👤 Carsten Sachse

Thoracic aortic aneurysms frequently go undetected until serious complications like acute dissections or ruptures arise. Therefore, this study aims to identify potential blood circulating biomarkers enabling an easy and early diagnosis of thoracic aortic disease. Potential biomarker candidates were identified through two different techniques, untargeted and targeted proteomic as well as extracellular vesicle (EV) analyses. The biomarker levels were compared between two patient groups with thoracic aortic aneurysms and two control groups without thoracic aortic disease. In total, 80 patients (TAA group (n = 40) vs. control group (n = 40)) were matched for untargeted and targeted proteome analysis, and 85 for EV analysis (TAA group (n = 42) vs. control group (n = 43)), based on the availability of blood samples and excised aortic tissue. Levels of biomarker candidates were correlated with aortic diameter, patient age, and histological alterations in aortic tissue using linear and logistic regression models. The untargeted proteomic and EV analysis identified 1,037 and 1,077 proteins, respectively, of which 11 and 28 proteins showed significant differences in concentration between the study groups. Of these, 9 proteins correlated with the aortic diameter: ACTN1 (Regression coefficient B = 1.633, p < 0.001), CRP (B = 0.001, p = 0.004), TGM3 (B=-0.293, p = 0.010), KRT84 (B=-0.477, p = 0.010), IGHG3 (-0.267, p = 0.018), DPYSL2 (B = 0.644, p = 0.020), TSPAN8 (B-0.838, p = 0.042), IGKV3D-11 (B=-0.242, p = 0.046), and VDAC1 (B=-0.491, p = 0.047). Moreover, IGKV3D-11 (B=-3.257, p = 0.029), IGHG3 (B=-0.003, p = 0.034), and APOC3 (B=-2.104, p = 0.037) showed significant correlations with the grade of aortic medial layer degeneration. None of the proteins correlated with patient age. The study identified 9 biomarker candidates correlating with the aortic diameter. To enable the clinical use for diagnosis and prognostic assessment, these biomarkers need to be validated in larger external cohorts. Show less

Brain vascular aging is increasingly recognized as a critical therapeutic target for age-related cognitive decline. Oxidative stress, bioenergetic dysfunction, and molecular damage play central roles in the progression of vascular aging, contributing to cerebrovascular dysfunction and impaired cognitive function. While naturally occurring polyphenols such as resveratrol (RSV) have demonstrated potential in mitigating aging-related pathologies, their poor bioavailability and limited brain targeting efficiency significantly constrain their therapeutic impact. As a result, high doses or advanced drug delivery strategies are necessary to achieve meaningful physiological effects. We introduce a novel nanocarrier system designed to enhance RSV delivery to the cerebral endothelium by leveraging the natural formation of an apolipoprotein E (ApoE)-enriched protein corona around fusogenic liposomes (FL) Show less

The phosphatidylinositol 3-kinase Vps34 is part of several protein complexes. The structural organization of heterotetrameric complexes is starting to emerge, but little is known about organization of additional accessory subunits that interact with these assemblies. Combining hydrogen-deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography and electron microscopy (EM), we have characterized Atg38 and its human ortholog NRBF2, accessory components of complex I consisting of Vps15-Vps34-Vps30/Atg6-Atg14 (yeast) and PIK3R4/VPS15-PIK3C3/VPS34-BECN1/Beclin 1-ATG14 (human). HDX-MS shows that Atg38 binds the Vps30-Atg14 subcomplex of complex I, using mainly its N-terminal MIT domain and bridges the coiled-coil I regions of Atg14 and Vps30 in the base of complex I. The Atg38 C-terminal domain is important for localization to the phagophore assembly site (PAS) and homodimerization. Our 2.2 Å resolution crystal structure of the Atg38 C-terminal homodimerization domain shows 2 segments of α-helices assembling into a mushroom-like asymmetric homodimer with a 4-helix cap and a parallel coiled-coil stalk. One Atg38 homodimer engages a single complex I. This is in sharp contrast to human NRBF2, which also forms a homodimer, but this homodimer can bridge 2 complex I assemblies. Show less