 'Noto Sans', sans-serif;\n$__font__family--brand: 'Arapey', serif;\n$__font__rem: 16px;\n\n$__font__rem--article: 18px;\n\n$__font__line-height: 1.2em;\n$__font__line-height--article: 1.6em;"]} \ No newline at end of file diff --git a/tests/fixtures/novo-menu-flutuante/css/bootstrap-grid.css b/tests/fixtures/novo-menu-flutuante/css/bootstrap-grid.css new file mode 100644 index 000000000..9a9b456db --- /dev/null +++ b/tests/fixtures/novo-menu-flutuante/css/bootstrap-grid.css @@ -0,0 +1,7 @@ +/*! + * Bootstrap Grid v5.0.0-beta1 (https://getbootstrap.com/) + * Copyright 2011-2020 The Bootstrap Authors + * Copyright 2011-2020 Twitter, Inc. + * Licensed under MIT 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* Bootstrap Grid v5.0.0-beta1 (https://getbootstrap.com/)\n * Copyright 2011-2020 The Bootstrap Authors\n * Copyright 2011-2020 Twitter, Inc.\n * Licensed under MIT (https://github.com/twbs/bootstrap/blob/main/LICENSE)\n */\n\n $include-column-box-sizing: true !default;\n\n @import \"scss/functions\";\n\n @import \"../../common/scss/itcssImports/vars\";\n @import \"../../common/scss/itcssImports/mixins\";\n @import \"./settings/variables\";\n \n @import \"scss/mixins/lists\";\n @import \"scss/mixins/breakpoints\";\n @import \"scss/mixins/container\";\n @import \"scss/mixins/grid\";\n @import \"scss/mixins/utilities\";\n \n @import \"scss/vendor/rfs\";\n \n @import \"scss/containers\";\n @import \"scss/grid\";\n \n @import \"scss/utilities\";\n // Only use the utilities we need\n // stylelint-disable-next-line scss/dollar-variable-default\n $utilities: map-get-multiple(\n $utilities,\n (\n \"display\",\n \"order\",\n \"flex\",\n \"flex-direction\",\n \"flex-grow\",\n \"flex-shrink\",\n \"flex-wrap\",\n \"justify-content\",\n \"align-items\",\n \"align-content\",\n \"align-self\",\n \"margin\",\n \"margin-x\",\n \"margin-y\",\n \"margin-top\",\n \"margin-end\",\n \"margin-bottom\",\n \"margin-start\",\n \"negative-margin\",\n \"negative-margin-x\",\n \"negative-margin-y\",\n \"negative-margin-top\",\n \"negative-margin-end\",\n \"negative-margin-bottom\",\n \"negative-margin-start\",\n \"padding\",\n \"padding-x\",\n \"padding-y\",\n \"padding-top\",\n \"padding-end\",\n \"padding-bottom\",\n \"padding-start\",\n )\n );\n \n @import \"scss/utilities/api\";\n ","@mixin __on-theme--dark {\n @at-root .#{$__classPrefix}__theme--dark & {\n @content;\n }\n}\n\n@mixin __on-theme--light {\n @at-root .#{$__classPrefix}__theme--light & {\n @content;\n }\n}\n\n\n@mixin animated($time: .5s, $prop: background, $prop2: text-indent){\n -webkit-animation-fill-mode: both;\n -moz-animation-fill-mode: both;\n -ms-animation-fill-mode: both;\n -o-animation-fill-mode: both;\n animation-fill-mode: both;\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time;\n\n -o-transition: $prop $time ease-out, $prop2 $time ease-out;\n -ms-transition: $prop $time ease-out, $prop2 $time ease-out;\n -moz-transition: $prop $time ease-out, $prop2 $time ease-out;\n -webkit-transition: $prop $time ease-out, $prop2 $time ease-out;\n transition: $prop $time ease-out, $prop2 $time ease-out;\n}\n\n@-webkit-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-webkit-transform: translateY(0);}\n 40% {-webkit-transform: translateY(30px);}\n 60% {-webkit-transform: translateY(15px);}\n}\n\n@-moz-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-moz-transform: translateY(0);}\n 40% {-moz-transform: translateY(30px);}\n 60% {-moz-transform: translateY(15px);}\n}\n\n@-ms-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-ms-transform: translateY(0);}\n 40% {-ms-transform: translateY(30px);}\n 60% {-ms-transform: translateY(15px);}\n}\n\n@-o-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-o-transform: translateY(0);}\n 40% {-o-transform: translateY(30px);}\n 60% {-o-transform: translateY(15px);}\n}\n@keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {transform: translateY(0);}\n 40% {transform: translateY(30px);}\n 60% {transform: translateY(15px);}\n}\n\n@mixin bounce($time: .5s){\n -webkit-animation-name: bounce;\n -moz-animation-name: bounce;\n -ms-animation-name: bounce;\n -o-animation-name: bounce;\n animation-name: bounce;\n\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time; \n}\n\n@mixin slideInUp($time: .5s){\n -webkit-animation-name: slideInUp;\n animation-name: slideInUp;\n\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time;\n}\n\n@-webkit-keyframes slideInUp {\n from {\n -webkit-transform: translate3d(0, 30%, 0);\n transform: translate3d(0, 30%, 0);\n visibility: visible;\n opacity: 0;\n }\n\n to {\n -webkit-transform: translate3d(0, 0, 0);\n transform: translate3d(0, 0, 0);\n opacity: 1;\n }\n}\n","// Container widths\n//\n// Set the container width, and override it for fixed navbars in media queries.\n\n@if $enable-grid-classes {\n // Single container class with breakpoint max-widths\n .container,\n // 100% wide container at all breakpoints\n .container-fluid {\n @include make-container();\n }\n\n // Responsive containers that are 100% wide until a breakpoint\n @each $breakpoint, $container-max-width in $container-max-widths {\n .container-#{$breakpoint} {\n @extend .container-fluid;\n }\n\n @include media-breakpoint-up($breakpoint, $grid-breakpoints) {\n %responsive-container-#{$breakpoint} {\n max-width: $container-max-width;\n }\n\n // Extend each breakpoint which is smaller or equal to the current breakpoint\n $extend-breakpoint: true;\n\n @each $name, $width in $grid-breakpoints {\n @if ($extend-breakpoint) {\n .container#{breakpoint-infix($name, $grid-breakpoints)} {\n @extend %responsive-container-#{$breakpoint};\n }\n\n // Once the current breakpoint is reached, stop extending\n @if ($breakpoint == $name) {\n $extend-breakpoint: false;\n }\n }\n }\n }\n }\n}\n","// Container mixins\n\n@mixin make-container($gutter: $container-padding-x) {\n width: 100%;\n padding-right: var(--#{$variable-prefix}gutter-x, #{$gutter});\n padding-left: var(--#{$variable-prefix}gutter-x, #{$gutter});\n margin-right: auto;\n margin-left: auto;\n}\n","// Breakpoint viewport sizes and media queries.\n//\n// Breakpoints are defined as a map of (name: minimum width), order from small to large:\n//\n// (xs: 0, sm: 576px, md: 768px, lg: 992px, xl: 1200px)\n//\n// The map defined in the `$grid-breakpoints` global variable is used as the `$breakpoints` argument by default.\n\n// Name of the next breakpoint, or null for the last breakpoint.\n//\n// >> breakpoint-next(sm)\n// md\n// >> breakpoint-next(sm, (xs: 0, sm: 576px, md: 768px, lg: 992px, xl: 1200px))\n// md\n// >> breakpoint-next(sm, $breakpoint-names: (xs sm md lg xl))\n// md\n@function breakpoint-next($name, $breakpoints: $grid-breakpoints, $breakpoint-names: map-keys($breakpoints)) {\n $n: index($breakpoint-names, $name);\n @if not $n {\n @error \"breakpoint `#{$name}` not found in `#{$breakpoints}`\";\n }\n @return if($n < length($breakpoint-names), nth($breakpoint-names, $n + 1), null);\n}\n\n// Minimum breakpoint width. Null for the smallest (first) breakpoint.\n//\n// >> breakpoint-min(sm, (xs: 0, sm: 576px, md: 768px, lg: 992px, xl: 1200px))\n// 576px\n@function breakpoint-min($name, $breakpoints: $grid-breakpoints) {\n $min: map-get($breakpoints, $name);\n @return if($min != 0, $min, null);\n}\n\n// Maximum breakpoint width.\n// The maximum value is reduced by 0.02px to work around the limitations of\n// `min-` and `max-` prefixes and viewports with fractional widths.\n// See https://www.w3.org/TR/mediaqueries-4/#mq-min-max\n// Uses 0.02px rather than 0.01px to work around a current rounding bug in Safari.\n// See https://bugs.webkit.org/show_bug.cgi?id=178261\n//\n// >> breakpoint-max(md, (xs: 0, sm: 576px, md: 768px, lg: 992px, xl: 1200px))\n// 767.98px\n@function breakpoint-max($name, $breakpoints: $grid-breakpoints) {\n $max: map-get($breakpoints, $name);\n @return if($max and $max > 0, $max - .02, null);\n}\n\n// Returns a blank string if smallest breakpoint, otherwise returns the name with a dash in front.\n// Useful for making responsive utilities.\n//\n// >> breakpoint-infix(xs, (xs: 0, sm: 576px, md: 768px, lg: 992px, xl: 1200px))\n// \"\" (Returns a blank string)\n// >> breakpoint-infix(sm, (xs: 0, sm: 576px, md: 768px, lg: 992px, xl: 1200px))\n// \"-sm\"\n@function breakpoint-infix($name, $breakpoints: $grid-breakpoints) {\n @return if(breakpoint-min($name, $breakpoints) == null, \"\", \"-#{$name}\");\n}\n\n// Media of at least the minimum breakpoint width. No query for the smallest breakpoint.\n// Makes the @content apply to the given breakpoint and wider.\n@mixin media-breakpoint-up($name, $breakpoints: $grid-breakpoints) {\n $min: breakpoint-min($name, $breakpoints);\n @if $min {\n @media (min-width: $min) {\n @content;\n }\n } @else {\n @content;\n }\n}\n\n// Media of at most the maximum breakpoint width. No query for the largest breakpoint.\n// Makes the @content apply to the given breakpoint and narrower.\n@mixin media-breakpoint-down($name, $breakpoints: $grid-breakpoints) {\n $max: breakpoint-max($name, $breakpoints);\n @if $max {\n @media (max-width: $max) {\n @content;\n }\n } @else {\n @content;\n }\n}\n\n// Media that spans multiple breakpoint widths.\n// Makes the @content apply between the min and max breakpoints\n@mixin media-breakpoint-between($lower, $upper, $breakpoints: $grid-breakpoints) {\n $min: breakpoint-min($lower, $breakpoints);\n $max: breakpoint-max($upper, $breakpoints);\n\n @if $min != null and $max != null {\n @media (min-width: $min) and (max-width: $max) {\n @content;\n }\n } @else if $max == null {\n @include media-breakpoint-up($lower, $breakpoints) {\n @content;\n }\n } @else if $min == null {\n @include media-breakpoint-down($upper, $breakpoints) {\n @content;\n }\n }\n}\n\n// Media between the breakpoint's minimum and maximum widths.\n// No minimum for the smallest breakpoint, and no maximum for the largest one.\n// Makes the @content apply only to the given breakpoint, not viewports any wider or narrower.\n@mixin media-breakpoint-only($name, $breakpoints: $grid-breakpoints) {\n $min: breakpoint-min($name, $breakpoints);\n $next: breakpoint-next($name, $breakpoints);\n $max: breakpoint-max($next);\n\n @if $min != null and $max != null {\n @media (min-width: $min) and (max-width: $max) {\n @content;\n }\n } @else if $max == null {\n @include media-breakpoint-up($name, $breakpoints) {\n @content;\n }\n } @else if $min == null {\n @include media-breakpoint-down($next, $breakpoints) {\n @content;\n }\n }\n}\n","$__grid__columns: 12;\n\n$__grid__container--xsmall: ($__breakpoints--small - 1px);\n$__grid__container--small: 100%;\n$__grid__container--medium: 720px;\n$__grid__container--large: 960px;\n$__grid__container--xlarge: 1140px;\n$__grid__container--xxlarge: 1320px;\n\n$__module__xsmall: 16px;\n$__module__small: 20px;\n$__module__medium: 24px;\n$__module__large: 32px;\n$__module__xlarge: 40px;\n\n$__module__xsmall--half: $__module__xsmall / 2;\n$__module__small--half: $__module__small / 2;\n$__module__medium--half: $__module__medium / 2;\n$__module__large--half: $__module__large / 2;\n$__module__xlarge--half: $__module__xlarge / 2;\n\n$__module__xsmall--quarter: $__module__xsmall / 4;\n$__module__small--quarter: $__module__small / 4;\n$__module__medium--quarter: $__module__medium / 4;\n$__module__large--quarter: $__module__large / 4;\n$__module__xlarge--quarter: $__module__xlarge / 4;\n\n$__grid__gutter--xsmall: $__module__xsmall;\n$__grid__gutter--small: $__module__small;\n$__grid__gutter--medium: $__module__medium;\n$__grid__gutter--large: $__module__large;\n$__grid__gutter--xlarge: $__module__xlarge;\n\n$__module__space--small: 12;\n$__module__space--default: 24;\n$__module__space--large: 48;","// Row\n//\n// Rows contain your columns.\n\n@if $enable-grid-classes {\n .row {\n @include make-row();\n\n > * {\n @include make-col-ready();\n }\n }\n}\n\n\n// Columns\n//\n// Common styles for small and large grid columns\n\n@if $enable-grid-classes {\n @include make-grid-columns();\n}\n","/// Grid system\n//\n// Generate semantic grid columns with these mixins.\n\n@mixin make-row($gutter: $grid-gutter-width) {\n --#{$variable-prefix}gutter-x: #{$gutter};\n --#{$variable-prefix}gutter-y: 0;\n display: flex;\n flex-wrap: wrap;\n margin-top: calc(var(--#{$variable-prefix}gutter-y) * -1); // stylelint-disable-line function-disallowed-list\n margin-right: calc(var(--#{$variable-prefix}gutter-x) / -2); // stylelint-disable-line function-disallowed-list\n margin-left: calc(var(--#{$variable-prefix}gutter-x) / -2); // stylelint-disable-line function-disallowed-list\n}\n\n@mixin make-col-ready($gutter: $grid-gutter-width) {\n // Add box sizing if only the grid is loaded\n box-sizing: if(variable-exists(include-column-box-sizing) and $include-column-box-sizing, border-box, null);\n // Prevent columns from becoming too narrow when at smaller grid tiers by\n // always setting `width: 100%;`. This works because we set the width\n // later on to override this initial width.