Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Silver catfish, Rhamdia quelen, is one of the most cultivated fish species in southern Brazil. Products destined for improving rearing and production of this species are required due to its importance for aquaculture. Oxidative stress (OS) is one of the main challenges in fish culture, so the use of compounds with antioxidant capacity may be valuable. The flavonoid rutin has several beneficial effects and represents an important alternative to reduce the physiological changes that arise from rearing-related stress. This study evaluated the influence of three diets containing rutin (0, 0.15 and 0.30 % rutin) on blood parameters and the antioxidant response of silver catfish. After a 21-day feeding period, blood was withdrawn for biochemical analysis and determination of plasma cortisol levels. The fish were then euthanized for sampling of the brain, gills, liver, kidney and muscle. Biomarkers of OS, thiobarbituric reactive substances (TBARS), lipid hydroperoxides (LOOH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), content of non-protein thiol groups (NPSH), content of ascorbic acid (AA) and total antioxidant capacity (TRAP) were determined. Fish fed the diet having 0.15 % rutin had lower cortisol levels compared to control. Nonetheless, the diet with rutin did not affect the hematological parameters. The levels of lipid peroxidation measured by determination of TBARS and LOOH in the brain, gills, liver and muscle decreased in the fish fed the diet containing rutin; in the kidney, however, only the levels of LOOH were reduced in these fish. When compared to control, the rutin-enriched diet increased the activity of SOD, CAT, NPSH content, AA and TRAP in the brain, GST and TRAP in the gills, SOD, CAT, GST, NPSH content, AA and TRAP in the liver, CAT, GST and TRAP in the kidney, and GPx, NPSH content, AA and TRAP in the muscle. In conclusion, these results suggest that rutin supplementation in silver catfish diet is recommended because it increases the tissue antioxidant response, thus preventing oxidative damage. / O jundiá, Rhamdia quelen, é uma das espécies mais cultivadas no sul do Brasil. Produtos destinados a melhorar o cultivo e produção do jundiá são necessários devido à importância desta espécie para a aquicultura. O estresse oxidativo (OS, do inglês oxidative stress) é um dos principais desafios no domínio da piscicultura, portanto a utilização de compostos com capacidade antioxidante pode ser útil. O flavonoide rutina tem vários efeitos benéficos e torna-se uma alternativa importante a fim de reduzir as alterações fisiológicas resultantes do estresse atrelado ao cultivo. Este estudo avaliou a influência de três dietas contendo a rutina (0, 0,15 e 0,30 % rutina) sobre os parâmetros sanguíneos e resposta antioxidante em jundiás. Após um período de 21 dias de alimentação, o sangue foi coletado para a análise sanguínea. Os peixes foram então eutanasiados para amostragem do encéfalo, brânquias, fígado, rim e músculo. Uma alíquota de sangue foi amostrada para a análise bioquímica e do cortisol plasmático. Os biomarcadores de OS, substâncias que reagem ao ácido tiobarbitúrico (TBARS), hidroperóxidos lipídicos (LOOH), superóxido dismutase (SOD), catalase (CAT), glutationa peroxidase (GPx), glutationa S-transferase (GST), o conteúdo dos grupos tióis não proteicos (NPSH), conteúdo de ácido ascórbico (AA) e a capacidade antioxidante total (TRAP) foram determinados. Os peixes que receberam a dieta contendo 0,15 % rutina apresentaram níveis de cortisol mais baixos do que o controle. No entanto, a dieta contendo rutina não influenciou os parâmetros hematológicos. Os níveis de lipoperoxidação medidos por determinação de TBARS e LOOH no encéfalo, brânquias, fígado e músculo diminuíram nos peixes que receberam a dieta contendo rutina; exceto no rim onde houve apenas a redução dos níveis de LOOH em todas as dietas. Quando comparado ao controle, a dieta enriquecida com rutina aumentou a atividade da SOD, CAT, o conteúdo de NPSH, AA e TRAP no encéfalo, GST e TRAP nas brânquias, SOD, CAT e GST, o conteúdo de NPSH, AA e TRAP no fígado, CAT, GST e TRAP no rim, GPx, conteúdo de NPSH, AA e TRAP no músculo. Em conclusão, estes resultados sugerem que a suplementação contendo rutina na dieta do jundiá é recomendada pois aumenta a resposta antioxidante no tecido, evitando o dano oxidativo.

