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This thesis focuses on the importance of intermediate products of biosynthetic and catabolic pathway of cholesterol. The aim of the first part of the thesis is mainly to investigate, whether statins (HMG- CoA reductase inhibitors) possess antitumor properties and to compare the differences in antitumor potential of individual statins. The other part of the thesis aims at the utilization of 7α-hydroxycholest-4-en-3-one (C4), a promising marker of cholesterol 7α-monooxygenase (CYP7A1) activity and bile acid malabsorption. We demonstrated antitumor effect of statins on an experimental model of pancreatic cancer. Individual statins, however, differed significantly in their efficacy, depending on their physico-chemical properties. Our data suggests, that the most likely (but not the only) mechanism of antitumor effect of statins is decreased prenylation of signaling proteins, especially Ras protooncogene. We set up a reliable method for measurement of C4, which facilitated our research in CYP7A1 regulation. We demonstrated, that promoter polymorphism -203A>C might affect CYP7A1 activity, that diurnal variability of CYP7A1 activity might be triggered by insulin, and that insulin resistance in patients with non-alcoholic fatty liver disease impedes the feedback regulation of CYP7A1, which may lead to disease...

Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / This paper describes obtaining eight lithocholic acid derivatives, as well as inhibitory activity. Interest in the use of lithocholic acid as starting material for the preparation of derivatives arose because of it being widely studied in order to discover new biological activities and such studies have shown good results. In this work it was used for the synthesis of a series of derivatives with modifications at the C-3 and/or C-24 of the steroid skeleton. The series was prepared using simple chemical and showed good yields. Aiming to investigate the antibacterial activity of the same and its derivatives, aiming to structure-activity relationships, tests were performed with bacteria Escherichia coli, Staphylococcus aureus, Bacillus cereus and Pseudomonas aeruginosa, try some of them presented significant results. And lithocholic acid derivatives were characterized by spectroscopic IR, 1H NMR, 13C-BB NMR and 13C-DEPT NMR and mass spectrometry as well as comparison with data in the literature and described constitute the body of the dissertation. / Esse trabalho descreve a obtenÃÃo de oito derivados do Ãcido litocÃlico, bem como, suas atividades antimicrobianas. O interesse pela utilizaÃÃo do Ãcido litocÃlico como material de partida na preparaÃÃo de derivados surgiu pelo fato do mesmo sendo bastante estudado com o objetivo de descobrir novas atividades biolÃgicas e tais estudos terem apresentado bons resultados. Nesse trabalho, o Ãcido litocÃlico foi submetido a modificaÃÃes moleculares nas posiÃÃes C-3 e/ou C-24 do esqueleto esteroidal. A sÃrie foi preparada utilizando quÃmica convencional e apresentando bons rendimentos. Com o objetivo de investigar a atividade antimicrobiana dos compostos, foram realizados testes com as bactÃrias Escherichia coli, Staphylococcus aureus, Bacillus cereus e Pseudomonas aeruginosa, tento alguns deles apresentado resultados bastante significativos. O Ãcido litocÃlico e seus derivados foram caracterizados por mÃtodos espectroscÃpicos de IV, RMN 1H, RMN 13C-BB e RMN 13C-DEPT e por espectrometria de massa, bem como comparaÃÃo com dados descritos na literatura.

