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Background & Aim: Dietary shifts replacing animal protein (AP) with plant protein (PP) sources have been associated with lowering cardiometabolic risk (CMR), but underlying mechanisms are poorly characterized. This nutritional intervention aims to characterize the metabolic changes induced by diets containing different proportions of AP and PP sources in males at CMR., Design: This study is a 4-week, crossover, randomized, controlled-feeding trial in which 19 males with CMR followed two diets providing either 36 % for the control diet (CON-D) or 64 % for the flexitarian diet (FLEX-D) of total protein intake from PP sources. Plasma nontargeted metabolomes (LC-MS method) were measured in the fasted state and after a high-fat challenge meal at the end of each intervention arm. Lipogenesis and protein synthesis fluxes, flow-mediated dilatation (FMD) and gluco-lipidic responses were assessed after the challenge meal. Data were analyzed with mixed models, and univariate and multivariate models for metabolomics data., Results: In both arms CMR improved with time, with decreased body weight (-0.9 %), insulin resistant (-34 %, HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) and low-density lipoproteins (LDL)-cholesterol (-11 %). Diet had no effect on FMD or metabolic fluxes, but a trend (0.05

Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes., (© 2024 SSIEM.)

In this community effort, we compare measurements between 34 laboratories from 19 countries, utilizing mixtures of labelled authentic synthetic standards, to quantify by mass spectrometry four clinically used ceramide species in the NIST (National Institute of Standards and Technology) human blood plasma Standard Reference Material (SRM) 1950, as well as a set of candidate plasma reference materials (RM 8231). Participants either utilized a provided validated method and/or their method of choice. Mean concentration values, and intra- and inter-laboratory coefficients of variation (CV) were calculated using single-point and multi-point calibrations, respectively. These results are the most precise (intra-laboratory CVs ≤ 4.2%) and concordant (inter-laboratory CVs < 14%) community-derived absolute concentration values reported to date for four clinically used ceramides in the commonly analyzed SRM 1950. We demonstrate that calibration using authentic labelled standards dramatically reduces data variability. Furthermore, we show how the use of shared RM can correct systematic quantitative biases and help in harmonizing lipidomics. Collectively, the results from the present study provide a significant knowledge base for translation of lipidomic technologies to future clinical applications that might require the determination of reference intervals (RIs) in various human populations or might need to estimate reference change values (RCV), when analytical variability is a key factor for recall during multiple testing of individuals., (© 2024. The Author(s).)

Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies.

Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field. Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Müller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype. Together, our findings reveal the essential role of YAP in preserving the integrity of the ciliary body and retinal ganglion cells, thereby preventing the onset of uveitic glaucoma-like features., (© 2024. The Author(s).)