RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta dissertação será disponibilizado somente a partir de 20/08/2025. UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” FACULDADE DE MEDICINA Matheus Antônio Filiol Belin Potencial terapêutico da suplementação com extrato do fruto de bergamota (Citrus bergamia) na prevenção da disfunção cardíaca induzida pela obesidade: relação com mediadores inflamatórios, estresse oxidativo e a participação de aminas biogênicas Dissertação apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Câmpus de Botucatu, para obtenção do título de Mestre em Ciências, Área de Patologia. Orientadora: Profª. Drª. Camila Renata Côrrea Botucatu 2024 2 Matheus Antônio Filiol Belin Potencial terapêutico da suplementação com extrato do fruto de bergamota (Citrus bergamia) na prevenção da disfunção cardíaca induzida pela obesidade: relação com mediadores inflamatórios, estresse oxidativo e a participação de aminas biogênicas Dissertação apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Câmpus de Botucatu, para obtenção do título de Mestre em Ciências, área de Patologia. Orientadora: Profª. Drª. Camila Renata Côrrea Botucatu 2024 3 4 Impacto potencial da pesquisa Título da Dissertação: “Potencial terapêutico da suplementação com extrato do fruto de bergamota (Citrus bergamia) na prevenção da disfunção cardíaca induzida pela obesidade: relação com mediadores inflamatórios, estresse oxidativo e a participação de aminas biogênicas” Impacto científico esperado: Utilização de um extrato natural de fruta cítrica rico em compostos bioativos, sem efeitos colaterais, na prevenção de doenças cardiovasculares, as maiores causas de morte no mundo atualmente. Em adição, utilizar as aminas biogênicas como novos biomarcadores para doenças cardiovasculares. Impacto social: Promoção de saúde e bem-estar ao diminuir a prevalência de doenças com o extrato. Melhorar a sustentabilidade da produção da bergamota, por promover o uso integral desta fruta, e não apenas a parte lipofílica, como costumava ser usada anteriormente. O extrato utilizado neste trabalho é considerado um subproduto, pois era descartado. Conseguimos evitar o seu desperdício e utilizá-lo para aplicação na saúde. Auxiliar no diagnóstico e tratamento de doenças cardiovasculares com a avaliação das aminas biogênicas. Impacto econômico: Melhorar o faturamento dos produtores de bergamota por aumentar o valor agregado da produção. Possível desenvolvimento de novos testes diagnósticos baseado no perfil de aminas biogênicas, dando origem a novos produtos. E, diminuição do gasto dos mais de US$1 trilhão anuais gerados direto e indiretamente por doenças cardiovasculares. Mestrando: Matheus Antônio Filiol Belin Orientadora: Camila Renata Correa 5 Potential research impact Dissertation Title: “Therapeutic potential of supplementation with bergamot fruit extract (Citrus bergamia) in the prevention of obesity- induced cardiac dysfunction: relationship with inflammatory mediators, oxidative stress and the participation of biogenic amines” Expected scientific impact: Use of a natural citrus fruit extract rich in bioactive compounds, without side effects, in the prevention of cardiovascular diseases, the biggest causes of death worldwide today. In addition, biogenic amines as new biomarkers for cardiovascular diseases. Social impact: Promotion of health and well-being by reducing the prevalence of diseases with the extract. Improve the sustainability of bergamot production, by promoting the full use of this fruit, and not just the lipophilic part, as was previously used. The extract used in this work is considered a by-product, as it was discarded. We managed to avoid waste and use it for health applications. Assist in diagnosing and treating cardiovascular diseases with the evaluation of biogenic amines. Economic impact: Improve the revenue of bergamot producers by increasing the added value of production. Possible development of new diagnostic tests based on the profile of biogenic amines, giving rise to new products. And reduced spending of more than US$1 trillion annually generated directly and indirectly by cardiovascular