Anti-Inflammatory Effects of Fucoxanthinol in LPS-Induced RAW264.7 Cells through the NAAA-PEA Pathway
Anti-Inflammatory Effects of Fucoxanthinol in LPS-Induced RAW264.7 Cells through the NAAA-PEA Pathway
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岩藻黄醇通过 NAAA-PEA 途径在 LPS 诱导的 RAW264.7 细胞中的抗炎作用
DOI：
10.3390/md18040222
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发表时间：
2020-04-01
期刊：
影响因子：
5.4
通讯作者：
Li, Long
中科院分区：
文献类型：
--
作者：
Jin, Wenhui;Yang, Longhe;Li, Long
棕榈酰乙醇酰胺（PEA）是一种内源性脂质介质，具有强大的抗炎和镇痛功能。PEA可被溶酶体酶n -酰基乙醇胺酸酰胺酶（NAAA）水解，该酶在巨噬细胞和其他免疫细胞中高表达。药物抑制NAAA活性是治疗炎症相关疾病的一种潜在的治疗策略。岩藻黄嘌呤（FXOH）是从褐藻中提取的一种海洋类胡萝卜素，具有多种有益作用。然而，FXOH对脂多糖（LPS）刺激的巨噬细胞的抗炎作用和作用机制尚不清楚。本研究旨在探讨FXOH在NAAA-PEA通路中的作用及基于该机制的抗炎作用。体外实验结果表明，FXOH可直接结合NAAA蛋白的活性位点，特异性抑制NAAA酶的活性。在lps诱导的巨噬细胞炎症模型中，FXOH预处理可显著逆转lps诱导的PEA水平下调。FXOH还能显著降低炎性因子的mRNA表达，包括诱导型一氧化氮合酶（iNOS）、白细胞介素-6 （IL-6）和肿瘤坏死因子-α (TNF-α)，并显著降低TNF-α、IL-6、IL-1β和一氧化氮（NO）的产生。此外，FXOH对NO诱导的抑制作用被过氧化物酶体增殖物激活受体α (PPAR-α)抑制剂GW6471显著消除。上述结果表明，FXOH可预防lps诱导的巨噬细胞炎症，其机制可能与调控NAAA-PEA-PPAR-α通路有关。
Palmitoylethanolamide (PEA) is an endogenous lipid mediator with powerful anti-inflammatory and analgesic functions. PEA can be hydrolyzed by a lysosomal enzyme N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and other immune cells. The pharmacological inhibition of NAAA activity is a potential therapeutic strategy for inflammation-related diseases. Fucoxanthinol (FXOH) is a marine carotenoid from brown seaweeds with various beneficial effects. However, the anti-inflammatory effects and mechanism of action of FXOH in lipopolysaccharide (LPS)-stimulated macrophages remain unclear. This study aimed to explore the role of FXOH in the NAAA–PEA pathway and the anti-inflammatory effects based on this mechanism. In vitro results showed that FXOH can directly bind to the active site of NAAA protein and specifically inhibit the activity of NAAA enzyme. In an LPS-induced inflammatory model in macrophages, FXOH pretreatment significantly reversed the LPS-induced downregulation of PEA levels. FXOH also substantially attenuated the mRNA expression of inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and markedly reduced the production of TNF-α, IL-6, IL-1β, and nitric oxide (NO). Moreover, the inhibitory effect of FXOH on NO induction was significantly abolished by the peroxisome proliferator-activated receptor α (PPAR-α) inhibitor GW6471. All these findings demonstrated that FXOH can prevent LPS-induced inflammation in macrophages, and its mechanisms may be associated with the regulation of the NAAA-PEA-PPAR-α pathway.