Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural
Ano de defesa: | 2023 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências da Saúde |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Farmacologia
|
Departamento: |
Farmacologia
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/28699 |
Resumo: | Natural deep eutectic solvents (NADES) are biosustainable solvents proposed as a safe alternative for obtaining bioactive extracts. Despite the low absorption, the phytochemicals widely present in the blueberry, have beneficial effects related to the intestine and brain. However, studies on the in vivo effects of NADES are scarce and their influence on the bioavailability and tissue distribution of phenolic compounds extracted with NADES has not been elucidated. Thus, the objective of this work was to study the pharmacokinetic characteristics and the tissue distribution profile of the bioactive compounds of a biocompatible and ready-to-use blueberry extract obtained with NADES solvent. Rats received (via gavage) a single dose (10.0 mg of polyphenols/kg of body weight) of crude blueberry extract obtained using NADES (EB-NADES) or organic solvent (EB-SORG), the latter being previously dried and reconstituted in water. Non-compartmental pharmacokinetic analysis revealed that EB-NADES increased the bioavailability of anthocyanins by 140% compared to EB-SORG. Compared to SORG, NADES delayed gastric chyme neutralization, increasing the stability of phenolic compounds during in vitro digestion. EB-NADES increased the extent of tissue absorption of anthocyanins by 460% and 17% in the brain and small intestine, respectively, compared to EB-SORG. Furthermore, EB-NADES increased tissue concentrations of phenolic metabolites in the stomach and small intestine. The third stage of this work is described in the appendices and composes the second block of objectives initially established for this Thesis. This step aimed to compare the effect of two antibiotic treatment regimens to induce intestinal dysbiosis and behavioral changes in Wistar rats. The animals were divided into 3 groups: control, cocktail of antibiotics-AB, and vancomycinVAN, which received water or antibiotics by gavage for 10 days (2 mL/kg p.c.). Treatment with AB or VAN reduced the diversity of the intestinal microbiota, through the depletion of Firmicutes phyla and increase of Proteobacteria. AB increased gram-negative bacteria such as Cianobacteria and Desulfobacteria, while VAN reduced Actinobacterota and increased Bacteroidata. Dysbiosis induced by AB or VAN impaired short-term memory, reduced the production of microbial metabolites, dysregulated the immune system, and increased intestinal and blood-brain barrier permeability. Only AB treatment promoted long-term memory damage, parallel to the emergence of pathogenic genera such as Staphylococcus and Curtobacterium, as well as increased the relative abundance of gram-negative microorganisms. AB also promoted complete depletion of microbial metabolites, increased permeability in the hippocampus, and induced immune system dysregulation to a greater extent than VAN. Taken together, the data from the first block of this Thesis indicate that NADES can be used as a ready-to-use vehicle or solvent extractor to enhance plasma and tissue absorption of blueberry phenolic compounds. In addition, we concluded in the second step that the microbiota and its metabolites play an important role in cognitive impairment and that the differences between AB and VAN may be linked to the type of microbiota affected, since the treatment regimens have different bacterial targets. |
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2023-04-14T17:26:29Z2023-04-14T17:26:29Z2023-02-01http://repositorio.ufsm.br/handle/1/28699Natural deep eutectic solvents (NADES) are biosustainable solvents proposed as a safe alternative for obtaining bioactive extracts. Despite the low absorption, the phytochemicals widely present in the blueberry, have beneficial effects related to the intestine and brain. However, studies on the in vivo effects of NADES are scarce and their influence on the bioavailability and tissue distribution of phenolic compounds extracted with NADES has not been elucidated. Thus, the objective of this work was to study the pharmacokinetic characteristics and the tissue distribution profile of the bioactive compounds of a biocompatible and ready-to-use blueberry extract obtained with NADES solvent. Rats received (via gavage) a single dose (10.0 mg of polyphenols/kg of body weight) of crude blueberry extract obtained using NADES (EB-NADES) or organic solvent (EB-SORG), the latter being previously dried and reconstituted