\n flex-shrink: 0;\n width: 100%;\n max-width: 100%; // Prevent `.col-auto`, `.col` (& responsive variants) from breaking out the grid\n padding-right: calc(var(--#{$variable-prefix}gutter-x) / 2); // stylelint-disable-line function-disallowed-list\n padding-left: calc(var(--#{$variable-prefix}gutter-x) / 2); // stylelint-disable-line function-disallowed-list\n margin-top: var(--#{$variable-prefix}gutter-y);\n}\n\n@mixin make-col($size, $columns: $grid-columns) {\n flex: 0 0 auto;\n width: percentage($size / $columns);\n}\n\n@mixin make-col-auto() {\n flex: 0 0 auto;\n width: auto;\n}\n\n@mixin make-col-offset($size, $columns: $grid-columns) {\n $num: $size / $columns;\n margin-left: if($num == 0, 0, percentage($num));\n}\n\n// Row columns\n//\n// Specify on a parent element(e.g., .row) to force immediate children into NN\n// numberof columns. Supports wrapping to new lines, but does not do a Masonry\n// style grid.\n@mixin row-cols($count) {\n > * {\n flex: 0 0 auto;\n width: 100% / $count;\n }\n}\n\n// Framework grid generation\n//\n// Used only by Bootstrap to generate the correct number of grid classes given\n// any value of `$grid-columns`.\n\n@mixin make-grid-columns($columns: $grid-columns, $gutter: $grid-gutter-width, $breakpoints: $grid-breakpoints) {\n @each $breakpoint in map-keys($breakpoints) {\n $infix: breakpoint-infix($breakpoint, $breakpoints);\n\n @include media-breakpoint-up($breakpoint, $breakpoints) {\n // Provide basic `.col-{bp}` classes for equal-width flexbox columns\n .col#{$infix} {\n flex: 1 0 0%; // Flexbugs #4: https://github.com/philipwalton/flexbugs#flexbug-4\n }\n\n .row-cols#{$infix}-auto > * {\n @include make-col-auto();\n }\n\n @if $grid-row-columns > 0 {\n @for $i from 1 through $grid-row-columns {\n .row-cols#{$infix}-#{$i} {\n @include row-cols($i);\n }\n }\n }\n\n .col#{$infix}-auto {\n @include make-col-auto();\n }\n\n @if $columns > 0 {\n @for $i from 1 through $columns {\n .col#{$infix}-#{$i} {\n @include make-col($i, $columns);\n }\n }\n\n // `$columns - 1` because offsetting by the width of an entire row isn't possible\n @for $i from 0 through ($columns - 1) {\n @if not ($infix == \"\" and $i == 0) { // Avoid emitting useless .offset-0\n .offset#{$infix}-#{$i} {\n @include make-col-offset($i, $columns);\n }\n }\n }\n }\n\n // Gutters\n //\n // Make use of `.g-*`, `.gx-*` or `.gy-*` utilities to change spacing between the columns.\n @each $key, $value in $gutters {\n .g#{$infix}-#{$key},\n .gx#{$infix}-#{$key} {\n --#{$variable-prefix}gutter-x: #{$value};\n }\n\n .g#{$infix}-#{$key},\n .gy#{$infix}-#{$key} {\n --#{$variable-prefix}gutter-y: #{$value};\n }\n }\n }\n }\n}\n","// Utility generator\n// Used to generate utilities & print utilities\n@mixin generate-utility($utility, $infix, $is-rfs-media-query: false) {\n $values: map-get($utility, values);\n\n // If the values are a list or string, convert it into a map\n @if type-of($values) == \"string\" or type-of(nth($values, 1)) != \"list\" {\n $values: zip($values, $values);\n }\n\n @each $key, $value in $values {\n $properties: map-get($utility, property);\n\n // Multiple properties are possible, for example with vertical or horizontal margins or paddings\n @if type-of($properties) == \"string\" {\n $properties: append((), $properties);\n }\n\n // Use custom class if present\n $property-class: if(map-has-key($utility, class), map-get($utility, class), nth($properties, 1));\n $property-class: if($property-class == null, \"\", $property-class);\n\n // State params to generate pseudo-classes\n $state: if(map-has-key($utility, state), map-get($utility, state), ());\n\n $infix: if($property-class == \"\" and str-slice($infix, 1, 1) == \"-\", str-slice($infix, 2), $infix);\n\n // Don't prefix if value key is null (eg. with shadow class)\n $property-class-modifier: if($key, if($property-class == \"\" and $infix == \"\", \"\", \"-\") + $key, \"\");\n\n @if map-get($utility, rfs) {\n // Inside the media query\n @if $is-rfs-media-query {\n $val: rfs-value($value);\n\n // Do not render anything if fluid and non fluid values are the same\n $value: if($val == rfs-fluid-value($value), null, $val);\n }\n @else {\n $value: rfs-fluid-value($value);\n }\n }\n\n $is-rtl: map-get($utility, rtl);\n\n @if $value != null {\n @if $is-rtl == false {\n /* rtl:begin:remove */\n }\n .#{$property-class + $infix + $property-class-modifier} {\n @each $property in $properties {\n #{$property}: $value if($enable-important-utilities, !important, null);\n }\n }\n\n @each $pseudo in $state {\n .#{$property-class + $infix + $property-class-modifier}-#{$pseudo}:#{$pseudo} {\n @each $property in $properties {\n #{$property}: $value if($enable-important-utilities, !important, null);\n }\n }\n }\n @if $is-rtl == false {\n /* rtl:end:remove */\n }\n }\n }\n}\n","// stylelint-disable indentation\n\n// Utilities\n\n$utilities: () !default;\n// stylelint-disable-next-line scss/dollar-variable-default\n$utilities: map-merge(\n (\n // scss-docs-start utils-vertical-align\n \"align\": (\n property: vertical-align,\n class: align,\n values: baseline top middle bottom text-bottom text-top\n ),\n // scss-docs-end utils-vertical-align\n // scss-docs-start utils-float\n \"float\": (\n responsive: true,\n property: float,\n values: (\n start: left,\n end: right,\n none: none,\n )\n ),\n // scss-docs-end utils-float\n // scss-docs-start utils-overflow\n \"overflow\": (\n property: overflow,\n values: auto hidden visible scroll,\n ),\n // scss-docs-end utils-overflow\n // scss-docs-start utils-display\n \"display\": (\n responsive: true,\n print: true,\n property: display,\n class: d,\n values: inline inline-block block grid table table-row table-cell flex inline-flex none\n ),\n // scss-docs-end utils-display\n // scss-docs-start utils-shadow\n \"shadow\": (\n property: box-shadow,\n class: shadow,\n values: (\n null: $box-shadow,\n sm: $box-shadow-sm,\n lg: $box-shadow-lg,\n none: none,\n )\n ),\n // scss-docs-end utils-shadow\n // scss-docs-start utils-position\n \"position\": (\n property: position,\n values: static relative absolute fixed sticky\n ),\n \"top\": (\n property: top,\n values: $position-values\n ),\n \"bottom\": (\n property: bottom,\n values: $position-values\n ),\n \"start\": (\n property: left,\n class: start,\n values: $position-values\n ),\n \"end\": (\n property: right,\n class: end,\n values: $position-values\n ),\n \"translate-middle\": (\n property: transform,\n class: translate-middle,\n values: (\n null: translate(-50%, -50%),\n x: translateX(-50%),\n y: translateY(-50%),\n )\n ),\n // scss-docs-end utils-position\n // scss-docs-start utils-borders\n \"border\": (\n property: border,\n values: (\n null: $border-width solid $border-color,\n 0: 0,\n )\n ),\n \"border-top\": (\n property: border-top,\n values: (\n null: $border-width solid $border-color,\n 0: 0,\n )\n ),\n \"border-end\": (\n property: border-right,\n class: border-end,\n values: (\n null: $border-width solid $border-color,\n 0: 0,\n )\n ),\n \"border-bottom\": (\n property: border-bottom,\n values: (\n null: $border-width solid $border-color,\n 0: 0,\n )\n ),\n \"border-start\": (\n property: border-left,\n class: border-start,\n values: (\n null: $border-width solid $border-color,\n 0: 0,\n )\n ),\n \"border-color\": (\n property: border-color,\n class: border,\n values: map-merge($theme-colors, (\"white\": $white))\n ),\n \"border-width\": (\n property: border-width,\n class: border,\n values: $border-widths\n ),\n // scss-docs-end utils-borders\n // Sizing utilities\n // scss-docs-start utils-sizing\n \"width\": (\n property: width,\n class: w,\n values: (\n 25: 25%,\n 50: 50%,\n 75: 75%,\n 100: 100%,\n auto: auto\n )\n ),\n \"max-width\": (\n property: max-width,\n class: mw,\n values: (100: 100%)\n ),\n \"viewport-width\": (\n property: width,\n class: vw,\n values: (100: 100vw)\n ),\n \"min-viewport-width\": (\n property: min-width,\n class: min-vw,\n values: (100: 100vw)\n ),\n \"height\": (\n property: height,\n class: h,\n values: (\n 25: 25%,\n 50: 50%,\n 75: 75%,\n 100: 100%,\n auto: auto\n )\n ),\n \"max-height\": (\n property: max-height,\n class: mh,\n values: (100: 100%)\n ),\n \"viewport-height\": (\n property: height,\n class: vh,\n values: (100: 100vh)\n ),\n \"min-viewport-height\": (\n property: min-height,\n class: min-vh,\n values: (100: 100vh)\n ),\n // scss-docs-end utils-sizing\n // Flex utilities\n // scss-docs-start utils-flex\n \"flex\": (\n responsive: true,\n property: flex,\n values: (fill: 1 1 auto)\n ),\n \"flex-direction\": (\n responsive: true,\n property: flex-direction,\n class: flex,\n values: row column row-reverse column-reverse\n ),\n \"flex-grow\": (\n responsive: true,\n property: flex-grow,\n class: flex,\n values: (\n grow-0: 0,\n grow-1: 1,\n )\n ),\n \"flex-shrink\": (\n responsive: true,\n property: flex-shrink,\n class: flex,\n values: (\n shrink-0: 0,\n shrink-1: 1,\n )\n ),\n \"flex-wrap\": (\n responsive: true,\n property: flex-wrap,\n class: flex,\n values: wrap nowrap wrap-reverse\n ),\n \"gap\": (\n responsive: true,\n property: gap,\n class: gap,\n values: $spacers\n ),\n \"justify-content\": (\n responsive: true,\n property: justify-content,\n values: (\n start: flex-start,\n end: flex-end,\n center: center,\n between: space-between,\n around: space-around,\n evenly: space-evenly,\n )\n ),\n \"align-items\": (\n responsive: true,\n property: align-items,\n values: (\n start: flex-start,\n end: flex-end,\n center: center,\n baseline: baseline,\n stretch: stretch,\n )\n ),\n \"align-content\": (\n responsive: true,\n property: align-content,\n values: (\n start: flex-start,\n end: flex-end,\n center: center,\n between: space-between,\n around: space-around,\n stretch: stretch,\n )\n ),\n \"align-self\": (\n responsive: true,\n property: align-self,\n values: (\n auto: auto,\n start: flex-start,\n end: flex-end,\n center: center,\n baseline: baseline,\n stretch: stretch,\n )\n ),\n \"order\": (\n responsive: true,\n property: order,\n values: (\n first: -1,\n 0: 0,\n 1: 1,\n 2: 2,\n 3: 3,\n 4: 4,\n 5: 5,\n last: 6,\n ),\n ),\n // scss-docs-end utils-flex\n // Margin utilities\n // scss-docs-start utils-spacing\n \"margin\": (\n responsive: true,\n property: margin,\n class: m,\n values: map-merge($spacers, (auto: auto))\n ),\n \"margin-x\": (\n responsive: true,\n property: margin-right margin-left,\n class: mx,\n values: map-merge($spacers, (auto: auto))\n ),\n \"margin-y\": (\n responsive: true,\n property: margin-top margin-bottom,\n class: my,\n values: map-merge($spacers, (auto: auto))\n ),\n \"margin-top\": (\n responsive: true,\n property: margin-top,\n class: mt,\n values: map-merge($spacers, (auto: auto))\n ),\n \"margin-end\": (\n responsive: true,\n property: margin-right,\n class: me,\n values: map-merge($spacers, (auto: auto))\n ),\n \"margin-bottom\": (\n responsive: true,\n property: margin-bottom,\n class: mb,\n values: map-merge($spacers, (auto: auto))\n ),\n \"margin-start\": (\n responsive: true,\n property: margin-left,\n class: ms,\n values: map-merge($spacers, (auto: auto))\n ),\n // Negative margin utilities\n \"negative-margin\": (\n responsive: true,\n property: margin,\n class: m,\n values: $negative-spacers\n ),\n \"negative-margin-x\": (\n responsive: true,\n property: margin-right margin-left,\n class: mx,\n values: $negative-spacers\n ),\n \"negative-margin-y\": (\n responsive: true,\n property: margin-top margin-bottom,\n class: my,\n values: $negative-spacers\n ),\n \"negative-margin-top\": (\n responsive: true,\n property: margin-top,\n class: mt,\n values: $negative-spacers\n ),\n \"negative-margin-end\": (\n responsive: true,\n property: margin-right,\n class: me,\n values: $negative-spacers\n ),\n \"negative-margin-bottom\": (\n responsive: true,\n property: margin-bottom,\n class: mb,\n values: $negative-spacers\n ),\n \"negative-margin-start\": (\n responsive: true,\n property: margin-left,\n class: ms,\n values: $negative-spacers\n ),\n // Padding utilities\n \"padding\": (\n responsive: true,\n property: padding,\n class: p,\n values: $spacers\n ),\n \"padding-x\": (\n responsive: