title: A low toxicity synthetic cinnamaldehyde derivative ameliorates renal inflammation in mice by inhibiting NLRP3 inflammasome and its related signaling pathways.
abstract: Uncontrolled inflammation is a leading cause of various chronic diseases. Cinnamaldehyde (CA) is a major bioactive compound isolated from the essential oil of the leaves of Cinnamomum osmophloeum kaneh that exhibits anti-inflammatory activity; however, the use of CA is limited by its cytotoxicity. Here, we synthesized three CA derivatives and identified 4-hydroxycinnamaldehyde-galactosamine (HCAG) as a low toxicity anti-inflammatory compound in vitro (HCAG IC50 ≫ 1600 µM; CA IC50=40 µM) and in vivo. HCAG reduced pro-inflammatory mediator expression in LPS-activated macrophages by inhibiting MAPK and PKC-α/δ phosphorylation, decreasing ROS generation and reducing NF-κB activation. HCAG also reduced NLRP3 inflammasome-derived IL-1β secretion by inhibiting the ATP-mediated phosphorylation of AKT and PKC-α/δ. In a mouse model of LPS-induced renal inflammation, we observed reduced albuminuria and a mild degree of glomerular proliferation, glomerular sclerosis and periglomerular inflammation in the HCAG-treated mice compared with the vehicle-treated mice. The underlying mechanisms for these renoprotective effects involved: (1) inhibited NLRP3 inflammasome activation; (2) decreased superoxide anion levels and apoptosis; and (3) suppressed activation of NF-κB and related downstream inflammatory mediators.
authors.affiliation: Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.affiliation: Department of Cosmeceutics, China Medical University, Taichung, Taiwan.
authors.forename: Louis
authors.initials: L
authors.lastname: Kuoping Chao
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Shui-Tein
authors.initials: ST
authors.lastname: Chen
authors.affiliation: National Research institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Wen-Tai
authors.initials: WT
authors.lastname: Li
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
authors.forename: Chien-Nan
authors.initials: CN
authors.lastname: Lin
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
authors.forename: Jen-Che
authors.initials: JC
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Huei-Ling
authors.initials: HL
authors.lastname: Jheng
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. Electronic address: kuofenghua@gmail.com.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D005688:Galactosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058847:Inflammasomes / Q000037:antagonists & inhibitors; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors*; D009393:Nephritis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C000612187:4-hydroxycinnamaldehyde-galactosamine; D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D058847:Inflammasomes; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005688:Galactosamine; D000171:Acrolein
keywords: Cinnamaldehyde; NLRP3 inflammasome; Renal inflammation