隨著個人計算機運算能力的快速發展，虛擬藥物篩檢已被廣泛運用。目前運用於計算機輔助藥物虛擬篩選的化合物數據庫多為人工合成的數據庫，而用於天然產物藥物篩選的數據庫則較少報道。為了加速天然化合物的虛擬篩選，我們建立了包含約8000個天然產物的數據庫。他們中的大多數為傳統中藥。 / 為了驗證天然產物數據庫的可用性，其被用於篩選乙酰膽鹼酯酶抑製劑。該數據庫成功地確定了美國藥品監督管理局所批準的乙酰膽鹼酯酶抑製劑，如石杉鹼甲和他克林，表示該天然產物數據庫可以用於藥物虛擬對接篩選。 / 除了已知的乙酰膽鹼酯酶抑製劑，十二種植物化學物（大黃酸，大黃素，蘆薈大黃素，大黃酚，花椒毒素，珊瑚菜素，別異歐前胡素，歐前胡素，紫草素，乙酰紫草素，異戊紫草素和β，β-二甲基丙烯酰紫草素）被確定為新的乙酰膽鹼酯酶抑製劑。澱粉樣蛋白聚集可以導致神經細胞死亡；本研究中新發現的乙酰膽鹼酯酶抑製劑乙酰紫草素能夠阻止澱粉樣蛋白的聚集。除此之外，乙酰紫草素及其衍生物可以對抗過氧化氫誘導的神經細胞凋亡。其抗凋亡的活性作用是通過抑制活性氧的產生，以及保護線粒體膜電位的損失所實現的。亞鐵血紅素加氧酶在其神經細胞保護作用中起重要作用。 / 趨化因子受體4為跨膜G蛋白偶聯受體（GPCRs）。 CXCR4已被確定為一個新治療以及預防腫瘤轉移的新靶點。本研究利用分子對接篩選，從天然產物數據庫篩選選出CXCR4拮抗劑。通過分子對接和基於細胞的測定，黃芪甲苷，羥基紅花黃色素A和水飛薊賓已被確定為CXCR4拮抗劑。抗轉移的研究表明，黃芪甲苷和水飛薊賓抑制CXCL12誘導乳腺癌細胞的遷移和侵襲。此外，水飛薊賓也抑制CXCL12誘導的人臍靜脈內皮細胞管形成。另一方面，羥基紅花黃色素A對乳腺癌細胞的增殖表現出較強的抑製作用，因此很難進行抗轉移實驗。 / With the rapid advances in personal computing power, virtual drug screening has become increasingly popular. While there are numerous databases for synthetic compounds, there are few natural product databases that are specifically for in silico docking studies. To facilitate virtual docking on natural compounds, in-house Natural Products Database has been established, which contains approximately 8,000 naturally occurring chemicals so far. Most of them are documented Traditional Chinese Medicines. / In order to validate the usefulness of the database, in silico screening of acetylcholinesterase inhibitors (AChEIs) by virtual docking was performed. The database successfully identified the FDA-approved AChEIs such as huperzine and tacrine, indicating the in-house database is workable for natural products docking screening. / Apart from well-known AChE inhibitors, twelve phytochemicals (emodin, aloe-emodin, chrysophanol, rhein, xanthotoxin, phellopterin, alloisoimperatorin, imperatorin, shikonin, acetylshikonin, isovalerylshikonin and β, β-dimethylacrylshikonin) were identified as AChE inhibitors in this study that were not previously reported. Amyloid aggregation leads to toxic species that cause neuronal cell deaths, it was found that the newly identified AChEIs acetylshikonin and shikonin are able to prevent amyloid aggregation. A series of cell-based analysis were conducted for in vitro evaluation of the neuroprotective activities of the newly identified AChEIs. Acetylshikonin and its derivatives was found to prevent apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10 μM. Acetylshikonin exhibited the most potent anti-apoptotic activity through inhibition of reactive oxygen species (ROS) generation as well as protection of the loss of mitochondria membrane potential. Furthermore, acetylshikonin upregulates hemooxygenase 1(HO-1) which is a key step mediating its anti-apoptotic activity from oxidative stress in SH-SY5Y cells. / The C-X-C chemokine receptor type 4 (CXCR4) belongs to the class A family of seven transmembrane G protein-coupled receptors (GPCRs). CXCR4 has been identified as one of novel target against metastasis. A search for natural CXCR4 antagonists was conducted from natural product database by molecular docking for anti-metastasis study. Astragaloside IV, hydroxy safflower yellow A and silibinin have been identified as novel CXCR4 antagonists by both molecular docking and characterized by various cell-based assays. Anti-metastasis study showed that astragaloside IV and silibinin inhibited CXCL12-induced migration and invasion in breast cancer cells. In addition, silibinin also inhibited CXCL12-induced tube formation in human umbilical vein endothelial cells. On the other hand, hydroxy safflower yellow A exhibited a strong cytotoxicity on breast cancer cell proliferation, which is difficult to conduct anti-metastasis experiments. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wang, Yan. / Thesis (Ph.D.) Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 230-250). / Abstracts also in Chinese.