true,\n property: padding-right padding-left,\n class: px,\n values: $spacers\n ),\n \"padding-y\": (\n responsive: true,\n property: padding-top padding-bottom,\n class: py,\n values: $spacers\n ),\n \"padding-top\": (\n responsive: true,\n property: padding-top,\n class: pt,\n values: $spacers\n ),\n \"padding-end\": (\n responsive: true,\n property: padding-right,\n class: pe,\n values: $spacers\n ),\n \"padding-bottom\": (\n responsive: true,\n property: padding-bottom,\n class: pb,\n values: $spacers\n ),\n \"padding-start\": (\n responsive: true,\n property: padding-left,\n class: ps,\n values: $spacers\n ),\n // scss-docs-end utils-spacing\n // Text\n // scss-docs-start utils-text\n \"font-family\": (\n property: font-family,\n class: font,\n values: (monospace: var(--#{$variable-prefix}font-monospace))\n ),\n \"font-size\": (\n rfs: true,\n property: font-size,\n class: fs,\n values: $font-sizes\n ),\n \"font-style\": (\n property: font-style,\n class: fst,\n values: italic normal\n ),\n \"font-weight\": (\n property: font-weight,\n class: fw,\n values: (\n light: $font-weight-light,\n lighter: $font-weight-lighter,\n normal: $font-weight-normal,\n bold: $font-weight-bold,\n bolder: $font-weight-bolder\n )\n ),\n \"line-height\": (\n property: line-height,\n class: lh,\n values: (\n 1: 1,\n sm: $line-height-sm,\n base: $line-height-base,\n lg: $line-height-lg,\n )\n ),\n \"text-align\": (\n responsive: true,\n property: text-align,\n class: text,\n values: (\n start: left,\n end: right,\n center: center,\n )\n ),\n \"text-decoration\": (\n property: text-decoration,\n values: none underline line-through\n ),\n \"text-transform\": (\n property: text-transform,\n class: text,\n values: lowercase uppercase capitalize\n ),\n \"white-space\": (\n property: white-space,\n class: text,\n values: (\n wrap: normal,\n nowrap: nowrap,\n )\n ),\n \"word-wrap\": (\n property: word-wrap word-break,\n class: text,\n values: (break: break-word),\n rtl: false\n ),\n // scss-docs-end utils-text\n // scss-docs-start utils-color\n \"color\": (\n property: color,\n class: text,\n values: map-merge(\n $theme-colors,\n (\n \"white\": $white,\n \"body\": $body-color,\n \"muted\": $text-muted,\n \"black-50\": rgba($black, .5),\n \"white-50\": rgba($white, .5),\n \"reset\": inherit,\n )\n )\n ),\n // scss-docs-end utils-color\n // scss-docs-start utils-bg-color\n \"background-color\": (\n property: background-color,\n class: bg,\n values: map-merge(\n $theme-colors,\n (\n \"body\": $body-bg,\n \"white\": $white,\n \"transparent\": transparent\n )\n )\n ),\n // scss-docs-end utils-bg-color\n \"gradient\": (\n property: background-image,\n class: bg,\n values: (gradient: var(--#{$variable-prefix}gradient))\n ),\n // scss-docs-start utils-interaction\n \"user-select\": (\n property: user-select,\n values: all auto none\n ),\n \"pointer-events\": (\n property: pointer-events,\n class: pe,\n values: none auto,\n ),\n // scss-docs-end utils-interaction\n // scss-docs-start utils-border-radius\n \"rounded\": (\n property: border-radius,\n class: rounded,\n values: (\n null: $border-radius,\n 0: 0,\n 1: $border-radius-sm,\n 2: $border-radius,\n 3: $border-radius-lg,\n circle: 50%,\n pill: $border-radius-pill\n )\n ),\n \"rounded-top\": (\n property: border-top-left-radius border-top-right-radius,\n class: rounded-top,\n values: (null: $border-radius)\n ),\n \"rounded-end\": (\n property: border-top-right-radius border-bottom-right-radius,\n class: rounded-end,\n values: (null: $border-radius)\n ),\n \"rounded-bottom\": (\n property: border-bottom-right-radius border-bottom-left-radius,\n class: rounded-bottom,\n values: (null: $border-radius)\n ),\n \"rounded-start\": (\n property: border-bottom-left-radius border-top-left-radius,\n class: rounded-start,\n values: (null: $border-radius)\n ),\n // scss-docs-end utils-border-radius\n // scss-docs-start utils-visibility\n \"visibility\": (\n property: visibility,\n class: null,\n values: (\n visible: visible,\n invisible: hidden,\n )\n )\n // scss-docs-end utils-visibility\n ),\n $utilities\n);\n","// Variables\n//\n// Variables should follow the `$component-state-property-size` formula for\n// consistent naming. Ex: $nav-link-disabled-color and $modal-content-box-shadow-xs.\n\n// Color system\n\n// scss-docs-start gray-color-variables\n$white: $__white !default;\n$gray-100: $__bg__gray--1 !default;\n$gray-200: $__bg__gray--2 !default;\n$gray-300: rgba($__black,.3) !default;\n$gray-400: rgba($__black,.4) !default;\n$gray-500: rgba($__black,.5) !default;\n$gray-600: rgba($__black,.6) !default;\n$gray-700: rgba($__black,.7) !default;\n$gray-800: $__bg__white--2 !default;\n$gray-900: $__bg__white--1 !default;\n$black: $__black !default;\n// scss-docs-end gray-color-variables\n\n// fusv-disable\n// scss-docs-start gray-colors-map\n$grays: (\n \"100\": $gray-100,\n \"200\": $gray-200,\n \"300\": $gray-300,\n \"400\": $gray-400,\n \"500\": $gray-500,\n \"600\": $gray-600,\n \"700\": $gray-700,\n \"800\": $gray-800,\n \"900\": $gray-900\n) !default;\n// scss-docs-end gray-colors-map\n// fusv-enable\n\n// scss-docs-start color-variables\n$blue: $__interaction--light !default;\n$indigo: $__support__purple--light !default;\n$purple: $__support__purple--dark !default;\n$pink: #C32AA3 !default;\n$red: $__negative--light !default;\n$orange: $__negative--dark !default;\n$yellow: $__warning--light !default;\n$green: $__positive--light !default;\n$teal: $__support__green--light !default;\n$cyan: $__info--light !default;\n// scss-docs-end color-variables\n\n// scss-docs-start colors-map\n$colors: (\n \"blue\": $blue,\n \"indigo\": $indigo,\n \"purple\": $purple,\n \"pink\": $pink,\n \"red\": $red,\n \"orange\": $orange,\n \"yellow\": $yellow,\n \"green\": $green,\n \"teal\": $teal,\n \"cyan\": $cyan,\n \"white\": $white,\n \"gray\": $__text--light,\n \"gray-dark\": $__text__emphasis--light\n) !default;\n// scss-docs-end colors-map\n\n// scss-docs-start theme-color-variables\n$primary: $blue !default;\n//$secondary: $gray-600 !default;\n$secondary: $white !default;\n$success: $green !default;\n$info: $cyan !default;\n$warning: $yellow !default;\n$danger: $red !default;\n$light: $gray-100 !default;\n$dark: $gray-900 !default;\n// scss-docs-end theme-color-variables\n\n// scss-docs-start theme-colors-map\n$theme-colors: (\n \"primary\": $primary,\n \"secondary\": $secondary,\n \"success\": $success,\n \"info\": $info,\n \"warning\": $warning,\n \"danger\": $danger,\n \"light\": $light,\n \"dark\": $dark\n) !default;\n// scss-docs-end theme-colors-map\n\n// The contrast ratio to reach against white, to determine if color changes from \"light\" to \"dark\". Acceptable values for WCAG 2.0 are 3, 4.5 and 7.\n// See https://www.w3.org/TR/WCAG20/#visual-audio-contrast-contrast\n$min-contrast-ratio: 4.5 !default;\n\n// Customize the light and dark text colors for use in our color contrast function.\n$color-contrast-dark: $black !default;\n$color-contrast-light: $white !default;\n\n// fusv-disable\n$blue-100: tint-color($blue, 80%) !default;\n$blue-200: tint-color($blue, 60%) !default;\n$blue-300: tint-color($blue, 40%) !default;\n$blue-400: tint-color($blue, 20%) !default;\n$blue-500: $blue !default;\n$blue-600: shade-color($blue, 20%) !default;\n$blue-700: shade-color($blue, 40%) !default;\n$blue-800: shade-color($blue, 60%) !default;\n$blue-900: shade-color($blue, 80%) !default;\n\n$indigo-100: tint-color($indigo, 80%) !default;\n$indigo-200: tint-color($indigo, 60%) !default;\n$indigo-300: tint-color($indigo, 40%) !default;\n$indigo-400: tint-color($indigo, 20%) !default;\n$indigo-500: $indigo !default;\n$indigo-600: shade-color($indigo, 20%) !default;\n$indigo-700: shade-color($indigo, 40%) !default;\n$indigo-800: shade-color($indigo, 60%) !default;\n$indigo-900: shade-color($indigo, 80%) !default;\n\n$purple-100: tint-color($purple, 80%) !default;\n$purple-200: tint-color($purple, 60%) !default;\n$purple-300: tint-color($purple, 40%) !default;\n$purple-400: tint-color($purple, 20%) !default;\n$purple-500: $purple !default;\n$purple-600: shade-color($purple, 20%) !default;\n$purple-700: shade-color($purple, 40%) !default;\n$purple-800: shade-color($purple, 60%) !default;\n$purple-900: shade-color($purple, 80%) !default;\n\n$pink-100: tint-color($pink, 80%) !default;\n$pink-200: tint-color($pink, 60%) !default;\n$pink-300: tint-color($pink, 40%) !default;\n$pink-400: tint-color($pink, 20%) !default;\n$pink-500: $pink !default;\n$pink-600: shade-color($pink, 20%) !default;\n$pink-700: shade-color($pink, 40%) !default;\n$pink-800: shade-color($pink, 60%) !default;\n$pink-900: shade-color($pink, 80%) !default;\n\n$red-100: tint-color($red, 80%) !default;\n$red-200: tint-color($red, 60%) !default;\n$red-300: tint-color($red, 40%) !default;\n$red-400: tint-color($red, 20%) !default;\n$red-500: $red !default;\n$red-600: shade-color($red, 20%) !default;\n$red-700: shade-color($red, 40%) !default;\n$red-800: shade-color($red, 60%) !default;\n$red-900: shade-color($red, 80%) !default;\n\n$orange-100: tint-color($orange, 80%) !default;\n$orange-200: tint-color($orange, 60%) !default;\n$orange-300: tint-color($orange, 40%) !default;\n$orange-400: tint-color($orange, 20%) !default;\n$orange-500: $orange !default;\n$orange-600: shade-color($orange, 20%) !default;\n$orange-700: shade-color($orange, 40%) !default;\n$orange-800: shade-color($orange, 60%) !default;\n$orange-900: shade-color($orange, 80%) !default;\n\n$yellow-100: tint-color($yellow, 80%) !default;\n$yellow-200: tint-color($yellow, 60%) !default;\n$yellow-300: tint-color($yellow, 40%) !default;\n$yellow-400: tint-color($yellow, 20%) !default;\n$yellow-500: $yellow !default;\n$yellow-600: shade-color($yellow, 20%) !default;\n$yellow-700: shade-color($yellow, 40%) !default;\n$yellow-800: shade-color($yellow, 60%) !default;\n$yellow-900: shade-color($yellow, 80%) !default;\n\n$green-100: tint-color($green, 80%) !default;\n$green-200: tint-color($green, 60%) !default;\n$green-300: tint-color($green, 40%) !default;\n$green-400: tint-color($green, 20%) !default;\n$green-500: $green !default;\n$green-600: shade-color($green, 20%) !default;\n$green-700: shade-color($green, 40%) !default;\n$green-800: shade-color($green, 60%) !default;\n$green-900: shade-color($green, 80%) !default;\n\n$teal-100: tint-color($teal, 80%) !default;\n$teal-200: tint-color($teal, 60%) !default;\n$teal-300: tint-color($teal, 40%) !default;\n$teal-400: tint-color($teal, 20%) !default;\n$teal-500: $teal !default;\n$teal-600: shade-color($teal, 20%) !default;\n$teal-700: shade-color($teal, 40%) !default;\n$teal-800: shade-color($teal, 60%) !default;\n$teal-900: shade-color($teal, 80%) !default;\n\n$cyan-100: tint-color($cyan, 80%) !default;\n$cyan-200: tint-color($cyan, 60%) !default;\n$cyan-300: tint-color($cyan, 40%) !default;\n$cyan-400: tint-color($cyan, 20%) !default;\n$cyan-500: $cyan !default;\n$cyan-600: shade-color($cyan, 20%) !default;\n$cyan-700: shade-color($cyan, 40%) !default;\n$cyan-800: shade-color($cyan, 60%) !default;\n$cyan-900: shade-color($cyan, 80%) !default;\n// fusv-enable\n\n// Characters which are escaped by the escape-svg function\n$escaped-characters: (\n (\"<\", \"%3c\"),\n (\">\", \"%3e\"),\n (\"#\", \"%23\"),\n (\"(\", \"%28\"),\n (\")\", \"%29\"),\n) !default;\n\n// Options\n//\n// Quickly modify global styling by enabling or disabling optional features.\n\n$enable-caret: true !default;\n$enable-rounded: true !default;\n$enable-shadows: false !default;\n$enable-gradients: false !default;\n$enable-transitions: true !default;\n$enable-reduced-motion: true !default;\n$enable-smooth-scroll: true !default;\n$enable-grid-classes: true !default;\n$enable-button-pointers: true !default;\n$enable-rfs: true !default;\n$enable-validation-icons: true !default;\n$enable-negative-margins: false !default;\n$enable-deprecation-messages: true !default;\n$enable-important-utilities: true !default;\n\n// Prefix for :root CSS variables\n\n$variable-prefix: #{$__classPrefix}- !default;\n\n// Gradient\n//\n// The gradient which is added to components if `$enable-gradients` is `true`\n// This gradient is also added to elements with `.bg-gradient` \n// scss-docs-start variable-gradient\n$gradient: linear-gradient(180deg, rgba($white, .15), rgba($white, 0)) !default;\n// scss-docs-end variable-gradient\n\n// Spacing \n//\n// Control the default styling of most Bootstrap elements by modifying these\n// variables. Mostly focused on spacing.\n// You can add more entries to the $spacers map, should you need more variation.