Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various derivatives and isosteres of neolignans of the 2,5-diaryl tetrahydrofuran type have been synthesized as antagonists of platelet-activating factor (PAF). A detailed analysis of their structure-activity relationship (SAR) has revealed a clear preference for an asymmetrical molecular configuration with a high degree of stereo and chiral specificity associated with greater potency. The trans-2S,5S enantiomers are generally 10-200 times more potent in vitro than their corresponding cis or trans-2R,5R isomers. A similar stereochemical preference is indicated by the recently reported PAF antagonist MK-287 which has undergone clinical evaluation. An azido derivative L-662,025 has been characterized as a photolabile irreversible antagonist of PAF for the investigation of solubilized and partially purified PAF binding proteins from cell membranes. The biological justification for concomitant inhibition of both PAF receptor and 5-lipoxygenase in inflammation is well recognized. The feasibility of developing such dual-functional agents has been demonstrated by a group of dithiolane analogs of neolignans and several derivatives of futoenone.
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PMID:Chemical and biochemical characterization of lignan analogs as novel PAF receptor antagonists. 166 10

Increased expression of 5-lipoxygenase is associated with various neuropathologies and may be related to epigenetic gene regulation. DNA methylation in promoter regions is typically associated with gene silencing. We found that human NT2 cells, which differentiate into neuron-like NT2-N cells, express 5-lipoxygenase and we investigated the relationship between 5-lipoxygenase expression and the methylation state of the 5-lipoxygenase core promoter. We used the demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor valproate to alter DNA methylation and to induce histone modifications. 5-Lipoxygenase expression and DNA methylation were assayed with RT-PCR and bisulfite genomic sequencing, respectively. Neuronal differentiation of proliferating NT2 precursors decreased 5-lipoxygenase expression. 5-Aza-2'-deoxycytidine increased 5-lipoxygenase mRNA levels only in proliferating cells, whereas valproate increased 5-lipoxygenase mRNA levels in a cell cycle-independent manner. In both precursors and differentiated cells, CpG dinucleotides of the promoter were poorly methylated. In precursors, both 5-aza-2'-deoxycytidine and valproate further reduced the number of methylated CpGs. Moreover, we found evidence for cytosine methylation in CpWpG (W=adenine or thymine) and other asymmetrical sequences; CpWpG methylation was reduced by valproate in NT2-N but not in NT2 cells. This is the first report demonstrating that the dynamics of DNA methylation relates to neural 5-lipoxygenase gene expression.
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PMID:DNA methylation as an epigenetic regulator of neural 5-lipoxygenase expression: evidence in human NT2 and NT2-N cells. 1500 43