Cadmium accumulation and interactions with zinc, copper, and manganese, analysed by ICP-MS in a long-term Caco-2 TC7 cell model

The influence of long-term exposure to cadmium (Cd) on essential minerals was investigated using a Caco-2 TC7 cells and a multi-analytical tool: microwave digestion and inductively coupled plasma mass spectrometry. Intracellular levels, effects on cadmium accumulation, distribution, and reference concentration ranges of the following elements were determined: Na, Mg, Ca, Cr, Fe, Mn, Co, Ni, Cu, Zn, Mo, and Cd. Results showed that Caco-2 TC7 cells incubated long-term with cadmium concentrations ranging from 0 to 10 lmol Cd/l for 5 weeks exhibited a significant increase in cadmium accumulation. Furthermore, this accumulation was more marked in cells exposed long-term to cadmium compared with controls, and that this exposure resulted in a significant accumulation of copper and zinc but not of the other elements measured. Interactions of Cd with three elements: zinc, copper, and manganese were particularly studied. Exposed to 30 lmol/l of the element, manganese showed the highest inhibition and copper the lowest on cadmium intracellular accumulation but Zn, Cu, and Mn behave differently in terms of their mutual competition with Cd. Indeed, increasing cadmium in the culture medium resulted in a gradual and significant increase in the accumulation of zinc. There was a significant decrease in manganese from 5 lmol Cd/l exposure, and no variation was observed with copper. Abbreviation: AAS – Atomic absorption spectrometry; CRM– Certified reference material; PBS – Phosphate buffered saline without calcium and magnesium; DMEM – Dubelcco’s modified Eagle’s medium

G-protein coupled receptors (GPCR) and environmental exposure. Consequences for cell metabolism using the β-adrenoceptors as example

International audienceThe impact of endocrine disruptors (EDs), compounds disturbing the normal action of hormones, represents a major field of toxicological research, in particular through the interference with steroid hormones and their nuclear receptors. By contrast, G-protein coupled receptors (GPCRs) have been a major focus of pharmacological research and drug-development, but have received limited attention in toxicology as potential targets of EDs. In this review we discuss the potential importance of GPCRs in the mode of action of EDs, using the recently observed interaction between polycyclic aromatic hydrocarbons (PAHs) and β-adrenergic receptors as an example. This ability to disturb adrenoceptor function represent a novel mode of action (MOA) for hormone disruption by EDs which may affect both metabolic processes and immune responses. The outcome may be of relevance to development or exacerbation of multifactorial non-communicable diseases (NCDs)

NPC1 repression contributes to lipid accumulation in human macrophages exposed to environmental aryl hydrocarbons.

International audienceAIMS: Aryl hydrocarbons (AHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo(a)pyrene (BP), are environmental contaminants promoting the development of atherosclerosis-related cardiovascular diseases. In order to identify molecular mechanisms involved in these effects, we have analysed AH-mediated regulation of the lipid trafficking Niemann-Pick type C1 protein (NPC1) and its contribution to AH-induced macrophage lipid accumulation. METHODS AND RESULTS: Exposure of primary human macrophages to TCDD and BP decreased NPC1 mRNA expression in a time-dependent manner. NPC1 protein expression and NPC1-related acid sphingomyelinase activity were reduced in parallel. NPC1 was also similarly down-regulated in mice exposed to BP. Moreover, TCDD and BP were demonstrated to trigger lipid accumulation in human macrophages, as assessed by Oil Red O and Nile Red staining and cholesterol determination. Such lipid loading occurred at least partly in endosomal/lysosomal compartments as demonstrated by immunolabelling of lipid vesicles by the lysosome-associated membrane protein 1. These cellular phenotypic effects were found to be similar to those triggered by knock-down of NPC1 expression using siRNAs and were counteracted by NPC1 overexpression, thus supporting the contribution of NPC1 to AH-mediated lipid accumulation in macrophages. Finally, both NPC1 down-expression and lipid accumulation in response to TCDD were found to be abolished through knock-down of the AH receptor (AHR), a ligand-activated transcription factor mediating many effects of AHs. CONCLUSION: Our data have shown that contaminants such as TCDD and BP repress NPC1 expression in macrophages in an AHR-dependent manner, which likely contributes to macrophage lipid accumulation caused by these environmental chemicals. Thus, NPC1 appears to be a new molecular target regulated by environmental AHs and putatively involved in their deleterious cardiovascular effects

TNFalpha- and NF-kappaB-dependent induction of the chemokine CCL1 in human macrophages exposed to the atherogenic lipoprotein(a).

