Hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts against cell death induced by nutrient deprivation, but not against apoptosis evoked by oxidized LDL

The neutral type 2 sphingomyelinase (nSMase2) hydrolyzes sphingomyelin and generates ceramide, a major bioactive sphingolipid mediator, involved in growth arrest and apoptosis. The role of nSMase2 in apoptosis is debated, and apparently contradictory results have been observed on fibroblasts isolated from nSMase2-deficient fragilitas ossium (homozygous fro/fro) mice. These mice exhibit a severe neonatal dysplasia, a lack of long bone mineralization and delayed apoptosis patterns of hypertrophic chondrocytes in the growth plate. We hypothesized that apoptosis induced by nutrient deprivation, which mimics the environmental modifications of the growth plate, requires nSMase2 activation. In this study, we have compared the resistance of fro/fro fibroblasts to different death inducers (oxidized LDL, hydrogen peroxide and nutrient starvation). The data show that nSMase2-deficient fro/fro cells resist to apoptosis evoked by nutrient starvation (fetal calf serum/glucose/pyruvate-free DMEM), whereas wt fibroblasts die after 48 h incubation in this medium. In contrast, oxidized LDL and hydrogen peroxide are similarly toxic to fro/fro and wt fibroblasts, indicating that nSMase2 is not involved in the mechanism of toxicity evoked by these agents. Interestingly, wt fibroblasts treated with the SMase inhibitor GW4869 were more resistant to starvation-induced apoptosis. The resistance of fro/fro cells to starvation-induced apoptosis is associated with an increased expression of hyaluronan synthase 2 (HAS2) mRNAs and protein, which is inhibited by ceramide. In wt fibroblasts, this HAS2 rise and its protective effect did not occur, but exogenously added HA exhibited a protective effect against starvation-induced apoptosis. The protective mechanism of HAS2 involves an increased expression of the heat-shock protein Hsp72, a chaperone with antiapoptotic activity. Taken together, these results highlight the role of nSMase2 in apoptosis evoked by nutrient starvation that could contribute to the delayed apoptosis of hypertrophic chondrocytes in the growth plate, and emphasize the antiapoptotic properties of HAS2

Protein disulfide isomerase modification and inhibition contribute to ER stress and apoptosis induced by oxidized low density lipoproteins.

International audienceAIMS: Protein disulfide isomerase (PDI) is an abundant endoplasmic reticulum (ER)-resident chaperone and oxidoreductase that catalyzes formation and rearrangement (isomerization) of disulfide bonds, thereby participating in protein folding. PDI modification by nitrosative stress is known to increase protein misfolding, ER stress, and neuronal apoptosis. As LDL oxidation and ER stress may play a role in atherogenesis, this work was designed to investigate whether PDI was inactivated by oxLDLs, thereby participating in oxLDL-induced ER stress and apoptosis. RESULTS: Preincubation of human endothelial HMEC-1 and of macrophagic U937 cells with toxic concentration of oxLDLs induced PDI inhibition and modification, as assessed by 4-HNE-PDI adducts formation. PDI inhibition by bacitracin potentiated ER stress (increased mRNA expression of CHOP and sXBP1) and apoptosis induced by oxLDLs. In contrast, increased PDI activity by overexpression of an active wild-type PDI was associated with reduced oxLDL-induced ER stress and toxicity, whereas the overexpression of a mutant inactive form was not protective. These effects on PDI were mimicked by exogenous 4-HNE and prevented by the carbonyl-scavengers N-acetylcysteine and pyridoxamine, which reduced CHOP expression and toxicity by oxLDLs. Interestingly, 4-HNE-modified PDI was detected in the lipid-rich areas of human advanced atherosclerotic lesions. Innovation and CONCLUSIONS: PDI modification by oxLDLs or by reactive carbonyls inhibits its enzymatic activity and potentiates both ER stress and apoptosis by oxLDLs. PDI modification by lipid peroxidation products in atherosclerotic lesions suggests that a loss of function of PDI may occur in vivo, and may contribute to local ER stress, apoptosis, and plaque progression

Irradiation of nitrogen-rich ices by swift heavy ions: clues for the formation of ultracarbonaceous micrometeorites

Context. Extraterrestrial materials, such as meteorites and interplanetary dust particles, provide constraints on the formation and evolution of organic matter in the young solar system. Micrometeorites represent the dominant source of extraterrestrial matter at the Earth’s surface, some of them originating from large heliocentric distances. Recent analyses of ultracarbonaceous micrometeorites recovered from Antarctica (UCAMMs) reveal an unusually nitrogen-rich organic matter. Such nitrogen-rich carbonaceous material could be formed in a N2-rich environment, at very low temperature, triggered by energetic processes. Aims. Several formation scenarios have been proposed for the formation of the N-rich organic matter observed in UCAMMs. We experimentally evaluate the scenario involving high energy irradiation of icy bodies subsurface orbiting at large heliocentric distances. Methods. The effect of Galactic cosmic ray (GCR) irradiation of ices containing N2 and CH4 was studied in the laboratory. The N2-CH4 (90:10 and 98:2) ice mixtures were irradiated at 14 K by 44 MeV Ni11+ and 160 MeV Ar15+ swift heavy ion beams. The evolution of the samples was monitored using in-situ Fourier transform infrared spectroscopy. The evolution of the initial ice molecules and new species formed were followed as a function of projectile fluence. After irradiation, the target was annealed to room temperature. The solid residue of the whole process left after ice sublimation was characterized in-situ by infrared spectroscopy, and the elemental composition was measured ex-situ. Results. The infrared bands that appear during irradiation allow us to identify molecules and radicals (HCN, CN−, NH3, ...). The infrared spectra of the solid residues measured at room temperature show similarities with that of UCAMMs. The results point towards the efficient production of a poly-HCN-like residue from the irradiation of N2-CH4 rich surfaces of icy bodies. The room temperature residue provides a viable precursor for the N-rich organic matter found in UCAMMs

Pathological aspects of lipid peroxidation

Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity

International audienceAbstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that—in the case of the interdependent tumor cell morphology and adapted immune response—reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM