Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway
Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway
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DOI：
10.1007/s10753-015-0265-3
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发表时间：
2016-02-01
期刊：
影响因子：
5.1
通讯作者：
Zhao, Feng
中科院分区：
文献类型：
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作者：
Jin, Xin;Wang, Jing;Zhao, Feng
本实验观察了丹皮酚对角叉菜胶诱导的大鼠急性足肿胀和葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的防治作用。经口给药后，丹皮酚（20和40 mg/kg）减少了爪体积的水肿增加，也减少了DSS诱导的小鼠结肠炎的发展。此外，通过体外抗炎和抗氧化试验，研究了丹皮酚（1）及其10种代谢产物（M2类似于M11）的抗炎和抗氧化活性。M3和M11具有显著的2，2-二苯基-1-苦基肼（DPPH）自由基清除活性（EC 50值分别为93.44和23.24 μ M）。除M8外，所有代谢产物均具有清除羟自由基的活性，M3和M11是最有效的药物（EC 50值分别为336.02和124.05 μ M）。还测试了丹皮酚M2对一氧化氮（NO）过量产生和TNF-α释放的抑制作用，与M11相似。M3和M11有效抑制脂多糖（LPS）诱导的巨噬细胞RAW 264.7中NO的过度产生。Western blot结果显示丹皮酚、M3和M11下调诱导型一氧化氮合酶（iNOS）和考克斯-2蛋白的高表达，且M3和M11的作用较丹皮酚更强。提示丹皮酚可能通过吸收后转化为活性代谢产物而发挥抗炎和抗氧化作用。此外，进一步的机制研究表明，丹皮酚，M3，M11阻断MAPK/ERK 1/2和p38的磷酸化，而对JNK的磷酸化没有影响。上述结果表明，丹皮酚预处理可能是一种有效的治疗干预，对炎症性疾病，包括结肠炎。
The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2 similar to M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 mu M, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 mu M, respectively). Inhibitory effects of paeonol, M2 similar to M11 on the overproduction of nitric oxide (NO), and the release of TNF-alpha were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis.