Over the past decades, numerous studies shown curcumin, a dietary compound derived from turmeric, has a variety of health-promoting actions, such as anti-oxidant, anti-microbial, anti-inflammatory, and anti-cancer effects, making curcumin the most promising dietary compound for disease prevention. However, the underlying mechanisms by which curcumin has these health-promoting effects are not well understood. A better understanding of the molecular mechanism of curcumin could help to develop novel strategies to reduce the risks of some human diseases. Protein thiols play important roles in cell signaling, and recent studies showed that curcumin could covalently react with protein thiols, supporting that curcumin-protein interactions could contribute to the health-promoting effects of curcumin. However, the curcumin-protein interactions are under-studied. Notably, it remains unknown whether oral intake of curcumin could covalently interact with protein in vivo. In this project, we synthesized a click chemistry probe of curcumin (Di-Cur), and used this probe to characterize curcumin-protein interactions both in vitro and in vivo using a click chemistry-based imaging approach. Our results demonstrate that orally administrated curcumin could form curcumin-protein adducts in specific tissues of the mice, which may contribute to the potent biological effects and poor pharmacokinetics of curcumin.

Les nerfs périphériques sont sujets à de nombreuses pathologies et l’étiologie des neuropathies périphériques (NP) est vaste (troubles métaboliques, infections, toxines, blessures physiques et mutations génétiques, ect.). Par exemple, les NP d’origine traumatique sont courantes et sont caractérisées par une dégénérescence dite Wallérienne des fibres nerveuses. Autre exemple, la maladie de Charcot-Marie-Tooth 1A (CMT1A) qui est la NP génétique héréditaire la plus fréquente. Elle est caractérisée par une surexpression de la protéine PMP22 impliquée dans le maintien de la gaine de myéline. Actuellement, il n’existe pas de traitement pharmacologique de ces deux affections des nerfs. Récemment, l’intérêt pour le rôle des antioxydants alimentaires, tels que la curcumine, a suscité de nombreuses recherches. Cette molécule est depuis longtemps utilisée en médecine asiatique pour ces propriétés thérapeutiques. Cependant, elle possède une très faible biodisponibilité et nécessite donc l’emploi de doses très élevées pour obtenir des effets bénéfiques. Dans une première étude, nos résultats ont montré que des faibles doses de curcumine administrées localement et en continu, améliorent la récupération fonctionnelle, les paramètres électrophysiologiques et histologiques, et l’expression des principales protéines de la myéline dans un modèle d’écrasement du nerf sciatique chez le rat. Ces effets bénéfiques ont été attribués aux propriétés antioxydantes de la curcumine. Dans une seconde étude, nos résultats ont montré qu’une faible dose de nanocristaux de curcumine (Nano-Cur), injectée en IP, améliorent le phénotype, les paramètres électrophysiologiques et histologiques dans un modèle transgénique de rat CMT1A. Dans cette étude, les effets positifs ont été attribués aux propriétés antioxydantes des Nano-Cur, couplés à l’activation de la voie de dégradation associée au réticulum endoplasmique, permettant la réduction de la surexpression nocive de PMP22 chez les rats CMT1A. L'ensemble de ces résultats démontrent que, l’administration de faibles doses de curcumine constitue un traitement prometteur dans la réparation des nerfs périphériques. / Peripheral nerves are subject to many pathologies and the etiology of peripheral neuropathies (PN) is vast (metabolic disorders, infections, toxins, physical injuries and genetic mutations, etc.). For example, PN of traumatic origin are common and are characterized by a called Wallerian degeneration of nerve fibres. Another example is Charcot-Marie-Tooth disease 1A (CMT1A), which is the most common hereditary genetic PN. It is characterized by an overexpression of the PMP22 protein involved in maintaining the myelin sheath. Currently, there is no pharmacological treatment for these two nerve disorders. Recently, interest in the role of dietary antioxidants, such as curcumin, has led to much research. This molecule has long been used in Asian medicine for its therapeutic properties. However, it has a very low bioavailability and therefore requires the use of very high doses to obtain beneficial effects. In a first study, our results showed that low doses of curcumin administered locally and continuously improve functional recovery, electrophysiological and histological parameters, and expression of major myelin proteins in a rat sciatic nerve crush model. These beneficial effects have been attributed to the antioxidant properties of curcumin. In a second study, our results showed that a low dose of curcumin nanocrystals (Nano-Cur), injected in IP, improves phenotype, electrophysiological and histological parameters in a transgenic model of CMT1A rats. In this study, the positive effects were attributed to the antioxidant properties of the Nano-cur, coupled with the activation of the endoplasmic reticulum associated degradation pathway, allowing the reduction of harmful overexpression of PMP22 in CMT1A rats. All these results show that the administration of low doses of curcumin is a promising treatment for peripheral nerve repair

