Cpcc 400518. Aspergillus Secondary Metabolite Extraction And Separation Of Cla-1 Raised The Activity Of Preliminary Research

Cardiovascular disease is one of the most common diseases that damage human health in developed countries and most developing countries, while atherosclerosis is the principal pathogenesis for many critical cardiovascular diseases. Although multiple epidemiological, experimental, and genetic studies have supported that the elevated level of HDL-C (high density lipoprotein cholesterol) is very important for protection against atherogenesis, the effective therapeutic methods aiming at selectively elevated HDL-C level in patients are not currently available.Recent studies reveal that the antiatherosclerotic effect of HDL is mainly due to its role in reverse cholesterol transport (RCT). Scavenger receptor class B type I (SR-BI) is the high-affinity HDL receptor at the molecular level, and the CLA-1 (CD36 and Lysosomal integral membrane protein-II Analogous-1)is the human HDL receptor. CLA-1/SR-BI has been suggested as a potential new preventative and/or therapeutic target for atherosclerosis due to its pivotal role in RCT. Promoting reverse cholesterol transport will decrease cholesterol in atherosclerotic plaques and reverse the develop-mental process of atherosclerosis. Thus increase of SR-BI/CLA-1 expression will lead to the acceleration of RCT and the clearance of abundant cholesterol ester. As a result, the active compounds which enhance SR-BI/CLA-1 expression may be developed as drug candidates or lead compounds for new antiatherosclerotic agents.With the SR-BI expression upregulators screening model established in our laboratory, the microbial fermentation broths were screened. Among them, the fermentation broth of Aspergillus sp. Stain CPCC 400518 (03F-09007) showed good upregulatory effect on CLA-1 expression. The active components were isolated by macroporous resin HP-20 and Sephadex LH-20 column and then purified by preparative HPLC. As a result, three compounds, named as 9007A,9007B and 9007C were obtained. The structures of 9007A,9007B and 9007C were determined by means of spectral data of LSI-MS and NMR analysis. Finally,9007A,9007B and 9007C were identified as 3a-hydroxyfuroindoline., cyclo(Trp-Ala),cyclo(Pro-Phe), respectively. Positive compounds 9007A,9007B,9007C significantly influenced CLA-1 transcriptional activity at low micromolar concentrations in the developed assay.This study revealed for the first time that 9007A,9007B and 9007C have up-regulating activity on human high density lipoprotein receptor CLA-1, which bears important theoretical and practical significance for further investigation of the transcriptional regulation of the CLA-1/SR-BI gene and the discovery of drug candidates or lead compounds of new antiatherosclerotic agents.