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Inhibition of cellular inflammatory mediator production and amelioration of learning deficit in flies by deep sea Aspergillus-derived cyclopenin

The Journal of Antibiotics volume 73, pages 622–629 (2020)Cite this article

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Abstract

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.

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Acknowledgements

The authors wish to thank Professor Yin Zhong (Tsinghua University, Beijing, China) for the supply of Drosophila flies and Beijing JoeKai Biotech LLC for conducting the Aβ42 transgenic fly assay. This study was financially supported in part by the National Natural Science Foundation of China (Grant No. 41276136), Science and Technology Project of Shenzhen City, Shenzhen Bureau of Science, Technology, and Information (Grant No. JCYJ20130408172946974), JSPS KAKENHI of Japan (Grant No. 17K01967), and AMED, Japan under Grant No. JP18fk0310118.

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Authors and Affiliations

  1. College of Life Sciences and Oceanography, Shenzhen Key Laboratory of Marine Bio-resource and Eco-environmental Science, Shenzhen University, 518060, Shenzhen, China

    Liyan Wang & Mengjie Li

  2. Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 480-1195, Nagakute, Japan

    Yinzhi Lin & Kazuo Umezawa

  3. Department of Microbiology and Immunology, Aichi Medical University School of Medicine, 480-1195, Nagakute, Japan

    Yinzhi Lin

  4. Beijing JoeKai Biotech LLC, 10094, Beijing, China

    Shuwen Du & Zhenyu Liu

  5. CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, Guangdong, China

    Jianhua Ju

  6. Brain Functions, Research Institute of Environmental Medicine, Nagoya University, 464-8601, Nagoya, Japan

    Hiromi Suzuki & Makoto Sawada

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  1. Liyan Wang
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Correspondence to Kazuo Umezawa.

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Conflict of interest

KU belongs to the donated fund laboratory supported by Meiji Seika Pharma Co., Ltd, Tokyo, Japan, Shenzhen Wanhe Pharmaceutical Co., Ltd, Shenzhen, China, Fukuyu Hospital, Nisshin, Japan, and Brunese Co., Ltd, Nagoya, Japan. Other authors declare no conflict of interest.

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Wang, L., Li, M., Lin, Y. et al. Inhibition of cellular inflammatory mediator production and amelioration of learning deficit in flies by deep sea Aspergillus-derived cyclopenin. J Antibiot 73, 622–629 (2020). https://doi.org/10.1038/s41429-020-0302-9

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