A low toxicity synthetic cinnamaldehyde derivative ameliorates renal inflammation in mice by inhibiting NLRP3 inflammasome and its related signaling pathways

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• 作者：Shuk-Man Ka^a ; Louis Kuoping Chao^b ; Jung-Chen Lin^c ; Shui-Tein Chen^d ; Wen-Tai Li^e ; Chien-Nan Lin^f ; Jen-Che Cheng^f ; Huei-Ling Jheng^c ; Ann Chen^c ; Kuo-Feng Hua^c ; ^f ; ^{kuofenghua@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cinnamaldehyde ; NLRP3 inflammasome ; Renal inflammation
• 刊名：Free Radical Biology and Medicine
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：91
• 期：Complete
• 页码：10-24
• 全文大小：6451 K

文摘

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.