Thesis (M.S.)--University of North Carolina at Wilmington, 2006. / Includes appendix pages: [42]-63. Includes bibliographical references (leaves: 39-41)

Resumo: Produtos naturais têm sido estudados com relação ao controle químico da microbiota patogênica do biofilme bucal. O objetivo desse estudo foi esclarecer o efeito do extrato da folha de Psidium cattleianum no metabolismo de S. mutans, no biofilme formado in situ e na capacidade em inibir a desmineralização do esmalte. O extrato foi obtido por decocção das folhas em água deionizada. O efeito do extrato foi avaliado in vitro com relação à viabilidade, expressão protéica e produção de ácido de biofilmes de S. mutans. No estudo in situ, blocos de esmalte bovino foram fixados em dispositivos acrílicos palatinos de dez voluntários. A fase experimental consistiu de três etapas de 14 dias cada, separadas por intervalo de sete dias. Os voluntários gotejaram solução de sacarose 20% (8x/dia) e a solução de tratamento (água, extrato ou um enxaguatório comercial; 2x/dia). O biofilme dentário foi analisado quanto à acidogenicidade, quantidade microorganismos e presença de polissacarídeos álcali-solúveis. Nos blocos de esmalte, foram realizadas as análises de microdureza superficial e em secção longitudinal. O extrato foi capaz de afetar a viabilidade, a produção de ácidos e a síntese protéica do biofilme formado in vitro. No biofilme formado in situ, o extrato foi capaz de diminuir a queda do pH, o acúmulo de microorganismos, a formação de polissacarídeos extracelulares e a desmineralização do esmalte. Conclui-se que o extrato foi capaz de diminuir a expressão de proteínas envolvidas no metabolismo bacteriano, a patogenicidade do biofilme bucal e a desmineralização do esmalte in situ. / Abstract: Natural products have been studied with relation to chemical control of pathogenical microorganisms of dental biofilm. The aim of this study was to clarify the effect of Psidium cattleianum leaf extract on S. mutans metabolism, on in situ biofilms and on enamel demineralization. The extract was obtained by decoction in deionized water. The extract was studied in vitro with relation to viability, protein expression and acid production of S. mutans biofilms. On the in situ study, enamel bovine blocks were placed in palatal appliances of ten volunteers. The experimental phase consisted of three stages with a duration of 14 days each and a washout period of seven days. The volunteers dripped 20% sucrose (8x/day) and the treatment solution (water, extract or a marketed mouthwash - 2x/day) on the enamel blocks. The dental biofilm was analyzed regarding the amount of microorganisms and presence of alkalisoluble polysaccharides. On the enamel blocks, surface and cross-sectional microhardnessess were evaluated. The extract was able to affect the viability, acid production and protein synthesis of the in vitro biofilm. On the in situ biofilm, the extract was able to decrease pH drop, microorganism accumulation, extracellular polysaccharides formation and enamel demineralization. It can be concluded that the extract was able to reduce the expression of proteins involved on bacterial metabolism, the pathogenicity of dental biofilm and in situ enamel demineralization. / Orientador: Alberto Carlos Botazzo Delbem / Coorientador: Elerson Gaetti-Jardim Júnior / Banca: Marília Afonso Rabelo Buzalaf / Banca: Cínthia Pereira Machado Tabchoury / Banca: Cristina Antoniali Silva / Banca: Maria Aparecida de Andrade Moreira Machado / Doutor

Orientador: Clarice Weis Arns / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-18T22:42:12Z (GMT). No. of bitstreams: 1 Padilla_MarinaAiello_M.pdf: 819976 bytes, checksum: ee10d49c35496b65a75f47504870ce54 (MD5) Previous issue date: 2011 / Resumo: Os herpesvírus são responsáveis por enfermidades importantes em humanos e animais. Em animais, estão associados a doenças que causam grandes perdas econômicas. Em humanos, a gravidade da enfermidade é maior quando os pacientes são imunossuprimidos. Além disso, já existem cepas mutantes resistentes aos medicamentos disponíveis. Visto as dificuldades associadas a prevenção e tratamento das infecções por herpesvírus, a utilização de produtos de plantas como antivirais apresenta - se como alternativa. O Cerrado Brasileiro é um bioma que localiza -se praticamente todo no Brasil e apresenta mais de 10.000 espécies de