Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CEACAM1 is the founder molecule of the family of 'carcinoembryonic antigen-related cell adhesion molecules' and part of the immunoglobulin superfamily. Due to its role as a coreceptor to many other receptors (e.g. Toll-like receptor 2, Toll-like receptor 4, T-cell receptor, B-cell receptor, epidermal growth factor receptor and vascular endothelial growth factor receptor) and its different isoforms, CEACAM1 is a multifunctional protein with an impact on proliferation and differentiation of multiple cell types. Although different modes of action in other tissues are described, the role of CEACAM1 in the developing brain remains elusive. Here we report for the first time that CEACAM1 is expressed ontogenetically in oligodendrocytes of the developing rat brain, and that CEACAM1 expression has a spatiotemporal relation to myelination. In addition, CEACAM1 expression is altered in a model of hyperoxia- and inflammation-induced encephalopathy of prematurity, a myelination disorder of children born preterm. Furthermore, primary oligodendrocytes stimulated with CEACAM1 show increased myelination. Therefore, we postulate that CEACAM1 is, at least in part, involved in hyperoxia- and inflammation-induced disruption of myelination, but may also play a role in intact myelination as it is ontogenetically expressed in myelinating oligodendrocytes.
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PMID:CEACAM1 expression in oligodendrocytes of the developing rat brain shows a spatiotemporal relation to myelination and is altered in a model of encephalopathy of prematurity. 2365 19

Vascular degeneration is a critical pathological process in many human degenerative diseases, which need efficient ways to revascularization. However, little is known about cellular and molecular mechanisms that are used during vascular degeneration and revascularization. Here, we show that Toll-like receptor 2 and 4 (TLR2/4) double deficiency suppressed hyperoxia induced retinal vessel regression in an oxygen-induced retinopathy (OIR) model. Notably, the TLR2/4-/- mice experienced more revascularization after reduced vessel regression compared with wild-type mice, accompanied with less activation of glial cells. Mechanistically, TLR2/4 activation can tip the balance between Th17 cells and regulatory T cells towards Th17 cells, a critical source of the IL-17A. Less migration and infiltration of IL-17A-expressing proinflammatory cells but elevated regulatory T cells were observed in OIR-retinae from TLR2/4-/- mice. Coincidentally, TLR2/4 deficiency suppressed IL-17A production and increased expressions of anti-inflammatory genes. Furthermore, IL-17A promoted activation of glial cells. IL-17A blockade using a neutralizing antibody alleviated retinal cell apoptosis and glial activation in C57/B6-OIR mice, demonstrating the important role of IL-17A pathway in glial function during revascularization. Thus TLR2/4-mediated IL-17A inflammatory signaling is involved in vessel degeneration and revascularization, indicating that modulation of the TLR2/4-IL-17A pathway may be a novel therapeutic strategy for degenerative diseases.
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PMID:TLR2/4 deficiency prevents oxygen-induced vascular degeneration and promotes revascularization by downregulating IL-17 in the retina. 2729 42

Signal transduction by the Toll-like receptors (TLRs) is a key component of innate immunity against many pathogens and also underlies a large burden of human diseases. Therefore, the mechanisms and regulation of signaling from the TLRs are of considerable interest. Here we seek to determine the molecular mechanism by which TLR2 and TLR4, members of the Toll-like receptor family, are activated by bacterial LPS, hyperoxia, and zymosan respectively. Our central hypothesis is that the oxidation state of cysteine thiols on the ectodomain of TLR2 and TLR4 are critical for pathogen-initiated intracellular signaling as well in hyperoxia. Cysteine thiols of TLR4 and its co-receptor MD2 have been shown to aid binding between the two molecules and also bacterial LPS binding to the receptor complex. We extend these findings by demonstrating the oxidation of free thiols on the ectodomain of hTLR4, after exposure to LPS or hyperoxia suggesting that the cysteines on the ectodomain of TLR4 could form intra- or intermolecular disulfide bonds. We also demonstrated blockade of intracellular signaling from TLR4 and TLR2 by thiol-modifying compounds which suggest a novel therapeutic intervention for sepsis, hyperoxia-induced cell injury and yeast infection. In these experiments CHO-3E10, HEK293 cells expressing hTLR2 or hTLR4 and mouse peritoneal macrophages cells were pretreated with cell impermeable maleimides to alkylate thiols on the extracellular domain of TLRs, cells were then exposed to LPS, hyperoxia or zymosan. In all of these models, we detected decreased intracellular signaling from TLR2 or TLR4. Furthermore, incubation with phenyl arsine oxide - which forms stable complexes with vicinal cysteine residues - prevented LPS induced HEK293/hTLR4 intracellular signaling which was reversed by DMPS. Sequence analysis of different TLRs revealed Leucine-Rich Repeat C-terminal (LRRCT) domain that contains 4 conserved cysteines. Further work is required to pinpoint the role of each cysteine in receptor dimerization, pathogen binding, hyperoxia modulation, and intracellular signaling.
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PMID:The oxidation state of cysteine thiols on the ectodomain of TLR2 and TLR4 influences intracellular signaling. 3184 60