STEROL REGULATION OF HEPATIC LIPASE. A NOVEL ROLE FOR STEROL REGULATORY ELEMENT BINDING PROTEIN IN CHOLESTEROL HOMEOSTASIS

Hepatic lipase (HL) plays a critical role in the modulation of plasma lipoprotein concentrations and specifically the concentrations of high density lipoproteins and small low density lipoproteins. HL is likely to play a role in cellular cholesterol homeostasis. Despite numerous studies aimed at characterizing HL regulation, the role of cholesterol in controlling HL expression and/or activity levels remains unclear. In Fu5AH and McA-RH7777 rat hepatoma cells, cholesterol treatment resulted in a marked decrease in secreted rat HL (rHL) mass. Similarly, the acyl-CoA:cholesterol acyltransferase inhibitor 58-035 decreased rHL secretion, suggesting that unesterified cholesterol mediated the downregulation. Cholesterol alone or in combination with 25-hydroxy-cholesterol, or 58-035 decreased rHL mRNA levels without affecting mRNA degradation rate. Sterol Regulatory Element Binding Proteins (SREBPs) are the major transcription factors mediating the feedback regulation of cholesterol levels. Sterol treatments decreased nuclear SREBPs in human HepG2 cells without affecting the activity of a -1480/+14 human HL (hHL) promoter luciferase construct in rat or human cells. In HepG2 cells, statin (compactin) treatment or over-expression of nuclear SREBP1a (nSREBP1a) decreased the activity of a -117/+14 hHL promoter construct and HL mRNA levels. Forced expression of nSREBP1a reversed the Upstream Stimulatory Factor 1 (USF1)-mediated activation of hHL promoter constructs. Gel-shift and supershift assays identified binding sites for Hepatocyte Nuclear Factor 1 (HNF1), HNF4 and USF1 within the hHL promoter at -70/-48, -252/-218, and -317/-298 respectively. Binding of these factors was diminished using nuclear extracts from sterol or compactin treated cells. No direct binding of nSREBP to the hHL promoter was identified. SREBP1a bound to USF1 in co-immunoprecipitation experiments, suggesting inhibition of HL transcription by cholesterol or compactin may occur through SREBP1 interaction with USF1 or its co-activators. In rat cells, cholesterol or 58-035 decreased rHL protein synthesis while protein turnover was unchanged. In vitro translation assays demonstrated a decrease in HL translation efficiency in sterol-treated cytoplasmic extracts. These experiments provide evidence for a novel aspect of the function of SREBPs in the crosstalk between cholesterol and fatty acid/triglyceride metabolism

Effect of body length, trophic position and habitat use on mercury concentrations of sharks from contrasted ecosystems in the southwestern Indian Ocean

International audienceThe non-essential metal mercury (Hg) can have deleterious effects on health of organisms, and tends to bioaccumulate with age in long-lived organisms and to biomagnify along food chains. Because sharks are fished for human consumption and their Hg levels are frequently above the maximum Hg concentration recommended for fish consumption, understanding the drivers of Hg concentration is of considerable interest. Total Hg concentrations were analysed in muscle tissues of 14 shark and 2 batoid species (n = 339 individuals) sampled across multiple habitats (coastal, oceanic and bathyal) in the southwestern Indian Ocean. Stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) were analysed to assess whether relative trophic position and foraging habitats affected Hg concentrations. Hg concentrations increased with δ15N and body length, highlighting the mechanisms of bioaccumulation and biomagnification in relation with the trophic position and size of the individuals. Habitats where elasmobranchs were collected also affected their Hg concentrations. Bathyal sharks had high Hg concentrations that were almost similar to those of oceanic species, despite their lower relative trophic position. Higher bioavailability of Hg due to its enhanced methylation in deeper waters was considered as the most likely explanation for this result. These results highlight that multiple factors contribute to mercury accumulation in elasmobranchs