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Introdução: O sucesso da cateterização da via biliar é de importância para o diagnóstico e terapêutica nas afecções biliopancreáticas nos procedimentos de colangiopancreatografia retrógrada endoscópica (CPRE) e está associado a complicações graves e mortalidade. O objetivo do estudo foi comparar o sucesso, perfil laboratorial e as complicações da técnica de fistulotomia papilar direta com o acesso cateter e fio-guia. Métodos: No período de julho de 2010 a maio de 2017 foram selecionados e randomizados para CPRE em dois grupos: cateterização com cateter e fioguia (Grupo I) e a fistulotomia papilar (Grupo II). As curvas de amilase, lipase e proteína C reativa (T0, 12 e 24 horas) e as complicações (pancreatite, sangramento e perfuração) foram avaliadas após CPRE. Resultados: Foram incluídos 102 pacientes (66 do sexo feminino e 36 do masculino, com idade média de 59,11±18,7 anos) e divididos em 51 pacientes para Grupo I e 51 no Grupo II. Os sucessos das cateterizações dos Grupos I e II foram de 76,47% e 100%, respectivamente (p=0,0002). Doze pacientes (23,53%) do Grupo I foram considerados pacientes de cateterização difícil e submetidos à fistulotomia papilar com sucesso no acesso biliar. Foram observadas 13,7% (2 perfurações e 5 pancreatites leves) e 2 % (1 paciente com perfuração e pancreatite) complicações nos Grupos I e II, respectivamente (p=0,062). Conclusão: A fistulotomia papilar demonstrou maior eficácia na cateterização da via biliar e com menor índice de amilasemia e lipasemia em comparação a cateterização com papilótomo e fio guia. As complicações foram semelhantes entre as duas técnicas / Background: The success of biliary tract cannulation is important for the diagnosis and treatment of biliopancreatic diseases in endoscopic retrograde cholangiopancreatography (ERCP) procedures. ERCP is associated with severe complications and mortality. The aim of the study was to compare the success, laboratory profile and complications of the direct papillary fistulotomy technique with standard catheter and guidewire access. Methods: In the period from July 2010 to May 2017, two groups were selected and randomized for ERCP: cannulation with catheter and guidewire (Group I) and papillary fistulotomy (Group II). The curves of amylase, lipase and C-reactive protein (T0, 12 and 24 hours) and complications (pancreatitis, bleeding and perforation) were evaluated after ERCP. Results: A total of 102 patients (66 females and 36 males, mean age 59.11 ± 18.7 years) were divided into 51 patients for Group I and 51 for Group II. The success of cannulation was 76.47% and 100%, in Groups I and II, respectively (p = 0.0002). Twelve patients (23.53%) of Group I were considered to have difficult cannulation and were submitted to fistulotomy with successful biliary access. There were 13.73% (2 perforations and 5 mild pancreatitis) and 2% (1 patient with perforation and pancreatitis) complications in Groups I and II, respectively (p=0,062). Conclusion: Papillary fistulotomy demonstrated greater efficacy in the bile duct cannulation and presented lower serum amylase and lipase compared with standard catheter and guidewire cannulation. Complications were similar in the two techniques

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-03-28T11:47:33Z No. of bitstreams: 0 / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-03-28T17:39:03Z (GMT) No. of bitstreams: 0 / Made available in DSpace on 2018-03-28T17:39:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-02-20 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As leishmanioses são um conjunto de doenças infecciosas causadas por protozoários do gênero Leishmania sp, responsáveis por um grande impacto socioeconômico mundial. Os tratamentos disponíveis para leishmanioses são limitados por apresentarem alta toxicidade, administração parenteral prolongada, alto custo e efeitos colaterais. Os esteroides constituem um grupo de compostos bastante diversificados com variada aplicabilidade na farmacologia. No entanto, a atividade antileishmanial desta classe ainda é pouco explorada. No presente trabalho, investigamos os efeitos antileishmanial de derivados sintéticos do colesterol e dos ácidos biliares cólico e desoxicólico. Além disso, determinamos, in vitro, possíveis alvos/alterações celulares importantes na atividade biológica do composto mais promissor, bem como analisamos in silico