\n\n// scss-docs-start spacer-variables-maps\n$spacer: 1rem !default;\n$spacers: (\n 0: 0,\n 1: $spacer / 4,\n 2: $spacer / 2,\n 3: $spacer,\n 4: $spacer * 1.5,\n 5: $spacer * 3,\n) !default;\n\n$negative-spacers: if($enable-negative-margins, negativify-map($spacers), null) !default;\n// scss-docs-end spacer-variables-maps\n\n// Position\n//\n// Define the edge positioning anchors of the position utilities.\n\n// scss-docs-start position-map\n$position-values: (\n 0: 0,\n 50: 50%,\n 100: 100%\n) !default;\n// scss-docs-end position-map\n\n// Body\n//\n// Settings for the `` element.\n\n$body-bg: $white !default;\n$body-color: $gray-900 !default;\n$body-text-align: null !default;\n\n\n// Links\n//\n// Style anchor elements.\n\n$link-color: $primary !default;\n$link-decoration: underline !default;\n$link-shade-percentage: 20% !default;\n$link-hover-color: shift-color($link-color, $link-shade-percentage) !default;\n$link-hover-decoration: null !default;\n\n$stretched-link-pseudo-element: after !default;\n$stretched-link-z-index: 1 !default;\n\n// Paragraphs\n//\n// Style p element.\n\n$paragraph-margin-bottom: 1rem !default;\n\n\n// Grid breakpoints\n//\n// Define the minimum dimensions at which your layout will change,\n// adapting to different screen sizes, for use in media queries.\n\n// scss-docs-start grid-breakpoints\n$grid-breakpoints: (\n xs: $__breakpoints--xsmall,\n sm: $__breakpoints--small,\n md: $__breakpoints--medium,\n lg: $__breakpoints--large,\n xl: $__breakpoints--xlarge,\n xxl: $__breakpoints--xxlarge\n) !default;\n// scss-docs-end grid-breakpoints\n\n@include _assert-ascending($grid-breakpoints, \"$grid-breakpoints\");\n@include _assert-starts-at-zero($grid-breakpoints, \"$grid-breakpoints\");\n\n\n// Grid containers\n//\n// Define the maximum width of `.container` for different screen sizes.\n\n// scss-docs-start container-max-widths\n$container-max-widths: (\n sm: $__grid__container--small,\n md: $__grid__container--medium,\n lg: $__grid__container--large,\n xl: $__grid__container--xlarge,\n xxl: $__grid__container--xxlarge\n) !default;\n// scss-docs-end container-max-widths\n\n@include _assert-ascending($container-max-widths, \"$container-max-widths\");\n\n\n// Grid columns\n//\n// Set the number of columns and specify the width of the gutters.\n\n$grid-columns: $__grid__columns !default;\n$grid-gutter-width: 1rem !default;\n$grid-row-columns: 6 !default;\n\n$gutters: $spacers !default;\n\n// Container padding\n\n$container-padding-x: $grid-gutter-width / 2 !default;\n\n\n// Components\n//\n// Define common padding and border radius sizes and more.\n\n// scss-docs-start border-variables\n$border-width: 1px !default;\n$border-widths: (\n 0: 0,\n 1: 1px,\n 2: 2px,\n 3: 3px,\n 4: 4px,\n 5: 5px\n) !default;\n\n$border-color: $gray-300 !default;\n\n$border-radius: .25rem !default;\n$border-radius-sm: .12.5rem !default;\n$border-radius-lg: .5rem !default;\n$border-radius-pill: 50rem !default;\n// scss-docs-end border-radius-variables\n\n// scss-docs-start box-shadow-variables\n$box-shadow: 0 .5rem 1rem rgba($black, .15) !default;\n$box-shadow-sm: 0 .125rem .25rem rgba($black, .075) !default;\n$box-shadow-lg: 0 1rem 3rem rgba($black, .175) !default;\n$box-shadow-inset: inset 0 1px 2px rgba($black, .075) !default;\n// scss-docs-end box-shadow-variables\n\n$component-active-color: $white !default;\n$component-active-bg: $primary !default;\n\n// scss-docs-start caret-variables\n$caret-width: .3em !default;\n$caret-vertical-align: $caret-width * .85 !default;\n$caret-spacing: $caret-width * .85 !default;\n// scss-docs-end caret-variables\n\n$transition-base: all .2s ease-in-out !default;\n$transition-fade: opacity .15s linear !default;\n$transition-collapse: height .35s ease !default;\n// scss-docs-end collapse-transition\n\n// stylelint-disable function-disallowed-list\n// scss-docs-start aspect-ratios\n$aspect-ratios: (\n \"1x1\": 100%,\n \"4x3\": calc(3 / 4 * 100%),\n \"16x9\": calc(9 / 16 * 100%),\n \"21x9\": calc(9 / 21 * 100%)\n) !default;\n// scss-docs-end aspect-ratios\n// stylelint-enable function-disallowed-list\n\n// Typography\n//\n// Font, line-height, and color for body text, headings, and more.\n\n// scss-docs-start font-variables\n// stylelint-disable value-keyword-case\n$font-family-sans-serif: $__font__family !default;\n$font-family-monospace: SFMono-Regular, Menlo, Monaco, Consolas, \"Liberation Mono\", \"Courier New\", monospace !default;\n// stylelint-enable value-keyword-case\n$font-family-base: var(--#{$variable-prefix}font-sans-serif) !default;\n$font-family-code: var(--#{$variable-prefix}font-monospace) !default;\n\n// $font-size-root effects the value of `rem`, which is used for as well font sizes, paddings and margins\n// $font-size-base effects the font size of the body text\n$font-size-root: null !default;\n$font-size-base: 1rem !default; // Assumes the browser default, typically `16px`\n$font-size-sm: $font-size-base * .875 !default;\n$font-size-lg: $font-size-base * 1.25 !default;\n\n$font-weight-lighter: lighter !default;\n$font-weight-light: 300 !default;\n$font-weight-normal: 400 !default;\n$font-weight-bold: 700 !default;\n$font-weight-bolder: bolder !default;\n\n$font-weight-base: $font-weight-normal !default;\n\n$line-height-base: 1.5 !default;\n$line-height-sm: 1.25 !default;\n$line-height-lg: 2 !default;\n\n$h1-font-size: $font-size-base * 2.5 !default;\n$h2-font-size: $font-size-base * 2 !default;\n$h3-font-size: $font-size-base * 1.75 !default;\n$h4-font-size: $font-size-base * 1.5 !default;\n$h5-font-size: $font-size-base * 1.25 !default;\n$h6-font-size: $font-size-base !default;\n// scss-docs-end font-variables\n\n// scss-docs-start font-sizes\n$font-sizes: (\n 1: $h1-font-size,\n 2: $h2-font-size,\n 3: $h3-font-size,\n 4: $h4-font-size,\n 5: $h5-font-size,\n 6: $h6-font-size\n) !default;\n// scss-docs-end font-sizes\n\n// scss-docs-start headings-variables\n$headings-margin-bottom: $spacer / 2 !default;\n$headings-font-family: null !default;\n$headings-font-style: null !default;\n$headings-font-weight: 500 !default;\n$headings-line-height: 1.2 !default;\n$headings-color: null !default;\n// scss-docs-end headings-variables\n\n// scss-docs-start display-headings\n$display-font-sizes: (\n 1: 5rem,\n 2: 4.5rem,\n 3: 4rem,\n 4: 3.5rem,\n 5: 3rem,\n 6: 2.5rem\n) !default;\n\n$display-font-weight: 300 !default;\n$display-line-height: $headings-line-height !default;\n// scss-docs-end display-headings\n\n// scss-docs-start type-variables\n$lead-font-size: $font-size-base * 1.25 !default;\n$lead-font-weight: 300 !default;\n\n$small-font-size: .875em !default;\n\n$sub-sup-font-size: .75em !default;\n\n$text-muted: $gray-600 !default;\n\n$initialism-font-size: $small-font-size !default;\n\n$blockquote-margin-y: $spacer !default;\n$blockquote-font-size: $font-size-base * 1.25 !default;\n$blockquote-footer-color: $gray-600 !default;\n$blockquote-footer-font-size: $small-font-size !default;\n\n$hr-margin-y: $spacer !default;\n$hr-color: inherit !default;\n$hr-height: $border-width !default;\n$hr-opacity: .25 !default;\n\n$legend-margin-bottom: .5rem !default;\n$legend-font-size: 1.5rem !default;\n$legend-font-weight: null !default;\n\n$mark-padding: .2em !default;\n\n$dt-font-weight: $font-weight-bold !default;\n\n$nested-kbd-font-weight: $font-weight-bold !default;\n\n$list-inline-padding: .5rem !default;\n\n$mark-bg: #fcf8e3 !default;\n// scss-docs-end type-variables\n\n\n// Tables\n//\n// Customizes the `.table` component with basic values, each used across all table variations.\n\n// scss-docs-start table-variables\n$table-cell-padding-y: .5rem !default;\n$table-cell-padding-x: .5rem !default;\n$table-cell-padding-y-sm: .25rem !default;\n$table-cell-padding-x-sm: .25rem !default;\n\n$table-cell-vertical-align: top !default;\n\n$table-color: $body-color !default;\n$table-bg: transparent !default;\n\n$table-th-font-weight: null !default;\n\n$table-striped-color: $table-color !default;\n$table-striped-bg-factor: .05 !default;\n$table-striped-bg: rgba($black, $table-striped-bg-factor) !default;\n\n$table-active-color: $table-color !default;\n$table-active-bg-factor: .1 !default;\n$table-active-bg: rgba($black, $table-active-bg-factor) !default;\n\n$table-hover-color: $table-color !default;\n$table-hover-bg-factor: .075 !default;\n$table-hover-bg: rgba($black, $table-hover-bg-factor) !default;\n\n$table-border-factor: .1 !default;\n$table-border-width: $border-width !default;\n$table-border-color: $border-color !default;\n\n$table-striped-order: odd !default;\n\n$table-group-separator-color: currentColor !default;\n\n$table-caption-color: $text-muted !default;\n\n$table-bg-scale: -80% !default;\n\n$table-variants: (\n \"primary\": shift-color($primary, $table-bg-scale),\n \"secondary\": shift-color($secondary, $table-bg-scale),\n \"success\": shift-color($success, $table-bg-scale),\n \"info\": shift-color($info, $table-bg-scale),\n \"warning\": shift-color($warning, $table-bg-scale),\n \"danger\": shift-color($danger, $table-bg-scale),\n \"light\": $light,\n \"dark\": $dark,\n) !default;\n\n\n $table-variants-scielo: (\n \"primary\": fade-out($__interaction--light, 0.3),\n \"secondary\": fade-out($secondary, 0.5),\n \"success\": fade-out($__positive--light, 0.3),\n \"info\": fade-out($__info--light, 0.3),\n \"warning\": fade-out($__warning--light, 0.3),\n \"danger\": fade-out($__negative--light, 0.3),\n \"light\": $light,\n \"dark\": $dark,\n ) !default;\n \n \n// scss-docs-end table-loop\n\n\n// Buttons + Forms\n//\n// Shared variables that are reassigned to `$input-` and `$btn-` specific variables.\n\n// scss-docs-start input-btn-variables\n$input-btn-padding-y: .375rem !default;\n$input-btn-padding-x: .75rem !default;\n$input-btn-font-family: null !default;\n$input-btn-font-size: $font-size-base !default;\n$input-btn-line-height: $line-height-base !default;\n\n$input-btn-focus-width: .25rem !default;\n$input-btn-focus-color-opacity: .25 !default;\n$input-btn-focus-color: rgba($component-active-bg, $input-btn-focus-color-opacity) !default;\n$input-btn-focus-blur: 0 !default;\n$input-btn-focus-box-shadow: 0 0 0 $input-btn-focus-width $input-btn-focus-color !default;\n\n$input-btn-padding-y-sm: .25rem !default;\n$input-btn-padding-x-sm: .5rem !default;\n$input-btn-font-size-sm: $font-size-sm !default;\n\n$input-btn-padding-y-lg: .5rem !default;\n$input-btn-padding-x-lg: 1rem !default;\n$input-btn-font-size-lg: $font-size-lg !default;\n\n$input-btn-border-width: $border-width !default;\n// scss-docs-end input-btn-variables\n\n\n// Buttons\n//\n// For each of Bootstrap's buttons, define text, background, and border color.\n\n// scss-docs-start btn-variables\n$btn-padding-y: $input-btn-padding-y !default;\n$btn-padding-x: $input-btn-padding-x !default;\n$btn-font-family: $input-btn-font-family !default;\n$btn-font-size: $input-btn-font-size !default;\n$btn-line-height: $input-btn-line-height !default;\n$btn-white-space: null !default; // Set to `nowrap` to prevent text wrapping\n\n$btn-padding-y-sm: $input-btn-padding-y-sm !default;\n$btn-padding-x-sm: $input-btn-padding-x-sm !default;\n$btn-font-size-sm: $input-btn-font-size-sm !default;\n\n$btn-padding-y-lg: $input-btn-padding-y-lg !default;\n$btn-padding-x-lg: $input-btn-padding-x-lg !default;\n$btn-font-size-lg: $input-btn-font-size-lg !default;\n\n$btn-border-width: $input-btn-border-width !default;\n\n$btn-font-weight: $font-weight-normal !default;\n$btn-box-shadow: inset 0 1px 0 rgba($white, .15), 0 1px 1px rgba($black, .075) !default;\n$btn-focus-width: $input-btn-focus-width !default;\n$btn-focus-box-shadow: $input-btn-focus-box-shadow !default;\n$btn-disabled-opacity: .65 !default;\n$btn-active-box-shadow: inset 0 3px 5px rgba($black, .125) !default;\n\n$btn-link-color: $link-color !default;\n$btn-link-hover-color: $link-hover-color !default;\n$btn-link-disabled-color: $gray-600 !default;\n\n// Allows for customizing button radius independently from global border radius\n$btn-border-radius: $border-radius !default;\n$btn-border-radius-sm: $border-radius-sm !default;\n$btn-border-radius-lg: $border-radius-lg !default;\n\n$btn-transition: color .15s ease-in-out, background-color .15s ease-in-out, border-color .15s ease-in-out, box-shadow .15s ease-in-out !default;\n\n$btn-hover-bg-shade-amount: 15% !default;\n$btn-hover-bg-tint-amount: 15% !default;\n$btn-hover-border-shade-amount: 20% !default;\n$btn-hover-border-tint-amount: 10% !default;\n$btn-active-bg-shade-amount: 20% !default;\n$btn-active-bg-tint-amount: 