plantas. Essas plantas podem potencialmente servi r de fonte de compostos farmacologicamente ativos. Assim, o presente trabalho teve como objetivos avaliar a atividade antiviral , atividade virucida e o índice de seletividade (SI) de extratos de plantas do Cerrado contra os herpesvírus suíno tipo 1 (SuHV-1), equinotipo 1 (EHV-1) e vírus do herpes simplex tipo 1 (HSV-1) . Inicialmente, os extratos liofilizados foram submetidos aos testes de citotoxicidade em células MDBK e Vero para determinar a concentração máxima não tóxica (CMNT). Dos extratos, quatro apresentaram as mesmas CMNT's em ambas as linhagens mas, em geral , os extratos foram mais citotóxicos para células Vero. A seguir, com base na CMNT, foram realizados os testes de atividade antiviral para os vírus HSV-1 e EHV-1 em células Vero, e SuHV-1 em MDBK. Os resultados demonstraram que 50% dos extratos apresentaram atividade contra pelo menos um dos herpesvírus estudados, com destaque para as espécies Banisteriopsis variabil is , Byrsonima intermedia e Xylopia aromática que foram ativas contra os t rês herpesvírus, e o extrato da Stryphnodendron adstringens , ativo contra o HSV-1 e SuHV-1. Os extratos que apresentaram atividade antiviral foram então testados quanto a atividade virucida e os resultados submetidos ao cálculo do SI. O extrato foi considerado ativo quando o índice de inibição viral ( IIV) foi maior ou igual a 1,5 ou apresentou PI% (porcentagem de inibição) maior ou igual a 97%. Quanto ao SI, foram considerados ativos os extratos que apresentaram valores iguais ou superiores a 4. A atividade virucida foi observada em 75% dos extratos contra pelo menos um dos herpesvírus testados. As espécies que apresentaram os resultados mais promissores foram: B. variabil is, X. aromática, S. adstringens e B. intermedia. Esta última foi então utilizada em testes adicionais com a variação da concentração, e demonstrou atividade antiviral e virucida em concentrações inferiores a CMNT contra os herpesvírus testados. Assim, o presente trabalho demonstra o potencial de plantas do Cerrado como fonte de compostos com atividade antiviral e virucida. Estudos adicionais são necessários para avaliar os mecanismos de ação e os compostos químicos responsáveis pela atividade observada / Abstract: Herpesviruses are responsible for important diseases in humans and animals. In animals, they are associated with economically important diseases worldwide. In humans, they represent serious threats to public health, and the severity of the illness increases in immunocompromised patients. In addition, there are mutant strains that are resistant to available drugs. Because of the difficulties associated with the prevent ion and treatment of herpesvirus infect ions, the use of plant products as antivirals can be an alternative. The Brazilian Cerrado is a biome located almost entirely in Brazil has over 10,000 species of plants. These plants can potentially be used as a source of pharmacologically active compounds. There for , this study aimed to evaluate the antiviral activity, virucidal activity and the selectivity index (SI) of extracts from Cerrado plants against suid herpesvirus type 1 (SuHV-1) equid type 1 (EHV-1) and herpes simplex virus type 1 (HSV-1). Initially, the lyophilized extracts were tested for cytotoxicity in MDBK and Vero cells to identify t he maximum nontoxic concentration (MNTC). Of the extracts, four showed the same MNTC for both cells, but the extracts were generally more toxic to Vero cells. Then, based on the MNTC, antiviral activity tests were performed against HSV-1 and EHV-1 in Vero cells and SuHV-1 in MDBK cells. The results demonstrated that 50% of the extracts showed activity against at least one of the herpesviruses studied. In particular, the extracts from Banisteriopsis variabil is, Byrsonima intermedia and Xylopia aromatica, were active against all of the herpesviruses, and the extract from Stryphnodendron adstringens was active against HSV-1 and SuHV-1. The extracts that showed antiviral activity were also tested for virucidal activity, and the SI was calculated. An extract was considered active when the viral inhibition index (VII) was greater than or equal to 1.5 or showed a PI% (percent inhibition) greater than or equal to 97%. As for the SI, extracts were considered active when the displayed values greater than or equal to four. Virucidal activity