Made available in DSpace on 2015-05-14T12:59:49Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2147842 bytes, checksum: 4096aadcaa77b162c3d6533c50132e36 (MD5) Previous issue date: 2012-02-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The genus Piptadenia Benth. part of the Mimosoideae subfamily which is included to the Fabaceae family, the third largest family of angiosperms, widely distributed, being one of the largest in dicotyledonous and economic importance. Piptadenia stipulacea is widely distributed in the caatinga biome, and is used in popular medicine to treat inflammation, activity that has been proven pharmacologically. This paper aims to continue the chemical knowledge of P. stipulacea. The chemical compounds were identified using analysis of data obtained by spectroscopic methods, such as 1H and 13C NMR uni- and bidimensional. The phytochemical study of chloroform phase resulted in the isolation of two flavonoids: 3,3',5,7-tetrahydroxy-4 ,6-dimethoxyflavone and 4 ,5,7- trihydroxy-3 ,6-dimethoxyflavone, both previously described in the species, of ethyl acetate phase resulted in the isolation of a mixture of two novel flavonoids in the species (5,7,4 -trihydroxy-6-methoxyflavone e 3,5,7,4 -tetrahydroxyflavonol), whereas the remaining hydroalcoholic phase resulted in the isolation of an indolic alkaloid: methyl(2-{3-[2-(methylamino)ethyl]-1H-indol-1-yl}ethyl)amine, firstly described in the literature. / O gênero Piptadenia Benth. faz parte da subfamília Mimosoideae a qual pertence à família Fabaceae, a terceira maior família das angiospermas, de ampla distribuição geográfica, sendo uma das maiores em dicotiledôneas e de importância econômica. Piptadenia stipulacea apresenta ampla distribuição no bioma da caatinga nordestina, sendo utilizada na medicina popular no tratamento das inflamações, atividade esta, já comprovada farmacologicamente. O presente trabalho tem o objetivo de dar continuidade ao conhecimento químico de P. stipulacea. Os contituintes químicos isolados foram identificados por meio da análise de dados obtidos por métodos espectroscópicos, tais como RMN de 1H e 13C uni e bidimensionais. O estudo fitoquímico da fase clorofórmica resultou no isolamento de dois flavonoides: 3,3 ,5,7-tetrahidroxi-4 ,6-dimetoxiflavona e 4 ,5,7-trihidroxi-3 ,6-dimetoxiflavona, ambos já descritos na espécie, da fase acetato de etila uma mistura de dois flavonoides inéditos na espécie (5,7,4 trihidroxi-6-metoxiflavona e 3,5,7,4 -tetrahidroxi-6-flavonol) enquanto que, da fase hidroalcoolica remanescente resultou no isolamento de um alcaloide indólico: N-metil-indol-1,3-etanamina, descrito pela primeira vez na literatura.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2017-10-24T12:45:23Z No. of bitstreams: 1 PDF - Isabelly da Silva Venâncio de Macêdo.pdf: 21766192 bytes, checksum: 18670653de69a62d3b2eb439387816e8 (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2017-10-26T16:55:33Z (GMT) No. of bitstreams: 1 PDF - Isabelly da Silva Venâncio de Macêdo.pdf: 21766192 bytes, checksum: 18670653de69a62d3b2eb439387816e8 (MD5) / Made available in DSpace on 2017-10-26T16:55:33Z (GMT). No. of bitstreams: 1 PDF - Isabelly da Silva Venâncio de Macêdo.pdf: 21766192 bytes, checksum: 18670653de69a62d3b2eb439387816e8 (MD5) Previous issue date: 2017-03-07 / In recent decades to expand the development of nutraceuticals from the use of plants containing active metabolites for the support not treating various diseases.The rutin is a naturally occurring flavonoid widely known to exhibit a variety of pharmacological activities, such as antioxidant, antiplatelet and antitumor agonist making it a promising candidate for nutraceuticals for chemoprevention purposes. However, its low solubility in aqueous media hinders its permeation in biological systems, thus reducing its therapeutic activity. The development of solid dispersions has been shown to be an effective technique for promoting the increase of aqueous solubility of drugs. The aim of this work was to produce solid dispersion microparticles of rutin, aiming to increase their aqueous solubility. The microparticles were produced by spray-drying using a Box-Behnken factorial design. It was used as carrier polyvinylpyrrolidone (PVP K-30) and for drying colloidal silicon dioxide (Aerosil® 200). The variables of the process studied were the temperature, percentage of rutin and the percentage of Aerosil, totaling 15 experiments. Physical mixtures of the active compound with adjuvants in 1: 1 and 1:9 ratios were also prepared. The results obtained were analyzed by the surface response technique (ANOVA). The evaluated parameters, besides the aqueous solubility, were yield, moisture content, solubility, dissolution in vitro. The microparticles as well as the physical mixtures were characterized by thermal analysis techniques: differential thermal analysis and thermogravimetry, X-ray diffraction and scanning electron microscopy. Statistical analysis showed that the yield was influenced by only one variable, while the moisture content was influenced directly by temperature in combination with the percentage of aerosil. The microparticles showed good yield (31% - 52%) and low moisture content (lessthan 2%). Regarding