Amyotrophic lateral sclerosis (ALS), the commonest adult-onset motor neuron disorder, is characterized by a survival span of only 2–5 years after onset. Relevant biomarkers or specific metabolic signatures would provide powerful tools for the management of ALS. The main objective of this study was to investigate the cerebrospinal fluid (CSF) lipidomic signature of ALS patients by mass spectrometry to evaluate the diagnostic and predictive values of the profile. We showed that ALS patients (n = 40) displayed a highly significant specific CSF lipidomic signature compared to controls (n = 45). Phosphatidylcholine PC(36:4), higher in ALS patients (p = 0.0003) was the most discriminant molecule, and ceramides and glucosylceramides were also highly relevant. Analysis of targeted lipids in the brain cortex of ALS model mice confirmed the role of some discriminant lipids such as PC. We also obtained good models for predicting the variation of the ALSFRS-r score from the lipidome baseline, with an accuracy of 71% in an independent set of patients. Significant predictions of clinical evolution were found to be correlated to sphingomyelins and triglycerides with long-chain fatty acids. Our study, which shows extensive lipid remodelling in the CSF of ALS patients, provides a new metabolic signature of the disease and its evolution with good predictive performance.
PURPOSE. To investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG). METHODS. Plasma of 34 POAG individuals was compared to that of 30 age-and sex-matched controls using a semiquantitative method based on liquid chromatography coupled to highresolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls. RESULTS. Using the semiquantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to controls and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 lM (median: 0.12 lM; range, 0.06-0.28 lM) in the POAG group (À30%; P ¼ 0.022) and 0.19 lM (median: 0.18 lM; range, 0.08-0.47 lM) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (À33%; P ¼ 0.011) in the replicative cohort with mean concentrations of 0.14 lM (median: 0.14 lM; range, 0.09-0.25 lM) in the POAG group, and 0.19 lM (median: 0.21 lM; range, 0.09-0.26 lM) in the control group. CONCLUSIONS. Glaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.
In established tumors, tumor-associated macrophages (TAM) orchestrate nonresolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis, and angiogenesis. However, the factors conferring inflammatory and protumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including protumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines, and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with hypoxia-inducible factor-1a stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGF high CXCL8 þ IL1b þ ) are found in solid ovarian tumors. These results show that tumor-derived lactate links the protumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumorassociated acidosis may help combat cancer.
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