| Title | Spiromastixones Inhibit Foam Cell Formation via Regulation of Cholesterol Efflux and Uptake in RAW264.7 Macrophages |
| Authors | Wu, Chongming Chen, Ran Liu, Mingyue Liu, Dong Li, Xin Wang, Shuai Niu, Siwen Guo, Peng Lin, Wenhan |
| Affiliation | Chinese Acad Med Sci, Peking Union Med Coll, Inst Med Plant Dev, Pharmacol & Toxicol Res Ctr, Beijing 100193, Peoples R China. Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. |
| Keywords | spiromastixones Spiromastix sp. atherosclerosis foam cell PPAR gamma ABCA1/G1 CD36 ACTIVATED PROTEIN-KINASE STATIN THERAPY CORONARY ATHEROSCLEROSIS APOA-I ABCA1 HDL ABCG1 TRANSPORTERS PROGRESSION EXPRESSION |
| Issue Date | 2015 |
| Publisher | MARINE DRUGS |
| Citation | MARINE DRUGS.2015,13,(10),6352-6365. |
| Abstract | 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 (1-15). 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 6-8 and 12-14 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 (PPAR) were selectively up-regulated by 6 and 14. A transactivation reporter assay revealed that spiromastixones 6 and 14 remarkably enhanced the transcriptional activity of PPAR. These results suggest that spiromastixones inhibit foam cell formation through upregulation of PPAR and ABCA1/G1 and downregulation of CD36, indicating that spiromastixones 6 and 14 are promising lead compounds for further development as anti-atherogenic agents. |
| URI | http://hdl.handle.net/20.500.11897/415837 |
| ISSN | 1660-3397 |
| DOI | 10.3390/md13106352 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 天然药物与仿生药物国家重点实验室 |