the solubility, there was no significant change between the microparticles related to the studied parameters. However, there was a significant increase in the solubility of the microparticles when related to the pure drug, with a solubility increase of up to 9 times, besides the excellent increase in the dissolution profile of the drug. Regarding thermal analysis and complementary techniques, the results showed good thermal and physical stability profile of the microparticles. Therefore, the development of microparticulate solid dispersions containing rutin by spray drying was able to increase the solubility of this flavonoid, making it a potential candidate as a nutraceutical for use in complementary diets. / Nas últimas décadas tem se expandido o desenvolvimento de nutracêuticos a partir da utilização de plantas que contém metabólitos ativos para suporte no tratamento de diversas doenças. A rutina é um flavonoide natural extensamente conhecido por apresentar variedade de atividades farmacológicas como, por exemplo, antioxidante, anti-agregante plaquetária e antitumoral tornando-a um promissor candidato a nutracêutico para fins de quimioprevenção. Entretanto, sua baixa solubilidade em meio aquoso dificulta sua permeação nos sistemas biológicos diminuindo assim sua atividade terapêutica. O desenvolvimento de dispersões sólidas tem se mostrado como uma técnica eficaz para a promoção do incremento da solubilidade aquosa de fármacos. Esse trabalho teve como objetivo produzir micropartículas de dispersão sólida de rutina visando o incremento de sua solubilidade aquosa. As micropartículas foram produzidas por spray-drying usando um planejamento fatorial Box-Behnken. Foi usando como carreador polivinilpirrolidona (PVP K-30) e para secagem dióxido de silício coloidal (Aerosil® 200) . As variáveis do processo estudas foram a temperatura, porcentagem de Rutina e a porcentagem do Aerosil, totalizando 15 experimentos. Foram preparadas também misturas físicas do ativo com os adjuvantes nas proporções 1:1 e 1:9. Os resultados obtidos foram analisados pela técnica de superfície de resposta (ANOVA). Os parâmetros avaliados, além da solubilidade aquosa, foram rendimento, teor de umidade, solubilidade, dissolução in vitro. As micropartículas assim como as misturas físicas foram caracterizadas pelas técnicas de análise térmica: análise térmica diferencial e termogravimetria, difração de raios X e microscopia eletrônica de varredura. A análise estatística demonstrou que o rendimento sofreu influência de apenas uma variável, enquanto que o teor de umidade sofreu influência direta da temperatura em combinação com a porcentagem de aerosil. As micropartículas apresentaram bom rendimento (31% – 52%) e baixo teor de umidade (inferior a 2%). Quanto a solubilidade não houve alteração significativa entre as micropartículas relacionada aos parâmetros estudados. Porém, houve um aumento significativo da solubilidade das micropartículas quando relacionado ao fármaco puro, com incremento de solubilidade de até 9 vezes, além do excelente aumento no perfil de dissolução do fármaco. Com relação a análise térmica e técnicas complementares os resultados mostraram bom perfil de estabilidade térmica e física das micropartículas. Portanto, o desenvolvimento de dispersões sólidas microparticuladas contendo rutina por spray drying foi capaz de aumentar a solubilidade desse flavonóide, tornando-o um potencial candidato como nutracêutico para ser usado em dietas complementares.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Marcetia macrophylla à um planta endÃmica da Bahia pertencente à famÃlia Melastomataceae. O extrato hidroalcoÃlico das folhas de M. macrophylla foi submetido a sucessivas cromatografias resultando no isolamento e identificaÃÃo de seis metabÃlitos secundÃrios: o triterpeno esqualeno, a mistura esteroidal β-sitosterol e estigmasterol, o flavonÃide quercetina, a isoflavona 4â,5,7-trihidroxi-6,8-dimetilisoflavona e o derivado do Ãcido gÃlico, galato de etila. Os metabÃlitos foram isolados atravÃs de mÃtodos cromatogrÃficos clÃssicos, tais como: cromatografia de adsorÃÃo em coluna, partiÃÃo lÃquido-lÃquido e cromatografia de exclusÃo. A elucidaÃÃo estrutural foi efetuada atravÃs dos mÃtodos espectroscÃpicos IV, EM e RMN 1H e 13C, uni e bidimensional, e comparaÃÃo com os dados descritos na literatura. Este à o primeiro relato do estudo fitoquÃmico de M. macrophylla. / Marcetia macrophylla is an endemic plant of Bahia belonging to the Melastomataceae family. The hydroalcoholic extract of Marcetia macrophylla leaves was subjected to successive chromatographic analysis to afford six secondary metabolites: the triterpene squalene, the steroidal mixture of β-sitosterol and stigmasterol, the flavonoid quercetin,the isoflavone 4',5,7-trihydroxy-6,8-dimethylisoflavone and the gallic acid derived, ethyl gallate. The metabolites were isolated by conventional chromatographic methods such as adsorption column chromatography, liquid-liquid partition and exclusionchromatography. The identification of these compounds was possible by IR, MS and 1H and 13C NMR, uni and bidimensinal, and comparison with literature data. This is the first report of phytochemical studies of Marcetia macrophylla.

