BmNHR96 participate BV entry of BmN-SWU1 cells via affecting the cellular cholesterol level.

Science.gov (United States)

Dong, Xiao-Long; Liu, Tai-Hang; Wang, Wei; Pan, Cai-Xia; Du, Guo-Yu; Wu, Yun-Fei; Pan, Min-Hui; Lu, Cheng

2017-01-22

B.mori nucleopolyhedrovirus (BmNPV), which produces BV and ODV two virion phenotypes in its life cycle, caused the amount of economic loss in sericulture. But the mechanism of its infection was still unclear. In this study we characterized B.mori nuclear hormone receptor 96 (BmNHR96) as a NHR96 family member, which was localized in the nucleus. We also found BmNHR96 over-expression could enhance the entry of BV as well as cellular cholesterol level. Furthermore, we validated that BmNHR96 increased membrane fusion mediated by GP64, which could probably promote BV-infection. In summary, our study suggested that BmNHR96 plays an important role in BV infection and this function probably actualized by affecting cellular cholesterol level, and our results provided insights to the mechanisms of BV-infection of B.mori. Copyright © 2016 Elsevier Inc. All rights reserved.

Transintestinal cholesterol excretion in humans

NARCIS (Netherlands)

Reeskamp, Laurens F.; Meessen, Emma C. E.; Groen, Albert K.

2018-01-01

Purpose of review To discuss recent insights into the measurement and cellular basis of transintestinal cholesterol excretion (TICE) in humans and to explore TICE as a therapeutic target for increasing reverse cholesterol transport. Recent findings TICE is the net effect of cholesterol excretion by

Relationship between plasma cholesterol levels and cholesterol esterification in isolated human mononuclear cells

International Nuclear Information System (INIS)

Dallongeville, J.; Davignon, J.; Lussier-Cacan, S.

1990-01-01

The authors studied the relationship between plasma lipoprotein concentrations and cholesterol esterification in freshly isolated human mononuclear cells from 27 normolipidemic and 32 hyperlipidemic individuals. Cells were either incubated for 5 hours with radiolabeled oleate immediately after isolation or were preincubated for 18 hours in the presence of exogenous cholesterol, and then incubated with [ 14 C]sodium-oleate-albumin complex. In the absence of exogenous cholesterol, control and hypercholesterolemic subjects had similarly low values of intracellular cholesterol esterification. In the presence of exogenous cholesterol, both hypertriglyceridemic and hypercholesterolemic subjects had higher cholesterol esterification than controls. There was a significant correlation between the rate of cholesterol esterification and plasma total cholesterol. These results suggest that plasma cholesterol levels may regulate mononuclear cell intra-cellular cholesterol esterification in humans

Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling

Energy Technology Data Exchange (ETDEWEB)

Huang, Pengxiang; Nedelcu, Daniel; Watanabe, Miyako; Jao, Cindy; Kim, Youngchang; Liu, Jing; Salic, Adrian

2016-08-01

In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and is unique among CRD-containing receptors. We demonstrate that Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol.

Lack of P2Y(13) in mice fed a high cholesterol diet results in decreased hepatic cholesterol content, biliary lipid secretion and reverse cholesterol transport

NARCIS (Netherlands)

Lichtenstein, Laeticia; Serhan, Nizar; Annema, Wijtske; Combes, Guillaume; Robaye, Bernard; Boeynaems, Jean-Marie; Perret, Bertrand; Tietge, Uwe J. F.; Laffargue, Muriel; Martinez, Laurent O.

2013-01-01

Background: The protective effect of HDL is mostly attributed to their metabolic function in reverse cholesterol transport (RCT), a process whereby excess cellular cholesterol is taken up from peripheral cells, processed in HDL particles, and later delivered to the liver for further metabolism and

Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin

DEFF Research Database (Denmark)

Beedholm-Ebsen, Rasmus; van de Wetering, Koen; Hardlei, Tore

2010-01-01

transporters by cellular gene silencing showed a role in cellular Cbl efflux of the ATP-binding cassette (ABC)-drug transporter, ABCC1, alias multidrug resistance protein 1 (MRP1), which is present in the basolateral membrane of intestinal epithelium and in other cells. The ability of MRP1 to mediate ATP...... and kidney. In contrast, Cbl accumulates in the terminal part of the intestine of these mice, suggesting a functional malabsorption because of a lower epithelial basolateral Cbl efflux. The identification of this Cbl export mechanism now allows the delineation of a coherent pathway for Cbl trafficking from...

Apolipoprotein M promotes mobilization of cellular cholesterol in vivo

DEFF Research Database (Denmark)

Elsøe, Sara; Christoffersen, Christina; Luchoomun, Jayraz

2013-01-01

The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases prebeta-HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice.......The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases prebeta-HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice....

Phospholipase A2-treated human high-density lipoprotein and cholesterol movements: exchange processes and lecithin: cholesterol acyltransferase reactivity.