International audienceAIMS: CCL1 is a chemokine thought to contribute to cardiovascular diseases and recently reported to be regulated by the pro-atherogenic lipoprotein(a) (Lp(a)) and the ligand-activated aryl hydrocarbon receptor (AhR). The present study was designed to investigate molecular regulatory pathways involved in Lp(a)-mediated induction of CCL1. MAIN METHODS: CCL1 regulation was studied in Lp(a)-exposed human primary macrophages using mainly quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay and electrophoretic mobility shift assay (EMSA). KEY FINDINGS: Using the AhR antagonist alpha-napthtoflavone, the translational inhibitor cycloheximide and anti-tumor necrosis factor alpha (TNFalpha) neutralizing antibodies, we demonstrated that Lp(a)-mediated mRNA induction of CCL1 occurs in an AhR-independent manner and requires de novo protein synthesis of TNFalpha. Involvement of this cytokine was further underlined by the fact that it increased expression and secretion of CCL1 by itself in macrophages. DNA binding activity of NF-kappaB, a well-known molecular effector of TNFalpha, was moreover activated by Lp(a) in a TNFalpha-dependent manner and the use of the NF-kappaB inhibitor Bay 11-7082 blocked Lp(a)-triggered CCL1 induction. In addition, Lp(a) induced binding of NF-kappaB to a NF-kappaB consensus element on CCL1 promoter as assessed by EMSA. Co-exposure to Lp(a) and the AhR ligand benzo(a)pyrene was finally shown to superinduce CCL1 expression in human macrophages, supporting the conclusion that Lp(a) and AhR ligands act on CCL1 through independent ways. SIGNIFICANCE: These data suggest that Lp(a)-triggered induction of CCL1 expression is mediated by TNFalpha and subsequent activation of NF-kappaB, without AhR involvement

Nanocarb-21: a miniature Fourier-Transform spectro-imaging concept for a daily monitoring of greenhouse gas concentration on the earth surface

International audienceEarth's positive radiative forcing is significantly accelerated by massive anthropogenic emissions of greenhouse gases, like carbon dioxide and methane [1]. Since 2014 the concentration of CO2 exceeds 400 parts per million (ppm), and the concentration of CH4 climbs up to 1900 parts per billion (ppb) [2] with a constant annual increase. Thereby it is a major issue to quantify the impact and potential disturbances induced on the geophysical natural carbon cycle. To better constrain climate models, it is important to improve our knowledge of CO2 fluxes between terrestrial reservoirs (biosphere, atmosphere and ocean) and to be able to distinguish natural and anthropogenic sources and sinks of carbon. Currently, a few space missions are dedicated to the monitoring of greenhouse gas concentration, such as OCO and GOSAT, potentially soon relayed by ESA mission CarbonSat and CNES mission MicroCarb. This spatial constellation is backed on ground by a network of stations. The ultimate goal is to be able to monitoring the greenhouse gas emission from local (city) to global scale (Earth) systematically at any time [3].Nevertheless, the revisit frequency is not yet sufficient to reach a daily coverage. There is also not real continuous sampling of the surface (only obtain by averaging data over time).Within this context we propose the NanoCarb-21 space mission, to complete the observational data flows with high spatially resolved daily data, additionally to the MicroCarb mission. This goal requires a large constellation of satellites in orbit at a given moment. We can realistically achieve this by considering nanosatellites, cheaper to develop, product and launch. It is a huge challenge to make science with a cubesat, considering miniaturization issues of the payload. Thus we cannot aim to be independent of MicroCarb mission and of the existing constellation, for example concerning the limited on-board calibration systems.We present in this paper the design of an ultra-compact imaging spectrometer for the NanoCarb-21 mission, based on the last developments about μSPOC (Spectrometer on Chip) technology at the ONERA and IPAG. We firstly describe the preliminary mission elements in the section II. Then the section III presents the payload, by detailing μSPOC technology, conversion into imaging-spectrometer, and the current optical/implementation design. We finally expose in the sections IV and V our pre-phase-0 studies, consisting in optimizing the design, maximizing the sensitivity, and predicting some performances, according to numerical simulations presented in the section IV

Microalgal carotenoids and phytosterols regulate biochemical mechanisms involved in human health and disease prevention

International audienceMicroalgae are photosynthetic microorganisms that produce numerous bioactive molecules that can be used as food supplement to prevent chronic disease installation. Indeed, they produce phycobiliproteins, polysaccharides, lipids, carotenoids and sterolic compounds. The use of microalgae in human nutrition provide a mixture of these molecules with synergistic effect. The aim of this review is to present the specific roles played by the xanthophylls, and specifically astaxanthin and fucoxanthin, two high added value carotenoids, and by microalgal phytosterols such as β-sitosterol, campesterol and stigmasterol on several cell mechanisms involved in the prevention of cardiometabolic diseases and cancers. This review explains how these microalgal molecules modulate cell signaling pathways involved in carbohydrate and lipid metabolisms, inflammation, apoptosis, invasion and metastasis. Xanthophylls and phytosterols are involved in the reduction of inflammatory markers in relation with the regulation of the c-Jun N-terminal kinases and nuclear factor-kappa B signaling pathways, and suppression of production of pro-inflammatory mediators. Xanthophylls act on glucose and lipid metabolisms via both the upregulation of peroxisome proliferator-activated receptors (PPARs) and glucose transporters and its effects on the expression of enzymes involved in fatty acid synthesis and cholesterol metabolism. Their anti-cancer effects are related to the induction of intrinsic apoptosis due to down-regulation of key regulatory kinases. The anti-angiogenesis, anti-proliferative and anti-invasive effects are correlated with decreased production of endothelial growth factors and of matrix metalloproteinases. Phytosterols have a major role on cholesterol absorption via modification of the activities of Niemann-Pick C1 like 1 and ATP-binding cassette transporters and on cholesterol esterification. Their action are also related with the modulation of PPARs and sterol regulatory element-binding protein-1 activities

Combustion Particle-Induced Changes in Calcium Homeostasis A Contributing Factor to Vascular Disease?

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