Submitted by Celso Magalhaes (celsomagalhaes@ufrrj.br) on 2017-06-21T11:22:42Z No. of bitstreams: 1 2016 - Raquel Teixeira Ferreira.pdf: 4123117 bytes, checksum: d2271c63e8c851f1e25afd9a0bd8cf91 (MD5) / Made available in DSpace on 2017-06-21T11:22:42Z (GMT). No. of bitstreams: 1 2016 - Raquel Teixeira Ferreira.pdf: 4123117 bytes, checksum: d2271c63e8c851f1e25afd9a0bd8cf91 (MD5) Previous issue date: 2016-03-30 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Kalanchoe pinnata (KP) is popularly used for treating inflammatory diseases. This study investigated the antinociceptive and anti-inflammatory potential of the KP flower aqueous extract (KPFE), the ethyl acetate (EtOAcF), butanol (BuOHF) and aqueous (AqF) fractions and the main flavonoid [quercetin 3-O-?-L-arabinopyranosyl (1??) ?-L-rhamnopyranoside] (KPFV) of KP, as well as possible mechanisms of action. Swiss albino mice, male (25-35g) were pretreated with KPFE (30-300 mg/kg, s.c.) producing dose-related inhibition of acetic acid-induced writhing (ID50 164.8 mg/kg), and the subcutaneous administration of KPFE (300 mg/kg), EtOAcF (12 mg/kg), BuOHF (15 mg/kg) or AqF (210 mg/kg) reduced leukocyte migration on carrageenan-induced pleurisy in mice at 56.1%, 47.3%, 39.6% and 43.1%, respectively. At doses of up to 240 times smaller than KPFE, KPFV (0.3-3.0 mg/kg, s.c.), also inhibited leukocyte migration (ID50 1.78 mg/kg). In croton oil-induced ear edema in mice, KPFE (3-30 mg/kg, s.c.) and KPFV (0.3-3.0 mg/kg, s.c.) presented dose-related antiedematogenic activity (KPFE - ID50 4.3 mg/kg, KPFV - ID50 0.76 mg/kg). Treatment with KPFE reduced the MPO and TNF-? concentration in the pleural exudates on carrageenaninduced pleurisy test, while KPFV inhibited both isoforms of cyclooxygenase (COX), with IC50 3.8 x 10-5 M (22.1 ?g/mL) for COX-1 and a maximum COX-2 inhibition of 43.5% (IC50 >8.4 x10-5M or 50 ?g/mL). The selectivity index (COX-1 IC50/COX-2 IC50) was <0.44. These results indicate that KPFE and KPFV produced anti-inflammatory and antinociceptive activity through the COX inhibition and TNF-? reduction. This study reveals that the main flavonoid in KP flowers and leaves plays an important role in the ethnomedicinal use of this species for healing inflammatory processes / Kalanchoe pinnata (KP) ? popularmente utilizada para tratamento de doen?as inflamat?rias. Este estudo investigou o potencial antinociceptivo e anti-inflamat?rio do extrato aquoso das infloresc?ncias de KP (EAFL), a fra??o acetato de etila (FAcOEt), a fra??o butan?lica (FBuOH), a fra??o aquosa (FAq) e o flavonoide majorit?rio [quercetina 3-O-?-Larabinopiranosil (1??) ?-L-ramnopiranos?deo] (KPFV) de KP, assim como poss?veis mecanismos de a??o. Camundongos albinos, machos (25-35g) foram pr?-tratados com EAFL (30-300 mg/kg, s.c.), produzindo inibi??o dose dependente das contor??es induzidas por ?cido ac?tico (DI50 164,8 mg/kg), e a administra??o subcut?nea de EAFL (300 mg/kg), FAcOEt (12 mg/kg) ou FBuOH (15 mg/kg) reduziu a migra??o leucocit?ria na pleurisia induzida por carragenina em camundongos em 56,1%, 47,3%, 39,6% e 43,1%, respectivamente. Em doses at? 240 vezes menores que o EAFL, KPFV (0,3-3,0 mg/kg, s.c.), tamb?m foi capaz de inibir a migra??o leucocit?ria (DI50 1,78 mg/kg). No teste do edema de orelha induzido por ?leo de cr?ton em camundongos, EAFL (3-30 mg/kg, s.c.) e KPFV (0,3-3,0 mg/kg, s.c.) apresentaram atividade antiedematog?nica dose dependente (EAFL - DI50 4,3 mg/kg, KPFV - DI50 0,76 mg/kg). O tratamento com EAFL reduziu a concentra??o de MPO e de TNF-? no exsudato pleural obtido do teste da pleurisia induzida por carragenina, enquanto o KPFV inibiu ambas as isoformas de cicloxigenase (COX), com CI50 3,8 x 10-5M (22,1 ?g/mL) para COX-1 e um m?ximo de inibi??o da COX-2 de 43,5% (CI50 >8,4 x10-5M ou 50 ?g/mL). O ?ndice de seletividade (COX-1 CI50/COX-2 CI50) foi < 0,44. Estes resultados indicam que EAFL e KPFV produziram atividade anti-inflamat?ria e antinociceptiva envolvendo a inibi??o da COX e a redu??o de TNF-?. Este estudo revela que o principal flavonoide presente nas infloresc?ncias e folhas de KP possui papel importante no uso etnomedicinal desta esp?cie nos processos de natureza inflamat?ria