Science.gov (United States)

Chollet, F; Perret, B P; Chap, H; Douste-Blazy, L

1986-02-12

Human HDL3 (d 1.125-1.21 g/ml) were treated by an exogenous phospholipase A2 from Crotalus adamenteus in the presence of albumin. Phosphatidylcholine hydrolysis ranged between 30 and 90% and the reisolated particle was essentially devoid of lipolysis products. (1) An exchange of free cholesterol was recorded between radiolabelled erythrocytes at 5-10% haematocrit and HDL3 (0.6 mM total cholesterol) from 0 to 12-15 h. Isotopic equilibration was reached. Kinetic analysis of the data indicated a constant rate of free cholesterol exchange of 13.0 microM/h with a half-time of equilibration around 3 h. Very similar values of cholesterol exchange, specific radioactivities and kinetic parameters were measured when phospholipase-treated HDL replaced control HDL. (2) The lecithin: cholesterol acyltransferase reactivity of HDL3, containing different amounts of phosphatidylcholine, as achieved by various degrees of phospholipase A2 treatment, was measured using a crude preparation of lecithin: cholesterol acyltransferase (the d 1.21-1.25 g/ml plasma fraction). The rate of esterification was determined between 0 and 12 h. Following a 15-30% lipolysis, the lecithin: cholesterol acyltransferase reactivity of HDL3 was reduced about 30-40%, and then continued to decrease, though more slowly, as the phospholipid content was further lowered in the particle. (3) The addition of the lecithin: cholesterol acyltransferase preparation into an incubation medium made of labelled erythrocytes and HDL3 promoted a movement of radioactive cholesterol out of cells, above the values of exchange, and an accumulation of cholesteryl esters in HDL. This reflected a mass consumption of free cholesterol, from both the cellular and the lipoprotein compartments upon the lecithin: cholesterol acyltransferase action. As a consequence of a decreased reactivity, phospholipase-treated HDL (with 2/3 of phosphatidylcholine hydrolyzed) proved much less effective in the lecithin: cholesterol acyltransferase

The structure of a cholesterol-trapping protein

Science.gov (United States)

cholesterol-trapping protein Contact: Dan Krotz, dakrotz@lbl.gov Berkeley Lab Science Beat Lab website index Institute researchers determined the three-dimensional structure of a protein that controls cholesterol level in the bloodstream. Knowing the structure of the protein, a cellular receptor that ensnares

Synthesis of the oxysterol, 24(S, 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol

Directory of Open Access Journals (Sweden)

Brown Andrew J

2007-04-01

Full Text Available Abstract Aim The effects of 24(S,25-epoxycholesterol (24,25EC on aspects of cholesterol homeostasis is well-documented. When added to cells, 24,25EC decreases cholesterol synthesis and up-regulates cholesterol efflux genes, including ABCA1. Synthesis of 24,25EC occurs in a shunt of the mevalonate pathway which also produces cholesterol. Therefore, 24,25EC synthesis should be subject to the same negative feedback regulation as cholesterol synthesis. To date, no role has been ascribed to 24,25EC in light of the fact that increased accumulation of cholesterol should decrease formation of this oxysterol through feedback inhibition. This leads to the intriguing paradox: why inhibit production of an apparently important regulator of cholesterol homeostasis when it is needed most? Methods We used a combination of pharmacological and genetic approaches in Chinese Hamster Ovary cell-lines to investigate this paradox. Endogenous synthesis of 24,25EC was manipulated using partial inhibition of the enzyme, Oxidosqualene Cyclase. Changes in cholesterol and 24,25EC synthesis were determined using metabolic labelling with [1-14C]-acetate, thin-layer chromatography and phosphorimaging. Transcriptional effects mediated via SREBP and LXR were analysed by luciferase reporter assays. Results We showed that cholesterol addition to cells lead to a rapid and preferential inhibition of 24,25EC synthesis. Addition of 24,25EC resulted in parallel inhibition of 24,25EC and cholesterol synthesis. Furthermore, we used a variety of approaches to examine the relationship between cholesterol and 24,25EC synthesis, including cell-lines with different rates of cholesterol synthesis, varying cholesterol synthetic rates by pre-treatment with a statin, or lipoprotein cholesterol loading of macrophages. In all cases, we showed that 24,25EC synthesis faithfully tracked cholesterol synthesis. Moreover, changes in 24,25EC synthesis exerted downstream effects, reducing SREBP

Plasma cholesterol and endogenous cholesterol synthesis during refeeding in anorexia nervosa.

Science.gov (United States)

Feillet, F; Feillet-Coudray, C; Bard, J M; Parra, H J; Favre, E; Kabuth, B; Fruchart, J C; Vidailhet, M

2000-04-01

Normal or high levels of cholesterol have been measured in patients with anorexia nervosa (AN). Given that cholesterol intake in AN is usually very low, the reasons for this anomaly are not clearly understood. We studied lipid and lipoprotein profiles and endogenous cholesterol synthesis, estimated by serum lathosterol, in a population of 14 girls with AN, before and during a period of 30 days refeeding. The initial body mass index (BMI) of the patients was 13.41+/-1.62 kg/m(2). No changes were observed during refeeding in endocrine parameters (ACTH, cortisol and estradiol). At Day 0 the lipids data measured here showed normal levels of triglycerides, and total cholesterol at the upper limits of the normal range (5.44+/-1 mmol/l). At this time, total and LDL cholesterol were negatively correlated with transthyretin and BMI. Serum lathosterol (a precursor in cholesterol synthesis pathway) increased significantly (5.99+/-1.75 (Day 0) vs. 8.39+/-2.96 (Day 30); P=0.02) while there was a significant decrease in apo B (0.79+/-0.33 (Day 0) vs. 0. 60+/-0.17 g/l (Day 30), P=0.02) with refeeding. Thus, patients with initial high cholesterol levels have the worst nutritional status and high cholesterol levels are not related to a de novo synthesis. This profile returns to normal with refeeding. An increase of cellular cholesterol uptake may be responsible for this apparently paradoxical evolution with increase of cholesterol synthesis and decrease of apo B during renutrition.

Cholesterol transfer at endosomal-organelle membrane contact sites.

