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Jeffrey K Actor - One of the best experts on this subject based on the ideXlab platform.
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mycobacterial trehalose 6 6 dimycolate induced m1 type inflammation
American Journal of Pathology, 2020Co-Authors: Thao K T Nguyen, Shenan Hwang, John Daigle, Luis Chinea, Zainab Niaz, Robert L Hunter, Jeffrey K ActorAbstract:Murine models of Mycobacterium tuberculosis (Mtb) infection demonstrate progression of M1-like (proinflammatory) and M2-like (anti-inflammatory) macrophage morphology following primary granuloma formation. The Mtb cell wall cording factor, trehalose 6,6'-dimycolate (TDM), is a physiologically relevant and useful molecule for modeling early macrophage-mediated events during establishment of the tuberculosis-induced granuloma pathogenesis. Here, it is shown that TDM is a major driver of the early M1-like macrophage response as seen during initiation of the granulomas of primary pathology. Proinflammatory cytokines tumor necrosis factor-α, IL-1β, IL-6, and IL-12p40 are produced in lung tissue after administration of TDM to mice. Furthermore, CD11b+CD45+ macrophages with a high surface expression of the M1-like markers CD38 and CD86 were found present in regions of pathology in lungs of mice at 7 days post-TDM introduction. Conversely, only low phenotypic marker expression of M2-like markers CD206 and EGR-2 were present on macrophages. These findings suggest that TDM plays a role in establishment of the M1-like shift in the microenvironment during primary tuberculosis.
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trehalose 6 6 dimycolate a coat to regulate tuberculosis immunopathogenesis
Tuberculosis, 2013Co-Authors: Kerry J Welsh, Robert L Hunter, Jeffrey K ActorAbstract:Tuberculosis (TB) remains a significant public health burden worldwide. Treatment of this disease requires a minimum of six months and there is no vaccine available for the most common form of the disease. Increasing evidence suggests that the mycobacterial glycolipid trehalose 6,6' dimycolate (TDM; cord factor) plays a key role in the pathogenesis of TB disease. TDM protects the TB bacilli from macrophage-mediated killing, inhibits effective antigen presentation, and reduces the formation of protective T-cell responses. TDM promotes initiation of granuloma formation and likely plays a role in caseation. Furthermore, TDM may contribute to the development of post primary disease. Receptors for TDM were recently described and are expected to contribute to our knowledge of the molecular pathogenesis of TB disease. In this manner, understanding TDM may prove promising towards development of targeted TB therapeutics to limit clinical pathologies.
Pierre Vogel - One of the best experts on this subject based on the ideXlab platform.
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total asymmetric synthesis of castanospermine 6 deoxycastanospermine and 6 deoxy 6 fluorocastanospermine
Journal of Organic Chemistry, 1991Co-Authors: Jeanlouis Reymond, Alan A Pinkerton, Pierre VogelAbstract:Bromination of the dibenzyl acetal of (-)-(1S,4S)-7-oxabicyclo[2.2.1]hept-5-en-2-one ((-)-5) led to (+)-(1S,5S,6S,7S)-6-endo-(benzyloxy)-5-exo-bromo-7-oxabicyclo[2.2.1]hept an-2-one (25). Baeyer-Villiger oxidation of 25 gave 2-O-benzyl-3-bromo-3,5-dideoxy-beta-L-arabino-hexofuranosidurono-6,1-lac tone (26). Methanolysis of 26 afforded the corresponding methyl (methyl alpha-beta-L-arabinofuranosid)uronates (27 + 28). The alpha anomer 27 was reduced with DIBAH into methyl 2-O-benzyl-3-bromo-3,5-dideoxy-beta-L-arabino-hexofuranoside (29). Mesylation of the primary alcohol, followed by treatment with NH3 gave methyl 2-O-benzyl-3,5-6-trideoxy-3,6-imino-beta-L-lyxo-hexofuranoside (32). Acetylation of the amine with ClCH2COCl, acetolysis of the methyl furanoside followed by Arbuzov condensation with (EtO)3P, and then intramolecular Horner-Emmons reaction led to (5S,6S,7S)-7-hydroxy-5-(benzyloxy)-1-azabicyclo[4.3.0]non-3-en-2-one (37). Base-catalyzed hydrolysis of the corresponding epoxide 43 ((1S,6S,7S,8R,8aS)-8-(benzyloxy)-6,7-epoxy-1-hydroxyoctahydroindolizidin -5-one) followed by reduction of the lactam and deprotection of the alcoholic functions afforded (+)-castanospermine ((+)-1). The conversion of (-)-5 into (+)-1 was highly stereoselective, requiring the isolation of 10 synthetic intermediates and with an overall yield of 15.2%. Reduction of 43 with BH3.Me2S or its treatment with HF.Et3N allowed one to prepare readily (+)-6-deoxycastanospermine ((+)-2 and 6-deoxy-6-fluorocastanospermine ((+)-3). The crystal structure of (+)-3 is also reported.
Tomoya Kitazume - One of the best experts on this subject based on the ideXlab platform.
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preparation of 6 deoxy 6 6 6 trifluoro d mannose and d allose from enzymatically resolved 2 butenolides
Tetrahedron-asymmetry, 1993Co-Authors: Takashi Yamazaki, Kenji Mizutani, Tomoya KitazumeAbstract:Abstract Both 6-deoxy-6,6,6-trifluoro- d -mannose and d -allose, possessing a diastereomeric relationship, were conveniently prepared from trifluorinated 2-butenolides which was prepared via the enzymatic resolution with high efficiency.