Feeding ecology of Southern Ocean seastars inferred from stable isotopes ratios

The Southern Ocean is currently subjected to strong and contrasted impacts of climate change. The Western Antarctic Peninsula is one of the most rapidly warming regions of the world, resulting in sea ice cover decreases. Increasing seawater temperature and sea ice cover reduction in Western Antarctic Peninsula and associated regions will likely impact food web functioning through temperature-related changes in consumer physiology, modifications of benthic community structure (e.g. expansion of exogenous species such as predatory crabs), modifications of benthic-pelagic coupling intensity or disruption of benthic production. Asteroids (Echinoderms) are an important group of southern benthos. This group also has a great trophic variability and is potentially more resistant than other organisms to temperature changes (Peck et al. 2008). Consequently, they will be likely impacted by modifications in food webs functioning rather by direct warming and investigating their trophic ecology is necessary to infer how climate change will impact them. In this context, the aim of this study is to use stable isotopes ratios of C, N and S to infer sea stars trophic ecology. 16 species of sea stars spanning 10 different families sampled in multiple and contrasted habitats across Subantarctic (South Georgia, South Sandwich Islands, Falkland Islands) and Antarctic (South Shetland Islands, South Orkney Islands, Western Antarctic Peninsula) locations. In total, tegument samples from 213 specimens was analysed. Diversity and plasticity of asteroid diet along Southern Ocean coasts were explored through isotopic niche parametrisation (e.g. niche width and overlap between species and/or populations; Jackson et al. 2011). The data will also be used in a larger scale research project on the trophic ecology of Antarctic sea stars. This project will notably compare trophic resources supporting asteroid communities in Western Antarctic Peninsula, where sea ice cover is decreasing, and in Terre Adélie, where sea ice cover is increasing (Parkinson & Cavalieri 2012). Ultimately, this project will help understanding which ecological processes determine how an animal group copes with environmental modifications linked to climate change

β-N-Methylamino-L-alanine Induces Neurological Deficits and Shortened Life Span in Drosophila

The neurotoxic non-protein amino acid, β-N-methylamino-L-alanine (BMAA), was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam. Recently, BMAA has been implicated as a fierce environmental factor that contributes to the etiology of Alzheimer’s and Parkinson’s diseases, in addition to ALS. However, the toxicity of BMAA in vivo has not been clearly demonstrated. Here we report our investigation of the neurotoxicity of BMAA in Drosophila. We found that dietary intake of BMAA reduced life span, locomotor functions, and learning and memory abilities in flies. The severity of the alterations in phenotype is correlated with the concentration of BMAA detected in flies. Interestingly, developmental exposure to BMAA had limited impact on survival rate, but reduced fertility in females, and caused delayed neurological impairment in aged adults. Our studies indicate that BMAA exposure causes chronic neurotoxicity, and that Drosophila serves as a useful model in dissecting the pathogenesis of ALS/PDC

Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.

International audienceAn efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines

Trophic ecology of Southern Ocean sea stars inferred from stable isotopes ratios of C and N

The Southern Ocean undergoes strong and contrasted impacts of climate change. Increasing seawater temperature and sea ice cover reduction in Western Antarctic Peninsula and associated regions will likely impact food web structure and function. Sea stars (Echinoderms: Asteroidea) are an important group of the Southern Ocean benthos. They typically have highly variable feeding habits and are potentially more resistant than other organisms to temperature changes. Consequently, they will likely be impacted by modifications of the food web rather than by direct warming. Investigating their trophic ecology is therefore necessary to infer how climate change will impact them. In this context, the aim of this study was to use stable isotopes ratios of C, N and S to infer sea stars trophic ecology. During austral summers 2006 and 2009, sea stars were sampled in Subantarctic and Antarctic locations, with most of the samples coming from South Shetland Islands and South Georgia. The isotopic niche (proxy of the trophic niche) associated to each sea star population was explored through SIBER (Stable Isotope Bayesian Ellipses in R) metrics. Stable isotope ratios of sea stars were clearly different between South Shetland Islands and South Georgia. Sea stars of South Shetland Islands had smaller isotopic niches than sea stars of South Georgia. The overlap between the isotopic niches of sea star species was also important in South Shetland Islands, while isotopic niches of South Georgia were well separated. Difference of niche width and overlap between the two regions may be the result of different environmental conditions. In South Shetland Islands, sea star species may exploit a common benthic community relying on organic matter released during sea ice summer melting. In contrast, South Georgia is an oligotrophic environment with no sea ice. As resources are more limited, a higher trophic segregation between sea stars may appear to limit competition. Ultimately, this project highlighted the importance of sea ice in the trophic ecology of Antarctic sea stars. Our results suggest that future reduction of sea ice extent in Western Antarctica may have deleterious effect on sea star populations

