title: Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models.
abstract: Rheumatoid arthritis (RA) is an aggressive inflammatory disease in which cytokines/chemokines are thought to recruit leukocytes and induce angiogenesis. The aim of this study is to investigate the effect of flavonol-rich residual layer of hexane fraction from Rhus verniciflua Stokes (RVHxR) and its major compound fisetin on inflammatory cytokine/chemokine production and angiogenic factor in IL-1beta-stimulated RA fibroblast-like synovial cells (FLS) and inflammatory in vivo models. Flavonol-rich RVHxR and its major compound fisetin significantly inhibited IL-1beta-induced FLS proliferation in a dose-dependent manner. Flavonol-rich RVHxR and fisetin significantly decreased IL-1beta-induced inflammatory cytokines (TNF-alpha, interleukin (IL)-6)/chemokines (IL-8, monocyte chemoattractant protein (MCP)-1), and vascular endothelial growth factor (VEGF) of RA FLS. Flavonol-rich RVHxR dose dependently diminished the phophorylation of extracellular signal regulated kinase (ERK) and phospho-Jun NH((2))-terminal kinase (JNK), and its down regulation induced by RVHxR at nontoxic concentrations, while activated the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS. The p38 specific inhibitor SB203580 cotreatment with RVHxR effectively increased the expression of VEGF and blocked the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS, confirming a critical role of p38 MAPK pathway in angiogenesis inhibition. In experimental inflammation-related models, flavonol-rich RVHxR and fisetin have shown significant anti-inflammatory activities on vascular permeability, leukocyte migration and cellular immunity. Also, flavonol-rich RVHxR and fisetin treatments significantly reduced the incidence and severity of collagen-induced arthritis model. These results suggest that RVHxR and its major compound fisetin have shown potent suppressive effects on some inflammatory cytokines/chemokines and angiogenic factor in IL-1beta-stimulated RA FLS and inflammatory in vivo models. We believe that flavonol-rich RVHxR is a potential therapeutic agent in the treatment of inflammatory and angiogenesis related diseases.
authors.affiliation: Department of Acupuncture & Moxibustion, College of Oriental Medicine, Kyung Hee University, 1 Hoegidong, Dongdaemungu, Seoul 130-701, Republic of Korea.
authors.forename: Jae-Dong
authors.initials: JD
authors.lastname: Lee
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Huh
authors.forename: GeumSeon
authors.initials: G
authors.lastname: Jeon
authors.forename: Ha-Ru
authors.initials: HR
authors.lastname: Yang
authors.forename: Hyun-Su
authors.initials: HS
authors.lastname: Woo
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Dong-Suk
authors.initials: DS
authors.lastname: Park
mesh_terms: D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000302:isolation & purification / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D024043:Collagen Type II / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology; D010081:Oxazolone / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D029045:Rhus / Q000737:chemistry*; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D024043:Collagen Type II; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D044948:Flavonols; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D010081:Oxazolone; D011494:Protein Kinases; C017875:fisetin; C093642:SB 203580