Molecular Targets and Mechanisms of 6,7-Dihydroxy-2,4-dimethoxyphenanthrene from Chinese Yam Modulating NF-kappa B/COX-2 Signaling Pathway: The Application of Molecular Docking and Gene Silencing

文献类型： 外文期刊

第一作者： Nie, Congyi

作者： Nie, Congyi;Zou, Yuxiao;Liao, Sentai;Li, Qian;Nie, Congyi;Gao, Qunyu

作者机构：

关键词： Chinese yam polyphenols; phenanthrene; NF-kappa B; COX-2 signaling pathway; molecular docking; gene silencing

期刊名称：NUTRIENTS （ 影响因子：5.9； 五年影响因子：6.6 ）

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年卷期： 2023 年 15 卷 4 期

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收录情况： SCI

摘要： Chinese yam (Dioscorea opposita) tuber has a significant effect of invigorating the intestine and improving the symptoms of long-term diarrhea according to the records of the Chinese Pharmacopoeia. Phenanthrene polyphenols from Chinese yam, with higher inhibition of cyclooxygenase-2 (COX-2) than anti-inflammatory drugs, are an important material basis in alleviating ulcerative colitis via nuclear factor kappa-B (NF-kappa B)/COX-2 pathway, based on our previous research. The present study further explored the target and molecular mechanisms of phenanthrenes' modulation of the NF-kappa B/COX-2 signaling pathway by means of molecular docking and gene silencing. Firstly, interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) expression of 6-hydroxy-2,4,7-trimethoxyphenanthrene (PC2)/6,7-dihydroxy-2,4-dimethoxyphe-nanthrene (PC4) were compared on TNF-alpha induced human colon adenocarcinoma (Caco-2) cells. Secondly, molecular docking and dynamics simulation were implemented for PC2/PC4 and COX-2. Finally, COX-2 silencing was performed on TNF-alpha induced Caco-2 cells to confirm the target of PC4 on NF-kappa B/COX-2 pathway. Lower expression of IL-8 and TNF-alpha in PC4 treated Caco-2 cells indicated that PC4 had stronger anti-inflammatory activity than PC2. The binding of PC4 and COX-2 was stronger due to the hydrogen bond between hydroxyl group and Tyr385. No significant differences were found in phosphorylation nuclear factor kappa-B inhibitor alpha (pIkB alpha), phosphorylation NF-kappa B (pNF-kappa B) and phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2) expression between control and PC4 group after silencing, while these protein expressions significantly decreased in PC4 group without silencing, which confirmed that COX-2 was the important target for PC4 in alleviating ulcerative colitis. These findings indicate that PC4 was supposed to have inhibited NF-kappa B pathway mediated inflammation via suppression of positive feedback targeting COX-2.

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