Simultaneous Addition of Shikonin and Its Derivatives with Lipopolysaccharide Induces Rapid Macrophage Death.
Simultaneous Addition of Shikonin and Its Derivatives with Lipopolysaccharide Induces Rapid Macrophage Death.
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DOI：
10.1248/bpb.b15-00948
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发表时间：
2016-06
影响因子：
2
通讯作者：
Atsushi Koike;M. Shibano;H. Mori;K. Kohama;K. Fujimori;F. Amano
中科院分区：
文献类型：
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作者：
Atsushi Koike;M. Shibano;H. Mori;K. Kohama;K. Fujimori;F. Amano
巨噬细胞在炎症反应中起关键作用。以往的研究表明，多种天然产物通过调节巨噬细胞活化发挥抗炎作用。近年来的研究表明，紫草素（SHK）及其衍生物（β-羟基异缬草素、乙酰紫草素和异丁基紫草素）是从紫草根中提取的1,4-萘醌类色素，具有抗炎、抗肿瘤等多种药理作用。尽管关于SHK衍生物抗炎活性的研究很多，但描述其对巨噬细胞直接作用的研究很少。我们研究了SHK衍生物对脂多糖（LPS）处理巨噬细胞的影响。低剂量SHK衍生物在LPS存在下诱导巨噬细胞（小鼠巨噬细胞样J774.1/JA-4细胞和小鼠腹膜巨噬细胞）产生显著的细胞毒性。SHK激活caspase -3和-7，导致DNA断裂，但在lps处理的JA-4细胞中，通过泛caspase抑制剂可以防止这种细胞毒性。在LPS加入前立即加入SHK达到最大的细胞毒作用。这些结果表明，SHK衍生物诱导LPS处理巨噬细胞的caspase依赖性凋亡细胞死亡，并表明SHK在LPS信号传导的早期阶段起作用。
Macrophages play pivotal roles in inflammatory responses. Previous studies showed that various natural products exert antiinflammatory effects by regulating macrophage activation. Recent studies have shown that shikonin (SHK) and its derivatives (β-hydroxyisovalerylshikonin, acetylshikonin, and isobutylshikonin), which are 1,4-naphthoquinone pigments extracted from the roots of Lithospermum erythrorhizon, have various pharmacological, including antiinflammatory and antitumor, effects. Even though there have been many studies on the antiinflammatory activities of SHK derivatives, only a few have described their direct effects on macrophages. We investigated the effects of SHK derivatives on lipopolysaccharide (LPS)-treated macrophages. Low doses of SHK derivatives induced significant macrophage cytotoxicity (mouse macrophage-like J774.1/JA-4 cells and mouse peritoneal macrophages) in the presence of LPS. SHK activated caspases-3 and -7, which led to DNA fragmentation, but this cytotoxicity was prevented through a pan-caspase inhibitor in LPS-treated JA-4 cells. Maximal cytotoxic effects were achieved when SHK was added immediately before LPS addition. These results indicate that SHK derivatives induce caspase-dependent apoptotic cell death of LPS-treated macrophages and suggest that SHK acts during an early stage of LPS signaling.