É possível encontrar uma ciência, nos moldes da ciência cartesiana, na filosofia de Blaise Pascal? Buscaremos no texto apresentar algumas razões pelas quais seja inviável, na filosofia de Pascal, um conhecimento tal como imaginado por Descartes. A primeira destas razões é que, ao contrário de Pascal, a possibilidade de uma ciência em Descartes repousa sobre ideia de que entre os três entes da metafísica Deus, o homem e o mundo há uma comunicabilidade. Por esta razão, para o cogito é possível conhecer a Deus, pela ideia de infinito, e o mundo, através da Mathesis Universalis. Pascal não compartilha desta ideia, pois entre Deus, o homem, e o mundo, segundo o filósofo, há uma distância intransponível. A discussão das três ordens que traremos no texto nos revelará o quanto a ordem do espírito é heterogênea à ordem dos corpos. A impossibilidade de conhecermos a ordem dos corpos (física) unicamente através da razão lança-nos a reconhecer uma dimensão fundamental em nosso texto: a ideia de incerteza. A incerteza aparece no pensamento de Pascal na medida em que reconhecemos, através da crítica ao cartesianismo, o quão distantes estamos de qualquer fundamentação para o conhecimento. Sem fundamentos sólidos para o conhecimento, Pascal nos propõe as Regras dos Partidos e sua maneira de fazer física, partindo da experiência, como saídas racionais para o impasse que nos coloca a realidade da incerteza. / Est-ce qu´on peut trouver une science, similaire à la cartésienne, chez Pascal? Nous essaierons de présenter dans la suitequelques raisons pour lesquelles la conception de connaissance imaginée par Descartes n\'est pas possible dans la philosophie de Pascal. La première de ces raisons est que, contrairement à Pascal, la possibilité d\'une science chez Descartes repose sur l\'idée qu´ il y a une communicabilité entre les trois entités de la métaphysique - Dieu, l\'homme et le monde. Pour cette raison, pour le cogito il est possible de connaître Dieu, à travers l\'idée de l\'infini, et le monde, à travers la Mathesis Universalis. Pascal n´est pas d´accord avec cette idée, parce qu´il pense qu´entre Dieu, l´homme et le monde il y a une distance indépassable. La discussion des trois ordres que nous apporterons dans le texte révèlera comment l\'ordre des esprits et l\'ordre des corps sont hétérogènes. L\'impossibilité de connaître l\'ordre des corps (physique) uniquement à traversla raison, nous propose dede reconnaître une dimension fondamentale pour notre texte: l\'idée d\'incertitude. L\'incertitude apparaît dans la pensée de Pascal dès que nous reconnaissons, à travers la critique du cartésianisme, combien nous sommes éloignés de n´importe quelle fondation de la connaissance. Sans bases solides pour la connaissance, Pascal nous offre les règles des partis et sa façon de faire la physique, en partant de l\'expérience, comme des solutions rationnelles pour l´impasse que nous impose la réalité de l\'incertitude

Although the interpretation of Anselm's Cur Deus Homo in the tradition of Albrecht Ritschl, Adolf von Harnack and Gustaf Aulen has led to a suspicion about its usefulness for a Peace Theology, a reading through the lens of more recent scholarship, which assumes its original Catholic, sacramental and sacrificial framework, reveals a beautiful understanding of the cross in this medieval classic that is perfectly compatible with a commitment to nonviolence. Three Mennonite scholars writing in pursuit of an Anabaptist Peace Theology, John Howard Yoder, John Driver and J. Denny Weaver display varying degrees of dissatisfaction with the explanation that Anselm provided in Cur Deus Homo, and none held out many prospects for its usefulness. Yoder highlighted the weaknesses, Driver essentially repeated them, and Weaver went a step further to charge that Cur Deus Homo depicted divinely sanctioned violence and ought to be rejected. They did not demonstrate much awareness of or reliance on the contributions of scholars who have focused on Anselm's theology and context. Reading Cur Deus Homo through the lens of more recent anselmian scholarship reveals that the honour and justice of God are one with the mercy and love of God. Humanity is restored not through punishment, but through the means of satisfaction and reward, while the whole explanation is seen in a sacrificial framework. Anselm's insistence upon human participation, and on satisfaction are very congenial to certain emphases of a Peace Theology, namely, discipleship and restorative justice. The real death understood metaphorically as a sacrifice does not violate the commitment to nonviolence, but strengthens it. A rejection of Anselm's metaphysic, ontology and sacrificial framework, a failure to distinguish between punishment and satisfaction, a failure to reflect from the perspective of the guilty, and a neglect of or ambivalence about the doctrines of the two natures and the trinity all lead to a distorted impression of Cur Deus Homo, concealing the contribution Cur Deus Homo might make to a Peace Theology.

No description available.