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-27T15:36:18Z No. of bitstreams: 1 VANDREZA CARDOSO BORTOLOTTO.pdf: 2120802 bytes, checksum: d9c6e128c892e469fe3f24a3ebad9f86 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-27T15:36:32Z (GMT) No. of bitstreams: 1 VANDREZA CARDOSO BORTOLOTTO.pdf: 2120802 bytes, checksum: d9c6e128c892e469fe3f24a3ebad9f86 (MD5) / Made available in DSpace on 2018-09-27T15:36:32Z (GMT). No. of bitstreams: 1 VANDREZA CARDOSO BORTOLOTTO.pdf: 2120802 bytes, checksum: d9c6e128c892e469fe3f24a3ebad9f86 (MD5) Previous issue date: 2017-07-17 / A glândula tireoide é uma das maiores glândulas do corpo, responsável pela produção de triiodotironina (T3) e tiroxina (T4), hormônios responsáveis pela homeostase do organismo. A redução na produção destes hormônios leva a um quadro de hipotireoidismo. O hipotireoidismo é uma desordem endócrina, mais prevalente no sexo feminino, e que pode causar uma série de alterações comportamentais e neurológicas, dentre elas a depressão. O flavonoide crisina, presente no maracujá do mato, própolis e mel de abelha, vem sendo estudado a alguns anos, sendo relatados seus efeitos antioxidantes, anticancerígenos, antihiperglicêmicos, ansiolíticos, e atualmente tem-se demonstrado sua atividade antidepressiva. O objetivo deste estudo foi investigar a ação terapêutica da crisina em modelo tipo depressivo induzido pelo hipotireoidismo em camundongos fêmeas C57BL/6 adultas. Primeiramernte os animais foram divididos em dois grandes grupos (n=20): controle e hipotireoidismo. O hipotireoidismo foi induzido por exposição contínua ao fármaco antitireoideo metimazol (MTZ) 0,1% + 0,475% de sucralose, durante 31 dias na água. No 31º dia foi retirado sangue da veia caudal e determinado os níveis de T3 e T4. Após os animais foram separados em quatro grupos (n=10): controle, hipotireoidismo, crisina, hipotireoidismo + crisina. A crisina (20mg/kg) foi administrada diariamente por 28 dias, via oral. Ao final do tratamento, os animais passaram por testes comportamentais de campo aberto (TCA), nado forçado (TNF) e suspensão de cauda (TSC), após realizou-se eutanásia nos animais, e coletou-se o sangue por punção cardíaca para análise bioquímica de T3 e T4, e retirou-se as estruturas cerebrais hipocampo e córtex pré frontal, para análises neuroquímicas de serotonina (5-HT), dopamina (DA), norepinefrina (NA). Nossos resultados demonstraram que os animais com hipotireoidismo apresentaram um aumento no tempo de imobilidade nos testes de TNF e TSC e a crisina foi capaz de reverter este tempo em ambos os testes. Demonstrou-se também que a crisina foi capaz de restaurar os níveis de neurotransmissores: 5-HT em ambas estruturas cerebrais e DA no hipocampo dos animais com hipotireoidismo, corroborando com os resultados dos testes comportamentais, nos quais o TNF está relacionado com o sistema serotoninérgico e o TSC com o sistema dopaminérgico. Em conclusão, nossos resultados demonstram pela primeira vez que a crisina é capaz de reverter o estado tipo depressivo induzido pelo hipotireoidismo, possivelmente por normalizar os níveis de 5-HT e DA. / The thyroid gland is one of the largest glands in the body, it produces triiodothyronine (T3) and thyroxine (T4), these hormones are responsible for body homeostasis. The reduction in the production of these hormones leads to hypothyroidism. The hypothyroidism is an endocrine disorder, more prevalent in females, which can cause a number of behavioral and neurological changes, including depression. The chrysin flavonoid present in the passion fruit of the bush, propolis and bee honey, has been studied for some years, being reported your antioxidant