diseases. Master's student: Matheus Antônio Filiol Belin Advisor: Camila Renata Correa 6 7 Dedicatória Dedico este trabalho, especialmente, a minha família. Ao meu pai, José Benedito Filiol Belin (in memoriam). Ao falecer por doenças cardiovasculares aos 36 anos, quando eu tinha 10 anos, você deu origem ao motivo de eu ter estudado doenças cardiovasculares no mestrado. Você é meu grande exemplo de dedicação ao trabalho e à família. Te amo e te dedico este trabalho. Ao meu avô, Edson Geraldo da Silva (in memoriam). Você semeou e regou a semente do apreço pelo conhecimento na minha vida. Você nem sabia que existia Universidade Pública e agora seu neto está próximo do título de mestre em uma excelente. Você sempre foi um exemplo de trabalho e sucesso. Te amo e te dedico este trabalho. A minha mãe, Kelli Cristina da Silva Filiol Belin. Você sempre me quis e me amou desde muito antes de eu nascer. Sempre torceu por mim, e mesmo com vários desafios, nunca desistiu. Você é meu grande exemplo de resiliência. E eu puxei muita coisa de você. Te amo e te dedico este trabalho. A minha avó, Maria Pierini da Silva. Você, minha avó e madrinha, sempre me estimulou a ser corajoso e enfrentar os desafios. E, até hoje, é uma forte base para nossa família. Te amo e te dedico este trabalho. Aos meus irmãos, Pietra Antônia Filiol Belin e José Antônio Filiol Belin, nós crescemos juntos e amadurecemos juntos. Durante o mestrado, também foi assim, estivemos sempre juntos e enfrentando tudo. Amo vocês e dedico este trabalho a nossa família. 8 Agradecimentos Agradeço, primeiramente, a Deus. O Senhor me iluminou e me orientou durante todo este período. E, se não fosse por isso, sem dúvidas, eu não estaria aqui. Aqui, insiro um trecho de um livro importante e que me acompanhou durante este período: “O SENHOR é o meu pastor; nada me faltará. Ele me faz repousar em pastos verdejantes. Leva-me para junto das águas de descanso; refrigera-me a alma. Guia-me pelas veredas da justiça por amor do seu nome. Ainda que eu ande pelo vale da sombra da morte, não temerei mal nenhum, porque tu estás comigo; o teu bordão e o teu cajado me consolam. Preparas-me uma mesa na presença dos meus adversários, unges- me a cabeça com óleo; o meu cálice transborda. Bondade e misericórdia certamente me seguirão todos os dias da minha vida; e habitarei na Casa do SENHOR para todo o sempre”, Salmos 23:1-6. Agradeço, imensamente, a minha família. Meu pai (in memoriam) e meu avó (in memoriam), minha mãe e minha avó, meus irmãos e meu cunhado. Vocês são grandes exemplos e se esforçaram muito para que eu pudesse chegar aonde estou, me deram muitas forças. Vocês são grande parte disso, obrigado. Agradeço ao Colégio Universitário de Avaré, Anglo de Avaré, por me contemplarem com uma bolsa de estudos integral durante meu Ensino Fundamental e Ensino Médio. Vocês são parte essencial e indispensável desta jornada. Agradeço a todos com os quais tive o prazer de compartilhar momentos no Laboratório de Química e Bioquímica Vegetal (LBQV) do Instituto de Biociências de Botucatu (IBB) durante minha iniciação científica. Em especial, agradeço à Profa. Dra. Giuseppina Pace Pereira Lima, nossa querida Fina, e ao Prof. Dr. Igor Otávio Minatel. Considero vocês minha mãe e meu pai na ciência. Grande fonte de inspiração, proporcionaram meus primeiros contatos com a ciência e impulsionaram minha conexão e florescimento nesta área. 9 Agradeço à equipe do Laboratório RedOx e aos colaboradores da UNIPEX, especialmente, à Profa. Dra. Camila Renata Correa, minha orientadora neste período, e ao Prof. Dr. Dijon Henrique Salomé De Campos. Vocês me acolheram, compraram minhas ideias, acreditaram na minha palavra, no meu caráter, na minha capacidade, foram pacientes, me deram liberdade e me permitiram realizar um trabalho digno, ao mesmo tempo em que enfrentavam seus próprios desafios. Agradeço muito a vocês. Agradeço aos meus amigos Jordan, Seraki Formosa, Gijo, Chumbo e aos alunos de iniciação científica do laboratório. Vocês sempre tornaram tudo mais leve e mais gostoso de ser vivido. Foi e é um prazer e uma satisfação compartilhar momentos com vocês! Agradeço aos meus cachorros Billy (in