Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFS |
Texto Completo: | https://ri.ufs.br/jspui/handle/riufs/18471 |
Resumo: | Polycystic Ovary Syndrome (PCOS) is an endocrinopathy that commonly affects women of reproductive age and is associated with hyperandrogenism, ovarian dysfunction, insulin resistance, cardiometabolic complications and infertility. Hesperitin (HST) is a flavonoid with biological potential and stands out for its ability to modulate genes involved in the inflammatory process and redox homeostasis. Therefore, the objective of the present work was to gather scientific evidence on the biological properties and molecular targets of flavonoids in endocrine and metabolic disorders associated with PCOS, through systematic reviews, and to evaluate the effect of the HST-OH-γ-CD complex ( hesperitin-hydroxypropyl-γ-cyclodextrin) in the modulation of PCOS in an animal model. The first systematic review showed that the antiobesogenic properties of flavonoids are associated with modulation of proteins, transcription factors and target genes involved in adipogenesis, lipolysis, glucose metabolism, inflammation and oxidative stress. The findings described in the second review highlight that the mechanisms underlying the therapeutic potential of flavonoids are associated with their anti-inflammatory, antioxidant, lipid-lowering, anti-apoptotic, and regulatory target genes involved in steroidogenesis and intracellular insulin signaling. The effect of the HST-OH-γ-CD complex on PCOS modulation was evaluated in a letrozole-induced model. Initially, the antioxidant activity of HST was evaluated by different models in vitro and, in cell culture of macrophages against the production of ROS (reactive oxygen species), induced by hydrogen peroxide. The antioxidant action of the flavonoid HST was mainly associated with its potential to donate hydrogens, neutralizing radical species. For induction of PCOS, adult Wistar rats received letrozole (1mg/kg of body weight, orally) for 21 days. After induction of PCOS, confirmed by the presence of irregular estrous cycles, the animals were treated with free and complexed HST (200 mg/kg of body weight, orally) for another 21 days. At the end of the treatment, the rats were euthanized. Blood was collected for quantification of biochemical parameters. Ovaries, uterus, liver, periovarian adipose tissue and retroperitoneal measurement were collected for weight measurement. Ovarian tissues were collected for histological analysis and for the analysis of oxidative stress markers and quantification of proteins involved in folliculogenesis. For tabulation and statistical analysis of the data, the Prism 7 software (GraphPad) with analysis of variance (ANOVA) was used, followed by the Tukey test. The results of the preclinical trial showed that complexed HST aided in tissue weight loss of fat pads and restored the architecture of ovarian follicular cells. This effect was associated with a reduction in serum levels of total testosterone and body fat deposition, in addition to the maintenance of p-Akt/Akt indices in ovarian tissue. It is worth noting here the relevance of the complexation of hydrophobic molecules in cyclodextrins, which in the present study, potentiated the pharmacological effects of the flavonoid HST. As far as we know, our study is the first to demonstrate the promising potential of complexed HST against endocrine, reproductive and metabolic disorders characteristic of PCOS, providing support for pre-clinical and clinical trials that use complexed HST as an alternative therapeutic strategy in the management of PCOS. |
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Oliveira, Anne Karoline de SouzaQuintans, Jullyana de Souza SiqueiraSilva, Ana Mara de Oliveira e2023-10-06T14:32:05Z2023-10-06T14:32:05Z2022OLIVEIRA, Anne Karoline de Souza. Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas. 2022. 155f. Tese (doutorado em Ciências da Saúde) – Universidade Federal de Sergipe, Aracaju, 2022.https://ri.ufs.br/jspui/handle/riufs/18471Polycystic Ovary Syndrome (PCOS) is an endocrinopathy that commonly affects women of reproductive age and is associated with hyperandrogenism, ovarian dysfunction, insulin resistance, cardiometabolic complications and infertility. Hesperitin (HST) is a flavonoid with biological potential and stands out for its ability to modulate genes involved in the inflammatory process and redox homeostasis. Therefore, the objective of the present work was to gather scientific evidence on the biological properties and molecular targets of flavonoids in endocrine and metabolic disorders associated with PCOS, through systematic reviews, and to