Christoph Garbers - One of the best experts on this subject based on the ideXlab platform.
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minimal interleukin 6 il 6 receptor stalk composition for il 6 receptor shedding and il 6 classic signaling
Journal of Biological Chemistry, 2013Co-Authors: Paul Baran, Jurgen Scheller, Rebecca Nitz, Joachim Grotzinger, Christoph GarbersAbstract:Abstract Signaling of the pleiotropic cytokine Interleukin-6 (IL-6) is coordinated by membrane-bound and soluble forms of the IL-6 receptor (IL-6R) in processes called classic and trans-signaling, respectively. The soluble IL-6R is mainly generated by ADAM10- and ADAM17-mediated ectodomain shedding. Little is known about the role of the 52-amino acid-residue-long IL-6R stalk region in shedding and signal transduction. Therefore, we generated and analyzed IL-6R stalk region deletion variants for cleavability and biological activity. Deletion of 10 amino acids of the stalk region surrounding the ADAM17 cleavage site substantially blocked IL-6R proteolysis by ADAM17 but only slightly affected proteolysis by ADAM10. Interestingly, additional deletion of the remaining five juxtamembrane-located amino acids also abrogated ADAM10-mediated IL-6R shedding. Larger deletions within the stalk region, that do not necessarily include the ADAM17 cleavage site, also reduced ADAM10 and ADAM17-mediated IL-6R shedding, questioning the importance of cleavage site recognition. Furthermore, we show that a 22-amino acid-long stalk region is minimally required for IL-6 classic signaling. The gp130 cytokine binding sites are separated from the plasma membrane by ∼96 A. 22 amino acid residues, however, span maximally 83.6 A (3.8 A/amino acid), indicating that the three juxtamembrane fibronectin domains of gp130 are not necessarily elongated but somehow flexed to allow IL-6 classic signaling. Our findings underline a dual role of the IL-6R stalk region in IL-6 signaling. In IL-6 trans-signaling, it regulates proper proteolysis by ADAM10 and ADAM17. In IL-6 classic-signaling, it acts as a spacer to ensure IL-6·IL-6R·gp130 signal complex formation.
Colin M Hayman - One of the best experts on this subject based on the ideXlab platform.
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a stereoselective synthesis of 6 6 6 trifluoro l daunosamine and 6 6 6 trifluoro l acosamine
Organic and Biomolecular Chemistry, 2006Co-Authors: Colin M Hayman, David S Larsen, Jim Simpson, Karl B Bailey, Gurmit S GillAbstract:A short synthesis of 6,6,6-trifluoro-L-acosamine 15 and 6,6,6-trifluoro-L-daunosamine 19 has been accomplished. The pyranose ring system of these carbohydrate analogues was formed by a hetero-Diels–Alder reaction of vinylogous imide 11 and ethyl vinyl ether which gave adduct 12a in 40% yield. Hydroboration gave 13 and subsequent hydrogenolytic removal of the (R)-2-phenylethyl chiral auxiliary gave ethyl 6,6,6-trifluoro-L-acosaminide 14. Acid hydrolysis furnished target 15. Glycoside 13 was N-trifluoroacetylated to give 16, the structure was confirmed by single crystal X-ray diffraction. The C-4 stereochemistry of 16 was inverted by Swern oxidation of the 4-OH group, and subsequent borohydride reduction to give 17. Hydrogenolytic removal of the auxiliary gave ethyl-6,6,6-trifluoro-L-daunosaminide 18. Acid hydrolysis provided 19.
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a stereoselective synthesis of 2 6 dideoxy 6 6 6 trifluoro arabino hexoses via an asymmetric diels alder strategy
Australian Journal of Chemistry, 1999Co-Authors: Colin M Hayman, David S Larsen, Lyall R Hanton, Jenness M GuthrieAbstract:The enantioselective syntheses of each enantiomer of ethyl 2,6-dideoxy-6,6,6-trifluoro-β-arabino-hexopyranoside (3) and of 2,6-dideoxy-6,6,6-trifluoro-arabino-hexose (4) are described. The key step in the approach is the inverse electron demand Lewis acid catalysed Diels–Alder reaction of the heterodiene (E)-1,1,1-trifluoro-4-[(1R)-1- phenylethoxy]but-3-en-2-one (5) and either ethyl vinyl ether (7a) or benzyl vinyl ether (7b). The titanium(IV) chloride catalysed cycloadditions at low temperature displayed high endo-selectivity and modest diastereofacial selectivity. Hydroboration of the mixture of the cis-cycloadducts (8a) afforded the separable diastereoisomers (9a) and (10a). Hydrogenolysis of (9a) gave ethyl 2,6-dideoxy-6,6,6-trifluoro-β-L-arabino-hexopyranoside (+)-(3), and of (10a) gave the corresponding D-glycoside (−)-(3). Similarly, hydroboration of the cis-cycloadducts (8b) gave the protected benzyl glycosides (9b) and (10b). Hydrogenolysis of each gave 2,6-dideoxy-6,6,6-trifluoro-L-arabino-hexopyranose (−)-(4) and the corresponding D-sugar (+)-(4) respectively. The absolute configurations of fluorinated carbohydrates (+)- and (−)-(3) were determined by comparison of their molar rotations with those of the parent glycosides. These assignments were confirmed by an X-ray crystallographic structure determination of the glycoside (9a).
