A novel synthetic dibenzocyclooctadiene lignan analog XLYF-104-6 attenuates lipopolysaccharide-induced inflammatory response in RAW264.7 macrophage cells and protects BALB/c mice from sepsis.
The wide range of inflammation mechanisms under control by NF-κB makes this pathway as an attractive target for new anti-inflammatory drugs. Herein, we showed that a new dibenzocyclooctadiene lignan analog XLYF-104-6, with a chemical name of 1,2,3,10,11-pentamethoxydibenzocycloocta-6,7-[c] pyrrole-1,3-dione, inhibited lipopolysaccharide (LPS)-induced NF-κB activation in RAW264.7 cells through preventing IκBα degradation and p65 nuclear translocation. The inhibitory activity of this compound on NF-κB activation contributes to the reduction of LPS-induced TNF-α and IL-6 productions. Notably, XLYF-104-6 suppressed LPS-induced iNOS expression and NO production in a NF-κB independent manner, since IKK inhibitor BAY 11-7082 has failed to exert similar inhibitory effect on iNOS expression and NO production. In addition, XLFY-104-6 also exerted anti-inflammatory action in endotoxemic mice by decreasing plasma LPS-induced TNF-α and IL-1β levels as well as increasing plasma LPS-induced IL-10 concentrations. These findings suggest XLYF-104-6 could act as a leading compound for developing a potential anti-inflammatory drug.
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Chunping
C
Gu
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
Fang-Lin
FL
Yu
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Le
L
Yu
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
Xiao-Yang
XY
He
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Desheng
D
Zhong
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Longgang
L
He
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Longyun
L
Lv
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
Lan
L
Xie
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.
Shuwen
S
Liu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D034242:Cyclooctanes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D034242:Cyclooctanes; D018836:Inflammation Mediators; D017705:Lignans; D008070:Lipopolysaccharides; C510994:dibenzocyclooctadiene lignan
Anti-inflammatory drug; Aprotinin (Pubchem CID: 16130295); BAY 11-7082 (Pubchem CID: 5353431); DAPI (Pubchem CID: 2954); Dibenzocyclooctadiene lignin; G418 (Pubchem CID: 123865); Leupeptin (Pubchem CID: 72429); Lipopolysaccharide; Lipopolysaccharide (Pubchem CID: 11970143); MTT (Pubchem CID: 64965); NF-κB; PMSF (Pubchem CID: 4784); Pepstatin (Pubchem CID: 5478883); Sepsis; Sodium fluoride (Pubchem CID: 5235); iNOS expression and NO production