memoriam), Bob, Byllu, Bola e Peppa. Vocês sempre deram carinho, amor e abrigo nos momentos em que isso foi necessário. Agradeço aos animais (ratos Wistar) que foram utilizados no desenvolvimento desta pesquisa. Vocês foram essenciais para o avanço da ciência. Agradeço ao meu psicólogo, André, que acompanhou os desafios e vitórias do início e do final deste percurso, contribuindo para meu autoconhecimento, autodesenvolvimento e melhora de meu discernimento, mesmo em períodos turbulentos. Agradeço os membros da banca examinadora de Qualificação e Defesa, suplentes e titulares, pelo aceite do desafio e pelas importantes considerações que me fizeram evoluir e engrandeceram esta dissertação: Clelia Akiko Hiruma Lima, Jéssica Garcia Leite, Giuseppina Pace Pereira Lima, Igor Otávio Minatel, Aline Nunes, Fabio Rodrigues Ferreira Seiva e Dijon Henrique Salomé De Campos. Agradeço ao Programa de Pós-Graduação em Patologia da Faculdade de Medicina de Botucatu (FMB) por todo apoio, prontidão, auxílio e investimento fornecidos a mim, a meu trabalho, e aos alunos do programa. Agradeço, por fim, ao apoio financeiro da Fundação de Amparo à 10 Pesquisa do Estado de São Paulo (FAPESP) (Processo: 2022/01925-7), indispensável para a realização deste trabalho. 11 Epígrafe “O importante é não parar de questionar; a curiosidade tem sua própria razão de existir” Albert Einstein 12 RESUMO Objetivo: Avaliar o efeito da suplementação do extrato do fruto da bergamota (Citrus bergamia) na prevenção da disfunção cardíaca induzida pela obesidade e investigar os efeitos em mediadores inflamatórios e de estresse oxidativo. Adicionalmente, verificar a relação das aminas biogênicas com disfunção cardíaca. Materiais e métodos: 48 ratos Wistar foram divididos igualmente em 4 grupos: controle (C), C + Bergamota (B), obeso (O) e O + B. A obesidade foi induzida por dieta rica em açúcar e gordura. O extrato do fruto da bergamota foi administrado por gavagem (250 mg/Kg/dia) durante 20 semanas. A obesidade foi avaliada pelo índice de adiposidade. Foi realizado estudo Doppler-Ecocardiográfico, pletismografia de cauda, Western Blotting de proteínas relacionadas a inflamação no músculo cardíaco, marcadores inflamatórios e de estresse oxidativo cardíacos. O perfil de aminas biogênicas (ABs) da fruta e do tecido cardíaco foi mensurado por HPLC (µg/g). Resultados: A dieta rica em açúcar e gordura gerou obesidade. Os animais obesos tiveram remodelamento e disfunção cardíaca, hipertensão, aumento do perfil inflamatório e estresse oxidativo cardíaco. Os animais obesos que receberam bergamota tiveram menor níveis de pressão arterial, não desenvolveram remodelamento e disfunção cardíaca, estresse oxidativo e inflamação cardíaca. O extrato de fruto de bergamota contém ABs histamina (28), tiramina (6), triptamina (186), putrescina (29), cadaverina (11), espermina (2), serotonina (4), dopamina (2), destacando as antioxidantes espermidina (35) e agmatina (140). 8 ABs foram encontradas no tecido cardíaco. A obesidade aumentou a serotonina e diminuiu agmatina, putrescina, cadaverina e espermidina. Conclusão: A suplementação com o extrato do fruto bergamota previne a disfunção cardíaca induzida pela obesidade, controlando os mediadores inflamatórios, e, principalmente, os do estresse oxidativo. Aminas biogênicas como agmatina, putrescina, cadaverina e serotonina podem ser novos biomarcadores para a saúde cardiovascular na obesidade. Palavras-chave: subproduto, remodelamento cardíaco, hipertensão, agmatina, serotonina. 13 ABSTRACT Aim: To evaluate the effect of supplementation with bergamot fruit extract (Citrus bergamia) in preventing obesity-induced cardiac dysfunction and investigate the effects on inflammatory and oxidative stress mediators. Additionally, verify the relationship between biogenic amines and cardiac dysfunction. Materials and methods: 48 Wistar rats were divided equally into 4 groups: control (C), C + Bergamot (B), obese (O), and O + B. Obesity was induced by a diet rich in sugar and fat. Bergamot fruit extract was administered by gavage (250 mg/kg/day) for 20 weeks. Obesity was assessed using the adiposity index. A Doppler-Echocardiographic