8 research outputs found
Regulation of the severity of neuroinflammation and demyelination by TLRâASK1âp38 pathway
Convergent Functional Genomics of Oligodendrocyte Differentiation Identifies Multiple Autoinhibitory Signaling Circuitsâż â
Inadequate remyelination of brain white matter lesions has been associated with a failure of oligodendrocyte precursors to differentiate into mature, myelin-producing cells. In order to better understand which genes play a critical role in oligodendrocyte differentiation, we performed time-dependent, genome-wide gene expression studies of mouse Oli-neu cells as they differentiate into process-forming and myelin basic protein-producing cells, following treatment with three different agents. Our data indicate that different inducers activate distinct pathways that ultimately converge into the completely differentiated state, where regulated gene sets overlap maximally. In order to also gain insight into the functional role of genes that are regulated in this process, we silenced 88 of these genes using small interfering RNA and identified multiple repressors of spontaneous differentiation of Oli-neu, most of which were confirmed in rat primary oligodendrocyte precursors cells. Among these repressors were CNP, a well-known myelin constituent, and three phosphatases, each known to negatively control mitogen-activated protein kinase cascades. We show that a novel inhibitor for one of the identified genes, dual-specificity phosphatase DUSP10/MKP5, was also capable of inducing oligodendrocyte differentiation in primary oligodendrocyte precursors. Oligodendrocytic differentiation feedback loops may therefore yield pharmacological targets to treat disease related to dysfunctional myelin deposition
Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies
Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects
Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br /
GLEPP1/Protein-tyrosine Phosphatase Ï Inhibitors Block Chemotaxis in Vitro and in Vivo and Improve Murine Ulcerative ColitisSâ
We describe novel, cell-permeable, and bioavailable salicylic acid
derivatives that are potent and selective inhibitors of
GLEPP1/protein-tyrosine phosphatase Ï. Two previously described GLEPP1
substrates, paxillin and Syk, are both required for cytoskeletal rearrangement
and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1
inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and
block primary human monocyte and mouse bone marrow-derived macrophage
chemotaxis in a gradient of monocyte chemotactic protein-1. In mice, the
GLEPP1 inhibitors also reduce thioglycolate-induced peritoneal chemotaxis of
neutrophils, lymphocytes, and macrophages. In murine disease models, the
GLEPP1 inhibitors significantly reduce severity of contact hypersensitivity, a
model for allergic dermatitis, and dextran sulfate sodium-induced ulcerative
colitis, a model for inflammatory bowel disease. Taken together, our data
provide confirmation that GLEPP1 plays an important role in controlling
chemotaxis of multiple types of leukocytes and that pharmacological inhibition
of this phosphatase may have therapeutic use