Science.gov (United States)

Ridgway, Neale D; Zhao, Kexin

2018-06-01

Cholesterol is delivered to the limiting membrane of late endosomes by Niemann-Pick Type C1 and C2 proteins. This review summarizes recent evidence that cholesterol transfer from endosomes to the endoplasmic reticulum and other organelles is mediated by lipid-binding proteins that localize to membrane contact sites (MCS). LDL-cholesterol in the late endosomal/lysosomes is exported to the plasma membrane, where most cholesterol resides, and the endoplasmic reticulum, which harbors the regulatory complexes and enzymes that control the synthesis and esterification of cholesterol. A major advance in dissecting these cholesterol transport pathways was identification of frequent and dynamic MCS between endosomes and the endoplasmic reticulum, peroxisomes and plasma membrane. Positioned at these MCS are members of the oxysterol-binding protein (OSBP) and steroidogenic acute regulatory protein-related lipid-transfer family of lipid transfer proteins that bridge the opposing membranes and directly or indirectly mediate cholesterol transfer. OSBP-related protein 1L (ORP1L), ORP5 and ORP6 mediate cholesterol transfer to the endoplasmic reticulum that regulates cholesterol homeostasis. ORP1L and STARD3 also move cholesterol from the endoplasmic reticulum-to-late endosomal/lysosomes under low-cholesterol conditions to facilitate intraluminal vesicle formation. Cholesterol transport also occurs at MCS with peroxisomes and possibly the plasma membrane. Frequent contacts between organelles and the endo-lysosomal vesicles are sites for bidirectional transfer of cholesterol.

Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis

Science.gov (United States)

Chen, Jing; Zhang, Xiaolu; Kusumo, Handojo; Costa, Lucio G.; Guizzetti, Marina

2012-01-01

Disruption of cholesterol homeostasis in the central nervous system (CNS) has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. The CNS is a closed system with regard to cholesterol homeostasis, as cholesterol-delivering lipoproteins from the periphery cannot pass the blood-brain-barrier and enter the brain. Different cell types in the brain have different functions in the regulation of cholesterol homeostasis, with astrocytes producing and releasing apolipoprotein E and lipoproteins, and neurons metabolizing cholesterol to 24(S)-hydroxycholesterol. We present evidence that astrocytes and neurons adopt different mechanisms also in regulating cholesterol efflux. We found that in astrocytes cholesterol efflux is induced by both lipid-free apolipoproteins and lipoproteins, while cholesterol removal from neurons is triggered only by lipoproteins. The main pathway by which apolipoproteins induce cholesterol efflux is through ABCA1. By upregulating ABCA1 levels and by inhibiting its activity and silencing its expression, we show that ABCA1 is involved in cholesterol efflux from astrocytes but not from neurons. Furthermore, our results suggest that ABCG1 is involved in cholesterol efflux to apolipoproteins and lipoproteins from astrocytes but not from neurons, while ABCG4, whose expression is much higher in neurons than astrocytes, is involved in cholesterol efflux from neurons but not astrocytes. These results indicate that different mechanisms regulate cholesterol efflux from neurons and astrocytes, reflecting the different roles that these cell types play in brain cholesterol homeostasis. These results are important in understanding cellular targets of therapeutic drugs under development for the treatments of conditions associated with altered cholesterol homeostasis in the CNS. PMID:23010475

Nuclear Imprisonment: Viral Strategies to Arrest Host mRNA Nuclear Export

Directory of Open Access Journals (Sweden)

Beatriz M. A. Fontoura

2013-07-01

Full Text Available Viruses possess many strategies to impair host cellular responses to infection. Nuclear export of host messenger RNAs (mRNA that encode antiviral factors is critical for antiviral protein production and control of viral infections. Several viruses have evolved sophisticated strategies to inhibit nuclear export of host mRNAs, including targeting mRNA export factors and nucleoporins to compromise their roles in nucleo-cytoplasmic trafficking of cellular mRNA. Here, we present a review of research focused on suppression of host mRNA nuclear export by viruses, including influenza A virus and vesicular stomatitis virus, and the impact of this viral suppression on host antiviral responses.

Nuclear Imprisonment: Viral Strategies to Arrest Host mRNA Nuclear Export

Science.gov (United States)

Kuss, Sharon K.; Mata, Miguel A.; Zhang, Liang; Fontoura, Beatriz M. A.

2013-01-01

Viruses possess many strategies to impair host cellular responses to infection. Nuclear export of host messenger RNAs (mRNA) that encode antiviral factors is critical for antiviral protein production and control of viral infections. Several viruses have evolved sophisticated strategies to inhibit nuclear export of host mRNAs, including targeting mRNA export factors and nucleoporins to compromise their roles in nucleo-cytoplasmic trafficking of cellular mRNA. Here, we present a review of research focused on suppression of host mRNA nuclear export by viruses, including influenza A virus and vesicular stomatitis virus, and the impact of this viral suppression on host antiviral responses. PMID:23872491

Introducing inducible fluorescent split cholesterol oxidase to mammalian cells.

Science.gov (United States)

Chernov, Konstantin G; Neuvonen, Maarit; Brock, Ivonne; Ikonen, Elina; Verkhusha, Vladislav V

2017-05-26

Cholesterol oxidase (COase) is a bacterial enzyme catalyzing the first step in the biodegradation of cholesterol. COase is an important biotechnological tool for clinical diagnostics and production of steroid drugs and insecticides. It is also used for tracking intracellular cholesterol; however, its utility is limited by the lack of an efficient temporal control of its activity. To overcome this we have developed a regulatable fragment complementation system for COase cloned from Chromobacterium sp. The enzyme was split into two moieties that were fused to FKBP (FK506-binding protein) and FRB (rapamycin-binding domain) pair and split GFP fragments. The addition of rapamycin reconstituted a fluorescent enzyme, termed split GFP-COase, the fluorescence level of which correlated with its oxidation activity. A rapid decrease of cellular cholesterol induced by intracellular expression of the split GFP-COase promoted the dissociation of a cholesterol biosensor D4H from the plasma membrane. The process was reversible as upon rapamycin removal, the split GFP-COase fluorescence was lost, and cellular cholesterol levels returned to normal. These data demonstrate that the split GFP-COase provides a novel tool to manipulate cholesterol in mammalian cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of α1 Na/K-ATPase Expression by Cholesterol*

