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  • The American Association of Immunologists (AAI)  (1)
  • The American Society for Pharmacology and Experimental Therapeutics (ASPET)  (1)
  • 1
    Publication Date: 2018-10-23
    Description: Genome-wide association studies have recently illuminated that WDFY4 is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of WDFY4 in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated Wdfy4 B lymphocyte conditional knockout ( Wdfy4 -CKO) mice and found that loss of Wdfy4 led to a decrease in number of total B cells and several subpopulations of B cells in the periphery and a defect in the transition from the pro– to pre–B cell stage in bone marrow. Also, Wdfy4 -CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in Wdfy4 -CKO mice, with significantly diminished pristane-elicited production of autoantibodies and glomerulonephritis. Genetic silencing of WDFY4 in B cells increased lipidation of LC3 independent of p62 and Beclin1, which are essential proteins of canonical autophagy. Our in vivo and in vitro data suggest that WDFY4 facilitates noncanonical autophagic activity. Our findings provide a novel functional link underlying the mechanism of SLE in which WDFY4 influences B cell fate via noncanonical autophagy.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 2
    Publication Date: 2018-08-07
    Description: UDP-glucuronosyltransferase 2B7 (UGT2B7) is one of the most significant isoforms of UGTs in human liver. This research measured UGT2B7 protein content and activities, including maximum velocity (V max ) and intrinsic clearance (CL int ), in human liver at isoform, microsomal, liver tissue, and liver levels and identified the factors that influence expression. We determined absolute protein content by liquid chromatography–tandem mass spectroscopy and activities using the probe drug zidovudine in 82 normal human liver microsomes. Using a bottom-up method for derivation, we showed UGT2B7 content at the microsomal, liver tissue, and liver levels, as well as activities at the isoform, microsomal, liver tissue, and liver levels in vitro, and predicted hepatic clearance in vivo, with median, range, variation, and 95% and 50% prediction intervals. With regard to the intrinsic activities, the maximum velocity (V max ) had a median (range) of 7.5 (2–24) pmol/min per picomole of 2B7, and the CL int was 0.08 (0.02–0.31) μ l/min per picomole of 2B7. Determinations at liver level showed larger variations than at microsomal level, so it was more suitable for evaluating individual differences. By analyzing factors that affect UGT2B7, we found that: 1) The content at the liver tissue and liver levels correlated positively with activities; 2) the mutant heterozygotes of -327G〉A , -900A〉G , -161C〉T may lead to decreased protein content and increased intrinsic CL int ; and 3) the transcription factor pregnane X receptor mRNA expression level was positively associated with the measured protein content. In all, we showed that protein content and activities at different levels and the factors that influence content provide valuable information for UGT2B7 research and clinically individualized medication.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
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