study, tail plethysmography, Western Blotting of proteins related to inflammation in the heart muscle, and inflammatory and cardiac oxidative stress markers were performed. The profile of biogenic amines (BAs) of the fruit and heart tissue was measured by HPLC (µg/g). Results: The diet rich in sugar and fat led to obesity. Obese animals had cardiac remodeling and dysfunction, hypertension, increased inflammatory profile, and cardiac oxidative stress. Obese animals that received bergamot had lower blood pressure levels and did not develop cardiac remodeling and dysfunction, oxidative stress, and cardiac inflammation. Bergamot fruit extract contains ABs histamine (28), tyramine (6), tryptamine (186), putrescine (29), cadaverine (11), spermine (2), serotonin (4), dopamine (2), highlighting the antioxidants spermidine (35) and agmatine (140). 8 ABs were found in cardiac tissue. Obesity increased serotonin and decreased agmatine, putrescine, cadaverine, and spermidine. Conclusion: Supplementation with bergamot fruit extract prevents obesity-induced cardiac dysfunction, controlling inflammatory mediators, and especially oxidative stress. Biogenic amines such as agmatine, putrescine, cadaverine, and serotonin may be new biomarkers for cardiovascular health in obesity. Keywords: byproduct, cardiac remodeling, hypertension, agmatine, serotonin. 14 Resumo para sociedade Introdução: O principal objetivo da nossa espécie é sobreviver e, para isso, precisamos comer. Nos tempos dos homens das cavernas, tínhamos que caçar e não tínhamos fácil acesso a alimentos. Então, nosso corpo desenvolveu mecanismos para armazenar energia quando tivéssemos acesso a ela, como depois de matar um grande animal, e sobreviver. Nós armazenamos energia na forma de gordura no nosso tecido adiposo. Mas, os tempos mudaram. Já não precisamos mais caçar, o sedentarismo cresceu e, agora, é só pedir comida no aplicativo que em 30 minutos estará na porta da nossa casa. Além disso, esta comida, geralmente, é rica em açúcar e gordura, deixando os alimentos mais calóricos e menos saudáveis. Ou seja, nós temos fácil acesso a muita energia e não precisamos mais gastá-la. Resultado? Nosso corpo acumula gordura em excesso e nos tornamos obesos. A obesidade aumenta a produção de moléculas que fazem mal ao organismo, aumentando o estresse oxidativo e a inflamação. Quando estas moléculas atingem os órgãos, geram doenças, como as doenças cardiovasculares (DCV). As DCV são a maior causa de morte atualmente, sendo responsáveis por 1 a cada 3 mortes, e geram mais de U$ 1 bilhão de gastos anualmente. Mas, nem tudo está perdido. Se conseguimos controlar a inflamação e o estresse oxidativo gerados pela obesidade, talvez possamos prevenir as DCV. As frutas cítricas são promissoras. A Bergamota, que parece um limão siciliano da Itália, tem um suco rico em compostos antioxidantes e anti- inflamatórios. Ao mesmo tempo, se conseguirmos descobrir novas moléculas relacionadas ao desenvolvimento das DCV, poderemos tratá-las mais rápido e de maneira mais assertiva. As aminas biogênicas são moléculas relacionados ao metabolismo de proteínas, e adivinha só? O coração é um órgão proteico, um músculo! Então, também é importante identificar a relação destas moléculas com as DCV. Então, o objetivo deste mestrado foi ver a influência do suco da bergamota nas DCV na obesidade, e entender as relações das DCV com as aminas biogênicas. Como foi feito: Ratos foram divididos em 4 grupos para induzirmos a obesidade com uma dieta rica em açúcar e gordura, ou seja, uma dieta não saudável. Eles também receberam suco de bergamota todo dia durante 20 semanas. Nós medimos a pressão arterial dos animais, avaliamos a estrutura e função do coração e medimos marcadores de inflamação e estresse oxidativo cardíacos. Por fim, também vimos perfil de aminas biogênicas no coração. E, é claro, tudo isso foi aprovado por um comitê de ética responsável por avaliar todos os procedimentos e estudos com animais. Resultados: Os animais que consumiram a dieta não saudável ficaram obesos, pioraram a estrutura e a função do coração e tiveram hipertensão, ou seja, tiveram DCV. Estes animais obesos também tiveram maior estresse oxidativo e inflamação no coração. Quando os animais receberam o suco da bergamota, eles continuaram obesos, mas tiveram menor pressão arterial, não desenvolveram DCV, estresse oxidativo e nem inflamação no coração. Vimos também que as aminas agmatina e serotonina tem bastante relação com as DCV. Conclusão: O suco da bergamota diminuiu as DCV que a obesidade gerou, por controlar o estresse oxidativo e a inflamação no coração. Adicionalmente, agmatina e serotonina, tem forte relação com a saúde do coração e podem ajudar no diagnóstico e tratamento destas doenças no futuro. 