Epigenetic Manipulation to Trigger Production of Guaiane-Type Sesquiterpenes from a Marine-Derived Spiromastix sp. Fungus with Antineuroinflammatory Effects
Epigenetic Manipulation to Trigger Production of Guaiane-Type Sesquiterpenes from a Marine-Derived Spiromastix sp. Fungus with Antineuroinflammatory Effects
复制标题
表观遗传操作可触发海洋来源的螺旋鞭毛虫产生愈创木烷型倍半萜。
DOI：
10.1021/acs.jnatprod.1c00293
复制
发表时间：
2021-06-23
影响因子：
5.1
通讯作者：
Lin, Wenhan
中科院分区：
文献类型：
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作者：
Guo, Xiang;Meng, Qinyu;Lin, Wenhan
利用亚甲基苯胺羟肟酸（SAHA）诱导对深海沉积物来源的Spiromastix sp.真菌进行表观遗传处理，激活了一个萜烯相关的生物合成基因簇，并分离到9个新的瓜烷型倍半萜，即spiromaterpenes a - i（1-9）。利用各种光谱技术，结合改进的Mosher方法、计算电子圆二色性（ECD）光谱和化学转换来确定它们的结构。化合物4-6对脂多糖（LPS）诱导的小胶质细胞BV2的NO生成有显著的抑制作用，初步的SAR分析表明，2(R)，11-二醇单位是有利的。活性最强的5种可消除lps诱导的BV-2小胶质细胞中NF-kappa B从细胞质向细胞核的易位，同时在lps诱导的BV-2和BV-2细胞中，促炎细胞因子（包括IL-1 β、IL-6和tnf - α）的转录水平显著降低，iNOS和COX-2的蛋白和mRNA水平也显著降低。本研究补充了关于愈创木烷型倍半萜在细胞水平上抗神经炎症活性的知识空白，并表明5作为抗神经炎症的多功能药物有希望进一步优化。
Epigenetic manipulation of a deep-sea sediment-derived Spiromastix sp. fungus using suberoylanilide hydroxamic acid (SAHA) induction resulted in the activation of a terpenerelated biosynthetic gene cluster, and nine new guaiane-type sesquiterpenes, spiromaterpenes A-I (1-9), were isolated. Their structures were determined using various spectroscopic techniques, in association with the modified Mosher's method, computed electronic circular dichroism (ECD) spectra, and chemical conversion for configurational assignments. Compounds 4-6 exhibited significant effects against the NO production on lipopolysaccharide (LPS)-induced microglia cells BV2, and the preliminary SAR analyses demonstrated that a 2(R),11-diol unit is favorable. The most active 5 abolished LPS-induced NF-kappa B translocation from the cytosol to the nucleus in BV-2 microglial cells, accompanied by the marked reduction of the transcription levels of pro-inflammatory cytokines, including IL-1 beta, IL-6, and TNF-alpha dose-dependently in both LPS-induced BV-2 and BV-2 cells, as well as the protein and mRNA levels of iNOS and COX-2. This study complements the gap in knowledge regarding the antineuroinflammatory activity of guaiane-type sesquiterpenoids at the cellular level and suggests that 5 is promising for further optimization as a multifunctional agent for antineuroinflammation.