title: Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages.
abstract: Benfotiamine, a lipid-soluble analogue of vitamin B1, is a potent antioxidant that is used as a food supplement for the treatment of diabetic complications. Our recent study (U.C. Yadav et al., Free Radic. Biol. Med. 48:1423-1434, 2010) indicates a novel role for benfotiamine in the prevention of bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in murine macrophages. Nevertheless, it remains unclear how benfotiamine mediates anti-inflammatory effects. In this study, we investigated the anti-inflammatory role of benfotiamine in regulating arachidonic acid (AA) pathway-generated inflammatory lipid mediators in RAW264.7 macrophages. Benfotiamine prevented the LPS-induced activation of cPLA2 and release of AA metabolites such as leukotrienes, prostaglandin E2, thromboxane 2 (TXB2), and prostacyclin (PGI2) in macrophages. Further, LPS-induced expression of AA-metabolizing enzymes such as COX-2, LOX-5, TXB synthase, and PGI2 synthase was significantly blocked by benfotiamine. Furthermore, benfotiamine prevented the LPS-induced phosphorylation of ERK1/2 and expression of transcription factors NF-κB and Egr-1. Benfotiamine also prevented the LPS-induced oxidative stress and protein-HNE adduct formation. Most importantly, compared to specific COX-2 and LOX-5 inhibitors, benfotiamine significantly prevented LPS-induced macrophage death and monocyte adhesion to endothelial cells. Thus, our studies indicate that the dual regulation of the COX and LOX pathways in AA metabolism could be a novel mechanism by which benfotiamine exhibits its potential anti-inflammatory response.
authors: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Mohammad
authors: M
authors: Shoeb
authors: Kota V
authors: KV
authors: Ramana
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016326:Extracellular Matrix Proteins; D015289:Leukotrienes; D008070:Lipopolysaccharides; D016328:NF-kappa B; C077112:Lox protein, mouse; D016718:Arachidonic Acid; D013929:Thromboxane B2; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D008249:Protein-Lysine 6-Oxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; D013831:Thiamine; C013835:benphothiamine