15 Lista de Ilustrações Capítulo 2 Figure 1. Systolic blood pressure (mmHg) of Wistar rats fed with a high sugar-fat diet and that received bergamot by-product administration……..76 Capítulo 3 Graphical Abstract…………………………………………………………..…81 Figure 1. Obesity induced in male Wistar rats………………...……...……86 Figure 2. Cardiac NFKB and NFKB-P expression, normalized by GAPDH, by Western blot, and NFKB/NFKB-P expression ratio in cardiac tissue of obese rats supplemented with bergamot…..………………………………..90 Figure 3. Cardiac NRF2 and KEAP1 expression, normalized by GAPDH, by Western blot and NRF2/ KEAP1 expression ratio in cardiac tissue of obese rats supplemented with bergamot……………………………………91 Figure 4. Cardiac inflammatory markers in cardiac tissue of obese rats supplemented with bergamot……………………………………..………….92 Figure 5. Cardiac oxidative stress markers in cardiac tissue of obese rats supplemented with bergamot………………………………………………...93 Capítulo 4 Figure 1. Inflammatory (A and B) and oxidative stress (C , D, and E) markers in cardiac tissue of obese rats……………………………………112 Figure 2. Influence of obesity in the cardiac profile of biogenic amines...112 Figure 3. Correlation matrix among obesity, biochemical parameters, cardiovascular parameters, cardiac biogenic amines, cardiac inflammatory and oxidative stress markers………………………………………………..113 Figure 4. Pearson' s or Spearman' s correlation with simple linear regression between biogenic amines and markers of cardiac remodeling……………………………………………………………………113 Figure 5. Pearson' s or Spearman' s correlation with simple linear 16 regression between biogenic amines, markers of cardiac dysfunction , and hypertension………………………………………………………………….115 Figure 6. Principal Component Analysis (PCA) of the obesity, biochemical parameters, cardiovascular parameters, cardiac biogenic amines profile, and cardiac inflammatory and oxidative stress markers normalized by median and after auto-scaling (mean-centered and divided by the standard deviation of each variable)…………………………………………………..116 Graphical Abstract final...........................................................................120 17 Lista de tabelas Capítulo 2 Table 1. Total phenolic compounds, total flavonoids, total carotenoids, and total antioxidant capacity in bergamot by-product……………..…………...75 Table 2. Nutritional profile and cardiac tissue superoxide dismutase activity of Wistar rats fed with a high sugar-fat diet and that received bergamot by- product administration……………………………………………………..….76 Table 3. Biogenic amines profile of bergamot by-product…………………76 Capítulo 3 Table 1. Doppler echocardiography of obese rats supplemented with bergamot……………………………………………………………………….89 Capítulo 4 Table 1. Obesity and biochemical parameters………...………………….110 Table 2. Doppler echocardiography and systolic blood pressure study...111 18 LISTA DE ABREVIATURAS € Euros 5-HIAA 5-hidroxiindolacético 5-HT Serotonina 5-HTP 5-hidroxitriptofano ABs Aminas biogênicas AdipoR1 Receptor de adiponectina 1 AdipoR2 Receptor de adiponectina 2 AGL Ácidos Graxos Livres AOS Apneia obstrutiva do sono ATP Trifosfato de adenosina CAT Catalase CCR2 Receptor de quimiocina tipo 2 DCV Doenças cardiovasculares ECG Eletrocardiograma ECO Ecocardiograma ERNs Espécies reativas de nitrogênio EROs Espécies reativas de oxigênio GABA Ácido gama-aminobutírico GPx Glutationa peroxidase GSH Glutationa HDL Lipoproteína de alta densidade HMT Histamina-N-metiltransferase HPLC High-performance liquid chromatography IKKβ IκB Kinase Beta IL-1β Interleucina-1 beta IL-6 Interleucina-6 iNOS