20% !default;\n$btn-active-border-shade-amount: 25% !default;\n$btn-active-border-tint-amount: 10% !default;\n// scss-docs-end btn-variables\n\n\n// Forms\n\n// scss-docs-start form-text-variables\n$form-text-margin-top: .25rem !default;\n$form-text-font-size: $small-font-size !default;\n$form-text-font-style: null !default;\n$form-text-font-weight: null !default;\n$form-text-color: $text-muted !default;\n// scss-docs-end form-text-variables\n\n// scss-docs-start form-label-variables\n$form-label-margin-bottom: .5rem !default;\n$form-label-font-size: null !default;\n$form-label-font-style: null !default;\n$form-label-font-weight: null !default;\n$form-label-color: null !default;\n// scss-docs-end form-label-variables\n\n// scss-docs-start form-input-variables\n$input-padding-y: $input-btn-padding-y !default;\n$input-padding-x: $input-btn-padding-x !default;\n$input-font-family: $input-btn-font-family !default;\n$input-font-size: $input-btn-font-size !default;\n$input-font-weight: $font-weight-base !default;\n$input-line-height: $input-btn-line-height !default;\n\n$input-padding-y-sm: $input-btn-padding-y-sm !default;\n$input-padding-x-sm: $input-btn-padding-x-sm !default;\n$input-font-size-sm: $input-btn-font-size-sm !default;\n\n$input-padding-y-lg: $input-btn-padding-y-lg !default;\n$input-padding-x-lg: $input-btn-padding-x-lg !default;\n$input-font-size-lg: $input-btn-font-size-lg !default;\n\n$input-bg: $white !default;\n$input-disabled-bg: $gray-200 !default;\n$input-disabled-border-color: null !default;\n\n$input-color: $body-color !default;\n$input-border-color: $gray-400 !default;\n$input-border-width: $input-btn-border-width !default;\n$input-box-shadow: $box-shadow-inset !default;\n\n$input-border-radius: $border-radius !default;\n$input-border-radius-sm: $border-radius-sm !default;\n$input-border-radius-lg: $border-radius-lg !default;\n\n$input-focus-bg: $input-bg !default;\n$input-focus-border-color: tint-color($component-active-bg, 50%) !default;\n$input-focus-color: $input-color !default;\n$input-focus-width: $input-btn-focus-width !default;\n$input-focus-box-shadow: $input-btn-focus-box-shadow !default;\n\n$input-placeholder-color: $gray-600 !default;\n$input-plaintext-color: $body-color !default;\n\n$input-height-border: $input-border-width * 2 !default;\n\n$input-height-inner: add($input-line-height * 1em, $input-padding-y * 2) !default;\n$input-height-inner-half: add($input-line-height * .5em, $input-padding-y) !default;\n$input-height-inner-quarter: add($input-line-height * .25em, $input-padding-y / 2) !default;\n\n$input-height: add($input-line-height * 1em, add($input-padding-y * 2, $input-height-border, false)) !default;\n$input-height-sm: add($input-line-height * 1em, add($input-padding-y-sm * 2, $input-height-border, false)) !default;\n$input-height-lg: add($input-line-height * 1em, add($input-padding-y-lg * 2, $input-height-border, false)) !default;\n\n$input-transition: border-color .15s ease-in-out, box-shadow .15s ease-in-out !default;\n// scss-docs-end form-input-variables\n\n// scss-docs-start form-check-variables\n$form-check-input-width: 1em !default;\n$form-check-min-height: $font-size-base * $line-height-base !default;\n$form-check-padding-start: $form-check-input-width + .5em !default;\n$form-check-margin-bottom: .125rem !default;\n$form-check-label-color: null !default;\n$form-check-label-cursor: null !default;\n$form-check-transition: background-color .15s ease-in-out, background-position .15s ease-in-out, border-color .15s ease-in-out, box-shadow .15s ease-in-out !default; \n\n$form-check-input-active-filter: brightness(90%) !default;\n\n$form-check-input-bg: $body-bg !default;\n$form-check-input-border: 1px solid rgba(0, 0, 0, .25) !default;\n$form-check-input-border-radius: .25em !default;\n$form-check-radio-border-radius: 50% !default;\n$form-check-input-focus-border: $input-focus-border-color !default;\n$form-check-input-focus-box-shadow: $input-btn-focus-box-shadow !default;\n\n$form-check-input-checked-color: $component-active-color !default;\n$form-check-input-checked-bg-color: $component-active-bg !default;\n$form-check-input-checked-border-color: $form-check-input-checked-bg-color !default;\n$form-check-input-checked-bg-image: url(\"data:image/svg+xml,\") !default;\n$form-check-radio-checked-bg-image: url(\"data:image/svg+xml,\") !default;\n\n$form-check-input-indeterminate-color: $component-active-color !default;\n$form-check-input-indeterminate-bg-color: $component-active-bg !default;\n$form-check-input-indeterminate-border-color: $form-check-input-indeterminate-bg-color !default;\n$form-check-input-indeterminate-bg-image: url(\"data:image/svg+xml,\") !default;\n\n$form-check-input-disabled-opacity: .5 !default;\n$form-check-label-disabled-opacity: $form-check-input-disabled-opacity !default;\n$form-check-btn-check-disabled-opacity: $btn-disabled-opacity !default;\n\n$form-check-inline-margin-end: 1rem !default;\n// scss-docs-end form-check-variables\n\n// scss-docs-start form-switch-variables\n$form-switch-color: rgba(0, 0, 0, .25) !default;\n$form-switch-width: 2em !default;\n$form-switch-padding-start: $form-switch-width + .5em !default;\n$form-switch-bg-image: url(\"data:image/svg+xml,\") !default;\n$form-switch-border-radius: $form-switch-width !default;\n$form-switch-transition: background-position .15s ease-in-out !default;\n\n$form-switch-focus-color: $input-focus-border-color !default;\n$form-switch-focus-bg-image: url(\"data:image/svg+xml,\") !default;\n\n$form-switch-checked-color: $component-active-color !default;\n$form-switch-checked-bg-image: url(\"data:image/svg+xml,\") !default;\n$form-switch-checked-bg-position: right center !default;\n\n$form-check-inline-margin-end: 1rem !default;\n// scss-docs-end form-switch-variables\n\n// scss-docs-start input-group-variables\n$input-group-addon-padding-y: $input-padding-y !default;\n$input-group-addon-padding-x: $input-padding-x !default;\n$input-group-addon-font-weight: $input-font-weight !default;\n$input-group-addon-color: $input-color !default;\n$input-group-addon-bg: $gray-200 !default;\n$input-group-addon-border-color: $input-border-color !default;\n// scss-docs-end input-group-variables\n\n// scss-docs-start form-select-variables\n$form-select-padding-y: $input-padding-y !default;\n$form-select-padding-x: $input-padding-x !default;\n$form-select-font-family: $input-font-family !default;\n$form-select-font-size: $input-font-size !default;\n$form-select-indicator-padding: 1rem !default; // Extra padding to account for the presence of the background-image based indicator\n$form-select-font-weight: $input-font-weight !default;\n$form-select-line-height: $input-line-height !default;\n$form-select-color: $input-color !default;\n$form-select-bg: $input-bg !default;\n$form-select-disabled-color: $gray-600 !default;\n$form-select-disabled-bg: $gray-200 !default;\n$form-select-disabled-border-color: $input-disabled-border-color !default;\n$form-select-bg-position: right $form-select-padding-x center !default;\n$form-select-bg-size: 16px 12px !default; // In pixels because image dimensions\n$form-select-indicator-color: $gray-800 !default;\n$form-select-indicator: url(\"data:image/svg+xml,\") !default;\n\n$form-select-feedback-icon-padding-end: add(1em * .75, (2 * $form-select-padding-y * .75) + $form-select-padding-x + $form-select-indicator-padding) !default;\n$form-select-feedback-icon-position: center right ($form-select-padding-x + $form-select-indicator-padding) !default;\n$form-select-feedback-icon-size: $input-height-inner-half $input-height-inner-half !default;\n\n$form-select-border-width: $input-border-width !default;\n$form-select-border-color: $input-border-color !default;\n$form-select-border-radius: $border-radius !default;\n$form-select-box-shadow: $box-shadow-inset !default;\n\n$form-select-focus-border-color: $input-focus-border-color !default;\n$form-select-focus-width: $input-focus-width !default;\n$form-select-focus-box-shadow: 0 0 0 $form-select-focus-width $input-btn-focus-color !default;\n\n$form-select-padding-y-sm: $input-padding-y-sm !default;\n$form-select-padding-x-sm: $input-padding-x-sm !default;\n$form-select-font-size-sm: $input-font-size-sm !default;\n\n$form-select-padding-y-lg: $input-padding-y-lg !default;\n$form-select-padding-x-lg: $input-padding-x-lg !default;\n$form-select-font-size-lg: $input-font-size-lg !default;\n// scss-docs-end form-select-variables\n\n// scss-docs-start form-range-variables\n$form-range-track-width: 100% !default;\n$form-range-track-height: .5rem !default;\n$form-range-track-cursor: pointer !default;\n$form-range-track-bg: $gray-300 !default;\n$form-range-track-border-radius: 1rem !default;\n$form-range-track-box-shadow: $box-shadow-inset !default;\n\n$form-range-thumb-width: 1rem !default;\n$form-range-thumb-height: $form-range-thumb-width !default;\n$form-range-thumb-bg: $component-active-bg !default;\n$form-range-thumb-border: 0 !default;\n$form-range-thumb-border-radius: 1rem !default;\n$form-range-thumb-box-shadow: 0 .1rem .25rem rgba($black, .1) !default;\n$form-range-thumb-focus-box-shadow: 0 0 0 1px $body-bg, $input-focus-box-shadow !default;\n$form-range-thumb-focus-box-shadow-width: $input-focus-width !default; // For focus box shadow issue in Edge\n$form-range-thumb-active-bg: tint-color($component-active-bg, 70%) !default;\n$form-range-thumb-disabled-bg: $gray-500 !default;\n$form-range-thumb-transition: background-color .15s ease-in-out, border-color .15s ease-in-out, box-shadow .15s ease-in-out !default;\n// scss-docs-end form-range-variables\n\n// scss-docs-start form-file-variables\n$form-file-button-color: $input-color !default;\n$form-file-button-bg: $input-group-addon-bg !default;\n$form-file-button-hover-bg: shade-color($form-file-button-bg, 5%) !default;\n// scss-docs-end form-file-variables\n\n// scss-docs-start form-floating-variables\n$form-floating-height: add(3.5rem, $input-height-border) !default;\n$form-floating-padding-x: $input-padding-x !default;\n$form-floating-padding-y: 1rem !default;\n$form-floating-input-padding-t: 1.625rem !default;\n$form-floating-input-padding-b: .625rem !default;\n$form-floating-label-opacity: .65 !default;\n$form-floating-label-transform: scale(.85) translateY(-.5rem) translateX(.15rem) !default;\n$form-floating-transition: opacity .1s ease-in-out, transform .1s ease-in-out !default;\n// scss-docs-end form-floating-variables\n\n// Form validation\n\n// scss-docs-start form-feedback-variables\n$form-feedback-margin-top: $form-text-margin-top !default;\n$form-feedback-font-size: $form-text-font-size !default;\n$form-feedback-font-style: $form-text-font-style !default;\n$form-feedback-valid-color: $success !default;\n$form-feedback-invalid-color: $danger !default;\n\n$form-feedback-icon-valid-color: $form-feedback-valid-color !default;\n$form-feedback-icon-valid: url(\"data:image/svg+xml,\") !default;\n$form-feedback-icon-invalid-color: $form-feedback-invalid-color !default;\n$form-feedback-icon-invalid: url(\"data:image/svg+xml,\") !default;\n// scss-docs-end form-feedback-variables\n\n// scss-docs-start form-validation-states\n$form-validation-states: (\n \"valid\": (\n \"color\": $form-feedback-valid-color,\n \"icon\": $form-feedback-icon-valid\n ),\n \"invalid\": (\n \"color\": $form-feedback-invalid-color,\n \"icon\": $form-feedback-icon-invalid\n )\n) !default;\n// scss-docs-end form-validation-states\n\n// Z-index master list\n//\n// Warning: Avoid customizing these values. They're used for a bird's eye view\n// of components dependent on the z-axis and are designed to all work together.