evaluate the effect of the HST-OH-γ-CD complex ( hesperitin-hydroxypropyl-γ-cyclodextrin) in the modulation of PCOS in an animal model. The first systematic review showed that the antiobesogenic properties of flavonoids are associated with modulation of proteins, transcription factors and target genes involved in adipogenesis, lipolysis, glucose metabolism, inflammation and oxidative stress. The findings described in the second review highlight that the mechanisms underlying the therapeutic potential of flavonoids are associated with their anti-inflammatory, antioxidant, lipid-lowering, anti-apoptotic, and regulatory target genes involved in steroidogenesis and intracellular insulin signaling. The effect of the HST-OH-γ-CD complex on PCOS modulation was evaluated in a letrozole-induced model. Initially, the antioxidant activity of HST was evaluated by different models in vitro and, in cell culture of macrophages against the production of ROS (reactive oxygen species), induced by hydrogen peroxide. The antioxidant action of the flavonoid HST was mainly associated with its potential to donate hydrogens, neutralizing radical species. For induction of PCOS, adult Wistar rats received letrozole (1mg/kg of body weight, orally) for 21 days. After induction of PCOS, confirmed by the presence of irregular estrous cycles, the animals were treated with free and complexed HST (200 mg/kg of body weight, orally) for another 21 days. At the end of the treatment, the rats were euthanized. Blood was collected for quantification of biochemical parameters. Ovaries, uterus, liver, periovarian adipose tissue and retroperitoneal measurement were collected for weight measurement. Ovarian tissues were collected for histological analysis and for the analysis of oxidative stress markers and quantification of proteins involved in folliculogenesis. For tabulation and statistical analysis of the data, the Prism 7 software (GraphPad) with analysis of variance (ANOVA) was used, followed by the Tukey test. The results of the preclinical trial showed that complexed HST aided in tissue weight loss of fat pads and restored the architecture of ovarian follicular cells. This effect was associated with a reduction in serum levels of total testosterone and body fat deposition, in addition to the maintenance of p-Akt/Akt indices in ovarian tissue. It is worth noting here the relevance of the complexation of hydrophobic molecules in cyclodextrins, which in the present study, potentiated the pharmacological effects of the flavonoid HST. As far as we know, our study is the first to demonstrate the promising potential of complexed HST against endocrine, reproductive and metabolic disorders characteristic of PCOS, providing support for pre-clinical and clinical trials that use complexed HST as an alternative therapeutic strategy in the management of PCOS.A Síndrome dos Ovários Policísticos (SOP) é uma endocrinopatia que acomete comumente mulheres em idade reprodutiva e, está associada ao hiperandrogenismo, disfunção ovariana, resistência insulínica, complicações cardiometabólicas e infertilidade. A hesperitina (HST) é um flavonoide com potenciais biológicos e, se destaca por sua capacidade de modular genes envolvidos no processo inflamatório e na homeostase redox. Logo, o objetivo do presente trabalho foi reunir evidências científicas, sobre as propriedades biológicas e alvos moleculares dos flavonoides em distúrbios endócrinos e metabólicos associados à SOP, por meio de revisões sistemática e, avaliar o efeito do complexo HST-OH-γ-CD (hesperitina- hidroxipropil-γ-ciclodextrina) na modulação da SOP em modelo animal. A primeira revisão sistemática mostrou que as propriedades antiobesogênicas dos flavonoides estão associadas a modulação de proteínas, fatores de transcrição e genes-alvo envolvidos na adipogênese, lipólise, metabolismo glicídico, inflamação e estresse oxidativo. Os achados descritos na segunda revisão, destacam que os mecanismos subjacentes ao potencial terapêutico dos flavonoides estão associados às suas atividades anti-inflamatórias, antioxidantes, hipolipemiantes, antiapoptótocas, e reguladoras de genes-alvo envolvidos na esteroidogênese e na sinalização intracelular da insulina. O efeito do complexo HST-OH- γ-CD sobre a modulação da SOP, foi avaliado em modelo induzido por letrozol. Inicialmente a atividade antioxidante da HST foi avaliada por distintos modelos in vitro e, em cultura celular de macrófagos frente a produção de ERO (espécies reativas de oxigênio), induzida por peróxido de hidrogênio. A ação antioxidante do flavonoide HST foi associada principalmente ao seu potencial de doar hidrogênios, neutralizando espécies radicalares. Para