was observed in 75% of the extracts against at least one of the herpesviruses tested. The species that showed the most promising results were: B. variabil is , X. aromatica, S. adstringens and B. intermedia. Was used for additional testing with varying concentrations, and demonstrated antiviral and virucidal activities at concentrations lower than the MNTC against the herpesviruses tested. Therefore, this study demonstrates the potential of Cerrado as a source of compounds with antiviral and virucidal activities. Additional studies are necessary to evaluate the mechanisms of act ion and the chemical compounds responsible for the observed activity / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

Orientadores: Gonçalo Amarante Guimarães Pereira, Fabio Marcio Squina / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-20T10:42:15Z (GMT). No. of bitstreams: 1 FrancoCairo_JoaoPauloLourenco_M.pdf: 11009698 bytes, checksum: 254e86d9d04cefe39d74fdc50ea31f23 (MD5) Previous issue date: 2012 / Resumo: Os bioprodutos derivados de resíduos lignopolissacrídico, entre eles o etanol de segunda geração ou bioetanol lignocelulósico, são considerados um produto energético sustentável, sendo a transformação dos polissacarídeos da parede celular vegetal em açúcares fermentáveis, um dos principais desafios desta cadeia produtiva. O uso de enzimas (hidrolases glicolíticas) neste procedimento é de extrema importância e a descoberta e caracterização de novas hidrolases serão de grande avalia para o melhoramento e desenvolvimento dessa atividade econômica. Cupins exercem um papel importante na ciclagem de carbono e nitrogênio no meio ambiente. Responsabilizando-se por cerca de 90% da degradação da matéria vegetal-seca em florestas tropicais, os cupins são considerados ecologicamente como um biorreator natural de transformação de materiais lignocelulósicos em açúcares. Seu "arsenal" enzimático (endógeno e simbiôntico) é uma fonte de enzimas que agem em um sinergismo eficiente e que deve ser estudada visando a sua aplicação biotecnológica (Digestoma). O objetivo desse dissertação foi de obter informações sobre o digestoma de C. gestroi, em particular identificando hidrolases glicolíticas (polissacaridases) desse digestoma por abordagens de bioquímica e metaproteômica, além de caracterizar funcionalmente cinco hidrolases glicolíticas e enzimas acessórias do cupim C. gestroi identificados em seu metranscriptoma. A caracterização bioquímica do extrato bruto protéico de C. gestroi mostrou que o mesmo é capaz de hidrolisar diferentes tipos de ligações glicosídicas em diversos substratos polissacarídeos naturais em diversos pH diferentes (pH 4 - pH 8). A análise do metaproteoma identificou cerca de 55 proteínas com similaridades com hidrolases glicolíticas, sendo a ocorrência dessas proteínas validadas funcionalmente como dados de ensaios enzimáticos e análise de eletroforese capilar. A caracterização funcional de uma Endo-ß-1,4-glicosidase (EG1Cg - GH9) e uma ß-1,4-glicosidase (BG1Cg - GH1) endógenas que as enzimas possui uma atividade ótima em pH em torno de pH 5-6, a temperatura ótima de atividade foi em torno de 50-55 ºC, além de a cinética enzimática revelar um padrão michaeliano para as enzimas. O modo de operação dessas enzimas são conservados, bem como sua estrutura tridimensional e resíduos catalíticos. Concluímos que o cupim Coptotermes gestroi possui as principais classes de hidrolases glicolíticas envolvidas na degradação da biomassa vegetal, sendo essas enzimas de grande potencial biotecnológico / Abstract: The bioproducts derived from lignopolissascharides residues, such as, second-generation ethanol or lignocellulosic bioethanol, are considered a sustainable energy product, and the transformation of plant cell wall polysaccharides into fermentable sugars, one of the main challenges to enhance productivity of this bioproduct. The use of enzymes (glycoside hydrolases) in this procedure is substantial and discovery and characterizations of new hydrolases are high rating for the improvement and development of this economic activity. Termites play an important role in the cycling of carbon and nitrogen in the environment. They are responsible for about 90% o plant matter-dry degradation in tropical forests. Termites are ecologically considered as a natural bioreactor for conversion of lignocellulosic materials into sugar. It