OpenAIRE

Chen, Yiliang; Li, Xin; Ye, Qiqi; Tian, Jiang; Jing, Runming; Xie, Zijian

2011-01-01

We have reported that α1 Na/K-ATPase regulates the trafficking of caveolin-1 and consequently alters cholesterol distribution in the plasma membrane. Here, we report the reciprocal regulation of α1 Na/K-ATPase by cholesterol. Acute exposure of LLC-PK1 cells to methyl β-cyclodextrin led to parallel decreases in cellular cholesterol and the expression of α1 Na/K-ATPase. Cholesterol repletion fully reversed the effect of methyl β-cyclodextrin. Moreover, inhibition of intracellular cholesterol tr...

LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor

NARCIS (Netherlands)

Zelcer, Noam; Hong, Cynthia; Boyadjian, Rima; Tontonoz, Peter

2009-01-01

Cellular cholesterol levels reflect a balance between uptake, efflux, and endogenous synthesis. Here we show that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of low-density

Protein complexes and cholesterol in the control of late endosomal dynamicsCholesterol and multi-protein complexes in the control of late endosomal dynamics

NARCIS (Netherlands)

Kant, Rik Henricus Nicolaas van der

2013-01-01

Late endosomal transport is disrupted in several diseases such as Niemann-Pick type C, ARC syndrome and Alzheimer’s disease. This thesis describes the regulation of late endosomal dynamics by cholesterol and multi-protein complexes. We find that cholesterol acts as a cellular tomtom that steers the

The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA.

Science.gov (United States)

Booth, David S; Cheng, Yifan; Frankel, Alan D

2014-12-08

The HIV Rev protein routes viral RNAs containing the Rev Response Element (RRE) through the Crm1 nuclear export pathway to the cytoplasm where viral proteins are expressed and genomic RNA is delivered to assembling virions. The RRE assembles a Rev oligomer that displays nuclear export sequences (NESs) for recognition by the Crm1-Ran(GTP) nuclear receptor complex. Here we provide the first view of an assembled HIV-host nuclear export complex using single-particle electron microscopy. Unexpectedly, Crm1 forms a dimer with an extensive interface that enhances association with Rev-RRE and poises NES binding sites to interact with a Rev oligomer. The interface between Crm1 monomers explains differences between Crm1 orthologs that alter nuclear export and determine cellular tropism for viral replication. The arrangement of the export complex identifies a novel binding surface to possibly target an HIV inhibitor and may point to a broader role for Crm1 dimerization in regulating host gene expression.

Influence of the membrane environment on cholesterol transfer.

Science.gov (United States)

Breidigan, Jeffrey Michael; Krzyzanowski, Natalie; Liu, Yangmingyue; Porcar, Lionel; Perez-Salas, Ursula

2017-12-01

Cholesterol, an essential component in biological membranes, is highly unevenly distributed within the cell, with most localized in the plasma membrane while only a small fraction is found in the endoplasmic reticulum, where it is synthesized. Cellular membranes differ in lipid composition and protein content, and these differences can exist across their leaflets too. This thermodynamic landscape that cellular membranes impose on cholesterol is expected to modulate its transport. To uncover the role the membrane environment has on cholesterol inter- and intra-membrane movement, we used time-resolved small angle neutron scattering to study the passive movement of cholesterol between and within membranes with varying degrees of saturation content. We found that cholesterol moves systematically slower as the degree of saturation in the membranes increases, from a palmitoyl oleyl phosphotidylcholine membrane, which is unsaturated, to a dipalmitoylphosphatidylcholine (DPPC) membrane, which is fully saturated. Additionally, we found that the energetic barrier to move cholesterol in these phosphatidylcholine membranes is independent of their relative lipid composition and remains constant for both flip-flop and exchange at ∼100 kJ/mol. Further, by replacing DPPC with the saturated lipid palmitoylsphingomyelin, an abundant saturated lipid of the outer leaflet of the plasma membrane, we found the rates decreased by a factor of two. This finding is in stark contrast with recent molecular dynamic simulations that predict a dramatic slow-down of seven orders of magnitude for cholesterol flipping in membranes with a similar phosphocholine and SM lipid composition. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

Science.gov (United States)

Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A.; Ghosh, Partha Pratim; Mitra, Prasenjit

2016-06-01

Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.

Membrane Cholesterol Modulates Superwarfarin Toxicity

Energy Technology Data Exchange (ETDEWEB)

Marangoni, M. Natalia; Martynowycz, Michael W.; Kuzmenko, Ivan; Braun, David; Polak, Paul E.; Weinberg, Guy; Rubinstein, Israel; Gidalevitz, David; Feinstein, Douglas L.

2016-04-26

Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content.