indução da SOP, ratas Wistar adultas receberam letrozol (1mg/kg de peso, via oral) durante 21 dias. Após indução da SOP, confirmada pela presença de ciclos estrais irregulares, os animais foram tratados HST livre e complexada (200 mg/kg de peso, via oral) por mais 21 dias. Ao final do tratamento, as ratas foram eutanasiadas. O sangue foi coletadado para quantificação de parâmetros bioquímicos. Foram coletados ovários, útero, fígado, tecido adiposo periovariano e retroperitoneal aferição para aferição de peso. O tecidos ovariano foi coletado para análise histológica e para análise de marcadores de estresse oxidativo e quantificação de proteínas envolvidas na foliculogênese. Para tabulação e análise estatística dos dados foi utilizado o software Prism 7 (GraphPad) com análise de variância (ANOVA), seguida do teste Tukey. Os resultados do ensaio pré-clínico mostraram que a HST complexada auxiliou na perda de peso tecidual de coxins adiposos e restaurou a arquitetura de células foliculares ovarianas. Esse efeito foi associado a redução dos níveis séricos de testosterona total e da deposição de gordura corporal, além da manutenção dos ínidices de p-Akt/Akt no tecido ovariano. Cabe aqui ressaltar a relevância da complexação de moléculas hidrofóbicas em ciclodextrinas, que no presente estudo, potencializou os efeitos farmacológicos do flavonoide HST. Até onde sabemos, nosso estudo é o primeiro a demonstrar o potencial promissor da HST complexada frente à distúrbios endócrinos, reprodutivos e metabólicos característicos à SOP, fornecendo subsídios para ensaios pré-clínicos e clínicos que utilizem a HST complexada como estratégia terapêutica alternativa no manejo da SOP.AracajuporSíndrome dos ovários policísticos (SOP)FlavonoidesHiperandrogenismoDisfunção ovulatóriaTecido adiposoPolycystic ovary syndrome (PCOS)FlaavonoidsHiperandrogenismOvulatory disfunctionsAdipose tissueCIENCIAS DA SAUDE::MEDICINAPotencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadasPotencial terapêutico de flavonoides na síndrome dos ovários policísticos e distúrbios associadosinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisPós-Graduação em Ciências da SaúdeUniversidade Federal de Sergipereponame:Repositório Institucional da UFSinstname:Universidade Federal de Sergipe (UFS)instacron:UFSinfo:eu-repo/semantics/openAccessLICENSElicense.txtlicense.txttext/plain; charset=utf-81475https://ri.ufs.br/jspui/bitstream/riufs/18471/1/license.txt098cbbf65c2c15e1fb2e49c5d306a44cMD51ORIGINALAnne_Karoline_Oliveira.pdfAnne_Karoline_Oliveira.pdfapplication/pdf3134990https://ri.ufs.br/jspui/bitstream/riufs/18471/2/Anne_Karoline_Oliveira.pdfd11caadb63e3b28e4287b2931451b076MD52riufs/184712023-10-06 11:32:10.753oai:ufs.br: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Repositório InstitucionalPUBhttps://ri.ufs.br/oai/requestrepositorio@academico.ufs.bropendoar:2023-10-06T14:32:10Repositório Institucional da UFS - Universidade Federal de Sergipe (UFS)false |
dc.title.pt_BR.fl_str_mv |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
dc.title.alternative.por.fl_str_mv |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e distúrbios associados |
title |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
spellingShingle |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas Oliveira, Anne Karoline de Souza Síndrome dos ovários policísticos (SOP) Flavonoides Hiperandrogenismo Disfunção ovulatória Tecido adiposo Polycystic ovary syndrome (PCOS) Flaavonoids Hiperandrogenism Ovulatory disfunctions Adipose tissue CIENCIAS DA SAUDE::MEDICINA |
title_short |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
title_full |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
title_fullStr |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
title_full_unstemmed |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
title_sort |
Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas |
author |
Oliveira, Anne Karoline de Souza |
author_facet |
Oliveira, Anne Karoline de Souza |
author_role |
author |
dc.contributor.author.fl_str_mv |
Oliveira, Anne Karoline de Souza |
dc.contributor.advisor1.fl_str_mv |
Quintans, Jullyana de Souza Siqueira |
dc.contributor.advisor-co1.fl_str_mv |
Silva, Ana Mara de Oliveira e |
contributor_str_mv |
Quintans, Jullyana de Souza Siqueira Silva, Ana Mara de Oliveira e |
dc.subject.por.fl_str_mv |
Síndrome dos ovários policísticos (SOP) Flavonoides Hiperandrogenismo Disfunção ovulatória Tecido adiposo |
topic |
Síndrome dos ovários policísticos (SOP) Flavonoides Hiperandrogenismo Disfunção ovulatória Tecido adiposo Polycystic ovary syndrome (PCOS) Flaavonoids Hiperandrogenism Ovulatory disfunctions Adipose tissue CIENCIAS DA SAUDE::MEDICINA |