enzymatic repertoire (endogenous and symbiotic) is a source of enzymes that act in a effective synergism and should be studied to determine whether its biotechnological application. Initially, the aim of this thesis was to obtain information about the digestoma of lower termite Coptotermes gestroi, particularly the glycoside hydrolases (polissacharidases) by a biochemical and metaproteomic approach and the secondly aim were characterize functionally five enzymes from C. gestroi digestome (glycoside hydrolases and accessory proteins). Biochemical characterization of crude extract protein from C. gestroi showed that it is able to hydrolyze glycosidic linkages of different types in different natural polysaccharide substrates in several different pH (pH 4 - pH 8). The analysis of metaproteoma identified about 55 proteins with similarities to glycoside hydrolases, and the occurrence of these proteins were functionally validated with biochemical assays and capillary electrophoresis. The functional characterization of endogenous endo-ß-1,4- glucosidase (CgEG1 - GH9) and a ß-1 ,4-glucosidase (CgBG1 - GH1) from C. gestroi showed the optimum pH of activity around pH 5.6 , the optimum temperature for activity was around 50-55 °C, further than enzyme kinetics reveal a pattern michaeliano for enzymes. The modes of operation of these enzymes are conserved, as well as their three-dimensional structure and catalytic residues. Thus we conclude that the lower termite Coptotermes gestroi has the major classes of hydrolases involved in the glycolytic degradation of plant biomass being these enzymes of great biotechnological potential / Mestrado / Genetica Animal e Evolução / Mestre em Genética e Biologia Molecular

Orientador: Lea Maria Leme Strini Velho / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Geociencias / Made available in DSpace on 2018-08-14T09:18:38Z (GMT). No. of bitstreams: 1 Torres_OscarAlbertoDuarte_D.pdf: 931915 bytes, checksum: ce34f1d9f37e8e2224ef2bb0ddbe367b (MD5) Previous issue date: 2009 / Resumo: Na prática da bioprospecção se apresentam uma série de divergências e conflitos de distinta natureza, que fazem dela um objeto muito interessante de estudo, como os diferenciados poderes de negociação das partes (países do Norte e países do Sul); a interação entre diferentes tipos de conhecimento (tradicional e científico); a complexidade de um marco legal no nível internacional e a possibilidade de que os países em desenvolvimento, ricos em biodiversidade, aumentem suas capacidades para realizar atividades de C&T. À luz deste quadro geral esta pesquisa localiza a bioprospecção na Colômbia, que é um país muito interessante como estudo de caso desta prática devido ao fato de que é considerado um dos Estados mais biodiversos do planeta; apesar disso, é um país com poucos estudos realizados que contribuam a quantificar sua capacidade científica e tecnológica para realizar bioprospecção e possui um marco jurídico complexo para realizar acesso aos recursos genéticos. Este estudo avalia e analisa algumas das experiências da Colômbia na prática bioprospectiva, fazendo um paralelo entre as capacidades científicas e tecnológicas relevantes para esta prática, as limitações impostas pelo marco jurídico e o papel desempenhado pela política de C&T. Os resultados evidenciam que atualmente, a Colômbia tem avances em atividades de bioprospecção, o que ocorre sem que a política científica local tenha elegido a esta como um tema prioritário. Este país possui um marco legal normativo muito complexo e esta complexidade, associada à rigidez, faz com que a normativa existente se converta num impedimento para realizar de forma legal as atividades relacionadas com bioprospecção; assim, o marco regional andino, através da chamada Decisão Andina 391 de 1996, é a normativa que atualmente está impondo as maiores limitações para que se desenvolvam na Colômbia de uma forma adequada pesquisas que contemplem o acesso aos recursos genéticos. Evidencia-se a necessidade de um maior compromisso por parte dos organismos encarregados de planejar e apoiar a C&T como atores fundamentais para identificar oportunidades da bioprospecção e para fortalecer as atuais capacidades. O estudo recomenda a necessidade de adotar na Colômbia um enfoque mais pró-ativo que permitisse a negociação dos recursos e não um enfoque meramente defensivo de "guardião dos