effect, anticancer, antihyperglycemic, anxiolytic, and currently your antidepressant activity was demonstrated. The objective of this study was to investigate the therapeutic action of chrysin in a model of like-depression induced by hypothyroidism in adult C57BL/6 female mice. First, the animals were divided into two groups (n=20): control and hypothyroidism. Hypothyroidism was induced by continuous exposure to the antithyroid drug methimazole (MTZ) 0.1% + 0.475% sucralose for 31 days on water. On the 31st day blood was drawn from the caudal vein and T3 and T4 levels were determined. After the animals were separated into four groups (n=10): control, hypothyroidism, chrysin, hypothyroidism + chrysin. The treatment of chrysin (20mg/kg) was administered daily for 28 days, orally. At the end of treatment the animals they passed for behavioral tests of open field test (OFT), forced swimming test (FST) and tail suspension test (TST), performed euthanasia in the animals, and collected the blood by cardiac puncture for biochemical analyze of T3 and T4, and the hippocampus and prefrontal cortex brain structures were removed for neurochemical analyzes of serotonin (5-HT), dopamine (DA), norepinephrine (NA). Our results demonstrated that animals with hypothyroidism showed an increase in the time of immobility in the tests of FST and TST and the chrysin was able to reverse this time in both tests. It was also demonstrated that the chrysin was able to restore the levels of neurotransmitters: 5-HT in both structures cerebral and DA in the hippocampus of animals with hypothyroidism, corroborating with the results of behavioral tests, in which FST is related to the serotonergic system and the TST with the dopaminergic system. In conclusion, our results demonstrate for the first time that chrysin is able of reversing the depressive-induced state induced by hypothyroidism, possibly by normalizing 5-HT and DA levels.

Die enzymatischen Transformationen mit der pilzlichen Peroxygenase aus Agrocybe aegerita haben gezeigt, dass das Enzym insgesamt über ein sehr breites Substratspektrum bezüglich der Flavonoide verfügt. Die Flavonoide werden mittels AaeAPO regioselektiv in 6-Position hydroxyliert. Der Reaktionsmechanismus der AaeAPO bei Flavonoiden läuft über eine Epoxidstufe ab, wobei der eingefügte Sauerstoff bei Hydroxylierungen dem Wasserstoffperoxid entstammt (Hinweis auf eine echte Peroxygenase-Reaktion). Die Enzymproduktion der Agrocybe aegerita wird durch den Extraktzusatz (aus jeweils Aronia melanocarpa, Fragaria ananassa, Trifolium pratense und Bellis perennis) im Fall der Laccase stimuliert. Die AaeAPO -Aktivität wird dagegen gehemmt. Für Bjerkandera adusta kann eine moderate Stimulierung der MnP-Bildung nach der Extraktzugabe beobachtet werden. Der positive bzw. negative Einfluss auf die Enzymproduktion ist bei Agrocybe aegerita sowohl auf Flavonoide als auch auf das Lösungsmittel Ethanol zurückzuführen.

Die enzymatischen Transformationen mit der pilzlichen Peroxygenase aus Agrocybe aegerita haben gezeigt, dass das Enzym insgesamt über ein sehr breites Substratspektrum bezüglich der Flavonoide verfügt. Die Flavonoide werden mittels AaeAPO regioselektiv in 6-Position hydroxyliert. Der Reaktionsmechanismus der AaeAPO bei Flavonoiden läuft über eine Epoxidstufe ab, wobei der eingefügte Sauerstoff bei Hydroxylierungen dem Wasserstoffperoxid entstammt (Hinweis auf eine echte Peroxygenase-Reaktion). Die Enzymproduktion der Agrocybe aegerita wird durch den Extraktzusatz (aus jeweils Aronia melanocarpa, Fragaria ananassa, Trifolium pratense und Bellis perennis) im Fall der Laccase stimuliert. Die AaeAPO -Aktivität wird dagegen gehemmt. Für Bjerkandera adusta kann eine moderate Stimulierung der MnP-Bildung nach der Extraktzugabe beobachtet werden. Der positive bzw. negative Einfluss auf die Enzymproduktion ist bei Agrocybe aegerita sowohl auf Flavonoide als auch auf das Lösungsmittel Ethanol zurückzuführen.

