👤 Susana Feliu

Direct oral anticoagulants, including rivaroxaban, are widely prescribed for the prevention and treatment of thromboembolic disorders. Despite generally predictable pharmacokinetics (PK), real-world data reveal striking interindividual variability in exposure, raising concerns for both efficacy and bleeding risk. Known genetic and clinical determinants explain only part of this variability, underscoring the need to identify additional contributors. This study aimed to explore systemic protein signatures associated with rivaroxaban exposure intensity. Plasma samples were obtained from 64 participants in a phase I clinical study (NCT04180436) including healthy controls, obese patients, and post-bariatric surgery patients. Rivaroxaban PK was assessed after 20 mg once-daily dosing, and patients were stratified into high and low exposure groups. Untargeted plasma proteomic analysis was performed by liquid chromatography coupled with high-resolution mass spectrometry, followed by univariate and multivariate statistical analyses. Targeted C-reactive protein (CRP) quantification and multiplex cytokine assays were used to validate findings. Differential abundance and multivariate modeling identified inflammation and vascular related proteins associated with high rivaroxaban exposure. Notably, CRP and lipoprotein(a) (LPA) were consistently elevated in high exposure groups. Targeted CRP quantification confirmed these results, even in cases of mild to moderate inflammation. Cytokine analyses revealed a pro-inflammatory profile, characterized by increased interferon gamma and reduced Tumor Necrosis Factor alpha in high exposure patients. Protein-protein interaction networks highlighted CRP, LPA, albumin, and Apolipoprotein B as central hubs, while functional enrichment revealed pathways related to acute inflammation, oxidative stress, and vascular regulation. These findings suggest that systemic inflammation may contribute to rivaroxaban overexposure, with CRP emerging as a promising biomarker to support more personalized anticoagulant strategies. Show less

Abdominal obesity is an important cardiovascular disease risk factor. Plasma fatty acids display a complex network of both pro and antiatherogenic effects. High density lipoproteins (HDL) carry out the antiatherogenic pathway called reverse cholesterol transport (RCT), which involves cellular cholesterol efflux (CCE), and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. Our aim was to characterize RCT and its relation to fatty acids present in plasma in pediatric abdominal obesity. Seventeen children and adolescents with abdominal obesity and 17 healthy controls were studied. Anthropometric parameters were registered. Glucose, insulin, lipid levels, CCE employing THP-1 cells, LCAT and CETP activities, plus fatty acids in apo B-depleted plasma were measured. The obese group showed a more atherogenic lipid profile, plus lower CCE (Mean±Standard Deviation) (6 ± 2 vs. 7 ± 2%; P < 0.05) and LCAT activity (11 ± 3 vs. 15 ±5 umol/dL.h; P < 0.05). With respect to fatty acids, the obese group showed higher myristic (1.1 ± 0.3 vs. 0.7 ± 0.3; P < 0.01) and palmitic acids (21.5 ± 2.8 vs. 19.6 ± 1.9; P < 0.05) in addition to lower linoleic acid (26.4 ± 3.3 vs. 29.9 ± 2.6; P < 0.01). Arachidonic acid correlated with CCE (r = 0.37; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05), palmitioleic acid with CCE (r = -0.35; P < 0.05), linoleic acid with CCE (r = 0.37; P < 0.05), lauric acid with LCAT (r = 0.49; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05) ecoisatrienoic acid with CCE (r = 0.40; P < 0.05) and lignoseric acid with LCAT (r = -0.5; P < 0.01). Children and adolescents with abdominal obesity presented impaired RCT, which was associated with modifications in proinflammatory fatty acids, such as palmitoleic and myristic, thus contributing to increased cardiovascular disease risk. Show less

Mitochondria are pleomorphic organelles that have central roles in cell physiology. Defects in their localization and dynamics lead to human disease. Myosins are actin-based motors that power processes such as muscle contraction, cytokinesis, and organelle transport. Here we report the initial characterization of myosin-XIX (Myo19), the founding member of a novel class of myosin that associates with mitochondria. The 970 aa heavy chain consists of a motor domain, three IQ motifs, and a short tail. Myo19 mRNA is expressed in multiple tissues, and antibodies to human Myo19 detect an approximately 109 kDa band in multiple cell lines. Both endogenous Myo19 and GFP-Myo19 exhibit striking localization to mitochondria. Deletion analysis reveals that the Myo19 tail is necessary and sufficient for mitochondrial localization. Expressing full-length GFP-Myo19 in A549 cells reveals a remarkable gain of function where the majority of the mitochondria move continuously. Moving mitochondria travel for many micrometers with an obvious leading end and distorted shape. The motility and shape change are sensitive to latrunculin B, indicating that both are actin dependent. Expressing the GFP-Myo19 tail in CAD cells resulted in decreased mitochondrial run lengths in neurites. These results suggest that this novel myosin functions as an actin-based motor for mitochondrial movement in vertebrate cells. Show less