recursos". As evidências integrais deste estudo levam a concluir que a bioprospecção é uma alternativa extraordinária mediante a qual se aproveitaria a biodiversidade da Colômbia e as fortalezas endógenas dos grupos de pesquisa da agropecuária. / Abstract: The bioprospecting practice has a series of divergences and conflicts of diverse nature, that make it a very interesting subject for analysis; these include the different negotiating powers of the parties involved (Northern countries and Southern countries), the interaction between different types of knowledge (traditional and scientific), the complexity of a worldwide legal framework, and the possibility for developing countries, with a rich biodiversity, to improve their capabilities to accomplish S&T activities. Considering this general scenario, this study analyzes the bioprospecting practice in Colombia, as it constitutes a very interesting case study of this practice due to its status as one of the countries with the richest biodiversity. Despite the foregoing, Colombia has accomplished very few studies to help measure its bioprospecting scientific and technological capabilities and it has a complex legal framework to be able to access genetic resources. This study assesses and analyzes some of Colombia's experiences concerning the bioprospecting practice, making a parallel between the relevant scientific and technological capabilities of this practice, the limitations imposed by the legal framework, and the role of the S&T policy. Results obtained evidence that, to this day, Colombia has made significant progress in bioprospecting activities, regardless of the fact that bioprospection has not been selected as a priority topic by the scientific policy. Colombia is a country with a highly complex regulatory legal framework and, therefore, such complexity together with the lack of flexibility, turn the existing regulations into an obstacle for the accomplishment of activities related with this practice in a legal manner. That is why the Andean region legal framework, through the so-called Andean Decision 391 of 1996, is the regulatory framework currently imposing the greatest limitations for the proper development of research works contemplating access to genetic resources. The need for a stronger commitment by the entities in charge of planning and supporting the S&T is evidenced, as core players in the identification of bioprospecting opportunities aimed at strengthening the existing capacities. The study recommends the need to adopt in Colombia a more proactive focus allowing the negotiation of resources rather than the merely defensive focus as "guarding of the resources". The overall evidence of this study leads to conclude that bioprospection constitutes an extraordinary alternative whereby Colombian biodiversity could be exploited as well as the endogenous strengths of farming research groups. / Doutorado / Doutor em Política Científica e Tecnológica

Hyperuricemia is the hallmark of gout. Pathogenic mechanisms of hyperuricemia include uric acid overproduction in the liver or underexcretion in the kidney. Current antihyperuricemic agents include xanthine oxidase inhibitors in which allopurinol is the most often prescribed. Inhibitors of renal urate reabsorption such as probenecid and benzbromarone are also employed. However, these existing antihyperuricemic agents possess some undesirable effects such as hypersensitivity towards allopurinol and hepatotoxicity associated with benzbromarone. Therefore, search for alternative antihyperuricemic agents with a more favorable toxicological profile or via mechanisms other than the above two mentioned is highly warranted. / The present project represents such an effort. Four in vitro experimental models were developed for the screening of new antihyperuricemic agents. The effects of the potential compounds from natural sources on the activities of phosphoribosyl pyrophosphate synthetase, hypoxanthine-guanine phosphoribosyl transferase and xanthine oxidase, as well as the uptake of urate through rat renal brush border membrane vesicles were investigated. Several compounds emerged with strong urate uptake inhibitory activities in which morin (3, 5, 7, 2', 4'-pentahydroxyflavone) was the most potent. Interestingly some of these compounds including morin were also demonstrated to be xanthine oxidase inhibitors. The