\n\n// scss-docs-start zindex-stack\n$zindex-dropdown: 1000 !default;\n$zindex-sticky: 1020 !default;\n$zindex-fixed: 1030 !default;\n$zindex-offcanvas: 1040 !default;\n$zindex-modal-backdrop: 1050 !default;\n$zindex-modal: 1060 !default;\n$zindex-popover: 1070 !default;\n$zindex-tooltip: 1080 !default;\n// scss-docs-end zindex-stack\n\n\n// Navs\n\n// scss-docs-start nav-variables\n$nav-link-padding-y: .5rem !default;\n$nav-link-padding-x: 1rem !default;\n$nav-link-font-size: null !default;\n$nav-link-font-weight: null !default;\n$nav-link-color: null !default;\n$nav-link-hover-color: null !default;\n$nav-link-transition: color .15s ease-in-out, background-color .15s ease-in-out, border-color .15s ease-in-out !default;\n$nav-link-disabled-color: $gray-600 !default;\n\n$nav-tabs-border-color: $gray-300 !default;\n$nav-tabs-border-width: $border-width !default;\n$nav-tabs-border-radius: $border-radius !default;\n$nav-tabs-link-hover-border-color: $gray-200 $gray-200 $nav-tabs-border-color !default;\n$nav-tabs-link-active-color: $gray-700 !default;\n$nav-tabs-link-active-bg: $body-bg !default;\n$nav-tabs-link-active-border-color: $gray-300 $gray-300 $nav-tabs-link-active-bg !default;\n\n$nav-pills-border-radius: $border-radius !default;\n$nav-pills-link-active-color: $component-active-color !default;\n$nav-pills-link-active-bg: $component-active-bg !default;\n// scss-docs-end nav-variables\n\n\n// Navbar\n\n// scss-docs-start navbar-variables\n$navbar-padding-y: $spacer / 2 !default;\n$navbar-padding-x: null !default;\n\n$navbar-nav-link-padding-x: .5rem !default;\n\n$navbar-brand-font-size: $font-size-lg !default;\n// Compute the navbar-brand padding-y so the navbar-brand will have the same height as navbar-text and nav-link\n$nav-link-height: $font-size-base * $line-height-base + $nav-link-padding-y * 2 !default;\n$navbar-brand-height: $navbar-brand-font-size * $line-height-base !default;\n$navbar-brand-padding-y: ($nav-link-height - $navbar-brand-height) / 2 !default;\n$navbar-brand-margin-end: 1rem !default;\n\n$navbar-toggler-padding-y: .25rem !default;\n$navbar-toggler-padding-x: .75rem !default;\n$navbar-toggler-font-size: $font-size-lg !default;\n$navbar-toggler-border-radius: $btn-border-radius !default;\n$navbar-toggler-focus-width: $btn-focus-width !default;\n$navbar-toggler-transition: box-shadow .15s ease-in-out !default;\n// scss-docs-end navbar-variables\n\n// scss-docs-start navbar-theme-variables\n$navbar-dark-color: rgba($white, .55) !default;\n$navbar-dark-hover-color: rgba($white, .75) !default;\n$navbar-dark-active-color: $white !default;\n$navbar-dark-disabled-color: rgba($white, .25) !default;\n$navbar-dark-toggler-icon-bg: url(\"data:image/svg+xml,\") !default;\n$navbar-dark-toggler-border-color: rgba($white, .1) !default;\n\n$navbar-light-color: rgba($black, .55) !default;\n$navbar-light-hover-color: rgba($black, .7) !default;\n$navbar-light-active-color: rgba($black, .9) !default;\n$navbar-light-disabled-color: rgba($black, .3) !default;\n$navbar-light-toggler-icon-bg: url(\"data:image/svg+xml,\") !default;\n$navbar-light-toggler-border-color: rgba($black, .1) !default;\n\n$navbar-light-brand-color: $navbar-light-active-color !default;\n$navbar-light-brand-hover-color: $navbar-light-active-color !default;\n$navbar-dark-brand-color: $navbar-dark-active-color !default;\n$navbar-dark-brand-hover-color: $navbar-dark-active-color !default;\n// scss-docs-end navbar-theme-variables\n\n\n// Dropdowns\n//\n// Dropdown menu container and contents.\n\n// scss-docs-start dropdown-variables\n$dropdown-min-width: 10rem !default;\n$dropdown-padding-x: 0 !default;\n$dropdown-padding-y: .5rem !default;\n$dropdown-spacer: .125rem !default;\n$dropdown-font-size: $font-size-base !default;\n$dropdown-color: $body-color !default;\n$dropdown-bg: $white !default;\n$dropdown-border-color: rgba($black, .15) !default;\n$dropdown-border-radius: $border-radius !default;\n$dropdown-border-width: $border-width !default;\n$dropdown-inner-border-radius: subtract($dropdown-border-radius, $dropdown-border-width) !default;\n$dropdown-divider-bg: $dropdown-border-color !default;\n$dropdown-divider-margin-y: $spacer / 2 !default;\n$dropdown-box-shadow: $box-shadow !default;\n\n$dropdown-link-color: $gray-900 !default;\n$dropdown-link-hover-color: shade-color($gray-900, 10%) !default;\n$dropdown-link-hover-bg: $gray-100 !default;\n\n$dropdown-link-active-color: $component-active-color !default;\n$dropdown-link-active-bg: $component-active-bg !default;\n\n$dropdown-link-disabled-color: $gray-600 !default;\n\n$dropdown-item-padding-y: $spacer / 4 !default;\n$dropdown-item-padding-x: $spacer !default;\n\n$dropdown-header-color: $gray-600 !default;\n$dropdown-header-padding: $dropdown-padding-y $dropdown-item-padding-x !default;\n// scss-docs-end dropdown-variables\n\n// scss-docs-start dropdown-dark-variables\n$dropdown-dark-color: $gray-300 !default;\n$dropdown-dark-bg: $gray-800 !default;\n$dropdown-dark-border-color: $dropdown-border-color !default;\n$dropdown-dark-divider-bg: $dropdown-divider-bg !default;\n$dropdown-dark-box-shadow: null !default;\n$dropdown-dark-link-color: $dropdown-dark-color !default;\n$dropdown-dark-link-hover-color: $white !default;\n$dropdown-dark-link-hover-bg: rgba($white, .15) !default;\n$dropdown-dark-link-active-color: $dropdown-link-active-color !default;\n$dropdown-dark-link-active-bg: $dropdown-link-active-bg !default;\n$dropdown-dark-link-disabled-color: $gray-500 !default;\n$dropdown-dark-header-color: $gray-500 !default;\n// scss-docs-end dropdown-dark-variables\n\n\n// Pagination\n\n// scss-docs-start pagination-variables\n$pagination-padding-y: .375rem !default;\n$pagination-padding-x: .75rem !default;\n$pagination-padding-y-sm: .25rem !default;\n$pagination-padding-x-sm: .5rem !default;\n$pagination-padding-y-lg: .75rem !default;\n$pagination-padding-x-lg: 1.5rem !default;\n\n$pagination-color: $link-color !default;\n$pagination-bg: $white !default;\n$pagination-border-width: $border-width !default;\n$pagination-border-radius: $border-radius !default;\n$pagination-margin-start: -$pagination-border-width !default;\n$pagination-border-color: $gray-300 !default;\n\n$pagination-focus-color: $link-hover-color !default;\n$pagination-focus-bg: $gray-200 !default;\n$pagination-focus-box-shadow: $input-btn-focus-box-shadow !default;\n$pagination-focus-outline: 0 !default;\n\n$pagination-hover-color: $link-hover-color !default;\n$pagination-hover-bg: $gray-200 !default;\n$pagination-hover-border-color: $gray-300 !default;\n\n$pagination-active-color: $component-active-color !default;\n$pagination-active-bg: $component-active-bg !default;\n$pagination-active-border-color: $pagination-active-bg !default;\n\n$pagination-disabled-color: $gray-600 !default;\n$pagination-disabled-bg: $white !default;\n$pagination-disabled-border-color: $gray-300 !default;\n\n$pagination-transition: color .15s ease-in-out, background-color .15s ease-in-out, border-color .15s ease-in-out, box-shadow .15s ease-in-out !default;\n\n$pagination-border-radius-sm: $border-radius-sm !default;\n$pagination-border-radius-lg: $border-radius-lg !default;\n// scss-docs-end pagination-variables\n\n\n// Cards\n\n// scss-docs-start card-variables\n$card-spacer-y: $spacer !default;\n$card-spacer-x: $spacer !default;\n$card-title-spacer-y: $spacer / 2 !default;\n$card-border-width: $border-width !default;\n$card-border-radius: $border-radius !default;\n$card-border-color: rgba($black, .125) !default;\n$card-inner-border-radius: subtract($card-border-radius, $card-border-width) !default;\n$card-cap-padding-y: $card-spacer-y / 2 !default;\n$card-cap-padding-x: $card-spacer-x !default;\n$card-cap-bg: rgba($black, .03) !default;\n$card-cap-color: null !default;\n$card-height: null !default;\n$card-color: null !default;\n$card-bg: $white !default;\n$card-img-overlay-padding: $spacer !default;\n$card-group-margin: $grid-gutter-width / 2 !default;\n// scss-docs-end card-variables\n\n// Accordion\n\n// scss-docs-start accordion-variables\n$accordion-padding-y: 1rem !default;\n$accordion-padding-x: 1.25rem !default;\n$accordion-color: $body-color !default;\n$accordion-bg: transparent !default;\n$accordion-border-width: $border-width !default;\n$accordion-border-color: rgba($black, .125) !default;\n$accordion-border-radius: $border-radius !default;\n$accordion-inner-border-radius: subtract($accordion-border-radius, $accordion-border-width) !default;\n\n$accordion-body-padding-y: $accordion-padding-y !default;\n$accordion-body-padding-x: $accordion-padding-x !default;\n\n$accordion-button-padding-y: $accordion-padding-y !default;\n$accordion-button-padding-x: $accordion-padding-x !default;\n$accordion-button-color: $accordion-color !default;\n$accordion-button-bg: $accordion-bg !default;\n$accordion-transition: $btn-transition, border-radius .15s ease !default;\n$accordion-button-active-bg: tint-color($component-active-bg, 90%) !default;\n$accordion-button-active-color: shade-color($primary, 10%) !default;\n\n$accordion-button-focus-border-color: $input-focus-border-color !default;\n$accordion-button-focus-box-shadow: $btn-focus-box-shadow !default;\n\n$accordion-icon-width: 1.25rem !default;\n$accordion-icon-color: $accordion-color !default;\n$accordion-icon-active-color: $accordion-button-active-color !default;\n$accordion-icon-transition: transform .2s ease-in-out !default;\n$accordion-icon-transform: rotate(180deg) !default;\n\n$accordion-button-icon: url(\"data:image/svg+xml,\") !default;\n$accordion-button-active-icon: url(\"data:image/svg+xml,\") !default;\n// scss-docs-end accordion-variables\n\n// Tooltips\n\n// scss-docs-start tooltip-variables\n$tooltip-font-size: $font-size-sm !default;\n$tooltip-max-width: 200px !default;\n$tooltip-color: $white !default;\n$tooltip-bg: $black !default;\n$tooltip-border-radius: $border-radius !default;\n$tooltip-opacity: .9 !default;\n$tooltip-padding-y: $spacer / 4 !default;\n$tooltip-padding-x: $spacer / 2 !default;\n$tooltip-margin: 0 !default;\n\n$tooltip-arrow-width: .8rem !default;\n$tooltip-arrow-height: .4rem !default;\n$tooltip-arrow-color: $tooltip-bg !default;\n// scss-docs-end tooltip-variables\n\n// Form tooltips must come after regular tooltips\n// scss-docs-start tooltip-feedback-variables\n$form-feedback-tooltip-padding-y: $tooltip-padding-y !default;\n$form-feedback-tooltip-padding-x: $tooltip-padding-x !default;\n$form-feedback-tooltip-font-size: $tooltip-font-size !default;\n$form-feedback-tooltip-line-height: null !default;\n$form-feedback-tooltip-opacity: $tooltip-opacity !default;\n$form-feedback-tooltip-border-radius: $tooltip-border-radius !default;\n// scss-docs-start tooltip-feedback-variables\n\n\n// Popovers\n\n// scss-docs-start popover-variables\n$popover-font-size: $font-size-sm !default;\n$popover-bg: $white !default;\n$popover-max-width: 276px !default;\n$popover-border-width: $border-width !default;\n$popover-border-color: rgba($black, .2) !default;\n$popover-border-radius: $border-radius-lg !default;\n$popover-inner-border-radius: subtract($popover-border-radius, $popover-border-width) !default;\n$popover-box-shadow: $box-shadow !default;\n\n$popover-header-bg: shade-color($popover-bg, 6%) !default;\n$popover-header-color: $headings-color !default;\n$popover-header-padding-y: .5rem !default;\n$popover-header-padding-x: $spacer !default;\n\n$popover-body-color: $body-color !default;\n$popover-body-padding-y: $spacer !default;\n$popover-body-padding-x: $spacer !default;\n\n$popover-arrow-width: 1rem !default;\n$popover-arrow-height: .5rem !default;\n$popover-arrow-color: $popover-bg !default;\n\n$popover-arrow-outer-color: fade-in($popover-border-color, .05) !default;\n// scss-docs-end popover-variables\n\n\n// Toasts\n\n// scss-docs-start toast-variables\n$toast-max-width: 350px !default;\n$toast-padding-x: .75rem !default;\n$toast-padding-y: .5rem !default;\n$toast-font-size: .875rem !default;\n$toast-color: null !default;\n$toast-background-color: rgba($white, .85) !default;\n$toast-border-width: 1px !default;\n$toast-border-color: rgba(0, 0, 0, .1) !default;\n$toast-border-radius: $border-radius !default;\n$toast-box-shadow: $box-shadow !default;\n$toast-spacing: $container-padding-x !default;\n\n$toast-header-color: $gray-600 !default;\n$toast-header-background-color: rgba($white, .85) !default;\n$toast-header-border-color: rgba(0, 0, 0, .05) !default;\n// scss-docs-end toast-variables\n\n\n// Badges\n\n// scss-docs-start badge-variables\n$badge-font-size: .75em !default;\n$badge-font-weight: $font-weight-bold !default;\n$badge-color: $white !default;\n$badge-padding-y: .35em !default;\n$badge-padding-x: .65em !default;\n$badge-border-radius: $border-radius !default;\n// scss-docs-end badge-variables\n\n\n// Modals\n\n// scss-docs-start modal-variables\n$modal-inner-padding: $spacer !default;\n\n$modal-footer-margin-between: .5rem !default;\n\n$modal-dialog-margin: .5rem !default;\n$modal-dialog-margin-y-sm-up: 1.75rem !default;\n\n$modal-title-line-height: $line-height-base !default;\n\n$modal-content-color: null !default;\n$modal-content-bg: $white !default;\n$modal-content-border-color: rgba($black, .2) !default;\n$modal-content-border-width: $border-width !default;\n$modal-content-border-radius: $border-radius-lg !default;\n$modal-content-inner-border-radius: subtract($modal-content-border-radius, $modal-content-border-width) !default;\n$modal-content-box-shadow-xs: $box-shadow-sm !default;\n$modal-content-box-shadow-sm-up: $box-shadow !default;\n\n$modal-backdrop-bg: $black !default;\n$modal-backdrop-opacity: .5 !default;\n$modal-header-border-color: $border-color !default;\n$modal-footer-border-color: $modal-header-border-color !default;\n$modal-header-border-width: $modal-content-border-width !default;\n$modal-footer-border-width: $modal-header-border-width !default;\n$modal-header-padding-y: $modal-inner-padding !default;\n$modal-header-padding-x: $modal-inner-padding !default;\n$modal-header-padding: $modal-header-padding-y $modal-header-padding-x !default; // Keep this for backwards compatibility\n\n$modal-sm: 300px !default;\n$modal-md: 500px !default;\n$modal-lg: 800px !default;\n$modal-xl: 1140px !default;\n\n$modal-fade-transform: translate(0, -50px) !default;\n$modal-show-transform: none !default;\n$modal-transition: transform .3s ease-out !default;\n$modal-scale-transform: scale(1.02) !default;\n// scss-docs-end modal-variables\n\n\n// Alerts\n//\n// Define alert colors, border radius, and padding.