sua biodisponibilidade oral e propriedades farmacocinéticas. A atividade antipromastigota em Leishmania sp e citotoxicidade em macrófagos peritoneais foram determinadas pelo método colorimétrico MTT. A atividade antiamastigota foi avaliada em macrófagos infectados com L. amazonensis RFP após 72 horas de tratamento através de fluorimetria. Os efeitos do melhor composto em alvos celulares foram realizados utilizando marcação fluorescentes em promastigotas tratadas, e as análises in silico foram realizadas através de uma simulação computacional. Em uma análise geral dos resultados obtidos pelos testes in vitro, observa-se que entre os derivados esteroidais testados neste trabalho, os derivados do ácido desoxicólico apresentaram o melhor efeito antileishmanial para as formas promastigotas e amastigotas in vitro. Dentre esta série de compostos, o composto 11d (CI50 = 15,04 μM) é o mais seletivo para amastigotas de L. amazonensis (IS >9,78) e o mais específico para a forma intracelular desta espécie. Este composto tem como provável alvo celular a mitocôndria, aumentando a produção de EROs e diminuindo o potencial de membrana mitocondrial. Além do mais, o composto mostrou causar danos no conteúdo de DNA do parasito. Estudos das propriedades físico-químicas e farmacocinéticas do composto 11d mostrou que ele possui capacidade de permear por membranas biológicas sendo possível a administração por via oral. / Leishmaniasis is a group of infectious diseases caused by protozoa of the genus Leishmania sp, responsible for a great socioeconomic impact worldwide. The available treatments for leishmaniasis are limited because they present high toxicity, parenteral administration, high cost and side effects. Steroids are a diversified group of compounds with varied applicability in pharmacology. However, the antileishmanial activity of this class is still little explored. In the present work, we investigated the antileishmanial effects of groups of steroidal derivatives: cholesterol; colic and deoxycholic acid. In addition, we determined, in vitro, possible important cellular targets/alterations in the biological activity of the most promising compound and in silico analysis of its oral bioavailability and pharmacokinetics. The antipromastigote activity in Leishmania sp and cytotoxicity in peritoneal macrophages were determined by the colorimetric method MTT. The antiamastigote activity was evaluated in with L. amazonensis-infected macrophages after 72 hours of treatment. The effects of the best compound on promastigote targets were performed using fluorescent labeling on treated promastigotes, and in silico analyzes were performed using computational tools. In a general analysis of the results obtained by the in vitro tests, it is observed that among the steroid derivatives tested in this work, the derivatives of deoxycholic acid presented the best antileishmanial effect for the promastigote and amastigote forms in vitro. Among this series of compounds, compound 11d (IC50 = 15.34 μM) is the most selective for L. amazonensis (SI>9.78) and the most specific for the intracellular form of this species. This compound has as probable cellular target the mitochondria, increasing the ROS production and decreasing the ΔΨm. Moreover, the compound has been shown to cause damage to the DNA content of the parasite. In silico studies of the physicochemical and pharmacokinetic properties of compound 11d showed that it has the ability to permeate through biological membranes and oral administration is possible.

Orientador: Jaime Amaya Farfan / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-22T23:27:05Z (GMT). No. of bitstreams: 1 Jackix_ElisadeAlmeida_D.pdf: 1472562 bytes, checksum: 8830780df24de0113cef22e1e18df981 (MD5) Previous issue date: 2013 / Resumo: Diversos estudos têm sugerido que a ingestão frequente de vegetais reduz o risco de doenças crônicas não transmissíveis em função da presença de compostos como a fibra alimentar (FA) e demais substâncias bioativas associadas, os quais produzem efeitos positivos sobre a saúde humana. A FA inclui polissacarídeos não amiláceos, oligossacarídeos resistentes à digestão e lignina. Essas substâncias podem passar inalteradas pelo trato gastrintestinal ou serem fermentadas pela microbiota colônica, resultando em efeitos fisiológicos benéficos. A taioba (Xanthosoma sagittifolium) é uma arácea comestível originária da América tropical e possui considerável