subsequent in vivo experiment showed that morin indeed exhibited hypouricemic and uricosuric actions in an acute oxonate-induced hyperuricemic rat model. The uricosuric action of morin was hirther studied in transfected HEK293 cells expressing the human urate anion transporter 1 (hURATI) which is believed to regulate blood urate level by mediating urate reabsorption. In hURAT1-expressing HEK293 cells, urate uptake was significantly increased as compared to the non-transfected parental cells. Incorporation of morin into the uptake buffer could dose-dependently inhibit urate uptake in the transfected cells. Taken together our data indicated that morin is a potentially useful antihyperuricemic agent which acts by inhibiting xanthine oxidase and inhibiting urate reabsorption. In addition, the favorable safety profile of this natural compound makes it a potential candidate worthy of further investigations. / Yu Zhifeng. / "June 2006." / Advisers: Christopher H. K. Cheng; Wing Ping Fong. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1584. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 155-169). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

alpha-Glucosidase from yeast was used to screen for alpha-glucosidase inhibitory activities in Chinese herbal medicines. Seventy crude extracts were studied. The extracts of Semen Fagopyri Esculenti, Herba Euphorbiae Humifusae, Radix Polygoni Multiflori, Cortex Cinnamomi, Radix Paeoniae Rubra, and Radix Paeoniae Alba exhibited alpha-glucosidase inhibitory activities. These herbs have high potential for finding active compounds to develop into new antidiabetic drugs. / In this study, an assay technique involving brush border membrane vesicles was developed to screen for glucose uptake inhibitory actions in sixteen compounds from natural sources. Two compounds, namely naringenin and desoxyrhaponticin, were demonstrated to exhibit moderate inhibitory action on glucose uptake in rabbit intestinal brush border membrane vesicles, and showed very strong inhibitory action in rat everted intestinal sleeves. The kinetics study indicated that they behave as competitive inhibitors on glucose uptake. Moreover, they could reduce the level of the glucose uptake in the diabetic rat intestinal and renal membrane vesicles. In vivo study further demonstrated that desoxyrhaponticin could significantly reduce the glucose levels after a single oral administration of glucose in neonatal streptozotocin-induced diabetic rats, but not naringenin. These results suggest that naringenin and desoxyrhaponticin may be useful in the control of hyperglycemia. They act by inhibiting glucose uptake in the intestine and glucose reabsorption in the renal proximal tubules. / On the other hand, several synthetic compounds based on the structure of valienamine were found to show strong inhibition on intestinal alpha-glucosidases such as sucrase, glucoamylase and maltase. The strongest inhibitor was further studied. It could reduce the postprandial plasma glucose level of neonatal streptozotocin-induced diabetic rats. These results demonstrated that it has the potential to develop inter an oral antihyperglycemic agent. / The objective of this study is to improve the postprandial hyperglycemic conditions of diabetes by two approaches: (1) inhibiting the digestive enzymes (alpha-glucosidases), and (2) inhibiting active glucose transport in the small intestine. We have screened for new inhibitors of alpha-glucosidase and monosaccharide cotransporters from natural products and their derivatives. These compounds may be useful in the management of type 2 diabetes and diabetic complications. / Type 2 diabetes mellitus accounts for 90-95% of all diabetic cases and has become a major health concern over the world. There is increasing evidence that postprandial hyperglycemia, a hallmark of diabetes, plays a critical role in the development of type 2 diabetes and cardiovascular complications. Therefore the early identification of postprandial hyperglycemia and its effective control can offer the potential for early intervention and prevention of diabetic complications. / Li Jianmei. / "August 2006." / Adviser: Christopher H. K. Cheng. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1592. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 161-180). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 207-232).

