Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (ABCA1), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.

Background: Propofol is a widely used anesthetic for total IV anesthesia. Although it is generally safe, rare but serious complications can occur in vulnerable groups, such as critically ill patients and children. Clinicians often rely on surrogate measures ( e.g. , predicted effect-site concentrations or Bispectral Index), yet more direct indicators of anesthetic exposure and metabolic stress would be valuable. The authors hypothesized that pharmacometabolomics via breath analysis could yield real-time insights into propofol concentrations as well as accompanying metabolic responses to surgery. Methods: In this pilot study, 10 pediatric patients (median age, 5.9 yr; interquartile range, 4.3 to 6.6) undergoing propofol anesthesia contributed 47 breath samples (10 preinduction, 37 postinduction) and 37 blood samples. All samples were analyzed by high-resolution mass spectrometry. Linear mixed-effects models examined associations between exhaled compounds and serum propofol concentrations while accounting for repeated measures in individual patients. Volcano plots were used to identify differential changes in metabolites after propofol induction. Results: Propofol, its metabolites, and endogenous metabolites were readily detected in exhaled breath, demonstrating strong correlations with serum propofol concentrations (partial R ² ≥ 0.65; adjusted P < 0.001). Differential analysis showed significant upregulation of endogenous fatty aldehydes (log ₂ [postinduction/preinduction] ≥ 1; adjusted P ≤ 0.05), suggestive of lipid peroxidation and oxidative stress. Exogenous compounds, including benzene and phenols, were also observed, reflecting propofol metabolism in vivo . Conclusions: This pilot study highlights a robust breath–serum relationship for propofol and reveals surgery-associated shifts in metabolic pathways, including evidence of oxidative stress. These findings underscore the feasibility of exhaled-breath pharmacometabolomics for individualized anesthetic care. Further validation in larger cohorts is warranted to confirm clinical utility and to determine whether real-time breath analysis could ultimately serve as a useful adjunct for guiding anesthetic management and monitoring perioperative metabolic responses.

A liquid chromatography - tandem mass spectrometry (LC-MS/MS) method has been developed to simultaneously measure four sodium glucose co-transporter 2 (SGLT2) inhibitors and the transfer marker antipyrine (ANTI) in perfusion medium and placental tissue collected from ex vivo human placental perfusions. The four SGLT2 inhibitors were empagliflozin (EMPA), dapagliflozin (DAPA), ertugliflozin (ERTU) and canagliflozin (CANA). Chromatographic separation was achieved on an Uptisphere® C18 reversed phase column (50 mm × 4.6 mm × 5 µm) within 2.85 min, using a gradient elution with 10 mM ammonium formate in water (mobile phase A) and acetonitrile (mobile phase B) both with 0.1% formic acid. Analysis of ammonium adduct ions was performed on an AB SCIEX 6500+ triple quadrupole mass spectrometer using positive electrospray ionisation and scheduled multiple reaction monitoring (sMRM). The transitions were m/z 468.00 → 355.20 (EMPA), m/z 426.00 → 167.20 (DAPA), m/z 437.10 → 206.90 (ERTU), m/z 462.00 → 249.00 (CANA) and m/z 189.20 → 55.90 (ANTI). The method was validated according to the European Medicines Agency guidelines and was proven to be selective, linear within a concentration range of 1-1000 µg/L (DAPA, CANA, ANTI) and 1-500 µg/L (EMPA, ERTU), accurate, precise and free of carry-over, instabilities, recovery and matrix effect issues. This newly developed method is suitable to analyse perfusion medium and placenta tissue samples collected during ex vivo human placenta perfusions. It thereby enables quantification of transport across the placental barrier of the SGLT2 inhibitors EMPA, DAPA, ERTU and CANA as well as the transfer marker ANTI.

Sphingolipids including ceramides are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids are associated with various neurological pathologies, however, the entire spectrum of disorders affecting sphingolipid metabolism remains elusive. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous variant p.(Ala280Val) in DEGS1, encoding an enzyme of the ceramide synthesis pathway. The blood sphingolipid profile and patient-derived fibroblasts both showed a significant shift from the unsaturated to the dihydro-forms of sphingolipids. Moreover, an atypical and potentially toxic sphingolipid metabolite is formed as consequence of the altered synthesis pathway. The changes in the sphingolipid profile were recapitulated in a CRISPR/Cas-based DEGS1 knockout HAP1-cell model and by chemical inhibition of DEGS1, suggesting a loss of DEGS1 function in the disease. DEGS1 insufficiency is thus a novel cause for a multisystem neurological disorder. A sphingolipid-rich diet may correct the metabolic profile and improve the clinical outcome of affected individuals and suggests that this heritable condition might be treatable. Abbreviations: SL Sphingolipids SPT serine-palmitoyltransferase Cer Ceramides dhCer dihydroceramide S1P sphingosine-1-phosphate SO sphingosine HSAN hereditary sensory and autonomic neuropathy