Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.

The nuclear receptors-liver X receptors (LXR α and ß) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from Sargassum fusiforme and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXRα/ß activation in luciferase reporter assays and induction of LXR-target genes APOE, ABCA1 and ABCG1 involved in cellular cholesterol turnover in cultured cells: methyl 3ß-hydroxychol-5-en-24-oate (S1), methyl (3ß)-3-aldehydeoxychol-5-en-24-oate (S2), 24-ketocholesterol (S6), (3ß,22E)-3-hydroxycholesta-5,22-dien-24-one (N10) and fucosterol-24,28 epoxide (N12). These compounds induced SREBF1 but not SREBP1c-mediated lipogenic genes such as SCD1, ACACA and FASN in HepG2 cells or astrocytoma cells. Moreover, S2 and S6 enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the CYP46A1, encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; S1 and S6 may also act via the upregulation of desmosterol production. Thus, we identified five novel LXR-activating 24-oxidized sterols with a potential for therapeutic applications in neurodegenerative and cardiovascular diseases.

Saringosterol from Sargassum fusiforme Modulates Cholesterol Metabolism and Alleviates Atherosclerosis in ApoE-Deficient Mice.

Dysregulation of cholesterol homeostasis is a major risk factor of atherosclerosis, which can lead to serious health problems, including heart attack and stroke. Liver X receptor (LXR) α and ß are transcription factors belonging to the nuclear receptor superfamily, which play important roles in cholesterol homeostasis. Selectively activating LXRß provides a promising strategy for the treatment of atherosclerosis. Here, we employed atherosclerotic apoE-knockout mice to evaluate the effects of saringosterol, a phytosterol with potent and selective action for LXRß, which we identified previously in edible marine seaweed Sargassum fusiforme. We found that saringosterol treatment reduced the atherosclerotic plaque burden without having undesirable adverse hepatic effects in apoE-deficient mice fed an atherogenic diet. Meanwhile, reduced serum levels of cholesterol, accompanied by altered expression of LXR-regulated genes involved in cholesterol absorption, transport, efflux, excretion, and elimination, were observed in apoE-knockout mice after saringosterol treatment. Together, our study not only establishes saringosterol as an effective cholesterol-lowering and anti-atherogenic phytosterol but also provides insights into the underlying mechanism.

Preparation of ellagic acid molecularly imprinted polymeric microspheres based on distillation-precipitation polymerization for the efficient purification of a crude extract.

Molecularly imprinted polymeric microspheres with a high recognition ability toward the template molecule, ellagic acid, were synthesized based on distillation-precipitation polymerization. The as-obtained polymers were characterized by scanning electron microscopy, infrared spectroscopy, and thermogravimetric analysis. Static, dynamic, and selective binding tests were adopted to study the binding properties and the molecular recognition ability of the prepared polymers for ellagic acid. The results indicated that the maximum static adsorption capacity of the prepared polymers toward ellagic acid was 37.07 mg/g and the adsorption equilibrium time was about 100 min when the concentration of ellagic acid was 40 mg/mL. Molecularly imprinted polymeric microspheres were also highly selective toward ellagic acid compared with its analogue quercetin. It was found that the content of ellagic acid in the pomegranate peel extract was enhanced from 23 to 86% after such molecularly imprinted solid-phase extraction process. This work provides an efficient way for effective separation and enrichment of ellagic acid from complex matrix, which is especially valuable in industrial production.