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Spiromastixones Inhibit Foam Cell Formation via Regulation of Cholesterol Efflux and Uptake in RAW264.7 Macrophages

Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Peer B. Jacobson
Mar. Drugs 2015, 13(10), 6352-6365;
Received: 24 July 2015 / Revised: 29 September 2015 / Accepted: 29 September 2015 / Published: 14 October 2015
PDF [1061 KB, uploaded 14 October 2015]


Bioassay-guided evaluation shows that a deep sea-derived fungus, Spiromastix sp. MCCC 3A00308, possesses lipid-lowering activity. Chromatographic separation of a culture broth resulted in the isolation of 15 known depsidone-based analogues, labeled spiromastixones A–O (115). Each of these compounds was tested for its ability to inhibit oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in RAW264.7 macrophages. Spiromastixones 68 and 1214 significantly decreased oxLDL-induced lipid over-accumulation, reduced cell surface area, and reduced intracellular cholesterol concentration. Of these compounds, spiromastixones 6 and 14 exerted the strongest inhibitory effects. Spiromastixones 6 and 14 dramatically inhibited cholesterol uptake and stimulated cholesterol efflux to apolipoprotein A1 (ApoA1) and high-density lipoprotein (HDL) in RAW264.7 macrophages. Mechanistic investigation indicated that spiromastixones 6, 7, 12 and 14 significantly up-regulated the mRNA levels of ATP-binding cassette sub-family A1 (ABCA1) and down-regulated those of scavenger receptor CD36, while the transcription of ATP-binding cassette sub-family A1 (ABCG1) and proliferator-activated receptor gamma (PPARγ) were selectively up-regulated by 6 and 14. A transactivation reporter assay revealed that spiromastixones 6 and 14 remarkably enhanced the transcriptional activity of PPARγ. These results suggest that spiromastixones inhibit foam cell formation through upregulation of PPARγ and ABCA1/G1 and downregulation of CD36, indicating that spiromastixones 6 and 14 are promising lead compounds for further development as anti-atherogenic agents. View Full-Text
Keywords: spiromastixones; Spiromastix sp.; atherosclerosis; foam cell; PPARγ; ABCA1/G1; CD36 spiromastixones; Spiromastix sp.; atherosclerosis; foam cell; PPARγ; ABCA1/G1; CD36

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Wu, C.; Chen, R.; Liu, M.; Liu, D.; Li, X.; Wang, S.; Niu, S.; Guo, P.; Lin, W. Spiromastixones Inhibit Foam Cell Formation via Regulation of Cholesterol Efflux and Uptake in RAW264.7 Macrophages. Mar. Drugs 2015, 13, 6352-6365.

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