valor nutritivo. A porção tuberosa é consumida por diversas populações em todo mundo, no entanto, o consumo de suas folhas é menos difundido. O objetivo deste estudo foi caracterizar parcialmente a fração fibrosa da folha de taioba liofilizada (FTL), e avaliar possíveis efeitos fisiológicos in vivo em ratos Wistar machos alimentados com dieta AIN 93G, ou hiperlipídica. As folhas de taioba foram cozidas em água, liofilizadas e quimicamente caracterizadas. Por meio de ensaio biológico foram avaliados os efeitos da FTL sobre a produção de ácidos graxos de cadeia curta, sobre o metabolismo de ácidos biliares (AB) e indicadores bioquímicos. A FTL apresentou teores de fibra alimentar total, solúvel e insolúvel de 35,23 ± 0,26%, 6,82 ± 0,06% e 28,04 ± 0,21%, respectivamente. A análise da composição monossacarídica mostrou que a glicose é o monômero mais abundante (61%), sugerindo a presença de celulose em grandes quantidades. Os animais alimentados com dieta AIN 93G contendo taioba apresentaram maior peso e excreção de gordura fecal, e melhores perfis de ABs, por diminuir a proporção de ABs secundários. Nos ratos alimentados com dieta hiperlipídica a adição de FTL resultou em menor ganho de peso corporal e gordura hepática, e maior peso e conteúdo de gordura nas fezes; além disso, observaram-se maiores concentrações de ácidos graxos de cadeia curta e ABs fecais em comparação ao grupo controle, que recebeu baixos teores de fibra; também se observou menores concentrações de colesterol sérico e maior conteúdo de cinzas corporais nos grupos recebendo a FTL. Os resultados sugeriram que os componentes da folha de taioba possuem elevada capacidade de ligação com os ABs e alta fermentabilidade, indicando que a folha possui potencial para reduzir o risco de doenças cardiovasculares e câncer de cólon / Abstract: Several studies have suggested that frequent vegetable intake reduces the risk of coronary heart disease, diabetes, cancer and obesity due to the presence of compounds such as dietary fiber (DF) and other associated bioactive compounds, which exert positive effects on human health. DF includes non-starch polysaccharides, resistant oligosaccharides and lignin. These substances can pass unaltered through the gastrointestinal tract or be fermented by colonic microbiota, resulting in positive physiological effects. Taioba (Xanthosoma sagittifolium) is an edible aroid originated from tropical America that exhibits significant nutritive value. The tuberous portions are consumed by several populations worldwide, whereas the leafy portions of Taioba are generally discarded. The objective of this research was to partly characterize the DF of lyophilized taioba leaf (LTL), and to assess the possible in vivo physiological effects when fed to male Wistar rats receiving a normal AIN 93G diet, or a high-fat diet. Taioba leaves were boiled in water, lyophilized and chemically characterized. Biological evaluation was conducted to assess the effect of LTL on the intestinal short-chain fatty acid production, bile acid (BA) metabolism, and biochemical parameters. Total, soluble and insoluble dietary fiber contents in LTL were 35.23 ± 0.26%, 6.82 ± 0.06% and 28.04 ± 0.21%, respectively. Monosaccharide composition showed glucose as the main component (61%), suggesting the presence of cellulose. Animals fed the AIN 93G diets containing taioba leaf had increased fecal mass and fat excretion, in addition to improved BA profiles by diminishing the proportion of the secondary acids. In the rats fed the high-fat diet, the addition of LTL resulted in lower weight gain and liver fat concomitantly with higher fecal mass and lipids. Furthermore, these rats exhibited a higher fecal short chain fatty acid and bile salt concentration in the feces than the control group, which had a lower fiber intake. Additionally, lower serum cholesterol and higher body ash content were found in the groups receiving the leaf. The results suggested that taioba leaves have compounds with high BA binding capacity and high fermentability. These properties indicate that the leaf has the potential of lowering the risk of colon cancer and cardiovascular disease / Doutorado / Nutrição Experimental e Aplicada à Tecnologia de Alimentos / Mestre em Alimentos e Nutrição