in water. Non-compartmental pharmacokinetic analysis revealed that EB-NADES increased the bioavailability of anthocyanins by 140% compared to EB-SORG. Compared to SORG, NADES delayed gastric chyme neutralization, increasing the stability of phenolic compounds during in vitro digestion. EB-NADES increased the extent of tissue absorption of anthocyanins by 460% and 17% in the brain and small intestine, respectively, compared to EB-SORG. Furthermore, EB-NADES increased tissue concentrations of phenolic metabolites in the stomach and small intestine. The third stage of this work is described in the appendices and composes the second block of objectives initially established for this Thesis. This step aimed to compare the effect of two antibiotic treatment regimens to induce intestinal dysbiosis and behavioral changes in Wistar rats. The animals were divided into 3 groups: control, cocktail of antibiotics-AB, and vancomycinVAN, which received water or antibiotics by gavage for 10 days (2 mL/kg p.c.). Treatment with AB or VAN reduced the diversity of the intestinal microbiota, through the depletion of Firmicutes phyla and increase of Proteobacteria. AB increased gram-negative bacteria such as Cianobacteria and Desulfobacteria, while VAN reduced Actinobacterota and increased Bacteroidata. Dysbiosis induced by AB or VAN impaired short-term memory, reduced the production of microbial metabolites, dysregulated the immune system, and increased intestinal and blood-brain barrier permeability. Only AB treatment promoted long-term memory damage, parallel to the emergence of pathogenic genera such as Staphylococcus and Curtobacterium, as well as increased the relative abundance of gram-negative microorganisms. AB also promoted complete depletion of microbial metabolites, increased permeability in the hippocampus, and induced immune system dysregulation to a greater extent than VAN. Taken together, the data from the first block of this Thesis indicate that NADES can be used as a ready-to-use vehicle or solvent extractor to enhance plasma and tissue absorption of blueberry phenolic compounds. In addition, we concluded in the second step that the microbiota and its metabolites play an important role in cognitive impairment and that the differences between AB and VAN may be linked to the type of microbiota affected, since the treatment regimens have different bacterial targets.Os solventes eutéticos profundos naturais (NADES) são solventes biossustentáveis propostos como uma alternativa segura para a obtenção de extratos bioativos. Apesar da baixa absorção, os fitoquímicos amplamente presentes no mirtilo, apresentam efeitos benéficos relacionados ao intestino e cérebro. Contudo, os estudos sobre os efeitos in vivo dos NADES são escassos e não está elucidada a sua influência na biodisponibilidade e distribuição tecidual dos compostos fenólicos extraídos com NADES. Assim, o objetivo deste trabalho foi estudar as características farmacocinéticas e o perfil de distribuição tecidual dos compostos bioativos de um extrato de mirtilo biocompatível e pronto para uso obtido com solvente NADES. Ratos receberam (via gavagem) uma única dose (10,0 mg de polifenóis/kg de peso corporal) de extrato bruto de mirtilo obtido usando NADES (EB-NADES) ou solvente orgânico (EBSORG), sendo este último previamente seco e reconstituído em água. A análise farmacocinética não compartimental revelou que o EB-NADES aumentou a biodisponibilidade de antocianinas em 140% em comparação com EB-SORG. Comparado ao SORG, NADES retardou a neutralização do quimo gástrico, aumentando a estabilidade dos compostos fenólicos durante a digestão in vitro. O EB-NADES aumentou a extensão da absorção tecidual de antocianinas em 460% e 17% no cérebro e intestino delgado, respectivamente, em comparação com EB-SORG. Ademais, o EB-NADES aumentou as concentrações teciduais de metabólitos fenólicos no estômago e no intestino delgado. A terceira etapa deste trabalho encontra-se descrita nos apêndices e compõe o segundo bloco de objetivos inicialmente estabelecidos para esta Tese. Esta etapa teve o objetivo comparar o efeito de dois regimes de tratamento com antibióticos para induzir disbiose intestinal e alterações comportamentais em ratos Wistar. Os animais foram divididos em 3 grupos: controle, coquetel de antibióticos-AB, e vancomicina-VAN, que receberam água, ou antibióticos por gavagem, durante 10 dias (2 mL/kg p.c.). O tratamento com AB ou VAN reduziram a diversidade da microbiota intestinal, através do esgotamento dos filos Firmicutes e aumento de Proteobacteria. AB aumentou bactérias gram-negativas como Cianobacteria e Desulfobacteria, enquanto VAN reduziu Actinobacterota e aumentou