Made available in DSpace on 2014-06-11T19:33:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-03-07Bitstream added on 2014-06-13T21:05:40Z : No. of bitstreams: 1 brighenti_fl_dr_araca.pdf: 927914 bytes, checksum: df4ad06d38d262a61b9312138e94b9a9 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Produtos naturais têm sido estudados com relação ao controle químico da microbiota patogênica do biofilme bucal. O objetivo desse estudo foi esclarecer o efeito do extrato da folha de Psidium cattleianum no metabolismo de S. mutans, no biofilme formado in situ e na capacidade em inibir a desmineralização do esmalte. O extrato foi obtido por decocção das folhas em água deionizada. O efeito do extrato foi avaliado in vitro com relação à viabilidade, expressão protéica e produção de ácido de biofilmes de S. mutans. No estudo in situ, blocos de esmalte bovino foram fixados em dispositivos acrílicos palatinos de dez voluntários. A fase experimental consistiu de três etapas de 14 dias cada, separadas por intervalo de sete dias. Os voluntários gotejaram solução de sacarose 20% (8x/dia) e a solução de tratamento (água, extrato ou um enxaguatório comercial; 2x/dia). O biofilme dentário foi analisado quanto à acidogenicidade, quantidade microorganismos e presença de polissacarídeos álcali-solúveis. Nos blocos de esmalte, foram realizadas as análises de microdureza superficial e em secção longitudinal. O extrato foi capaz de afetar a viabilidade, a produção de ácidos e a síntese protéica do biofilme formado in vitro. No biofilme formado in situ, o extrato foi capaz de diminuir a queda do pH, o acúmulo de microorganismos, a formação de polissacarídeos extracelulares e a desmineralização do esmalte. Conclui-se que o extrato foi capaz de diminuir a expressão de proteínas envolvidas no metabolismo bacteriano, a patogenicidade do biofilme bucal e a desmineralização do esmalte in situ. / Natural products have been studied with relation to chemical control of pathogenical microorganisms of dental biofilm. The aim of this study was to clarify the effect of Psidium cattleianum leaf extract on S. mutans metabolism, on in situ biofilms and on enamel demineralization. The extract was obtained by decoction in deionized water. The extract was studied in vitro with relation to viability, protein expression and acid production of S. mutans biofilms. On the in situ study, enamel bovine blocks were placed in palatal appliances of ten volunteers. The experimental phase consisted of three stages with a duration of 14 days each and a washout period of seven days. The volunteers dripped 20% sucrose (8x/day) and the treatment solution (water, extract or a marketed mouthwash – 2x/day) on the enamel blocks. The dental biofilm was analyzed regarding the amount of microorganisms and presence of alkalisoluble polysaccharides. On the enamel blocks, surface and cross-sectional microhardnessess were evaluated. The extract was able to affect the viability, acid production and protein synthesis of the in vitro biofilm. On the in situ biofilm, the extract was able to decrease pH drop, microorganism accumulation, extracellular polysaccharides formation and enamel demineralization. It can be concluded that the extract was able to reduce the expression of proteins involved on bacterial metabolism, the pathogenicity of dental biofilm and in situ enamel demineralization.