Monomethylarsonous acid inhibited endogenous cholesterol biosynthesis in human skin fibroblasts

Energy Technology Data Exchange (ETDEWEB)

Guo, Lei [Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521-0403 (United States); Xiao, Yongsheng [Department of Chemistry, University of California, Riverside, CA 92521-0403 (United States); Wang, Yinsheng, E-mail: yinsheng.wang@ucr.edu [Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521-0403 (United States); Department of Chemistry, University of California, Riverside, CA 92521-0403 (United States)

2014-05-15

Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 human skin fibroblasts following acute MMA(III) exposure. Among the ∼ 6500 unique proteins quantified, ∼ 300 displayed significant changes in expression after exposure with 2 μM MMA(III) for 24 h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down-regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content. - Highlights: • MMA(III)-induced perturbation of the entire proteome of GM00637 cells is studied. • Quantitative proteomic approach revealed alterations of multiple cellular pathways. • MMA(III) inhibits de novo cholesterol biosynthesis. • MMA

Effect of apolipoprotein E-free high density lipoproteins on cholesterol metabolism in cultured pig hepatocytes

International Nuclear Information System (INIS)

Bachorik, P.S.; Virgil, D.G.; Kwiterovich, P.O. Jr.

1987-01-01

We studied cholesterol synthesis from [ 14 C]acetate, cholesterol esterification from [ 14 C]oleate, and cellular cholesterol and cholesteryl ester levels after incubating cells with apoE-free high density lipoproteins (HDL) or low density lipoproteins (LDL). LDL suppressed synthesis by up to 60%, stimulated esterification by up to 280%, and increased cell cholesteryl ester content about 4-fold. Esterification increased within 2 h, but synthesis was not suppressed until after 6 h. ApoE-free HDL suppressed esterification by about 50% within 2 h. Cholesterol synthesis was changed very little within 6 h, unless esterification was maximally suppressed; synthesis was then stimulated about 4-fold. HDL lowered cellular unesterified cholesterol by 13-20% within 2 h and promoted the removal of newly synthesized cholesterol and cholesteryl esters. These changes were transient; by 24 h, both esterification and cellular unesterified cholesterol returned to control levels, and cholesteryl esters increased 2-3-fold. HDL core lipid was taken up selectively from 125 I-labeled [ 3 H]cholesteryl ester- and ether-labeled HDL. LDL core lipid uptake was proportional to LDL apoprotein uptake. The findings suggest that 1) the cells respond initially to HDL or LDL with changes in esterification, and 2) HDL mediates both the removal of free cholesterol from the cell and the delivery of HDL cholesteryl esters to the cell

Serum starvation of ARPE-19 changes the cellular distribution of cholesterol and Fibulin3 in patterns reminiscent of age-related macular degeneration.

Science.gov (United States)

Rajapakse, Dinusha; Peterson, Katherine; Mishra, Sanghamitra; Wistow, Graeme

2017-12-15

Retinal pigment epithelium (RPE) has been implicated as key source of cholesterol-rich deposits at Bruch's membrane (BrM) and in drusen in aging human eye. We have shown that serum-deprivation of confluent RPE cells is associated with upregulation of cholesterol synthesis and accumulation of unesterified cholesterol (UC). Here we investigate the cellular processes involved in this response. We compared the distribution and localization of UC and esterified cholesterol (EC); the age-related macular degeneration (AMD) associated EFEMP1/Fibulin3 (Fib3); and levels of acyl-coenzyme A (CoA): cholesterol acyltransferases (ACAT) ACAT1, ACAT2 and Apolipoprotein B (ApoB) in ARPE-19 cells cultured in serum-supplemented and serum-free media. The results were compared with distributions of these lipids and proteins in human donor eyes with AMD. Serum deprivation of ARPE-19 was associated with increased formation of FM dye-positive membrane vesicles, many of which co-labeled for UC. Additionally, UC colocalized with Fib3 in distinct granules. By day 5, serum-deprived cells grown on transwells secreted Fib3 basally into the matrix. While mRNA and protein levels of ACTA1 were constant over several days of serum-deprivation, ACAT2 levels increased significantly after serum-deprivation, suggesting increased formation of EC. The lower levels of intracellular EC observed under serum-deprivation were associated with increased formation and secretion of ApoB. The responses to serum-deprivation in RPE-derived cells: accumulation and secretion of lipids, lipoproteins, and Fib3 are very similar to patterns seen in human donor eyes with AMD and suggest that this model mimics processes relevant to disease progression. Published by Elsevier Inc.

Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

Energy Technology Data Exchange (ETDEWEB)

Hamm, Rebecca; Zeino, Maen [Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany); Frewert, Simon [Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken (Germany); Efferth, Thomas, E-mail: efferth@uni-mainz.de [Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany)

2014-11-15

Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H{sup +}-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.

Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

International Nuclear Information System (INIS)

Hamm, Rebecca; Zeino, Maen; Frewert, Simon; Efferth, Thomas

2014-01-01

Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H + -ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation

Pectin penta-oligogalacturonide reduces cholesterol accumulation by promoting bile acid biosynthesis and excretion in high-cholesterol-fed mice.

Science.gov (United States)

Zhu, Ru-Gang; Sun, Yan-Di; Hou, Yu-Ting; Fan, Jun-Gang; Chen, Gang; Li, Tuo-Ping

2017-06-25

Haw pectin penta-oligogalacturonide (HPPS) has important role in improving cholesterol metabolism and promoting the conversion of cholesterol to bile acids (BA) in mice fed high-cholesterol diet (HCD). However, the mechanism is not clear. This study aims to investigate the effects of HPPS on cholesterol accumulation and the regulation of hepatic BA synthesis and transport in HCD-fed mice. Results showed that HPPS significantly decreased plasma and hepatic TC levels but increased plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, compared to HCD. BA analysis showed that HPPS markedly decreased hepatic and small intestine BA levels but increased the gallbladder BA levels, and finally decreased the total BA pool size, compared to HCD. Studies of molecular mechanism revealed that HPPS promoted hepatic ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor BI (SR-BI) expression but did not affect ATB binding cassette transporter G5/G8 (ABCG5/8) expression. HPPS inactivated hepatic farnesoid X receptor (FXR) and target genes expression, which resulted in significant increase of cholesterol 7α-hydroxylase 1 (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) expression, with up-regulations of 204.2% and 33.5% for mRNA levels, respectively, compared with HCD. In addition, HPPS markedly enhanced bile salt export pump (BSEP) expression but didn't affect the sodium/taurocholate co-transporting polypeptide (NTCP) expression. In conclusion, the study revealed that HPPS reduced cholesterol accumulation by promoting BA synthesis in the liver and excretion in the feces, and might promote macrophage-to-liver reverse cholesterol transport (RCT) but did not liver-to-fecal RCT. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of Dietary Cholesterol on the Pathophysiology of Infectious and Autoimmune Disease

