title: Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90 in human monocytes.
abstract: Ligation of advanced glycation end products (AGEs) with their receptor (RAGE) plays an important role in the development of various diabetes complications, including atherosclerosis. Monocyte activation, adhesion, and migration are key events in the pathogenesis of atherosclerosis. Previous studies showed that AGEs and S100b, a specific RAGE ligand, could augment monocyte inflammatory responses via RAGE. In this study, we examined whether LR-90, a compound belonging to a new class of AGE inhibitor, could inhibit inflammatory responses in human monocytes. Human THP-1 cells were pretreated with LR-90 and then stimulated with S100b. LR-90 significantly inhibited S100b-induced expression of RAGE and other proinflammatory genes including monocyte chemoattractant protein-1, interferon-gamma-inducible protein-10, and cyclooxygenase-2 in a dose-dependent manner. These inhibitory effects may be exerted via inhibition of nuclear factor-kappaB (NF-kappaB) activation, as LR-90 suppressed both S100b-and tumor necrosis factor-alpha-induced IkappaB-alpha degradation as well as NF-kappaB promoter transcriptional activity. LR-90 also prevented oxidative stress in activated monocytes, as demonstrated by its inhibitory effects on S100b-induced expression of NADPH oxidase and intracellular superoxide production. In addition, LR-90 blocked S100b-induced monocyte adhesion to human umbilical vein endothelial cell. These new data show that, in addition to its AGE inhibitory effects, LR-90 has novel anti-inflammatory properties and might therefore have additional protective effects against diabetic vascular complications.
authors.affiliation: Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Figarola
authors.forename: Narkunaraja
authors.initials: N
authors.lastname: Shanmugam
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
authors.forename: Samuel
authors.initials: S
authors.lastname: Rahbar
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002087:Butyrates; D017127:Glycation End Products, Advanced; C485003:LR-90; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D014409:Tumor Necrosis Factor-alpha; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases