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Biotech / Medical : Oxford GlycoSciences Plc -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (243)	11/8/2002 2:06:12 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 469

J Biol Chem 2002 Nov 4; [epub ahead of print] Pneumocystis carinii cell wall beta -glucan induces release of macrophage inflammatory protein-2 from alveolar epithelial cells via a lactosylceramide mediated mechanism. Hahn PY, Evans SE, Kottom TJ, Standing JE, Pagano RE, Limper AH. Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, MN 55905. Infiltration of the lungs with neutrophils promotes respiratory failure during severe Pneumocystis carinii (PC) pneumonia. Recent studies have shown that alveolar epithelial cells (AECs), in addition to promoting PC attachment, also participate in lung inflammation by the release of cytokines and chemokines. Herein, we demonstrate that a PC beta-glucan rich cell wall isolate (PCBG) stimulates the release of macrophage inflammatory protein-2 (MIP-2) from isolated AECs through a lactosylceramide dependent mechanism. The results demonstrate that MIP-2 mRNA and protein production is significantly increased at both early and late time points after PCBG challenge. Although CD11b/CD18 (Mac-1, CR3) is the most widely studied beta-glucan receptor, we demonstrate that CD11b/CD18 is not present on AECs. This study instead demonstrates that pre-incubation of AECs with an antibody directed against the membrane glycosphingolipid lactosylceramide (CDw17) results in a significant decrease in MIP-2 secretion. Preincubation of the anti-CDw17 antibody with solubilized lactosylceramide reverses this effect. Furthermore, incubation of AECs with inhibitors of glycosphingolipid biosynthesis, including N-butyldeoxynojirimycin (NB-DNJ) and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol-HCl (PDMP), also results in a significant decrease in AEC MIP-2 production following challenge with PCBG. These data demonstrate that PC beta-glucan induces significant production of MIP-2 from AECs and that CDw17 participates in the glucan-induced inflammatory signaling in lung epithelial cells during PC infection.

To: scaram(o)uche who wrote (243)	12/15/2002 2:10:26 PM
From: scaram(o)uche	Respond to of 469

here's a tad of insight re. the second generation candidate in phase I testing. I don't know what the difference might be (other than structural) between the deoxy molecule and OGT 923 (N-butylgalactonorjirimycin)........ Biochem Pharmacol 2000 Apr 1;59(7):821-9 Related Articles, Links N-butyldeoxygalactonojirimycin: a more selective inhibitor of glycosphingolipid biosynthesis than N-butyldeoxynojirimycin, in vitro and in vivo. Andersson U, Butters TD, Dwek RA, Platt FM. Glycobiology Institute, Department of Biochemistry, University of Oxford, UK. N-Butyldeoxynojirimycin (NB-DNJ) inhibits the ceramide glucosyltransferase which catalyses the first step in glycosphingolipid (GSL) biosynthesis. It has the potential to be used for the treatment of the GSL lysosomal storage diseases and is currently in clinical trials for the treatment of type 1 Gaucher's disease. However, NB-DNJ is also a potent inhibitor of other enzymes, including alpha-glucosidase I and II, which could potentially cause side effects in patients receiving life-long therapy. Wetherefore evaluated a potentially more selective GSL biosynthesis inhibitor, N-butyldeoxygalactonojirimycin (NB-DGJ), in vitro and in vivo. The distribution and degree of GSL depletion in the liver of mice treated with NB-DGJ or NB-DNJ were equivalent. Mice treated with NB-DGJ had normal body weights and lymphoid organ sizes, whereas NB-DNJ-treated mice showed weight loss and partial lymphoid organ shrinkage. NB-DNJ inhibited glycogen catabolism in the liver, whereas NB-DGJ did not. NB-DNJ was also a potent inhibitor of sucrase and maltase in vitro but not of lactase, while NB-DGJ inhibited lactase but not sucrase or maltase. NB-DGJ is therefore more selective than NB-DNJ, and deserves to be evaluated for human therapy.