Directory of Open Access Journals (Sweden)

Catherine J. Andersen

2018-06-01

Full Text Available Cellular cholesterol metabolism, lipid raft formation, and lipoprotein interactions contribute to the regulation of immune-mediated inflammation and response to pathogens. Lipid pathways have been implicated in the pathogenesis of bacterial and viral infections, whereas altered lipid metabolism may contribute to immune dysfunction in autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Interestingly, dietary cholesterol may exert protective or detrimental effects on risk, progression, and treatment of different infectious and autoimmune diseases, although current findings suggest that these effects are variable across populations and different diseases. Research evaluating the effects of dietary cholesterol, often provided by eggs or as a component of Western-style diets, demonstrates that cholesterol-rich dietary patterns affect markers of immune inflammation and cellular cholesterol metabolism, while additionally modulating lipoprotein profiles and functional properties of HDL. Further, cholesterol-rich diets appear to differentially impact immunomodulatory lipid pathways across human populations of variable metabolic status, suggesting that these complex mechanisms may underlie the relationship between dietary cholesterol and immunity. Given the Dietary Guidelines for Americans 2015–2020 revision to no longer include limitations on dietary cholesterol, evaluation of dietary cholesterol recommendations beyond the context of cardiovascular disease risk is particularly timely. This review provides a comprehensive and comparative analysis of significant and controversial studies on the role of dietary cholesterol and lipid metabolism in the pathophysiology of infectious disease and autoimmune disorders, highlighting the need for further investigation in this developing area of research.

Multiple Export Mechanisms for mRNAs

Science.gov (United States)

Delaleau, Mildred; Borden, Katherine L. B.

2015-01-01

Nuclear mRNA export plays an important role in gene expression. We describe the mechanisms of mRNA export including the importance of mRNP assembly, docking with the nuclear basket of the nuclear pore complex (NPC), transit through the central channel of the NPC and cytoplasmic release. We describe multiple mechanisms of mRNA export including NXF1 and CRM1 mediated pathways. Selective groups of mRNAs can be preferentially transported in order to respond to cellular stimuli. RNAs can be selected based on the presence of specific cis-acting RNA elements and binding of specific adaptor proteins. The role that dysregulation of this process plays in human disease is also discussed. PMID:26343730

Interaction of pathogens with host cholesterol metabolism.

Science.gov (United States)

Sviridov, Dmitri; Bukrinsky, Michael

2014-10-01

Pathogens of different taxa, from prions to protozoa, target cellular cholesterol metabolism to advance their own development and to impair host immune responses, but also causing metabolic complications, for example, atherosclerosis. This review describes recent findings of how pathogens do it. A common theme in interaction between pathogens and host cholesterol metabolism is pathogens targeting lipid rafts of the host plasma membrane. Many intracellular pathogens use rafts as an entry gate, taking advantage of the endocytic machinery and high abundance of outward-looking molecules that can be used as receptors. At the same time, disruption of the rafts' functional capacity, achieved by the pathogens through a number of various means, impairs the ability of the host to generate immune response, thus helping pathogen to thrive. Pathogens cannot synthesize cholesterol, and salvaging host cholesterol helps pathogens build advanced cholesterol-containing membranes and assembly platforms. Impact on cholesterol metabolism is not limited to the infected cells; proteins and microRNAs secreted by infected cells affect lipid metabolism systemically. Given an essential role that host cholesterol metabolism plays in pathogen development, targeting this interaction may be a viable strategy to fight infections, as well as metabolic complications of the infections.

The response of the prostate to circulating cholesterol: activating transcription factor 3 (ATF3 as a prominent node in a cholesterol-sensing network.

Directory of Open Access Journals (Sweden)

Jayoung Kim

Full Text Available Elevated circulating cholesterol is a systemic risk factor for cardiovascular disease and metabolic syndrome, however the manner in which the normal prostate responds to variations in cholesterol levels is poorly understood. In this study we addressed the molecular and cellular effects of elevated and suppressed levels of circulating cholesterol on the normal prostate. Integrated bioinformatic analysis was performed using DNA microarray data from two experimental formats: (1 ventral prostate from male mice with chronically elevated circulating cholesterol and (2 human prostate cells exposed acutely to cholesterol depletion. A cholesterol-sensitive gene expression network was constructed from these data and the transcription factor ATF3 was identified as a prominent node in the network. Validation experiments confirmed that elevated cholesterol reduced ATF3 expression and enhanced proliferation of prostate cells, while cholesterol depletion increased ATF3 levels and inhibited proliferation. Cholesterol reduction in vivo alleviated dense lymphomononuclear infiltrates in the periprostatic adipose tissue, which were closely associated with nerve tracts and blood vessels. These findings open new perspectives on the role of cholesterol in prostate health, and provide a novel role for ATF3, and associated proteins within a large signaling network, as a cholesterol-sensing mechanism.

Triglycerides, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol in rats exposed to premium motor spirit fumes.

