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841.
Pierre Deprez Taoues Temal Hélène Jary Marielle Auberval Sarah Lively Denis Guédin Jean-Paul Vevert 《Bioorganic & medicinal chemistry letters》2013,23(8):2455-2459
Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50 = 20 nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range. 相似文献
842.
Jean-Paul Pirnay Alain Vanderkelen Daniel De Vos Jean-Pierre Draye Thomas Rose Carl Ceulemans Nadine Ectors Isabelle Huys Serge Jennes Gilbert Verbeken 《Cell and tissue banking》2013,14(4):525-560
The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime—i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States’ health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe’s risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States’ health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on “placing on the market of ATMPs,” which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation. 相似文献
843.
Thierry Simonart Chantale Degraef Patrick Stordeur Jean-Christophe Noel Roger Mosselmans Jean-Paul Van Vooren 《Free radical research》2013,47(3):221-235
Iron is suspected to be involved in the induction and/or progression of various human tumors. The present study was designed to investigate the effects of iron on endothelial cells, keeping in mind that the homeostasis of microvessels plays a critical role in neo-angiogenesis. Applying a model of human dermal microvascular endothelial cell terminal differentiation and death induced by serum deprivation, we found that iron salts (iron chloride and ferric nitrilotriacetate) provided a survival advantage to endothelial cells. Using immunohistochemistry and Western Blot analysis, we found that the extended cellular life span induced by iron was paralleled by an increase of Bcl-2 protein expression. Taken together, these observations suggest that iron may give a survival advantage to endothelial cells and represent a novel mechanism through which iron may contribute to tumorigenesis. 相似文献
844.
Structure based discovery of small molecule suppressors targeting bacterial lysozyme inhibitors 总被引:1,自引:0,他引:1
Voet A Callewaert L Ulens T Vanderkelen L Vanherreweghe JM Michiels CW De Maeyer M 《Biochemical and biophysical research communications》2011,(4):527-532
The production of lysozyme inhibitors, competitively binding to the lysozyme active site, is a bacterial strategy to prevent the lytic activity of host lysozymes. Therefore, suppression of the lysozyme–inhibitor interaction is an interesting new approach for drug development since restoration of the bacterial lysozyme sensitivity will support bacterial clearance from the infected sites. Using molecular modelling techniques the interaction of the Salmonella PliC inhibitor with c-type lysozyme was studied and a protein–protein interaction based pharmacophore model was created. This model was used as a query to identify molecules, with potential affinity for the target, and subsequently, these molecules were filtered using molecular docking. The retained molecules were validated as suppressors of lysozyme inhibitory proteins using in vitro experiments revealing four active molecules. 相似文献
845.
Decuypere JP Monaco G Bultynck G Missiaen L De Smedt H Parys JB 《Biochimica et biophysica acta》2011,1813(5):1003-1013
The amount of Ca(2+) taken up in the mitochondrial matrix is a crucial determinant of cell fate; it plays a decisive role in the choice of the cell between life and death. The Ca(2+) ions mainly originate from the inositol 1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) stores of the endoplasmic reticulum (ER). The uptake of these Ca(2+) ions in the mitochondria depends on the functional properties and the subcellular localization of the IP(3) receptor (IP(3)R) in discrete domains near the mitochondria. To allow for an efficient transfer of the Ca(2+) ions from the ER to the mitochondria, structural interactions between IP(3)Rs and mitochondria are needed. This review will focus on the key proteins involved in these interactions, how they are regulated, and what are their physiological roles in apoptosis, necrosis and autophagy. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. 相似文献
846.
Sylla B Guégan JP Wieruszeski JM Nugier-Chauvin C Legentil L Daniellou R Ferrières V 《Carbohydrate research》2011,346(12):1490-1494
A full characterization of the high-resolution NMR spectrum of the laminarihexaose is described and used for the determination of the binding epitope of the more complex but structurally related laminarin. These biophysical data extend the current knowledge of β-glucans/Dectin-1 interactions and suggest different biological mechanisms in close relation with the size of the saccharidic chain. 相似文献
847.
Balla Sylla Jean-Paul Guégan Jean-Michel Wieruszeski Caroline Nugier-Chauvin Laurent Legentil Richard Daniellou Vincent Ferrières 《Carbohydrate research》2011,(12):1490
A full characterization of the high-resolution NMR spectrum of the laminarihexaose is described and used for the determination of the binding epitope of the more complex but structurally related laminarin. These biophysical data extend the current knowledge of β-glucans/Dectin-1 interactions and suggest different biological mechanisms in close relation with the size of the saccharidic chain. 相似文献
848.
849.
This paper presents fossil faecal pellets - also named coprolites or frass - attributed to termites, which were found in amber and lignitic clay from the Wealden (Hauterivian-Barremian?), Late Albian and Early Cenomanian of south-western France. These coprolites have a characteristic subcylindrical shape and hexagonal transverse section and are assignable to Microcarpolithes hexagonalis Vangerow. The termite families that possibly produced these coprolites are discussed. The noticeable lack of termite attacks on the fossil wood associated with amber and lignitic clay is taphonomically analyzed in relation with the palaeoflora and palaeoclimate of these amber forests. The different medium where coprolites were found (amber, wood, sediments) suggests that primitive Cretaceous termites had already developed various biologies, such as wood or cryptic foraging, but probably not yet soil-feeding. 相似文献
850.
Fish oil diets alter the phospholipid balance, fatty acid composition, and steroid hormone concentrations in testes of adult pigs 总被引:2,自引:0,他引:2
The objective was to determine the effect of long-term dietary supplementation of two types of fish oil on lipid composition and steroidogenesis in adult pig testis. Twenty-four Duroc boars, aged 204.5 ± 9.4 d (body weight 128.1 ± 16.7 kg) received daily 2.5 kg of an iso-caloric basal diet supplemented with: 1) 62 g of hydrogenated animal fat (AF); 2) 60 g of menhaden oil (MO) containing 16% of eicosapentaenoic acid (EPA) and 18% of docosahexaenoic acid (DHA); or 3) 60 g of tuna oil (TO) containing 7% of EPA and 33% of DHA. After these diets were consumed for 7 mo, testicular hormones, phospholipid content, and fatty acid composition of individual phospholipids in testis were determined. Body and reproductive organ weights were not significantly affected by dietary treatments. Testicular tissue from boars fed a TO diet, followed by those receiving MO and AF diets, had the lowest level of phosphatidylethanolamine (TO < MO < AF; P < 0.01) but the highest sphingomyelin (TO > MO > AF; P < 0.01). For each phospholipid, boars fed either the MO or TO diet had increased total omega-3 fatty acids, particularly DHA (P < 0.01), by reciprocal replacement of total omega-6 fatty acids (20:4n-6, 22:5n-6). The MO diet increased EPA more than the other diets. Testicular concentrations of testosterone and estradiol were lower in boars fed a TO diet than a MO diet (P < 0.02). In conclusion, long-term dietary supplementation of fish oil, regardless of the EPA/DHA ratio, modified the fatty acid compositions in testis and affected steroid production of healthy adult boars, which may represent a promising models for future studies on fertility. 相似文献