Óxido nítrico sintase induzível IκB Inibidor de κB JNK C-Jun N-terminal quinase 19 LDL Lipoproteína de baixa densidade MAO Monoamina oxidase MAP quinases Quinases ativadas por mitógeno MASLD Hepatite Esteatótica Associada ao Metabolismo MCP-1 Proteína quimiotática de monócitos 1 MDA Malondialdeído NF-kB Fator Nuclear Kappa B NK Natural Killer NO Óxido nítrico NOS Óxido nítrico sintase NRF2 Fator 2 Relacionado ao NF-E2 PAMPs Padrão molecular associado a patógenos R$ Reais RE Retículo endoplasmático SMOX Espermina oxidase SOD Superóxido dismutase SRAA Sistema renina-angiotensina-aldosterona Th1 Células T helper tipo 1 Th17 Células T helper tipo 17 TNF-α Fator de necrose tumoral-alfa Tregs T Regulatórias US$ Dólares americanos 20 SUMÁRIO Introdução à dissertação.......................................................................22 Capítulo 1. Revisão de Literatura..........................................................24 1. História................................................................................................25 2. Obesidade...........................................................................................31 2.1 Inflamação..........................................................................................32 2.2 Estresse oxidativo...............................................................................41 3. Disfunção cardíaca.............................................................................50 4. Bergamota (Citrus bergamia).............................................................55 5. Aminas biogênicas e saúde cardiovascular.....................................58 5.1 Triptamina e saúde cardiovascular.....................................................61 5.2 Espermina e saúde cardiovascular.....................................................62 5.3 Histamina e saúde cardiovascular......................................................63 5.4 Serotonina e saúde cardiovascular.....................................................64 5.5 Putrescina e saúde cardiovascular.....................................................66 5.6 Cadaverina e saúde cardiovascular....................................................67 5.7 Agmatina e saúde cardiovascular.......................................................68 5.8 Espermidina e saúde cardiovascular..................................................69 6. Justificativa e Hipótese......................................................................70 7. Objetivo geral......................................................................................70 7.1 Objetivos específicos..........................................................................71 Capítulo 2. Artigo científico 1.................................................................72 Bergamot by-product, a source of biogenic amines, reduces hypertension induced by high sugar-fat diet…………………..........................................73 Capítulo 3. Artigo científico 2.................................................................80 Bergamot supplementation prevents cardiac dysfunction and remodeling in obese rats………………………………………….......................................81 Capítulo 4. Artigo científico 3...............................................................107 Cardiac biogenic amine profile and its relationship with parameters of cardiovascular disease in obesity............................................................108 Conclusão.............................................................................................119 21 Considerações finais...........................................................................120 Realizações no período.......................................................................121 Referências bibliográficas...................................................................124 22 Introdução à dissertação Esta dissertação de Mestrado do aluno Matheus Antônio Filiol Belin, com o título “Potencial terapêutico da suplementação com extrato do fruto de bergamota (Citrus bergamia) na prevenção da disfunção cardíaca induzida pela obesidade: relação com mediadores inflamatórios, estresse oxidativo e a