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

1
Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China
2
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; https://doi.org/10.3390/md13106352
Received: 24 July 2015 / Revised: 29 September 2015 / Accepted: 29 September 2015 / Published: 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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