Influence of liquid structure on diffusive isotope separation in molten silicates and aqueous solutions

Molecular diffusion in natural volcanic liquids discriminates between isotopes of major ions (e.g., Fe, Mg, Ca, and Li). Although isotope separation by diffusion is expected on theoretical grounds, the dependence on mass is highly variable for different elements and in different media. Silicate liquid diffusion experiments using simple liquid compositions were carried out to further probe the compositional dependence of diffusive isotopic discrimination and its relationship to liquid structure. Two diffusion couples consisting of the mineral constituents anorthite (CaAl{sub 2}Si{sub 2}O{sub 8}; denoted AN), albite (NaAlSi{sub 3}O{sub 8}; denoted AB), and diopside (CaMgSi{sub 2}O{sub 6}; denoted DI) were held at 1450°C for 2 h and then quenched to ambient pressure and temperature. Major-element as well as Ca and Mg isotope profiles were measured on the recovered quenched glasses. In both experiments, Ca diffuses rapidly with respect to Si. In the AB–AN experiment, D{sub Ca}/D{sub Si} ~ 20 and the efficiency of isotope separation for Ca is much greater than in natural liquid experiments where D{sub Ca}/D{sub Si} ~ 1. In the AB–DI experiment, D{sub Ca}/D{sub Si} ~ 6 and the efficiency of isotope separation is between that of the natural liquid experiments and the AB–AN experiment. In the AB–DI experiment, D{sub Mg}/D{sub Si} ~ 1 and the efficiency of isotope separation for Mg is smaller than it is for Ca yet similar to that observed for Mg in natural liquids. The results from the experiments reported here, in combination with results from natural volcanic liquids, show clearly that the efficiency of diffusive separation of Ca isotopes is systematically related to the solvent-normalized diffusivity—the ratio of the diffusivity of the cation (D{sub Ca}) to the diffusivity of silicon (D{sub Si}). The results on Ca isotopes are consistent with available data on Fe, Li, and Mg isotopes in silicate liquids, when considered in terms of the parameter D{sub cation}/D{sub Si}. Cations diffusing in aqueous solutions display a similar relationship between isotopic separation efficiency and D{sub cation} =D{sub H 2 O} , although the efficiencies are smaller than in silicate liquids. Our empirical relationship provides a tool for predicting the magnitude of diffusive isotopic effects in many geologic environments and a basis for a more comprehensive theory of isotope separation in liquid solutions. We present a conceptual model for the relationship between diffusivity and liquid structure that is consistent with available data

Complementary and alternative medicine use in glioma patients in France

PURPOSE Complementary and alternative medicine (CAM) use increases in cancer patients, including adult patients with diffuse gliomas. METHODS Questionnaires addressing CAM use were distributed to adult patients with gliomas of WHO grades II-IV and ECOG performance score of 0-2 during hospital visits and filled in anonymously. The study was conducted in nine centers in France from May 2017 to May 2018. Descriptive cohort analyses and comparative analyses according to gender, age, WHO grade, and recurrent versus newly diagnosed disease were conducted. RESULTS Two hundred twenty-seven questionnaires were collected; 135 patients (59%) were male. Median age was 48 years, 105 patients (46%) declared having glioblastoma, 99 patients (43%) declared having recurrent disease. Hundred-three patients (45%) had modified their alimentary habits after the glioma diagnosis. At the time of the questionnaire, 100 patients (44%) were on complementary treatment, mainly vitamins and food supplements, and 73 patients (32%) used alternative medicine approaches, mainly magnetism and acupuncture. In total, 154 patients (68%) declared using at least one of these approaches. Expenditures exceeding 100 € per month were reported by users in 14% for modification of alimentary habits, in 25% for complementary treatment, and in 18% for alternative medicines. All approaches were commonly considered as improving quality of life and experienced as efficient, notably those associated with more expenditures. CONCLUSIONS CAM are frequently used by glioma patients in France. Underlying needs and expectations, as well as potential interactions with tumor-specific treatments, and financial and quality of life burden, should be discussed with patients and caregivers