Die Anwendung von Birkenblättern (Betulae folium) erfolgt zur Durchspülung der Harnwege. In der vorliegenden Arbeit wurde die Wirkungsweise der Birkenblätter auf verschiedenen Ebenen der Phytopharmakaforschung untersucht. Zunächst wurde in-vitro die Beeinflussung der Metallopeptidasen Neutrale Endopeptidase (NEP, EC 3.4.24.11), Angiotensin-Converting-Enzym (ACE, EC 3.4.15.1) und Leucin-Aminopeptidase (LAP, EC 3.4.11.2) durch Birkenblätterextrakte, -fraktionen und reine Naturstoffe untersucht. Die Auftrennung eines Methanol- und eines Ethylacetatextraktes führte nicht zur Gewinnung einzelner, für die Gesamtwirkungen der Extrakte verantwortlicher Fraktionen bzw. Komponenten. Die Eigenschaft der Flavonoide als wirksamkeitsmitbestimmende Inhaltsstoffe konnte jedoch bestätigt werden. Ein systematisches Screening von Flavonoiden ergab u.a., dass das Ausmaß der Enzymhemmung von der Anzahl der freien phenolischen OH-Funktionen bestimmt wurde und dass Flavonoidaglyka stärker die Enzyme hemmten, als die im Pflanzenmaterial vorliegenden Glykoside (IC50 NEP: Myricetin 42 Mikromol/L, Quercetin 192 Mikromol/L). Die in der Birkenrinde vorkommenden Triterpene Betulinsäure und Betulinol wurden als starke Inhibitoren der LAP erkannt (IC50 LAP: 7,3 +/- 1,4 bzw. 8,8 +/- 1,78 Mikromol/L). In einem nächsten Abschnitt der Arbeit wurden die Absorptionseigenschaften von Hyperosid und Rutin mit einem In-vitro-Perfusionsmodell am isolierten Rattendünndarm untersucht. Sowohl Rutin als auch Hyperosid traten unverändert als Glykoside durch den Darm in das Akzeptorkompartiment über. Auch in Form eines Birkenblätterextraktes wurde Hyperosid am Rattendünndarm absorbiert, der Extrakt veränderte jedoch nicht die Absorptionsrate. Als Mechanismus wurde der passive Transport durch die Poren der Tight junctions der Dünndarmzellen angenommen. Abschließend wurde eine Pilotstudie (n=14) durchgeführt, in der das ausgeschiedene Harnvolumen nach einmaliger Einnahme eines Birkenblättertees im Vergleich zu einer entsprechenden Menge Leitungswasser bestimmt wurde. Bei 50 % der Probanden wurde innerhalb der vierstündigen Testphase eine Zunahme der Harnproduktion beobachtet, bei den anderen 50 % stellte sich eine gegensätzliche Reaktion auf Tee und Placebo ein. Eine signifikante Erhöhung der Harnproduktion konnte somit, unter dem angegebenen Studiendesign, nicht nachgewiesen werden. / Irrigation of the urinary tract is the therapeutic indication for Birch leaf (Betulae folium). In the present thesis, effects and efficacy of Birch leaves were investigated in various fields of medicinal plant research. The effects of Birch leaf extracts, their fractions, and pure natural compounds on the metallopeptidases - Neutral Endopeptidase (NEP, EC 3.4.24.11), Angiotensin Converting Enzyme (ACE, EC 3.4.15.1), and Leucine Aminopeptidase (LAP, EC 3.4.11.2) - were investigated in vitro. Phytochemical separation of extracts obtained by methanol and ethyl acetate did not result in more active fractions compared to those of the whole extracts. The ability of flavonoids to contribute to the efficacy reached by Birch leaf extracts, could be confirmed. A systematic screening could show that the inhibitory potency of flavonoids is dependent on the number of phenolic hydroxyl functions in their chemical structure. Aglycones of flavonoids were more active than their corresponding glycosides occurring in the plant material (IC50 NEP: myricetin 42 mikromol/L, quercetin 192 mikromol/L). Betulinic acid and betulinol, triterpenes of the bark of Betula, inhibited LAP strongly by reaching an IC50 of 7,3 +/- 1,4 mikromol/L and 8,8 +/- 1,78 mikromol/L, respectively. Furthermore, this thesis showed the absorption profiles of hyperoside and rutin in an isolated small intestine model of the rat. Both glycosides were detected in the acceptor compartment without being metabolised. Administration of hyperoside by a Birch leaf extract did not influence the absorption rate. A passive transport through the pores of the tight junctions, localized between the intestinal cells, was considered to be the mechanism of absorption of the flavonol glycosides. Finally, a human pilot study (n=14) was carried out. The excreted urinary volume was determined after a single intake of a Birch leaf infusion or tap water. An increased urine output after 4 hours of the test period was found in 50% of the volunteers. In the contrary, an opposite effect was determined in 50% of the volunteers after administration of the herbal infusion and of a placebo solution. Thus, no significant increase of urine volume could be observed under these test conditions.