participação de aminas biogênicas”, sob orientação da Profa. Dra. Camila Renata Correa, será apresentada em cinco capítulos. No Capítulo 1, está inserida a Revisão de Literatura. Este tópico contempla uma introdução sobre a humanidade e os mecanismos desenvolvidos para preservação de energia e sobrevivência desta espécie; as mudanças no estilo de vida que culminaram no aumento da prevalência da obesidade; como esta doença gera estresse oxidativo e inflamação; e os mecanismos fisiopatológicos do desenvolvimento de doenças cardiovasculares, como a disfunção cardíaca, na obesidade. Adicionalmente, é revisada a bergamota (Citrus bergamia) e sua potencial aplicação na prevenção de doenças cardiovasculares; assim como o potencial uso das aminas biogênicas como marcadores das doenças cardiovasculares na obesidade, podendo contribuir tanto para identificação precoce, quanto para aumento da efetividade do tratamento destas doenças. Após a conexão com os objetivos, no Capítulo 2, é apresentado o artigo “Bergamot by-product, a source of biogenic amines, reduces hypertension induced by high sugar-fat diet” publicado na revista Pharmacological Research - Natural Products (https://doi.org/10.1016/j.prenap.2024.100022). No Capítulo 3, é apresentado o artigo “Bergamot supplementation prevents cardiac dysfunction and remodeling in obese rats”, submetido à revista Free Radical Biology and Medicine. E, no Capítulo 4, encontra-se o artigo “Cardiac biogenic amine profile and its relationship with parameters of cardiovascular disease in obesity”, aceito para publicação na revista Vascular Pharmacology (https://doi.org/10.1016/j.vph.2024.107412). https://doi.org/10.1016/j.prenap.2024.100022 https://doi.org/10.1016/j.vph.2024.107412 23 Por fim, há o Capítulo 5, com as considerações finais desta dissertação, seguido da conclusão e de outras atividades realizadas durante o período do mestrado. 120 Considerações finais Nestas breves considerações finais, serão verificadas as hipóteses deste trabalho. Em seguida, serão sugeridos novos estudos decorrentes dos achados desta dissertação. A hipótese deste trabalho é que a suplementação de com o extrato de bergamota previne o desenvolvimento de disfunção cardíaca em ratos obesos por modular mediadores inflamatórios e indicadores do estresse oxidativo no miocárdio. Além disso, também é hipotetizado que a concentração de aminas biogênicas no tecido cardíaco tem relação com a disfunção cardíaca. Ambas as hipóteses foram confirmadas. Foi visto que a suplementação com o extrato de bergamota preveniu o desenvolvimento de disfunção cardíaca em ratos obesos pelo controle de marcadores de inflamação e de estresse oxidativo cardíacos. De maneira complementar, foi visto que as concentrações cardíacas de putrescina, cadaverina e agmatina estão positivamente correlacionadas com a saúde cardiovascular, enquanto as concentrações cardíacas de serotonina estão positivamente correlacionadas com doenças cardiovasculares. A seguir, encontra um Graphical Abstract final representando os achados desta dissertação. 121 A partir dos achados desta dissertação, são sugeridos novos estudos visando avaliar em quais estruturas proteicas e lipídicas o extrato do fruto da bergamota age, diminuindo a inflamação e o estresse oxidativo cardíacos, e prevenindo a disfunção cardíaca gerada pela obesidade. Ao mesmo tempo, visto que não houve efeitos colaterais da bergamota, recomenda-se que seja avaliado o efeito do extrato do fruto da bergamota nas doenças cardiovasculares em estudos clínicos. Concomitantemente, recomendam-se novos estudos visando avaliar os níveis de aminas biogênicas no plasma, urina e saliva de pacientes com doenças cardiovasculares para confirmar as correlações encontradas neste estudo ou identificar novas. Da mesma maneira, recomenda-se a realização de novos estudos experimentais longitudinais avaliando os níveis das aminas biogênicas e o desenvolvimento de doenças cardiovasculares em diferentes momentos. Estes estudos trarão luz os mecanismos das correlações previamente observadas. Por fim, recomenda-se a realização de estudos visando modular o perfil de aminas biogênicas cardíaco (ou