Abstract α-Methylacyl-CoA racemase (Amacr) is an auxiliary enzyme of β-oxidation and participates in the elimination of methyl-branched fatty acids in peroxisomes and in mitochondria and in the synthesis of bile acids in peroxisomes. Amacr catalyzes in reversible manner the isomerization of fatty acyl-CoA esters with a methyl group in the R-configuration to the corresponding S-configuration, which allows them to serve as substrates for the next reaction in their metabolism. The substrates of Amacr include the acyl-CoA esters of 2R-pristanic acid, a metabolite derived from phytol, and 25R-THCA and 25R-DHCA (tri- and dihydroxycholestanoic acid), the bile acid intermediates derived from cholesterol. AMACR-deficiency in humans results in the accumulation of R-isoforms of its substrates. Patients with adult onset AMACR-deficiency suffer from neurological disorders. The more severe infantile form of the deficiency is characterized by liver disease. Amacr-deficient mice show a bile acid pattern similar to that of human patients with accumulation of bile acid intermediates in their body. In contrast to humans, Amacr-deficient mice are clinically symptomless on a regular laboratory chow diet. Supplementation of phytol in their diet triggers the disease state with liver abnormalities. In this study it was shown that in spite of the disruption of a major metabolic pathway, Amacr-deficient mice are able to readjust their cholesterol and bile acid metabolism to a new balanced level allowing them to live a normal life span. A double knockout mouse model deficient in Amacr and MFE-1 (peroxisomal multifunctional enzyme type 1) was generated in this work. Characterization of this mouse line showed that MFE-1 can contribute to peroxisomal side-chain shortening of C27 bile acid intermediates in both Amacr-dependent and Amacr-independent pathways. In addition, this work confirmed that Amacr-deficient mice are unable to thrive when phytol is supplemented in their chow. The main cause of death was liver failure accompanied by kidney and brain abnormalities. The detoxification of phytol metabolites in liver is accompanied by activation of multiple pathways and Amacr-deficient mice are not able to respond adequately. The results of this study emphasize the indispensable role of Amacr in detoxification of α-methyl branched fatty acids. / Tiivistelmä α-Metyyliasyyli-koentsyymi-A-rasemaasi (Amacr) osallistuu metyyli-haarautuvien rasvahappojen eliminointiin peroksisomeissa ja mitokondrioissa ja sappihappojen synteesiin kolesterolista peroksisomeissa. Amacr katalysoi käänteisesti rasvahappojen asyyli-koentsyymi-A-estereiden isomerisaatio-reaktiota, jossa stereokemiallisesti R-asemassa oleva metyyliryhmä siirtyy S-asemaan. Tämä on edellytys eliminointiketjun seuraavan reaktion tapahtumiselle. Amacr-entsyymin substraatteja ovat fytolin aineenvaihdunnassa syntyvän 2R-pristaanihapon ja kolesterolista sappihapposynteesireitin välituotteina syntyvien 25R-trihydroksikolestaanihapon ja 25R-dihydroksikolestaanihapon (25R-THCA ja 25R-DHCA) asyyli-koentsyymi-A-esterit. Ihmisellä Amacr-entsyymin puutos johtaa R-muodossa olevien substraattien kertymiseen, joka aiheuttaa neurologisia oireita aikuisiässä alkavassa sairauden muodossa. Lapsuusiässä alkavassa tautimuodossa potilaille kehittyy vakava maksasairaus. Tutkimuksen tulokset osoittivat, että Amacr-poistogeenisten hiirten elinikä ei lyhene huolimatta yhden tärkeän aineenvaihduntareitin estymisestä. Tämä on hyvä esimerkki siitä, kuinka nisäkäs pystyy mukauttamaan kolesteroli- ja sappihappoaineenvaihduntaansa vastaamaan muuttunutta tilannetta aineenvaihdunnassa. Tässä työssä tuotettiin myös kaksoispoistogeeninen hiirimalli, jonka Amacr- ja peroksisomaalinen monitoiminnallinen entsyymi tyyppi 1- (MFE-1) entsyymit ovat toimimattomat. Tämä hiirimalli paljasti, että MFE-1 pystyy osallistumaan 27:ää hiiltä sisältävien sappihappovälituotteiden sivuketjun lyhentämiseen sekä Amacr entsyymin kanssa että ilman sitä. Työn tulokset myös osoittivat, että Amacr-poistogeeniset hiiret eivät ole elinkykyisiä, jos niiden ravinto sisältää fytolia. Maksan toiminnanvajaus oli näiden hiirten tärkein kuolinsyy, mutta hiirten munuaisten ja aivojen kudosrakenteissa oli myös muutoksia. Maksassa fytolin metaboliittien vaarattomaksi tekeminen aiheuttaa villityypin hiirillä useamman aineenvaihduntareitin aktivoitumisen, mutta Amacr-poistogeeniset hiiret eivät pysty reagoimaan tähän samalla tavalla. Tämä työ osoittaa, että Amacr-entsyymin elintärkeä tehtävä on osallistua ravinnon mukana elimistöön joutuvien α-metyylihaarautuvien rasvahappojen eliminaatioon.

