Wang Ning, Chen Xiao, Ji Yingying, Lan Tian, Yan Wei, Xu Yungen, Gong Guoqing
Department of Pharmacology, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing, Jiangsu, 210009, China.
Zhuhai Natural Pharmaceutical Institute Ltd, Zhuhai High-tech Enterprise Zone, Zhuhai, Guangdong, 519085, China.
Inflammation. 2023 Feb;46(1):190-201. doi: 10.1007/s10753-022-01722-0. Epub 2022 Aug 20.
A potential new limonoid derivative, (12S,12aS)-6,6,8a,12a-tetramethyl-12-(5-(4-(piperidin-1-yl)butanoyl)furan-3-yl)decahydro-1H,3H-oxireno[2,3-d]pyrano[4',3':3,3a]isobenzofuro[5,4-f]isochromene-3,8,10(6H,9aH)-trione (I-C-1), has been screened for its anti-inflammatory activity. This study aimed to demonstrate the anti-inflammatory activities of I-C-1 and to further explore the underlying mechanisms of these activities in RAW264.7 macrophages. We verified the anti-inflammatory activity of I-C-1 in vivo by a carrageenan-induced paw edema model in rats and cotton pellet-induced granuloma in mice. Further, we found that I-C-1 significantly inhibited levels of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-induced RAW264.7 cells. I-C-1 demonstrated strong inhibition of the NF-κB activation through repression of the IKKα and IKKβ phosphorylations, as well as a significant suppression of the phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt) pathway, an upstream of the NF-κB pathway. Additionally, we verified the inhibitory effect of I-C-1 on PI3K phosphorylation by immunofluorescence assay and compared the effects of I-C-1 with the PI3K inhibitor LY294002 in IL-1β, IL-6, and TNF-α levels. The data indicated that I-C-1 likely acts as an inhibitor of PI3K, exerting anti-inflammatory effects by inhibiting the PI3K/AKT/NF-κB signaling pathway. Based on these findings, we believe that I-C-1 has the potential to be further developed as a potential therapeutic agent for inflammatory-related diseases.
一种潜在的新型柠檬苦素衍生物，(12S,12aS)-6,6,8a,12a-四甲基-12-(5-(4-(哌啶-1-基)丁酰基)呋喃-3-基)十氢-1H,3H-环氧乙烷并[2,3-d]吡喃并[4',3':3,3a]异苯并呋喃并[5,4-f]异色烯-3,8,10(6H,9aH)-三酮（I-C-1），已对其抗炎活性进行了筛选。本研究旨在证明I-C-1的抗炎活性，并进一步探讨其在RAW264.7巨噬细胞中这些活性的潜在机制。我们通过角叉菜胶诱导的大鼠足肿胀模型和棉球诱导的小鼠肉芽肿模型在体内验证了I-C-1的抗炎活性。此外，我们发现I-C-1在脂多糖（LPS）诱导的RAW264.7细胞中显著抑制促炎细胞因子如白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNF）-α的水平。I-C-1通过抑制IKKα和IKKβ磷酸化表现出对NF-κB激活的强烈抑制，以及对NF-κB途径上游的磷脂酰肌醇3-激酶（PI3K）/丝氨酸-苏氨酸激酶（Akt）途径的显著抑制。此外，我们通过免疫荧光测定验证了I-C-1对PI3K磷酸化的抑制作用，并比较了I-C-1与PI3K抑制剂LY294002对IL-1β、IL-6和TNF-α水平的影响。数据表明I-C-1可能作为PI3K的抑制剂，通过抑制PI3K/AKT/NF-κB信号通路发挥抗炎作用。基于这些发现，我们认为I-C-1有潜力进一步开发成为炎症相关疾病的潜在治疗药物。
