Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's disease; Parkinson's disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders.

2009-07-01·Journal of Chemical Information and Modeling

Multiple-docking and affinity fingerprint methods for protein classification and inhibitors selection.

Article

作者: Li, Bo ; Liu, Zhenming ; Zhang, Liangren ; Zhang, Lihe

The function-based protein classification holds tremendous promise for molecular recognition and the structure-based design process. We describe here a new strategy combined with multiple-docking tools and "affinity fingerprint" analysis technology to detect functional relationships among proteins based on the substrate binding features and protein-ligand interaction matrix and apply it successfully for the family of phospholipase A2 to investigate protein-ligand binding, function-based protein classification, and inhibitor selection, evaluation. Binding data and matrix were generated by multiple versus multiple-docking among 12 PLA2s and 84 PLA2 inhibitors. Three kinds of statistic techniques, principal component analysis, multidimensional scaling, and cluster algorithms, were chosen to distinguish the groups with similar binding characteristics. The 12 PLA2s were automatically categorized into reasonable subfamilies on the basis of the protein-ligand binding matrix, and the classifying problem of cPLA2 (PDB ID: 1CJY ) with relatively low homology was successfully dealt with. This approach was also used to identify and group the selective inhibitors against human nonpancreatic sPLA2. A sound pharmacophore has been defined from these selective inhibitors. It shows that the method is quite robust against individual data deviation, especially false positive, which makes it possible to be used in virtual screening with large enzyme families to generate selective inhibitors of targets on the basis of limited structural/function information.

2004-09-15·Cancer research1区 · 医学

Estrogen Enhances Angiogenesis through a Pathway Involving Platelet-Activating Factor-Mediated Nuclear Factor-κB Activation

1区 · 医学

Article

作者: Lee, Hern-Ku ; Choi, Il-Hwan ; Lee, Hyun-Suk ; Choi, Jung-Hwa ; Seo, Kook Heon ; Im, Suhn-Young ; Park, Sung Jun ; Jung, Bongnam ; Ko, Hyun-Mi

Abstract:

In this study, we investigated the molecular events involved in estrogen-induced angiogenesis. Treatment of the human endometrial adenocarcinoma cells, HEC-1A, with estrogen up-regulated mRNA expression and protein synthesis of various angiogenic factors such as tumor necrosis factor-α, interleukin-1, basic fibroblast growth factor, and vascular endothelial growth factor. The estrogen-dependent induction of the expression was blocked by the platelet-activating factor (PAF) antagonists, WEB 2170. Estrogen treatment caused the activation of nuclear factor (NF)-κB in HEC-1A cells and was also blocked by PAF antagonist. Inhibitors of NF-κB activation inhibited estrogen-induced mRNA expression and protein synthesis of the angiogenic factors. Estrogen led to a pronounced angiogenesis as assessed by a mouse Matrigel model in vivo and endothelial cell sprouting in vitro. PAF antagonists or NF-κB inhibitors significantly inhibited this estrogen-dependent angiogenesis. Estrogen caused phospholipase A2 (PLA2) gene and protein expression. Estrogen-induced vascular endothelial growth factor mRNA expression and sprouting were significantly inhibited by PLA2 inhibitors, suggesting PLA2 expression is the upstream pathway in the estrogen-induced angiogenesis. Taken together, these results suggest that estrogen induces the production of angiogenic factors via a mechanism involving PAF-mediated NF-κB activation.

100 项与 PLA2 inhibitors( University of Athens) 相关的药物交易

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