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Des microparticules d’héparine de bas poids moléculaire (HBPM) ont été fabriquées suivant la méthode de la double émulsion à partir d’un polymère non biodégradable polycationique (Eudragit® RS) utilisé seul ou en mélange à différents pourcentages avec un polymère biodégradable (acide poly(lactique-co-glycolique)). Deux HBPM aux rapports anti-Xa/anti-IIa différents ont été testées : la nadroparine (3,6) et la tinzaparine (1,8). Les microparticules d’HBPM favorisent i) l’encapsulation des chaines longues actives (ACL) d’héparine par rapport aux chaines courtes actives (BCL) (diminution du rapport anti-Xa/anti-IIa) ii) la libération in vitro des chaines BCL (augmentation du rapport anti-Xa/anti-IIa), les chaines ACL étant fortement retenues au sein des microparticules. Cependant, la proportion de chaine BCL libérées par rapport à celle d’ACL est dépendante (cas de la nadroparine) ou non (cas de la tinzaparine) de la composition polymérique. Cette différence de comportement s’explique principalement par la capacité de l’Eudragit® RS à retenir les chaines ACL de nadroparine. Suite à l’administration orale de microparticules de nadroparine chez le lapin, une absorption des chaines ACL et BCL a été mise en évidence avec certaines formulations : dans ce cas, des rapports anti-Xa/anti-IIa plasmatique similaires à ceux résultant de l’injection sous-cutanée ont été obtenus, témoignant ainsi du potentiel de ces microparticules à remplacer la forme commerciale injectable. Lors d’études de localisation par microscopie confocale, le site d’absorption intestinal n’a pas été identifié. En revanche, des études de passage sur un épithélium issu de la culture cellulaire (Caco-2) semblent démontrer, contrairement aux résultats in vivo, que seules les chaines BCL de nadroparine seraient absorbées. Cependant, le mécanisme responsable du passage cellulaire reste à identifier. / Microparticles of low molecular weight heparin (LMWH) were prepared according to the double emulsion and extraction method using a non biodegradable polycationic polymer (Eudragit® RS) alone or blended according to different ratios with a biodegradable polymer (poly(lactic-co-glycolic) acid). Two LMWH presenting different anti-Xa/anti-IIa ratios were tested: nadroparin (3.6) and tinzaparin (1.8). LMWH microparticles facilitate i) the encapsulation of heparin active long chains (ACL) compared to active short chains (BCL) (anti-Xa/anti-IIa ratio decreased) ii) the in vitro release of short chains (anti-Xa/anti-IIa ratio increased) whereas long chains are held inside the microparticles. Nevertheless, when compared to ACL chains, the relative amount of BCL chains released is dependent (case of nadroparine) or not (case of tinzaparin) on the polymeric composition. This difference can be mainly due to the properties of Eudragit® RS to hold ACL chains of nadroparin. After an oral administration in rabbits of nadroparin microparticles, some formulations exhibited absorption of ACL and BCL chains: in this case, plasmatic anti-Xa/anti-IIa ratios in the same range than those observed following the subcutaneous injection were obtained. Such a result shows the potential of microparticles to be a good substitute of the commercial injectable dosage form, if the oral absorption is confirmed in human. During gastro-intestinal studies by confocal microscopy, the absorption site was not identified. Nevertheless, contrary to in vivo results, permeation studies on a cell cultured epithelium (Caco-2) demonstrated that BCL heparin chains were absorbed whereas ACL chains were not. However, the mechanism responsible of the cell permeation is still to be identified.

