title: (E)-3-(3,4-Dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one ameliorates the collagen-arthritis via blocking ERK/JNK and NF-κB signaling pathway.
abstract: Our previous report has shown a natural pyranochalcones-derived compound, (E)-3-(3,4-Dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one (5b), that exerted protection against carrageenan-induced hind paw edema and adjuvant-induced arthritis. In this study, collagen-induced arthritis (CIA) model was used to further examine the anti-arthritic effects of 5b in vivo; the underlying molecular mechanisms of action were also investigated using a murine monocytic cell line, RAW264.7 cells. Here we showed that oral administration of 5b (20mg/kg) significantly suppressed the progression of arthritis. Improvement in disease severity was accompanied by inhibition of CD68-positive cells in knee joint and reduced pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in serum. In vitro, 5b suppressed expressions of iNOS, cyclooxygenase-2 (COX-2), TNF-α, IL-6 and IL-1β as well as productions of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated macrophages. This compound also significantly suppressed LPS-induced NF-κB activation, including phosphorylation of I-κB, degradation of I-κB, and nuclear translocation of p65 and p50. Treatment with 5b also blocked LPS-induced expression of TLR4 remarkably, suppressed degradation of IRAKs and phosphorylations of JNK and ERK, but had little effect to p38 kinase activation. These findings indicated that 5b might be a therapeutic agent for rheumatoid arthritis, and exerted an anti-inflammatory effect mainly through mediating TLR4, NF-κB and ERK/JNK signaling pathways in monocytes.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China; Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Peng
authors.forename: Caifeng
authors.initials: C
authors.lastname: Xie
authors.forename: Wenshuang
authors.initials: W
authors.lastname: Wu
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Han
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D033023:Foot Joints / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C000591160:3-(3,4-dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one; D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D047188:Chalcones; D016207:Cytokines; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone
keywords: (E)-3-(3, 4-Dimethoxyphenyl)-1-(5-hydroxy-2, 2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one; 5b; CIA; CMC; COX-2; Collagen-induced arthritis (CIA); DMSO; ELISA; EMSA; ERK; H&E; IFA; IKKα; IL-1β; IL-6; IRAKs; IκB kinase α; IκBα; JNK; LPS; MAPK; NF-κB; NO; NSAIDs; RA; TNF-α; c-Jun-N-terminal kinase; carboxymethylcellulose sodium; collagen induced arthritis; cyclooxygenase-2; dimethylsulfoxide; electrophoretic mobility-shift assay; enzyme-linked immunosorbent assay; extracellular signal-regulated kinase; hematoxylin and eosin; iNOS; incomplete Freund's adjuvant; inducible nitric oxide synthase; inhibitor kappa B-alpha; interleukin 6; interleukin-1 receptor associated kinases; interleukin-1β; lipopolysaccharide; mitogen-activated protein kinase; nitric oxide; non-steroidal anti-inflammatory drugs; nuclear factor-κB; p38; p38 MAP kinase; rheumatoid arthritis; tumor necrosis factor-α