\n\n// scss-docs-start alert-variables\n$alert-padding-y: $spacer !default;\n$alert-padding-x: $spacer !default;\n$alert-margin-bottom: 1rem !default;\n$alert-border-radius: $border-radius !default;\n$alert-link-font-weight: $font-weight-bold !default;\n$alert-border-width: $border-width !default;\n$alert-bg-scale: -80% !default;\n$alert-border-scale: -70% !default;\n$alert-color-scale: 40% !default;\n$alert-dismissible-padding-r: $alert-padding-x * 3 !default; // 3x covers width of x plus default padding on either side\n// scss-docs-end alert-variables\n\n\n// Progress bars\n\n// scss-docs-start progress-variables\n$progress-height: 1rem !default;\n$progress-font-size: $font-size-base * .75 !default;\n$progress-bg: $gray-200 !default;\n$progress-border-radius: $border-radius !default;\n$progress-box-shadow: $box-shadow-inset !default;\n$progress-bar-color: $white !default;\n$progress-bar-bg: $primary !default;\n$progress-bar-animation-timing: 1s linear infinite !default;\n$progress-bar-transition: width .6s ease !default;\n// scss-docs-end progress-variables\n\n\n// List group\n\n// scss-docs-start list-group-variables\n$list-group-color: null !default;\n$list-group-bg: $white !default;\n$list-group-border-color: rgba($black, .125) !default;\n$list-group-border-width: $border-width !default;\n$list-group-border-radius: $border-radius !default;\n\n$list-group-item-padding-y: $spacer / 2 !default;\n$list-group-item-padding-x: $spacer !default;\n$list-group-item-bg-scale: -80% !default;\n$list-group-item-color-scale: 40% !default;\n\n$list-group-hover-bg: $gray-100 !default;\n$list-group-active-color: $component-active-color !default;\n$list-group-active-bg: $component-active-bg !default;\n$list-group-active-border-color: $list-group-active-bg !default;\n\n$list-group-disabled-color: $gray-600 !default;\n$list-group-disabled-bg: $list-group-bg !default;\n\n$list-group-action-color: $gray-700 !default;\n$list-group-action-hover-color: $list-group-action-color !default;\n\n$list-group-action-active-color: $body-color !default;\n$list-group-action-active-bg: $gray-200 !default;\n// scss-docs-end list-group-variables\n\n\n// Image thumbnails\n\n// scss-docs-start thumbnail-variables\n$thumbnail-padding: .25rem !default;\n$thumbnail-bg: $body-bg !default;\n$thumbnail-border-width: $border-width !default;\n$thumbnail-border-color: $gray-300 !default;\n$thumbnail-border-radius: $border-radius !default;\n$thumbnail-box-shadow: $box-shadow-sm !default;\n// scss-docs-end thumbnail-variables\n\n\n// Figures\n\n// scss-docs-start figure-variables\n$figure-caption-font-size: $small-font-size !default;\n$figure-caption-color: $gray-600 !default;\n// scss-docs-end figure-variables\n\n\n// Breadcrumbs\n\n// scss-docs-start breadcrumb-variables\n$breadcrumb-font-size: null !default;\n$breadcrumb-padding-y: 0 !default;\n$breadcrumb-padding-x: 0 !default;\n$breadcrumb-item-padding-x: .5rem !default;\n$breadcrumb-margin-bottom: 1rem !default;\n$breadcrumb-bg: null !default;\n$breadcrumb-divider-color: $gray-600 !default;\n$breadcrumb-active-color: $gray-600 !default;\n$breadcrumb-divider: quote(\"/\") !default;\n$breadcrumb-divider-flipped: $breadcrumb-divider !default;\n$breadcrumb-border-radius: null !default;\n// scss-docs-end breadcrumb-variables\n\n// Carousel\n\n// scss-docs-start carousel-variables\n$carousel-control-color: $white !default;\n$carousel-control-width: 15% !default;\n$carousel-control-opacity: .5 !default;\n$carousel-control-hover-opacity: .9 !default;\n$carousel-control-transition: opacity .15s ease !default;\n\n$carousel-indicator-width: 30px !default;\n$carousel-indicator-height: 3px !default;\n$carousel-indicator-hit-area-height: 10px !default;\n$carousel-indicator-spacer: 3px !default;\n$carousel-indicator-opacity: .5 !default;\n$carousel-indicator-active-bg: $white !default;\n$carousel-indicator-active-opacity: 1 !default;\n$carousel-indicator-transition: opacity .6s ease !default;\n\n$carousel-caption-width: 70% !default;\n$carousel-caption-color: $white !default;\n$carousel-caption-padding-y: 1.25rem !default;\n$carousel-caption-spacer: 1.25rem !default;\n\n$carousel-control-icon-width: 2rem !default;\n\n$carousel-control-prev-icon-bg: url(\"data:image/svg+xml,\") !default;\n$carousel-control-next-icon-bg: url(\"data:image/svg+xml,\") !default;\n\n$carousel-transition-duration: .6s !default;\n$carousel-transition: transform $carousel-transition-duration ease-in-out !default; // Define transform transition first if using multiple transitions (e.g., `transform 2s ease, opacity .5s ease-out`)\n\n$carousel-dark-indicator-active-bg: $black !default;\n$carousel-dark-caption-color: $black !default;\n$carousel-dark-control-icon-filter: invert(1) grayscale(100) !default;\n// scss-docs-end carousel-variables\n\n\n// Spinners\n\n// scss-docs-start spinner-variables\n$spinner-width: 2rem !default;\n$spinner-height: $spinner-width !default;\n$spinner-border-width: .25em !default;\n$spinner-animation-speed: .75s !default;\n\n$spinner-width-sm: 1rem !default;\n$spinner-height-sm: $spinner-width-sm !default;\n$spinner-border-width-sm: .2em !default;\n// scss-docs-end spinner-variables\n\n\n// Close\n\n// scss-docs-start close-variables\n$btn-close-width: 1em !default;\n$btn-close-height: $btn-close-width !default;\n$btn-close-padding-x: .25em !default;\n$btn-close-padding-y: $btn-close-padding-x !default;\n$btn-close-color: $black !default;\n$btn-close-bg: url(\"data:image/svg+xml,\") !default;\n$btn-close-focus-shadow: $input-btn-focus-box-shadow !default;\n$btn-close-opacity: .5 !default;\n$btn-close-hover-opacity: .75 !default;\n$btn-close-focus-opacity: 1 !default;\n$btn-close-disabled-opacity: .25 !default;\n$btn-close-white-filter: invert(1) grayscale(100%) brightness(200%) !default;\n// scss-docs-end close-variables\n\n\n// Offcanvas\n\n// scss-docs-start offcanvas-variables\n$offcanvas-padding-y: $modal-inner-padding !default;\n$offcanvas-padding-x: $modal-inner-padding !default;\n$offcanvas-horizontal-width: 400px !default;\n$offcanvas-vertical-height: 30vh !default;\n$offcanvas-transition-duration: .3s !default;\n$offcanvas-border-color: $modal-content-border-color !default;\n$offcanvas-border-width: $modal-content-border-width !default;\n$offcanvas-title-line-height: $modal-title-line-height !default;\n$offcanvas-bg-color: $modal-content-bg !default;\n$offcanvas-color: $modal-content-color !default;\n$offcanvas-body-backdrop-color: rgba($modal-backdrop-bg, $modal-backdrop-opacity) !default;\n$offcanvas-box-shadow: $modal-content-box-shadow-xs !default;\n// scss-docs-end offcanvas-variables\n\n// Code\n\n$code-font-size: $small-font-size !default;\n$code-color: $pink !default;\n\n$kbd-padding-y: .2rem !default;\n$kbd-padding-x: .4rem !default;\n$kbd-font-size: $code-font-size !default;\n$kbd-color: $white !default;\n$kbd-bg: $gray-900 !default;\n\n$pre-color: null !default;\n","// Loop over each breakpoint\n@each $breakpoint in map-keys($grid-breakpoints) {\n\n // Generate media query if needed\n @include media-breakpoint-up($breakpoint) {\n $infix: breakpoint-infix($breakpoint, $grid-breakpoints);\n\n // Loop over each utility property\n @each $key, $utility in $utilities {\n // The utility can be disabled with `false`, thus check if the utility is a map first\n // Only proceed if responsive media queries are enabled or if it's the base media query\n @if type-of($utility) == \"map\" and (map-get($utility, responsive) or $infix == \"\") {\n @include generate-utility($utility, $infix);\n }\n }\n }\n}\n\n// RFS rescaling\n@media (min-width: $rfs-mq-value) {\n @each $breakpoint in map-keys($grid-breakpoints) {\n $infix: breakpoint-infix($breakpoint, $grid-breakpoints);\n\n @if (map-get($grid-breakpoints, $breakpoint) < $rfs-breakpoint) {\n // Loop over each utility property\n @each $key, $utility in $utilities {\n // The utility can be disabled with `false`, thus check if the utility is a map first\n // Only proceed if responsive media queries are enabled or if it's the base media query\n @if type-of($utility) == \"map\" and map-get($utility, rfs) and (map-get($utility, responsive) or $infix == \"\") {\n @include generate-utility($utility, $infix, true);\n }\n }\n }\n }\n}\n\n\n// Print utilities\n@media print {\n @each $key, $utility in $utilities {\n // The utility can be disabled with `false`, thus check if the utility is a map first\n // Then check if the utility needs print styles\n @if type-of($utility) == \"map\" and map-get($utility, print) == true {\n @include generate-utility($utility, \"-print\");\n }\n }\n}\n"]} \ No newline at end of file diff --git a/tests/fixtures/novo-menu-flutuante/css/bootstrap-reboot.css b/tests/fixtures/novo-menu-flutuante/css/bootstrap-reboot.css new file mode 100644 index 000000000..85f5bb2cc --- /dev/null +++ b/tests/fixtures/novo-menu-flutuante/css/bootstrap-reboot.css @@ -0,0 +1,8 @@ +/*! + * Bootstrap Reboot v5.0.0-beta1 (https://getbootstrap.com/) + * Copyright 2011-2020 The Bootstrap Authors + * Copyright 2011-2020 Twitter, Inc. + * Licensed under MIT (https://github.com/twbs/bootstrap/blob/main/LICENSE) + * Forked from Normalize.css, licensed MIT (https://github.com/necolas/normalize.css/blob/master/LICENSE.md) + */@-webkit-keyframes bounce{0%,100%,20%,50%,80%{-webkit-transform:translateY(0)}40%{-webkit-transform:translateY(30px)}60%{-webkit-transform:translateY(15px)}}@-moz-keyframes bounce{0%,100%,20%,50%,80%{-moz-transform:translateY(0)}40%{-moz-transform:translateY(30px)}60%{-moz-transform:translateY(15px)}}@-ms-keyframes bounce{0%,100%,20%,50%,80%{-ms-transform:translateY(0)}40%{-ms-transform:translateY(30px)}60%{-ms-transform:translateY(15px)}}@-o-keyframes bounce{0%,100%,20%,50%,80%{-o-transform:translateY(0)}40%{-o-transform:translateY(30px)}60%{-o-transform:translateY(15px)}}@keyframes bounce{0%,100%,20%,50%,80%{transform:translateY(0)}40%{transform:translateY(30px)}60%{transform:translateY(15px)}}@-webkit-keyframes slideInUp{from{-webkit-transform:translate3d(0,30%,0);transform:translate3d(0,30%,0);visibility:visible;opacity:0}to{-webkit-transform:translate3d(0,0,0);transform:translate3d(0,0,0);opacity:1}}*,::after,::before{box-sizing:border-box}@media (prefers-reduced-motion:no-preference){:root{scroll-behavior:smooth}}body{margin:0;font-family:"Noto Sans",sans-serif;font-size:1rem;font-weight:400;line-height:1.5;color:#393939;background-color:#fff;-webkit-text-size-adjust:100%;-webkit-tap-highlight-color:transparent}hr{margin:1rem 0;color:inherit;background-color:currentColor;border:0;opacity:.25}hr:not([size]){height:1px}h1,h2,h3,h4,h5,h6{margin-top:0;margin-bottom:.5rem;font-weight:500;line-height:1.2}h1{font-size:calc(1.375rem + 1.5vw)}@media (min-width:1200px){h1{font-size:2.5rem}}h2{font-size:calc(1.325rem + .9vw)}@media (min-width:1200px){h2{font-size:2rem}}h3{font-size:calc(1.3rem + .6vw)}@media (min-width:1200px){h3{font-size:1.75rem}}h4{font-size:calc(1.275rem + .3vw)}@media (min-width:1200px){h4{font-size:1.5rem}}h5{font-size:1.25rem}h6{font-size:1rem}p{margin-top:0;margin-bottom:1rem}abbr[data-bs-original-title],abbr[title]{text-decoration:underline dotted;cursor:help;text-decoration-skip-ink:none}address{margin-bottom:1rem;font-style:normal;line-height:inherit}ol,ul{padding-left:2rem}dl,ol,ul{margin-top:0;margin-bottom:1rem}ol ol,ol ul,ul ol,ul ul{margin-bottom:0}dt{font-weight:700}dd{margin-bottom:.5rem;margin-left:0}blockquote{margin:0 0 1rem}b,strong{font-weight:bolder}small{font-size:.875em}mark{padding:.2em;background-color:#fcf8e3}sub,sup{position:relative;font-size:.75em;line-height:0;vertical-align:baseline}sub{bottom:-.25em}sup{top:-.5em}a{color:#3867ce;text-decoration:underline}a:hover{color:#2d52a5}a:not([href]):not([class]),a:not([href]):not([class]):hover{color:inherit;text-decoration:none}code,kbd,pre,samp{font-family:SFMono-Regular,Menlo,Monaco,Consolas,"Liberation Mono","Courier New",monospace;font-size:1em;direction:ltr;unicode-bidi:bidi-override}pre{display:block;margin-top:0;margin-bottom:1rem;overflow:auto;font-size:.875em}pre code{font-size:inherit;color:inherit;word-break:normal}code{font-size:.875em;color:#c32aa3;word-wrap:break-word}a>code{color:inherit}kbd{padding:.2rem .4rem;font-size:.875em;color:#fff;background-color:#393939;border-radius:.12 .5rem}kbd kbd{padding:0;font-size:1em;font-weight:700}figure{margin:0 0 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mode 100644 index 000000000..602e6d2bc --- /dev/null +++ b/tests/fixtures/novo-menu-flutuante/css/bootstrap-reboot.css.map @@ -0,0 +1 @@ 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* Bootstrap Reboot v5.0.0-beta1 (https://getbootstrap.com/)\n * Copyright 2011-2020 The Bootstrap Authors\n * Copyright 2011-2020 Twitter, Inc.