Endokrin aktive Substanzen (EACs) sind exogene Substanzen natürlichen oder synthetischen Ursprungs, die mit der Feedbackregulation hormoneller Netzwerke interferieren können und somit deren Homöostase beeinflussen. Störungen der Hypothalamus-Hypophysen-Schilddrüsenachse (HPT-Achse) haben weitreichende Konsequenzen, da Schilddrüsenhormone essentiell für die Regulation von Entwicklung, Wachstum und Stoffwechsel sind. In der vorliegenden Arbeit wurde das Wirkprofil potenter Inhibitoren der thyreotropen Achse am Beispiel von 4-Methylbenzyliden-campher (4-MBC) und Genistein (GEN) untersucht. Der UV-Filter 4-MBC wurde in der ovariektomierten Ratte als goitrogene Substanz identifiziert. 4-MBC interferiert auf Ebene von Hypothalamus und Hypophyse mit der Expression Feedback-assoziierter Gene und beeinflusst daher die Feedbackregulation der thyreotropen Achse. Darüber hinaus wird die Biosynthese von Schilddrüsenhormonen durch Inhibition des Iodidtransports bei gleichzeitig erhöhter messenger RNA (mRNA)-Konzentration des Natrium-Iodid-Symporters (NIS) durch 4-MBC beeinträchtigt. Parallel dazu lässt die verstärkte Expression des Angiogenesemarkers vascular endothelial growth factor (VEGF) nach subakuter Exposition auf die Entstehung einer Hypothyreose schließen. Die damit einhergehenden Veränderungen sind auch in peripheren Organen durch die Analyse 3,3‘,5-Triiod-L-thyronin (T3)-regulierter Zielgene dokumentiert. Zudem wurden diese Effekte maßgeblich durch die Expositionszeit beeinflusst, da nach chronischer Exposition vermutlich auch kompensatorische Prozesse eine wichtige Rolle spielen. Die gezeigten speziesspezifischen Effekte lassen sich möglicherweise auf Unterschiede in der Pharmakokinetik zurückführen, z.B. in Folge differentieller Expression von Cytochrom P450-Genen. / Endocrine active compounds (EACs) can be of natural or synthetic origin and show hormone-like effects that interfere with feedback regulation of hormonal networks. Interferences with the hypothalamic-pituitary-thyroid axis (HPT-axis) result in extensive consequences as thyroid hormones are essential for regulation of development, growth, and metabolism. In the work presented here, the active profile of potent inhibitors of the HPT-axis namely 4-methylbenzylidene-camphor (4-MBC) and genistein (GEN) was investigated. 4-MBC, a UV filter used in sunscreens and various cosmetics, was identified as a goiter causing agent using ovariectomized rats. 4-MBC acts at the level of hypothalamus and pituitary gland by modulating the expression of thyrotropin-releasing hormone (TRH) as well as thyroid-stimulating hormone (TSH) that regulate feedback on the HPT-axis. Furthermore, biosynthesis of thyroid hormones was impaired by 4-MBC secondary to the inhibition of iodide transport with concomitantly increased messenger RNA (mRNA)-levels of the sodium-iodide symporter (NIS). In parallel expression of the angiogenesis marker vascular endothelial growth factor (VEGF) was increased, indicating hypothyroidism. After the application of 4-MBC the expression of L-3,3’,5-triiodothyronine (T3)-regulated target genes was reduced in the periphery both on the mRNA and protein level. The documented species-specific effects indicate a difference in pharmacokinetics, possibly secondary to differential expression of cytochrome P450 genes. GEN is contained in soy and red clover and its mechanistic analysis was carried out in thyroid hormone receptor (TR) deficient mice (TRα0/0). The gender-dependent effects of GEN on tissue specificity did not follow an obvious pattern and warrant continuative analysis. The work presented here supports the assumption that EACs can interfere with function and regulation of the HPT-axis at levels that were previously considered safe.