The Journal of Antibiotics ( IF 3.3 ) Pub Date : 2020-03-24 , DOI: 10.1038/s41429-020-0302-9 Liyan Wang 1 , Mengjie Li 1 , Yinzhi Lin 2, 3 , Shuwen Du 4 , Zhenyu Liu 4 , Jianhua Ju 5 , Hiromi Suzuki 6 , Makoto Sawada 6 , Kazuo Umezawa 2
In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1β, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer’s disease, amyloid-β-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer’s model using flies. Learning deficits were induced by the overexpression of amyloid-β42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.
中文翻译:
深海曲霉菌衍生的环peninin抑制果蝇细胞炎性介质的产生和学习障碍的改善。
在筛选脂多糖(LPS)诱导的一氧化氮(NO)生成抑制剂的过程中,从一种深海生的真菌菌株曲霉菌的提取物中分离了两种相关的苯并二氮杂derivatives衍生物环戊醇和环penin。sp。SCSIOW2。Cyclopenol和cyclopenin在无毒浓度下抑制RAW264.7细胞中LPS诱导的NO形成和IL-6分泌。就这些作用的潜在机制而言,发现环penol和环penin抑制了NF-κB激活的上游信号。这些化合物还抑制小鼠小胶质细胞(大脑中的巨噬细胞)中IL-1β,IL-6和诱导型一氧化氮合酶(iNOS)的表达。关于阿尔茨海默氏病的病因,已知淀粉样β肽可诱发大脑炎症。因此,本研究利用果蝇研究了这些抑制剂对体内阿尔茨海默氏病模型的改善作用。苍蝇中淀粉样蛋白-β42的过表达诱导了学习障碍,而发现环penin而不是cyclopenol可以缓解学习障碍。因此,