EBI2 agonists(Euroscreen)

The blood-brain barrier (BBB) is essential for central nervous system homeostasis, and its dysfunction is implicated in neuroinflammatory disorders such as Alzheimer's disease and multiple sclerosis. Oxysterols, cholesterol-derived metabolites, modulate lipid metabolism, immune responses, and BBB physiology, but their specific metabolic effects remain poorly defined. Using an in vitro human BBB model, we examined the impact of tumor necrosis factor-α (TNFα) and selected oxysterols (24S-hydroxycholesterol, 25-hydroxycholesterol, 7α,25-dihydroxycholesterol) on metabolomic profiles of brain-like endothelial cells (hBLEC) and pericytes (hBP) via targeted LC-MS/MS analysis of over 300 metabolites. TNFα markedly increased phenylpyruvic acid, indicating dysregulated phenylalanine metabolism. Oxysterols elicited minimal effects in hBLEC, but significantly altered glycolysis and fatty acid metabolism in hBP, notably reducing fructose 6-phosphate, glucose 6-phosphate, and myristoleic acid, while increasing specific fatty acids under inflammatory conditions. These results identify phenylpyruvic acid as a candidate biomarker of BBB inflammation and highlight pericyte metabolic reprogramming as a key mechanism of oxysterol action.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with increasing prevalence and limited targeted therapeutic options. Oxysterols, i.e., oxidative derivatives of cholesterol, have been implicated in various cardiovascular pathologies through pro-apoptotic, pro-inflammatory, and cytotoxic mechanisms. However, their potential role in HFpEF pathophysiology remains unexplored.

This study aimed to investigate the relationship between serum oxysterol levels and HFpEF, and to evaluate their potential as novel biomarkers in this patient population.

In this prospective, single-center study, 101 participants were enrolled between September 27, 2022, and March 27, 2023. The study group consisted of 51 patients diagnosed with HFpEF, according to the current European Society of Cardiology (ESC) guidelines, while 50 age- and sex-matched individuals without HFpEF served as controls. Serum levels of 7-ketocholesterol, 25-hydroxycholesterol, and 7α,25-dihydroxycholesterol were measured using liquid chromatography-mass spectrometry (LC/MS). Clinical, biochemical, and echocardiographic parameters were recorded and compared between groups. Correlation analyses were performed to assess the relationship between oxysterol levels and other variables, including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and echocardiographic measurements.

Median serum levels of 7-ketocholesterol, 25-hydroxycholesterol, and 7α,25-dihydroxycholesterol were significantly higher in the HFpEF group compared to controls (p < 0.001 for all). Strong positive correlations were found between oxysterol levels and NT-proBNP concentrations (r = 0.778, r = 0.733, and r = 0.630, respectively; p < 0.001). Additionally, oxysterol levels showed weak positive correlations with body mass index and left atrial diameter. No significant associations were observed between oxysterol levels and comorbidities such as hypertension, diabetes mellitus, hyperlipidemia, or coronary artery disease.

This is the first study to demonstrate significantly elevated serum oxysterol levels in HFpEF patients compared to healthy controls. The strong correlation with NT-proBNP suggests that oxysterols may serve as potential biomarkers for HFpEF, reflecting underlying pathophysiological mechanisms involving inflammation and myocardial remodeling. Larger, multicenter studies are warranted to confirm these findings and explore their prognostic value.