Science.gov (United States)

Aberare, Ogbevire L; Okuonghae, Patrick; Mukoro, Nathaniel; Dirisu, John O; Osazuwa, Favour; Odigie, Elvis; Omoregie, Richard

2011-06-01

Deliberate and regular exposure to premium motor spirit fumes is common and could be a risk factor for liver disease in those who are occupationally exposed. A possible association between premium motor spirit fumes and plasma levels of triglyceride, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol using a rodent model could provide new insights in the pathology of diseases where cellular dysfunction is an established risk factor. The aim of this study was to evaluate the possible effect of premium motor spirit fumes on lipids and lipoproteins in workers occupationally exposed to premium motor spirit fumes using rodent model. Twenty-five Wister albino rats (of both sexes) were used for this study between the 4(th) of August and 7(th) of September, 2010. The rats were divided into five groups of five rats each. Group 1 rats were not exposed to premium motor spirit fumes (control group), group 2 rats were exposed for 1 hour daily, group 3 for 3 hours daily, group 4 for 5 hours daily and group 5 for 7 hours daily. The experiment lasted for a period of 4 weeks. Blood samples obtained from all the groups after 4 weeks of exposure were used for the estimation of plasma levels of triglyceride, total cholesterol, high density lipoprotein- cholesterol and low density lipoprotein- cholesterol. Results showed significant increase in means of plasma total cholesterol and low density lipoprotein levels (P<0.05). The mean triglyceride and total body weight were significantly lower (P<0.05) in the exposed group when compared with the unexposed. The plasma level of high density lipoprotein, the ratio of low density lipoprotein to high density lipoprotein and the ratio of total cholesterol to high density lipoprotein did not differ significantly in exposed subjects when compared with the control group. These results showed that frequent exposure to petrol fumes may be highly deleterious to the liver cells.

Molecular View of Cholesterol Flip-Flop and Chemical Potential in Different Membrane Environments

NARCIS (Netherlands)

Bennett, W. F. Drew; MacCallum, Justin L.; Hinner, Marlon J.; Marrink, Siewert J.; Tieleman, D. Peter

2009-01-01

The relative stability of cholesterol in cellular membranes and the thermodynamics of fluctuations from equilibrium have important consequences for sterol trafficking and lateral domain formation. We used molecular dynamics computer simulations to investigate the partitioning of cholesterol in a

Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans

NARCIS (Netherlands)

Bernelot Moens, Sophie J.; Verweij, Simone L.; Schnitzler, Johan G.; Stiekema, Lotte C. A.; Bos, Merijn; Langsted, Anne; Kuijk, Carlijn; Bekkering, Siroon; Voermans, Carlijn; Verberne, Hein J.; Nordestgaard, Børge G.; Stroes, Erik S. G.; Kroon, Jeffrey

2017-01-01

Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation,

Cholesterol-Lowering Probiotics as Potential Biotherapeutics for Metabolic Diseases

Directory of Open Access Journals (Sweden)

Manoj Kumar

2012-01-01

Full Text Available Cardiovascular diseases are one of the major causes of deaths in adults in the western world. Elevated levels of certain blood lipids have been reported to be the principal cause of cardiovascular disease and other disabilities in developed countries. Several animal and clinical trials have shown a positive association between cholesterol levels and the risks of coronary heart disease. Current dietary strategies for the prevention of cardiovascular disease advocate adherence to low-fat/low-saturated-fat diets. Although there is no doubt that, in experimental conditions, low-fat diets offer an effective means of reducing blood cholesterol concentrations on a population basis, these appear to be less effective, largely due to poor compliance, attributed to low palatability and acceptability of these diets to the consumers. Due to the low consumer compliance, attempts have been made to identify other dietary components that can reduce blood cholesterol levels. Supplementation of diet with fermented dairy products or lactic acid bacteria containing dairy products has shown the potential to reduce serum cholesterol levels. Various approaches have been used to alleviate this issue, including the use of probiotics, especially Bifidobacterium spp. and Lactobacillus spp.. Probiotics, the living microorganisms that confer health benefits on the host when administered in adequate amounts, have received much attention on their proclaimed health benefits which include improvement in lactose intolerance, increase in natural resistance to infectious disease in gastrointestinal tract, suppression of cancer, antidiabetic, reduction in serum cholesterol level, and improved digestion. In addition, there are numerous reports on cholesterol removal ability of probiotics and their hypocholesterolemic effects. Several possible mechanisms for cholesterol removal by probiotics are assimilation of cholesterol by growing cells, binding of cholesterol to cellular surface

An Interaction between KSHV ORF57 and UIF Provides mRNA-Adaptor Redundancy in Herpesvirus Intronless mRNA Export

Science.gov (United States)

Jackson, Brian R.; Boyne, James R.; Noerenberg, Marko; Taylor, Adam; Hautbergue, Guillaume M.; Walsh, Matthew J.; Wheat, Rachel; Blackbourn, David J.; Wilson, Stuart A.; Whitehouse, Adrian

2011-01-01

The hTREX complex mediates cellular bulk mRNA nuclear export by recruiting the nuclear export factor, TAP, via a direct interaction with the export adaptor, Aly. Intriguingly however, depletion of Aly only leads to a modest reduction in cellular mRNA nuclear export, suggesting the existence of additional mRNA nuclear export adaptor proteins. In order to efficiently export Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs from the nucleus, the KSHV ORF57 protein recruits hTREX onto viral intronless mRNAs allowing access to the TAP-mediated export pathway. Similarly however, depletion of Aly only leads to a modest reduction in the nuclear export of KSHV intronless mRNAs. Herein, we identify a novel interaction between ORF57 and the cellular protein, UIF. We provide the first evidence that the ORF57-UIF interaction enables the recruitment of hTREX and TAP to KSHV intronless mRNAs in Aly-depleted cells. Strikingly, depletion of both Aly and UIF inhibits the formation of an ORF57-mediated nuclear export competent ribonucleoprotein particle and consequently prevents ORF57-mediated mRNA nuclear export and KSHV protein production. Importantly, these findings highlight that redundancy exists in the eukaryotic system for certain hTREX components involved in the mRNA nuclear export of intronless KSHV mRNAs. PMID:21814512

The cellular origin of the hepatic cholesterol synthesis (1961)

International Nuclear Information System (INIS)

Chevallier, F.