\n * Licensed under MIT (https://github.com/twbs/bootstrap/blob/main/LICENSE)\n * Forked from Normalize.css, licensed MIT (https://github.com/necolas/normalize.css/blob/master/LICENSE.md)\n */\n\n @import \"scss/functions\";\n\n @import \"../../common/scss/itcssImports/vars\";\n @import \"../../common/scss/itcssImports/mixins\";\n @import \"./settings/variables\";\n \n // Prevent the usage of custom properties since we don't add them to `:root` in reboot\n $font-family-base: $font-family-sans-serif; // stylelint-disable-line scss/dollar-variable-default\n $font-family-code: $font-family-monospace; // stylelint-disable-line scss/dollar-variable-default\n @import \"scss/mixins\";\n @import \"scss/reboot\";\n ","@mixin __on-theme--dark {\n @at-root .#{$__classPrefix}__theme--dark & {\n @content;\n }\n}\n\n@mixin __on-theme--light {\n @at-root .#{$__classPrefix}__theme--light & {\n @content;\n }\n}\n\n\n@mixin animated($time: .5s, $prop: background, $prop2: text-indent){\n -webkit-animation-fill-mode: both;\n -moz-animation-fill-mode: both;\n -ms-animation-fill-mode: both;\n -o-animation-fill-mode: both;\n animation-fill-mode: both;\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time;\n\n -o-transition: $prop $time ease-out, $prop2 $time ease-out;\n -ms-transition: $prop $time ease-out, $prop2 $time ease-out;\n -moz-transition: $prop $time ease-out, $prop2 $time ease-out;\n -webkit-transition: $prop $time ease-out, $prop2 $time ease-out;\n transition: $prop $time ease-out, $prop2 $time ease-out;\n}\n\n@-webkit-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-webkit-transform: translateY(0);}\n 40% {-webkit-transform: translateY(30px);}\n 60% {-webkit-transform: translateY(15px);}\n}\n\n@-moz-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-moz-transform: translateY(0);}\n 40% {-moz-transform: translateY(30px);}\n 60% {-moz-transform: translateY(15px);}\n}\n\n@-ms-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-ms-transform: translateY(0);}\n 40% {-ms-transform: translateY(30px);}\n 60% {-ms-transform: translateY(15px);}\n}\n\n@-o-keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {-o-transform: translateY(0);}\n 40% {-o-transform: translateY(30px);}\n 60% {-o-transform: translateY(15px);}\n}\n@keyframes bounce {\n 0%, 20%, 50%, 80%, 100% {transform: translateY(0);}\n 40% {transform: translateY(30px);}\n 60% {transform: translateY(15px);}\n}\n\n@mixin bounce($time: .5s){\n -webkit-animation-name: bounce;\n -moz-animation-name: bounce;\n -ms-animation-name: bounce;\n -o-animation-name: bounce;\n animation-name: bounce;\n\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time; \n}\n\n@mixin slideInUp($time: .5s){\n -webkit-animation-name: slideInUp;\n animation-name: slideInUp;\n\n -webkit-animation-duration: $time;\n -moz-animation-duration: $time;\n -ms-animation-duration: $time;\n -o-animation-duration: $time;\n animation-duration: $time;\n}\n\n@-webkit-keyframes slideInUp {\n from {\n -webkit-transform: translate3d(0, 30%, 0);\n transform: translate3d(0, 30%, 0);\n visibility: visible;\n opacity: 0;\n }\n\n to {\n -webkit-transform: translate3d(0, 0, 0);\n transform: translate3d(0, 0, 0);\n opacity: 1;\n }\n}\n","// stylelint-disable declaration-no-important, selector-no-qualifying-type, property-no-vendor-prefix\n\n\n// Reboot\n//\n// Normalization of HTML elements, manually forked from Normalize.css to remove\n// styles targeting irrelevant browsers while applying new styles.\n//\n// Normalize is licensed MIT. https://github.com/necolas/normalize.css\n\n\n// Document\n//\n// Change from `box-sizing: content-box` so that `width` is not affected by `padding` or `border`.\n\n*,\n*::before,\n*::after {\n box-sizing: border-box;\n}\n\n\n// Root\n//\n// Ability to the value of the root font sizes, affecting the value of `rem`.\n// null by default, thus nothing is generated.\n\n:root {\n font-size: $font-size-root;\n\n @if $enable-smooth-scroll {\n @media (prefers-reduced-motion: no-preference) {\n scroll-behavior: smooth;\n }\n }\n}\n\n\n// Body\n//\n// 1. Remove the margin in all browsers.\n// 2. As a best practice, apply a default `background-color`.\n// 3. Prevent adjustments of font size after orientation changes in iOS.\n// 4. Change the default tap highlight to be completely transparent in iOS.\n\nbody {\n margin: 0; // 1\n font-family: $font-family-base;\n @include font-size($font-size-base);\n font-weight: $font-weight-base;\n line-height: $line-height-base;\n color: $body-color;\n text-align: $body-text-align;\n background-color: $body-bg; // 2\n -webkit-text-size-adjust: 100%; // 3\n -webkit-tap-highlight-color: rgba($black, 0); // 4\n}\n\n\n// Content grouping\n//\n// 1. Reset Firefox's gray color\n// 2. Set correct height and prevent the `size` attribute to make the `hr` look like an input field\n\nhr {\n margin: $hr-margin-y 0;\n color: $hr-color; // 1\n background-color: currentColor;\n border: 0;\n opacity: $hr-opacity;\n}\n\nhr:not([size]) {\n height: $hr-height; // 2\n}\n\n\n// Typography\n//\n// 1. Remove top margins from headings\n// By default, `

      `-`

      ` all receive top and bottom margins. We nuke the top\n// margin for easier control within type scales as it avoids margin collapsing.\n\n%heading {\n margin-top: 0; // 1\n margin-bottom: $headings-margin-bottom;\n font-family: $headings-font-family;\n font-style: $headings-font-style;\n font-weight: $headings-font-weight;\n line-height: $headings-line-height;\n color: $headings-color;\n}\n\nh1 {\n @extend %heading;\n @include font-size($h1-font-size);\n}\n\nh2 {\n @extend %heading;\n @include font-size($h2-font-size);\n}\n\nh3 {\n @extend %heading;\n @include font-size($h3-font-size);\n}\n\nh4 {\n @extend %heading;\n @include font-size($h4-font-size);\n}\n\nh5 {\n @extend %heading;\n @include font-size($h5-font-size);\n}\n\nh6 {\n @extend %heading;\n @include font-size($h6-font-size);\n}\n\n\n// Reset margins on paragraphs\n//\n// Similarly, the top margin on `

      `s get reset. However, we also reset the\n// bottom margin to use `rem` units instead of `em`.\n\np {\n margin-top: 0;\n margin-bottom: $paragraph-margin-bottom;\n}\n\n\n// Abbreviations\n//\n// 1. Duplicate behavior to the data-bs-* attribute for our tooltip plugin\n// 2. Add the correct text decoration in Chrome, Edge, Opera, and Safari.\n// 3. Add explicit cursor to indicate changed behavior.\n// 4. Prevent the text-decoration to be skipped.\n\nabbr[title],\nabbr[data-bs-original-title] { // 1\n text-decoration: underline dotted; // 2\n cursor: help; // 3\n text-decoration-skip-ink: none; // 4\n}\n\n\n// Address\n\naddress {\n margin-bottom: 1rem;\n font-style: normal;\n line-height: inherit;\n}\n\n\n// Lists\n\nol,\nul {\n padding-left: 2rem;\n}\n\nol,\nul,\ndl {\n margin-top: 0;\n margin-bottom: 1rem;\n}\n\nol ol,\nul ul,\nol ul,\nul ol {\n margin-bottom: 0;\n}\n\ndt {\n font-weight: $dt-font-weight;\n}\n\n// 1. Undo browser default\n\ndd {\n margin-bottom: .5rem;\n margin-left: 0; // 1\n}\n\n\n// Blockquote\n\nblockquote {\n margin: 0 0 1rem;\n}\n\n\n// Strong\n//\n// Add the correct font weight in Chrome, Edge, and Safari\n\nb,\nstrong {\n font-weight: $font-weight-bolder;\n}\n\n\n// Small\n//\n// Add the correct font size in all browsers\n\nsmall {\n @include font-size($small-font-size);\n}\n\n\n// Mark\n\nmark {\n padding: $mark-padding;\n background-color: $mark-bg;\n}\n\n\n// Sub and Sup\n//\n// Prevent `sub` and `sup` elements from affecting the line height in\n// all browsers.\n\nsub,\nsup {\n position: relative;\n @include font-size($sub-sup-font-size);\n line-height: 0;\n vertical-align: baseline;\n}\n\nsub { bottom: -.25em; }\nsup { top: -.5em; }\n\n\n// Links\n\na {\n color: $link-color;\n text-decoration: $link-decoration;\n\n &:hover {\n color: $link-hover-color;\n text-decoration: $link-hover-decoration;\n }\n}\n\n// And undo these styles for placeholder links/named anchors (without href).\n// It would be more straightforward to just use a[href] in previous block, but that\n// causes specificity issues in many other styles that are too complex to fix.\n// See https://github.com/twbs/bootstrap/issues/19402\n\na:not([href]):not([class]) {\n &,\n &:hover {\n color: inherit;\n text-decoration: none;\n }\n}\n\n\n// Code\n\npre,\ncode,\nkbd,\nsamp {\n font-family: $font-family-code;\n @include font-size(1em); // Correct the odd `em` font sizing in all browsers.\n direction: ltr #{\"/* rtl:ignore */\"};\n unicode-bidi: bidi-override;\n}\n\n// 1. Remove browser default top margin\n// 2. Reset browser default of `1em` to use `rem`s\n// 3. Don't allow content to break outside\n\npre {\n display: block;\n margin-top: 0; // 1\n margin-bottom: 1rem; // 2\n overflow: auto; // 3\n @include font-size($code-font-size);\n color: $pre-color;\n\n // Account for some code outputs that place code tags in pre tags\n code {\n @include font-size(inherit);\n color: inherit;\n word-break: normal;\n }\n}\n\ncode {\n @include font-size($code-font-size);\n color: $code-color;\n word-wrap: break-word;\n\n // Streamline the style when inside anchors to avoid broken underline and more\n a > & {\n color: inherit;\n }\n}\n\nkbd {\n padding: $kbd-padding-y $kbd-padding-x;\n @include font-size($kbd-font-size);\n color: $kbd-color;\n background-color: $kbd-bg;\n @include border-radius($border-radius-sm);\n\n kbd {\n padding: 0;\n @include font-size(1em);\n font-weight: $nested-kbd-font-weight;\n }\n}\n\n\n// Figures\n//\n// Apply a consistent margin strategy (matches our type styles).\n\nfigure {\n margin: 0 0 1rem;\n}\n\n\n// Images and content\n\nimg,\nsvg {\n vertical-align: middle;\n}\n\n\n// Tables\n//\n// Prevent double borders\n\ntable {\n caption-side: bottom;\n border-collapse: collapse;\n}\n\ncaption {\n padding-top: $table-cell-padding-y;\n padding-bottom: $table-cell-padding-y;\n color: $table-caption-color;\n text-align: left;\n}\n\n// 1. Removes font-weight bold by inheriting\n// 2. Matches default `` alignment by inheriting `text-align`.\n// 3. Fix alignment for Safari\n\nth {\n font-weight: $table-th-font-weight; // 1\n text-align: inherit; // 2\n text-align: -webkit-match-parent; // 3\n}\n\nthead,\ntbody,\ntfoot,\ntr,\ntd,\nth {\n border-color: inherit;\n border-style: solid;\n border-width: 0;\n}\n\n\n// Forms\n//\n// 1. Allow labels to use `margin` for spacing.\n\nlabel {\n display: inline-block; // 1\n}\n\n// Remove the default `border-radius` that macOS Chrome adds.\n// See https://github.com/twbs/bootstrap/issues/24093\n\nbutton {\n // stylelint-disable-next-line property-disallowed-list\n border-radius: 0;\n}\n\n// Explicitly remove focus outline in Chromium when it shouldn't be\n// visible (e.g. as result of mouse click or touch tap). It already\n// should be doing this automatically, but seems to currently be\n// confused and applies its very visible two-tone outline anyway.\n\nbutton:focus:not(:focus-visible) {\n outline: 0;\n}\n\n// 1. Remove the margin in Firefox and Safari\n\ninput,\nbutton,\nselect,\noptgroup,\ntextarea {\n margin: 0; // 1\n font-family: inherit;\n @include font-size(inherit);\n line-height: inherit;\n}\n\n// Remove the inheritance of text transform in Firefox\nbutton,\nselect {\n text-transform: none;\n}\n// Set the cursor for non-`',nextArrow:'',autoplay:!1,autoplaySpeed:3e3,centerMode:!1,centerPadding:"50px",cssEase:"ease",customPaging:function(t,e){return c('