Bacteroidata. A disbiose induzida por AB ou VAN prejudicou a memória de curto prazo, reduziu a produção de metabólitos microbianos, desregulou o sistema imunológico, e aumentou a permeabilidade intestinal e da barreira hematoencefálica. Somente o tratamento com AB promoveu danos na memória de longo prazo, paralelamente ao surgimento de gêneros patogênicos como Staphylococcus e Curtobacterium bem como aumentou a abundância relativa de microorganismos gram-negativos. AB também promoveu a depleção completa de metabólitos microbianos, aumentou a permeabilidade no hipocampo e induziu uma desregulação do sistema imunológico em maiores proporções do que VAN. Tomados em conjunto, os dados do primeiro bloco desta Tese indicam que o NADES, pode ser usado como veículo ou solvente extrator pronto para uso para aumentar a absorção plasmática e tecidual de compostos fenólicos do mirtilo. Além disso, concluímos na segunda etapa que a microbiota e seus metabólitos desempenham um papel importante no comprometimento cognitivo e que as diferenças entre AB e VAN podem estar ligadas ao tipo de microbiota afetada, uma vez que os esquemas de tratamento têm diferentes alvos bacterianos.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em FarmacologiaUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessSolventes verdesCompostos bioativosMicrobiotaDisbiose intestinalCérebroGreen solventsBioactive compoundsGut dysbiosisBrainCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIABiodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo naturalBioavailability and tissue distribution of blueberry phenolic compounds (Vaccinium sp.) obtained with natural deep eutetic solventinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisEmanuelli, Tatianahttp://lattes.cnpq.br/2165391096880394Barcia, Milene TeixeiraSerra, Ana Teresa de Carvalho NegrãoLozano-Sánchez, JesúsNogueira, Cristina WayneBruker, Natáliahttp://lattes.cnpq.br/7798168059539845Silva, Dariane Trivisiol da2010000000006006006006006006006006007812e191-0e91-4b97-bc2b-b442502f01863d627ad1-3b4b-40eb-95a1-0d7eabda4c8ce773fba0-af9a-4af8-89af-911d0d50b8a285c57ac3-326b-4008-a815-08f853f947f204086808-56c4-424a-a7cd-f0d3cea361cfa78214c4-5fd7-4098-a440-5ce0af58d9b2a5fcd776-fba8-45f0-8d21-ab973af34fd9reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGFARMACOLOGIA_2023_SILVA_DARIANE.pdfTES_PPGFARMACOLOGIA_2023_SILVA_DARIANE.pdfTese de Doutoradoapplication/pdf19500771http://repositorio.ufsm.br/bitstream/1/28699/1/TES_PPGFARMACOLOGIA_2023_SILVA_DARIANE.pdf63b33c5831e2e7add648017d1d56ce60MD51LICENSElicense.txtlicense.txttext/plain; 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dc.title.por.fl_str_mv |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
dc.title.alternative.eng.fl_str_mv |
Bioavailability and tissue distribution of blueberry phenolic compounds (Vaccinium sp.) obtained with natural deep eutetic solvent |
title |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
spellingShingle |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural Silva, Dariane Trivisiol da Solventes verdes Compostos bioativos Microbiota Disbiose intestinal Cérebro Green solvents Bioactive compounds Gut dysbiosis Brain CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
title_full |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
title_fullStr |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
title_full_unstemmed |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
title_sort |
Biodisponibilidade e distribuição tecidual de compostos fenólicos do mirtilo (Vaccinium sp.) obtidos com solvente eutético profundo natural |
author |
Silva, Dariane Trivisiol da |
author_facet |
Silva, Dariane Trivisiol da |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Emanuelli, Tatiana |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2165391096880394 |
dc.contributor.advisor-co1.fl_str_mv |
Barcia, Milene Teixeira |
dc.contributor.referee1.fl_str_mv |
Serra, Ana Teresa de Carvalho Negrão |
dc.contributor.referee2.fl_str_mv |
Lozano-Sánchez, Jesús |
dc.contributor.referee3.fl_str_mv |
Nogueira, Cristina Wayne |
dc.contributor.referee4.fl_str_mv |
Bruker, Natália |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/7798168059539845 |
dc.contributor.author.fl_str_mv |
Silva, Dariane Trivisiol da |
contributor_str_mv |
Emanuelli, Tatiana Barcia, Milene Teixeira Serra, Ana Teresa de Carvalho Negrão Lozano-Sánchez, Jesús Nogueira, Cristina Wayne Bruker, Natália |
dc.subject.por.fl_str_mv |
Solventes verdes Compostos bioativos Microbiota Disbiose intestinal Cérebro |
topic |