dc.subject.eng.fl_str_mv |
Polycystic ovary syndrome (PCOS) Flaavonoids Hiperandrogenism Ovulatory disfunctions Adipose tissue |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::MEDICINA |
description |
Polycystic Ovary Syndrome (PCOS) is an endocrinopathy that commonly affects women of reproductive age and is associated with hyperandrogenism, ovarian dysfunction, insulin resistance, cardiometabolic complications and infertility. Hesperitin (HST) is a flavonoid with biological potential and stands out for its ability to modulate genes involved in the inflammatory process and redox homeostasis. Therefore, the objective of the present work was to gather scientific evidence on the biological properties and molecular targets of flavonoids in endocrine and metabolic disorders associated with PCOS, through systematic reviews, and to evaluate the effect of the HST-OH-γ-CD complex ( hesperitin-hydroxypropyl-γ-cyclodextrin) in the modulation of PCOS in an animal model. The first systematic review showed that the antiobesogenic properties of flavonoids are associated with modulation of proteins, transcription factors and target genes involved in adipogenesis, lipolysis, glucose metabolism, inflammation and oxidative stress. The findings described in the second review highlight that the mechanisms underlying the therapeutic potential of flavonoids are associated with their anti-inflammatory, antioxidant, lipid-lowering, anti-apoptotic, and regulatory target genes involved in steroidogenesis and intracellular insulin signaling. The effect of the HST-OH-γ-CD complex on PCOS modulation was evaluated in a letrozole-induced model. Initially, the antioxidant activity of HST was evaluated by different models in vitro and, in cell culture of macrophages against the production of ROS (reactive oxygen species), induced by hydrogen peroxide. The antioxidant action of the flavonoid HST was mainly associated with its potential to donate hydrogens, neutralizing radical species. For induction of PCOS, adult Wistar rats received letrozole (1mg/kg of body weight, orally) for 21 days. After induction of PCOS, confirmed by the presence of irregular estrous cycles, the animals were treated with free and complexed HST (200 mg/kg of body weight, orally) for another 21 days. At the end of the treatment, the rats were euthanized. Blood was collected for quantification of biochemical parameters. Ovaries, uterus, liver, periovarian adipose tissue and retroperitoneal measurement were collected for weight measurement. Ovarian tissues were collected for histological analysis and for the analysis of oxidative stress markers and quantification of proteins involved in folliculogenesis. For tabulation and statistical analysis of the data, the Prism 7 software (GraphPad) with analysis of variance (ANOVA) was used, followed by the Tukey test. The results of the preclinical trial showed that complexed HST aided in tissue weight loss of fat pads and restored the architecture of ovarian follicular cells. This effect was associated with a reduction in serum levels of total testosterone and body fat deposition, in addition to the maintenance of p-Akt/Akt indices in ovarian tissue. It is worth noting here the relevance of the complexation of hydrophobic molecules in cyclodextrins, which in the present study, potentiated the pharmacological effects of the flavonoid HST. As far as we know, our study is the first to demonstrate the promising potential of complexed HST against endocrine, reproductive and metabolic disorders characteristic of PCOS, providing support for pre-clinical and clinical trials that use complexed HST as an alternative therapeutic strategy in the management of PCOS. |
publishDate |
2022 |
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2022 |
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2023-10-06T14:32:05Z |
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2023-10-06T14:32:05Z |
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OLIVEIRA, Anne Karoline de Souza. Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas. 2022. 155f. Tese (doutorado em Ciências da Saúde) – Universidade Federal de Sergipe, Aracaju, 2022. |
dc.identifier.uri.fl_str_mv |
https://ri.ufs.br/jspui/handle/riufs/18471 |
identifier_str_mv |
OLIVEIRA, Anne Karoline de Souza. Potencial terapêutico de flavonoides na síndrome dos ovários policísticos e complicações clínicas associadas. 2022. 155f. Tese (doutorado em Ciências da Saúde) – Universidade Federal de Sergipe, Aracaju, 2022. |
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Universidade Federal de Sergipe |
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