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Anti-inflammatory effects of Aureusidin in LPS-stimulated RAW264.7 macrophages via suppressing NF-κB and activating ROS- and MAPKs-dependent Nrf2/HO-1 signaling pathways.
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2019-11-29 , DOI: 10.1016/j.taap.2019.114846
Jie Ren 1 , Dan Su 2 , Lixia Li 1 , Heng Cai 1 , Meiju Zhang 1 , Jingchen Zhai 1 , Minyue Li 1 , Xinyue Wu 1 , Kun Hu 1
Affiliation  

Aureusidin, a naturally-occurring flavonoid, is found in various plants of Cyperaceae such as Heleocharis dulcis (Burm. f.) Trin., but its pharmacological effect and active mechanism are rarely reported. This study aimed to investigate the anti-inflammatory effect and action mechanism of Aureusidin in LPS-induced mouse macrophage RAW264.7 cells. The results suggested that lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) production were obviously inhibited by Aureusidin. Moreover, Aureusidin also significantly decreased the mRNA expression of various inflammatory factors in LPS-stimulated RAW264.7 cells. Furthermore, mechanistic studies showed that Aureusidin significantly inhibited nuclear transfer of nuclear factor-κB (NF-κB), while increasing the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) as well as expression of Nrf2 target genes such as heme oxygenase (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), but the addition of the HO-1 inhibitor Sn-protoporphyrin (Snpp) significantly abolished the anti-inflammatory effect of Aureusidin in LPS-stimulated RAW264.7 cells, confirming the view that HO-1 was involved in the anti-inflammatory effect. In addition, Aureusidin increased the levels of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) phosphorylation in RAW264.7 cells. Antioxidant N-acetylcysteine (NAC) or three MAPK inhibitors blocked the nuclear translocation of Nrf2 and HO-1 expression induced by Aureusidin, indicating that Aureusidin activated the Nrf2/HO-1 signaling pathway through ROS and MAPKs pathways. At the same time, co-treatment with the NAC blocked the phosphorylation of MAPKs. Results from molecular docking indicated that Aureusidin inhibited the NF-κB pathway by covalently binding to NF-κB. Thus, Aureusidin exerted the anti-inflammatory activity through blocking the NF-κB signaling pathways and activating the MAPKs and Nrf2/HO-1 signaling pathways. Based on the above results, Aureusidin may be an attractive therapeutic candidate for the inflammation-related diseases.

中文翻译:

金黄色素对LPS刺激的RAW264.7巨噬细胞的抗炎作用是通过抑制NF-κB并激活ROS和MAPKs依赖性Nrf2 / HO-1信号通路而实现的。

金黄色素,一种天然存在的类黄酮,被发现在莎草的各种植物中,如Heleocharis dulcis(Burm。f。)Trin。,但鲜有其药理作用和活性机制的报道。本研究旨在探讨金黄色素对LPS诱导的小鼠巨噬细胞RAW264.7细胞的抗炎作用及其作用机制。结果表明,金黄色素能明显抑制脂多糖(LPS)诱导的一氧化氮(NO),肿瘤坏死因子-α(TNF-α)和前列腺素E2(PGE2)的产生。此外,金黄色素还显着降低了LPS刺激的RAW264.7细胞中各种炎症因子的mRNA表达。此外,机理研究表明,金黄色素可显着抑制核因子-κB(NF-κB)的核转移,同时增加了核因子E2相关因子2(Nrf2)的核易位以及血红素加氧酶(HO-1)和NAD(P)H:醌氧化还原酶1(NQO1)等Nrf2靶基因的表达,但增加了HO-1抑制剂Sn-原卟啉(Snpp)的作用明显消除了金黄色素对LPS刺激的RAW264.7细胞的抗炎作用,证实了HO-1参与抗炎作用的观点。此外,金黄色素增加了RAW264.7细胞中的活性氧(ROS)和有丝分裂原激活的蛋白激酶(MAPK)磷酸化水平。抗氧化剂N-乙酰半胱氨酸(NAC)或三种MAPK抑制剂阻断了金黄色素诱导的Nrf2和HO-1表达的核易位,表明金黄色素通过ROS和MAPK途径激活了Nrf2 / HO-1信号通路。同时,与NAC共同处理可阻断MAPK的磷酸化。分子对接的结果表明,Aureusidin通过与NF-κB共价结合来抑制NF-κB通路。因此,Aureusidin通过阻断NF-κB信号通路并激活MAPKs和Nrf2 / HO-1信号通路发挥抗炎活性。基于以上结果,金黄色葡萄球菌素可能是与炎症有关的疾病的有吸引力的治疗候选物。
更新日期:2019-11-30
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