Les orosomucoïdes, membres de la superfamille des lipocalines, sont parmi les protéinesplasmatiques les plus abondantes. Ce sont des protéines de la phase aiguë de l’inflammationsecrétées par les hépatocytes en réponse à un stress (inflammation, cancer, cirrhose…), etutilisées couramment en clinique comme marqueur d’un état pathologique. Elles vont lorsd’un état inflammatoire inhiber la prolifération des neutrophiles et des lymphocytes. J’ai pumontrer que le récepteur nucléaire FXR, impliqué dans de nombreuses voies métaboliques etplus récemment comme ayant un rôle anti-inflammatoire dans le foie, régule l’expression desorosomucoïdes exclusivement au niveau hépatique chez la souris. Cela suggère que larégulation de certains processus inflammatoire par FXR pourrait être expliqué par larégulation transcriptionelle des orosomucoïdes.Le second sujet met en évidence une relation entre le récepteur nucléaire Rev-Erba et la OGlcNAcylationau niveau hépatique. La O-GlcNAcylation est une modification posttraductionnelledes protéines qui permet l’ajout d’un groupement O-GlcNAc. De nombreusesprotéines impliquées dans de multiples processus biologiques comme la régulation du cyclecellulaire, du rythme circadien, ou encore dans de nombreuses voies métaboliques, vont êtreO-GlcNAcylées. La dérégulation de la O-GlcNAcylation est également impliquée dans denombreuses pathologies telles que le diabète, le cancer ou encore la maladie d’Alzheimer. Lerythme circadien est un important régulateur du métabolisme. De plus en plus d’indicesindiquent que la O-GlcNAcylation est un intermédiaire essentiel dans la régulationcircadienne du métabolisme. Des modulations circadiennes de la O-GlcNAcylation deBMAL1, CLOCK et PER ont été mises en évidence. Ce lien entre la O-GlcNAcylation et lerythme circadien nous a poussé à essayer d’identifier le rôle potentiel de Rev-Erba, récepteurnucléaire impliqué dans le contrôle de la ryhtmicité circadienne, dans la régulation de la OGlcNAcylation.Nous avons pu montrer par ces travaux que Rev-Erba est un régulateurimportant de la O-GlcNAcylation. La déficience en Rev-Erba induisant une baisse importantede la O-GlcNAcylation. Rev-Erba ne régule pas le niveau de transcription des enzymesimpliquées dans la O-GlcNAcylation mais est capable d’intéragir avec l’OGT (enzymeresponsable de la O-GlcNAcylation) et d’inhiber sa dégradation par le protéasome. Par cemécanisme de stabilisation de l’enzyme OGT, Rev-Erba se révèle être un régulateurimportant de la O-GlcNAcylation. / Orosomucoïdes, members of the superfamily of lipocalines, are among proteins plasmatiques the most plentiful. They are proteins of the acute(sharp) phase of the inflammation secreted by hépatocytes in answer to a stress (inflammation, cancer, cirrhosis), and usually used in private hospital as marker(scorer) of a pathological state. They go during an inflammatory state to inhibit the proliferation of neutrophiles and lymphocytes. I was able to show that the nuclear receiver FXR, implied(involved) in numerous metabolic ways and more recently as having an anti-inflammatory role in the liver, regulates the expression of orosomucoïdes exclusively at the hepatic level to the mouse. (...]