The neuroprotective effects of AF4, a flavonoid-enriched extract derived from the peel of Northern Spy apples (containing quercetin-3-O-glucoside, quercetin-3-O-galactoside, quercetin-3-O-rhamnoside, quercetin-3-O-rutinoside, epicatechin, and cyanidin-3-O-galactoside) were examined by assessing neuronal loss and motor impairment resulting from hypoxic-ischemic (HI) brain injury in adult C57BL/6 mice. Relative to vehicle treatment (water, 10mL/kg/day), oral administration of AF4 (50 mg/kg/day) for 3 days reduces HI-induced neuronal loss in the striatum and hippocampus, motor impairments, and reduces the ability of LPS to stimulate the production of TNF-alpha in whole blood. Pretreatment with AF4 (1 ug/mL) decreased the death of mouse primary cortical neurons subjected to oxygen glucose deprivation (12 hours) in comparison to vehicle (DMSO) or the same concentration of quercetin or its metabolites. Taken together these findings indicate that AF4 reduces HI-induced brain injury and motor deficits by increasing the resistance of vulnerable neurons to ischemic cell death and decreasing the production of inflammatory cytokines.

bstract Cancer has been the first lethal factor in Taiwan, and hepatitis B is also a serious problem in our country. We have identified that the extracts of Taiwanese Schisandraceous plants, including Schizandra arisanensis, Kadsura matsudai and K. japonica, have inhibitory effect on type B hepatitis surface antigen (HBsAg) and e-antigen (HBeAg). Besides, we also find that the extracts of Echinops grijsii can inhibit the growth of human cancer cell line, KB and Hela. To purify active compounds by using column chromatography and high-performance liquid chromatography, we have furnished fifty-eight compounds from above Schisandraceous plants, including thirty-seven C18 lignans composed of [6.8.6]-dibenzocyclooctadiene skeleton, nine C19 homolignans, four triterpenes, three steroids and five cyclic-aromatic compounds. In the case of Echinops grijsii, we got thirteen major compounds containing eight thiophenes, four triterpenes, and a sterol. Structural elucidation of the novel homolignan and ten lignans are based on the spectral and chemical analyses, mainly by using two-dimensional nuclear magnetic resonance (NMR) of 1H and 13C nucleus. From the anti-HBsAg and anti-HBeAg assay, we found that four of new C18 lignans and one known (+)-gomisin K3 (33) lignan exhibited the significant inhibitory effects on surface antigen of hepatitis B virus. Moreover, to modify the known lignans, kadsurarin with different halogens and functional group having nitrogen atom, as well as (+)-gomisin K3 with several kinds of phenyl compounds and sulfur functional groups are processed. The preliminary structures and bioactivity relationships (SAR) studies demonstrated that (+)-gomisin K3 with sulfuric functional group could decrease cytotoxicity and increase inhibitory effect on surface antigen and e-antigen of hepatitis B virus. In the part of studying synthesis by using inactive 5¡¦-(but-3-en-1-ynyl)-2,2¡¦ -bithiophene (1) from Echinops grijsii, the yne-ene moiety of its structure was hydrolyzed into carbonyl group and then was attached a serious of various carbon number of hydroxy groups. Besides the above experiment, £\-trithienyl (1) was served as a substrate and made it into unsaturated carbonyl group, which then was linked with a series of hydroxy groups. Cytotoxicity datum showed that the derivatives of bi-thiophene have better anticancer activity than derivatives of tri-thiophene. And the assay results also exhibited that the bi-thiophene derivatives with hydroxy group with less than three carbon numbers have better inhibitory activity against cancer cells.

The neuroprotective effects of AF4, a flavonoid-enriched extract derived from the peel of Northern Spy apples (containing quercetin-3-O-glucoside, quercetin-3-O-galactoside, quercetin-3-O-rhamnoside, quercetin-3-O-rutinoside, epicatechin, and cyanidin-3-O-galactoside) were examined by assessing neuronal loss and motor impairment resulting from hypoxic-ischemic (HI) brain injury in adult C57BL/6 mice. Relative to vehicle treatment (water, 10mL/kg/day), oral administration of AF4 (50 mg/kg/day) for 3 days reduces HI-induced neuronal loss in the striatum and hippocampus, motor impairments, and reduces the ability of LPS to stimulate the production of TNF-alpha in whole blood. Pretreatment with AF4 (1 ug/mL) decreased the death of mouse primary cortical neurons subjected to oxygen glucose deprivation (12 hours) in comparison to vehicle (DMSO) or the same concentration of quercetin or its metabolites. Taken together these findings indicate that AF4 reduces HI-induced brain injury and motor deficits by increasing the resistance of vulnerable neurons to ischemic cell death and decreasing the production of inflammatory cytokines.