Made available in DSpace on 2014-07-29T15:29:09Z (GMT). No. of bitstreams: 1 Dissertacao Monica Canedo.pdf: 1399065 bytes, checksum: d8dbbf45d1c8e0d832e311c7d2c9c8f7 (MD5) Previous issue date: 2011-03-02 / Background: Actually the Chlamydia trachomatis is responsible for the major number of cases of sexual transmitted bacterial infections. The likelihood of tubal damage in infertile women is associated to the evidence of chlamydia infection. Objectives: To evaluate the ability of indirect immunofluorescence for Chlamydia trachomatis on tubal occlusion and to establish the cutoff point (best sensitivity and specificity) of antibodies IgG titres (indirect immunofluorescence) to detect tubal occlusion (ROC curve). Methodology: This is a retrospective study with 204 electronic records of patients attended at a university and private infertility center in the city of Goiania, in the period of 2006 to 2009. Patients had 17 to 47 years old. To evaluate the risk of tubal occlusion the patients were divided into two groups: patients exposed to chlamydia (significant IFI &#8805; 1:16) e unexposed (no significant IFI < 1:16). It was verified patients who had the disease (tubal occlusion) and not sick (without tubal occlusion) in the hysterosalpingography. For the calculations the Chi-square (&#967;2) were used, corrected to small samples (Fisher Exact Test) when necessary. The p chosen level was 0.05. The ROC curve was calculated with BioEstat® software, using the standard methodology. This study was submitted and approved by Ethics Committee of Hospital Clinics of the Federal University of Goias.Results: Of the 72 patients with significant titres, 34 (47,2%) showed the occurrence of tubal occlusion. In relation the 132 patients with no significant titres, only 18 (13,7%) had tubal occlusion (p < 0,001). We also observed a progressive increase in the levels of antibodies and the likelihood of tubal occlusion (p < 0,001). The best cutoff point of the ROC curve with the titre was 1:64. However, we believe that we can continue using a cutoff titre to &#8805; 1:16 by interfering little in sensitivity and specificity and because it is currently used in the Clinical Laboratory of Hospital Clinics. Conclusions: The results indicate that serology for Chlamydia trachomatis (indirect immunofluorescence) is valid for screening of tubal damage. We also showed that the best cutoff (ROC) indirect immunofluorescence to detect tubal occlusion is 1:64, but between 1:16 and 1:64 there is a slight change in sensitivity and specificity. / Introdução: Atualmente, a Chlamydia trachomatis é responsável pelo maior número de casos de infecções bacterianas sexualmente transmissíveis. A probabilidade de lesão tubária em mulheres inférteis é relacionada com evidência de infeccção passada por clamídia. Objetivos: Avaliar a capacidade da imunofluorescência indireta para Chlamydia trachomatis em rastrear obstrução tubária e estabelecer o ponto de corte (melhor sensibilidade e especificidade) de títulos de anticorpos IgG imunofluorescência indireta) para detectar obstrução tubária (curva ROC). Métodos: Este é um estudo retrospectivo com 204 prontuários eletrônicos de pacientes atendidas em um centro universitário e particular de infertilidade na cidade de Goiânia, no período de 2006 a 2009, com faixa etária entre 17 e 47 anos. Para avaliar o risco de obstrução tubária as pacientes foram divididas em dois grupos: pacientes expostas à clamídia (IFI significativa &#8805; 1:16) e não expostas (IFI não significativa < 1:16). Verificou-se então, as pacientes que tiveram a doença (obstrução tubária) e não doentes (sem obstrução tubária) na histerossalpingografia. Para os cálculos foi utilizado o teste Qui-quadrado (&#967;2), corrigido para pequenas amostras (teste Exato de Fisher) quando necessário. O nível de p escolhido foi 0,05. A curva ROC foi calculada com o programa BioEstat® utilizando a metodologia usual. Este estudo foi submetido e aprovado pelo Comitê de Ética do Hospital das Clínicas da Universidade Federal de Goiás. Resultados: Das 72 pacientes com titulação significativa, 34 (47,2%) apresentaram a ocorrência de obstrução tubária. Em relação as 132 pacientes com titulação não significativa, somente 18 (13,7%) apresentaram obstrução tubária (p < 0,001). Foi observado também um aumento progressivo entre os níveis de anticorpos e a probabilidade de obstrução tubária (p < 0,001). O melhor ponto de corte na curva ROC foi com a titulação de 1:64. Porém, consideramos que pode-se continuar utilizando como ponto de corte a titulação &#8805; 1:16, por interferir pouco na sensibilidade e especificidade e por ser a atualmente utilizada no Laboratório Clínico do Hospital das Clínicas. Conclusões: Os resultados deste estudo revelaram que a sorologia para Chlamydia trachomatis (imunofluorescência indireta) é válida para rastreamento de lesão tubária. Verificamos ainda que o melhor ponto de corte (curva ROC) da imunofluorescência indireta em detectar obstrução tubária é 1:64, mas, entre 1:16 e 1:64 há uma discreta mudança na sensibilidade e especificidade do teste.

科学研究費補助金 研究種目:基盤研究(A)(2) 課題番号:11306009 研究代表者:大澤 俊彦 研究期間:1999-2000年度

No description available.