Author: Zhou, Yiwei ; Tan, Qiuxiang ; Yang, Linlin ; Yi, Cuiying ; Liu, Jianfeng ; Zhao, Yongfang ; Zhou, Ye ; Han, Gye Won ; Lu, Minmin ; Wu, Beili ; Yang, Huaiyu ; Zhao, Qiang ; Stevens, Raymond C ; He, Lingli ; Wang, Xianping ; Qiao, Anna ; Li, Xuemei ; Jiang, Hualiang ; Rao, Zihe ; Zhang, Xuejun C ; Cao, Can ; Xu, Chanjuan

Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-Å and 2.9-Å resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR-SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 Å and 4 Å, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.

01 Jun 2004·Clinica Chimica ActaQ3 · MEDICINE

Activation of PAF receptor by oxidised LDL in human monocytes stimulates chemokine releases but not urokinase-type plasminogen activator expression

Q3 · MEDICINE

Article

Author: Ewa Ninio ; Jean-Louis Beaudeux ; Toihiri Said ; A Legrand ; Claudine Soria ; Jacqueline Peynet ; Jeannette Soria ; Florence Ganné ; Jacques Delattre

BACKGROUNDWe investigated whether the increase of urokinase-type plasminogen activator (uPA) monocyte expression and chemokine releases induced by oxidised low density lipoproteins (LDL), which participate to vascular tissue remodeling and to atherosclerotic plaque rupture, involved proinflammatory phospholipid products having platelet-activating factor (PAF)-like activity via the PAF-receptor pathway.METHODSuPA monocyte expression was stimulated by either copper ions-oxidised or O2*-/HO* free radical-oxidised LDL. The effects of PAF and oxidised LDL on the production of monocyte chemoattractant protein-1 and interleukin-8 were also examined.RESULTSSynthetic PAF significantly enhanced chemokine releases (P<0.001) without modifying uPA expression. Copper-oxidised LDL, which exhibit a higher content in lysophosphatidylcholines than free radical-oxidised LDL, induced a significantly higher enhancement in uPA expression (P<0.05). By contrast, free radical-oxidised LDL were more efficient than copper-oxidised LDL to increase chemokine releases (P<0.01). Oxidised LDL-enhanced uPA expressions were not altered by the PAF-receptor antagonist SR27417, whereas increases in chemokine releases induced by oxidised LDL and by PAF were abolished. PAF-acetylhydrolase activity was rapidly and largely inhibited in free radical-oxidised LDL when compared to copper-oxidised LDL, suggesting that free radical-oxidised LDL would contain a higher content in PAF-like products than copper-oxidised LDL.CONCLUSIONOur results indicated that PAF-like oxidation products are responsible for the monocyte chemokine releases, but did not contribute to the enhanced monocyte uPA expression by oxidised LDL.

01 Apr 2002·American Journal of Physiology-Gastrointestinal and Liver PhysiologyQ3 · MEDICINE

Putative effect ofHelicobacter pyloriand gastritis on gastric acid secretion in cat

Q3 · MEDICINE

Article

Author: Mignon, Michel ; Sobhani, Iradj ; Chevalier, Catherine ; Alchepo, Beatriz ; Moizo, Laurent ; Canedo, Sergio ; Bado, André ; Buyse, Marion ; Laigneau, J. Pierre ; Vissuzaine, Christiane ; Lewin, J. Miguel

Helicobacter pylori may increase or inhibit gastric acid. We studied acid variations and plasma gastrin in cats harboring Helicobacter felis, harboring H. pylori, or free of gastric pathogens with reference to thioperamide (H3receptor antagonist) and SR-27417A (PAF receptor antagonist). In cats harboring H. felis, gastric mucosa were histologically normal. After H. feliseradication, pentagastrin-stimulated acid secretion was increased (40%) compared with the situation before eradication. Thioperamide abolished this inhibitory effect of H. felis, whereas SR-27417A did not. Basal and meal-stimulated plasma gastrin levels were not affected by eradication therapy. Acid secretion was inhibited (−80%) in week 3, increased from weeks 5 to 9, and remained constant for up to 42 weeks after H. pylori infection. SR-27417A had no effect on acid secretion before week 8 but inhibited it thereafter, and thioperamide increased it (20%) only before week 7 in those cats. Helicobacter inhibits gastric acid via an H3receptor pathway. Inflammatory mediators are thus involved in adaptation to the inhibitory effects of H. pylori on acid secretion.

100 Deals associated with Foropafant

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 3	-	Sanofi	-
Asthma	Phase 3	FR	Sanofi-Synthelabo, Inc.	-
Asthma	Phase 3	US	-	-
Thrombosis	Phase 3	FR	Sanofi-Synthelabo, Inc.	-

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