Thesis (M. Phil.)--University of Glasgow, 2004. / Electronic thesis available via Glasgow University DSpace service. Includes bibliographical references.

Thesis (M.A.) B.Y.U. Dept. of History. / Includes bibliographical references (leaves 155-160).

Thesis (M.S.)--Villanova University, 2007. / Chemistry Dept. Includes bibliographical references.

La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire le plus fréquent. Cette maladie s’accompagne d’une hyperplasie de la membrane synoviale qui entoure les articulations. La formation du pannus synovial est sous la dépendance de cytokines pro-inflammatoires et pro-angiogéniques. Les immunothérapies anti-TNF utilisées dans le traitement de la PR présentent des inconvénients (perte d’efficacité, risque infectieux), ce qui laisse la place pour le développement d’une stratégie vaccinale anti-TNF. Dans la première partie de mes travaux, nous avons développé des vaccins anti-VEGF afin d’étudier les liens entre angiogenèse et inflammation dans l’arthrite expérimentale au collagène (AEC). Dans la deuxième partie, nous avons développé un vaccin anti-TNF de souris afin d’évaluer les conséquences de la neutralisation du TNF-α par la vaccination dans des modèles infectieux. Le ciblage du VEGF avec un vaccin constitué de VEGF entier ou de peptides du VEGF couplés à la KLH, a permis une protection clinique et histologique dans l’AEC. Dans notre deuxième axe de recherche, nous avons développé un vaccin anti-TNF de souris (TNF-KLH). Ce vaccin est aussi efficace que l’etanercept dans l’AEC, mais n’augmente pas le risque infectieux dans un modèle d’infection à Mycobacterium tuberculosis. Dans le modèle d’infection à Listeria monocytogenes, TNF-KLH n’augmente pas la charge bactérienne et n’induit pas de mortalité, contrairement à l’etanercept. Mes travaux de thèse montrent que la stratégie vaccinale anti-cytokine est efficace dans l’arthrite, et que le ciblage du TNF par une telle stratégie ne semble pas altérer la réponse anti-infectieuse dans nos modèles. / Rheumatoid arthritis (RA) is the most frequent inflammatory rheumatism. This disease is accompanied by hyperplasia of the synovial membrane surrounding the joint. Pannus formation is controlled by pro-inflammatory and pro-angiogenic cytokines. Anti-TNF immunotherapies used in the treatment of RA presents many drawbacks (loss of efficacy, infections), which leaves some place for the development of an anti-TNF immunization strategy. In the first part of my work, we developed an anti-VEGF vaccine to study the links between angiogenesis and inflammation in collagen-induced arthritis (CIA) model. In the second part, we developed a mouse anti-TNF vaccine to assess the consequences of the neutralization of TNF-α by vaccination in infectious models. Inhibition of VEGF with a vaccine consisting of whole VEGF or VEGF peptide coupled to KLH, showed a clinical and histological protection in the CIA model. In the second part of my work, we developed a mouse anti-TNF vaccine (TNF-KLH). This vaccine is as effective as etanercept in CIA, but does not increase the risk of infection in Mycobacterium tuberculosis model. In Listeria monocytogenes model, unlike etanercept, immunization with TNF-KLH does not increase the bacterial burden and mortality. My work contributed to the development of active anti-VEGF vaccine and our results show a partial protection with this strategy. Also, we demonstrate that targeting TNF by active immunotherapy does not alter the immune response in our models of infections.

From introduction : "Inflammation per se, has been defined sufficiently to permit a rational approach to the search for drugs that modify this process, but satisfactory animal models for most rheumatoid diseases are not available". (Swingle 1974) In the search for new meaningful procedures for the detection and evaluation of anti-inflammatory drugs, the rabbit eye as a test system was studied.