title: BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages.
abstract: Peroxisome proliferator-activated receptor-gamma (PPARγ) is considered to be an important transcriptional factor in regulation of macrophages differentiation and activation. We have synthesized a series of novel structural molecules based on GW9662's structure (named BZ-24, BZ-25 and BZ-26), and interaction activity was calculated by computational docking. BZ-26 had shown stronger interaction with PPARγ and had higher transcriptional inhibitory activity of PPARγ with lower dosage compared with GW9662. BZ-26 was proved to inhibit inflammatory macrophage differentiation. LPS-induced acute inflammation mouse model was applied to demonstrate its anti-inflammatory activity. And the results showed that BZ-26 administration attenuated plasma tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) secretion, which are vital cytokines in acute inflammation. The anti-inflammatory activity was examined in THP-1 cell line, and TNF-α, IL-6 and MCP-1, were significantly inhibited. The results of Western blot and luciferase reporter assay indicated that BZ-26 not only inhibited NF-κB transcriptional activity, but also abolished LPS-induce nuclear translocation of P65. We also test BZ-26 action in tumor-bearing chronic inflammation mouse model, and BZ-26 was able to alter macrophages phenotype, resulting in antitumor effect. All our data revealed that BZ-26 modulated LPS-induced acute inflammation via inhibiting inflammatory macrophages differentiation and activation, potentially via inhibition of NF-κB signal pathway.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210093, China.
authors.forename: Yuncheng
authors.initials: Y
authors.lastname: Bei
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210093, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210093, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210093, China.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Functional Biomolecules, Medical School, Nanjing University, Nanjing, 210093, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Institute of Functional Biomolecules, Medical School, Nanjing University, Nanjing, 210093, China. Electronic address: renxiangtan@nju.edu.cn.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210093, China. Electronic address: ppshen@nju.edu.cn.
authors.forename: Pingping
authors.initials: P
authors.lastname: Shen
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018836:Inflammation Mediators
keywords: Inflammation; Macrophage; NF-κB; PPARγ; Tumor