plasmático/urinário/salivar) como estratégia terapêutica para doenças cardiovasculares, provenientes ou não da obesidade. Realizações no período Durante o mestrado, várias atividades foram realizadas. Faz-se necessário registrar aqui, no fim desta dissertação, algumas destas, visando o reconhecimento do trabalho do pós-graduando. Os destaques deste período foram as premiações de 1º Lugar no Departamento de Nutrição na sessão de temas lives – E poster – do 43o Congresso da Sociedade de Cardiologia do Estado de São Paulo (SOCESP), segundo melhor poster e melhor apresentação oral no 1st International Workshop on Biotechnology in Healthcare: Paths to Innovation; e, principalmente, as publicações nos periódicos. No mestrado, foram realizadas 9 publicações, sendo 5 com o aluno como primeiro autor. A seguir, encontram-se as revistas e os DOIs (Digital Object Identifier) destas publicações: 122 - Journal of Functional Foods, 2024 (https://doi.org/10.1016/j.jff.2024.106042); - Pharmacological Research - Natural Products, 2024 (https://doi.org/10.1016/j.prenap.2024.100022); - Revista Brasileira de Hipertensão, 2024 (http://dx.doi.org/10.47870/1519-7522/202431016-10); - Vascular Pharmacology, 2024 (https://doi.org/10.1016/j.vph.2024.107412); - Molecular and Cellular Endocrinology, 2023 (https://doi.org/10.1016/j.mce.2023.111908); - Livers, 2023 (https://doi.org/10.3390/livers3020017); - Atherosclerosis, 2023 (https://doi.org/10.1016/j.atherosclerosis.2023.06.856); - Atherosclerosis, 2023 (https://doi.org/10.1016/j.atherosclerosis.2023.06.598); - Arquivos Brasileiros de Cardiologia, 2023 (https://doi.org/10.36660/abc.20220770). Adicionalmente, o aluno tirou a nota máxima (A) em todas as disciplinas que cursou, atingindo 21 créditos, sendo 12 obrigatórios; obteve 107 créditos em atividades complementares, sendo 12 obrigatórios; concluiu o curso de Pós-graduação Lato Sensu em Nutrição Clínica, Esportiva e Exames Laboratoriais com carga horária de 390 horas; foi ouvinte em 62 eventos científicos, sendo um na Alemanha (91th European Atherosclerosis Society Congress), em 2023, e outro nos Estados Unidos (A Hypertension Summer School in Chicago-IL, do American Journal of Hypertension), em 2024; ministrou 17 aulas/palestras; realizou um estágio de docência na pós-graduação; teve 34 participações/apresentações de trabalhos científicos (com duas apresentações no 91th EAS Congress em Mannheim, na Alemanha); com 8 premiações, sendo 2 em eventos internacionais; organizou 5 eventos científicos; participou de 8 atividades de extensão; orientou 2 atividades em estágio curricular de nutrição; https://doi.org/10.1016/j.jff.2024.106042 https://doi.org/10.1016/j.prenap.2024.100022 http://dx.doi.org/10.47870/1519-7522/202431016-10 https://doi.org/10.1016/j.vph.2024.107412 https://doi.org/10.1016/j.mce.2023.111908 https://doi.org/10.3390/livers3020017 https://doi.org/10.1016/j.atherosclerosis.2023.06.856 https://doi.org/10.1016/j.atherosclerosis.2023.06.598 https://doi.org/10.36660/abc.20220770 123 orientou 7 estagiários em nutrição clínica no consultório; tutorou, em espanhol, o estágio de duas intercambistas internacionais; e melhorou sua fluência em inglês, alcançando nota 600 no TOEFL ITP, com classificação B2-C1 de acordo com o Common European Framework of Reference (CEFR), representando um nível intermediário/avançado de fluência. Por fim, com a finalidade de divulgação científica à comunidade, o “Resumo para sociedade” desta dissertação foi enviado por Whatsapp para cerca de 15 pessoas com idade entre 15 e 60 anos. Esta pequena amostra representa a sociedade em geral, ou seja, o público sem “contato direto” com o ambiente acadêmico. A seguir, encontram-se algumas respostas obtidas após esta amostra ser questionada em relação a quão entendível/compreensível o texto estava: I) “Deu para entender tudo bonitinho”; II) “Caramba, muito boom! ”; III) “Pelo pouco conhecimento q tenho; está perfeito. Objetivo e informativo. Sem blá blá blá. Ou seja, está muito bem elaborado e de fácil compreensão. Parabéns!!!”; IV) “Eu tb achei excelente. Muito claro e direto, sem encheção de linguiça. 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