Solventes verdes Compostos bioativos Microbiota Disbiose intestinal Cérebro Green solvents Bioactive compounds Gut dysbiosis Brain CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Green solvents Bioactive compounds Gut dysbiosis Brain |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Natural deep eutectic solvents (NADES) are biosustainable solvents proposed as a safe alternative for obtaining bioactive extracts. Despite the low absorption, the phytochemicals widely present in the blueberry, have beneficial effects related to the intestine and brain. However, studies on the in vivo effects of NADES are scarce and their influence on the bioavailability and tissue distribution of phenolic compounds extracted with NADES has not been elucidated. Thus, the objective of this work was to study the pharmacokinetic characteristics and the tissue distribution profile of the bioactive compounds of a biocompatible and ready-to-use blueberry extract obtained with NADES solvent. Rats received (via gavage) a single dose (10.0 mg of polyphenols/kg of body weight) of crude blueberry extract obtained using NADES (EB-NADES) or organic solvent (EB-SORG), the latter being previously dried and reconstituted in water. Non-compartmental pharmacokinetic analysis revealed that EB-NADES increased the bioavailability of anthocyanins by 140% compared to EB-SORG. Compared to SORG, NADES delayed gastric chyme neutralization, increasing the stability of phenolic compounds during in vitro digestion. EB-NADES increased the extent of tissue absorption of anthocyanins by 460% and 17% in the brain and small intestine, respectively, compared to EB-SORG. Furthermore, EB-NADES increased tissue concentrations of phenolic metabolites in the stomach and small intestine. The third stage of this work is described in the appendices and composes the second block of objectives initially established for this Thesis. This step aimed to compare the effect of two antibiotic treatment regimens to induce intestinal dysbiosis and behavioral changes in Wistar rats. The animals were divided into 3 groups: control, cocktail of antibiotics-AB, and vancomycinVAN, which received water or antibiotics by gavage for 10 days (2 mL/kg p.c.). Treatment with AB or VAN reduced the diversity of the intestinal microbiota, through the depletion of Firmicutes phyla and increase of Proteobacteria. AB increased gram-negative bacteria such as Cianobacteria and Desulfobacteria, while VAN reduced Actinobacterota and increased Bacteroidata. Dysbiosis induced by AB or VAN impaired short-term memory, reduced the production of microbial metabolites, dysregulated the immune system, and increased intestinal and blood-brain barrier permeability. Only AB treatment promoted long-term memory damage, parallel to the emergence of pathogenic genera such as Staphylococcus and Curtobacterium, as well as increased the relative abundance of gram-negative microorganisms. AB also promoted complete depletion of microbial metabolites, increased permeability in the hippocampus, and induced immune system dysregulation to a greater extent than VAN. Taken together, the data from the first block of this Thesis indicate that NADES can be used as a ready-to-use vehicle or solvent extractor to enhance plasma and tissue absorption of blueberry phenolic compounds. In addition, we concluded in the second step that the microbiota and its metabolites play an important role in cognitive impairment and that the differences between AB and VAN may be linked to the type of microbiota affected, since the treatment regimens have different bacterial targets. |
publishDate |
2023 |
dc.date.accessioned.fl_str_mv |
2023-04-14T17:26:29Z |
dc.date.available.fl_str_mv |
2023-04-14T17:26:29Z |
dc.date.issued.fl_str_mv |
2023-02-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/28699 |
url |
http://repositorio.ufsm.br/handle/1/28699 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
201000000000 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 600 600 600 600 |
dc.relation.authority.fl_str_mv |
7812e191-0e91-4b97-bc2b-b442502f0186 3d627ad1-3b4b-40eb-95a1-0d7eabda4c8c e773fba0-af9a-4af8-89af-911d0d50b8a2 85c57ac3-326b-4008-a815-08f853f947f2 04086808-56c4-424a-a7cd-f0d3cea361cf a78214c4-5fd7-4098-a440-5ce0af58d9b2 a5fcd776-fba8-45f0-8d21-ab973af34fd9 |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
bitstream.url.fl_str_mv |
http://repositorio.ufsm.br/bitstream/1/28699/1/TES_PPGFARMACOLOGIA_2023_SILVA_DARIANE.pdf http://repositorio.ufsm.br/bitstream/1/28699/3/license.txt http://repositorio.ufsm.br/bitstream/1/28699/2/license_rdf |
bitstream.checksum.fl_str_mv |
63b33c5831e2e7add648017d1d56ce60 2f0571ecee68693bd5cd3f17c1e075df 4460e5956bc1d1639be9ae6146a50347 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
|
_version_ |
1794524285775118336 |