1961-01-01

If rats are sacrificed within minutes after an injection of acetate 1 - 14 C the specific radioactivities of sterols precipitable with digitonine, extracted from liver parenchyma cells and from Kupffer cells are very close to each other, whatever the duration of the experiment may be. It follows that cholesterol synthesis probably occurs in both types of cells. A validation of this conclusion requires that the validity of certain assumptions be established. (authors) [fr

The cellular origin of the hepatic cholesterol synthesis (1961); Origine cellulaire du cholesterol hepatique de synthese (1961)

Energy Technology Data Exchange (ETDEWEB)

Chevallier, F [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

1961-07-01

If rats are sacrificed within minutes after an injection of acetate 1 - {sup 14}C the specific radioactivities of sterols precipitable with digitonine, extracted from liver parenchyma cells and from Kupffer cells are very close to each other, whatever the duration of the experiment may be. It follows that cholesterol synthesis probably occurs in both types of cells. A validation of this conclusion requires that the validity of certain assumptions be established. (authors) [French] Si l'on sacrifie des rats dans les minutes qui suivent une injection d'acetate 1- {sup 14}C, les valeurs des radioactivites specifiques des sterols, precipitables par la digitonine, extraits des cellules parenchymateuses du foie et des cellules de Kupffer sont tres proches l'une de l'autre quelle que soit la duree de l'experience. On en deduit que la synthese du cholesterol s'effectue probablement dans les deux types de cellules. Cette conclusion pour etre valable, exige que le bien fonde de certaines hypotheses soit verifie. (auteurs)

Ordering effects of cholesterol and its analogues

DEFF Research Database (Denmark)

Róg, Tomasz; Pasenkiewicz-Gierula, Marta; Vattulainen, Ilpo

2009-01-01

Without any exaggeration, cholesterol is one of the most important lipid species in eukaryotic cells. Its effects on cellular membranes and functions range from purely mechanistic to complex metabolic ones, besides which it is also a precursor of the sex hormones (steroids) and several vitamins....... In this review, we discuss the biophysical effects of cholesterol on the lipid bilayer, in particular the ordering and condensing effects, concentrating on the molecular level or inter-atomic interactions perspective, starting from two-component systems and proceeding to many-component ones e.g., modeling lipid...... rafts. Particular attention is paid to the roles of the methyl groups in the cholesterol ring system, and their possible biological function. Although our main research methodology is computer modeling, in this review we make extensive comparisons between experiments and different modeling approaches....

The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes.

Science.gov (United States)

Wei, Jian; Zhang, Ying-Yu; Luo, Jie; Wang, Ju-Qiong; Zhou, Yu-Xia; Miao, Hong-Hua; Shi, Xiong-Jie; Qu, Yu-Xiu; Xu, Jie; Li, Bo-Liang; Song, Bao-Liang

2017-06-27

Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown. Through amphotericin B-based selection, we isolated two cholesterol transport-defective cell lines. Subsequent whole-transcriptome-sequencing analysis revealed two cell lines bearing the same mutation in the vacuolar protein sorting 53 (Vps53) gene. Depletion of VPS53 or other subunits of the Golgi-associated retrograde protein (GARP) complex impaired NPC2 sorting to lysosomes and caused cholesterol accumulation. GARP deficiency blocked the retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR) to the trans-Golgi network. Further, Vps54 mutant mice displayed reduced cellular NPC2 protein levels and increased cholesterol accumulation, underscoring the physiological role of the GARP complex in cholesterol transport. We conclude that the GARP complex contributes to intracellular cholesterol transport by targeting NPC2 to lysosomes in a CI-MPR-dependent manner. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis.

Science.gov (United States)

Ahsan, Fadhil; Maertzdorf, Jeroen; Guhlich-Bornhof, Ute; Kaufmann, Stefan H E; Moura-Alves, Pedro

2018-01-24

Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process. We report that, in Mtb-infected macrophages, IL-36 signaling modulates cholesterol biosynthesis and efflux via LXR. Moreover, IL-36 induces the expression of cholesterol-converting enzymes and the accumulation of LXR ligands, such as oxysterols. Ultimately, both IL-36 and LXR signaling play a role in the regulation of antimicrobial peptides expression and in Mtb growth restriction. These data provide novel evidence for the importance of IL-36 and cholesterol metabolism mediated by LXR in cellular host defense against Mtb.

How cholesterol interacts with proteins and lipids during its intracellular transport

DEFF Research Database (Denmark)

Wüstner, Daniel; Solanko, Katarzyna

2015-01-01

as well as by non-vesicular sterol exchange between organelles. In this article, we will review recent progress in elucidating sterol-lipid and sterol-protein interactions contributing to proper sterol transport in living cells. We outline recent biophysical models of cholesterol distribution and dynamics...... for characterization of sterol-protein interactions and for monitoring intracellular sterol transport. Finally, we review recent work on the molecular mechanisms underlying lipoprotein-mediated cholesterol import into mammalian cells and describe the process of cellular cholesterol efflux. Overall, we emphasize how......Sterols, as cholesterol in mammalian cells and ergosterol in fungi, are indispensable molecules for proper functioning and nanoscale organization of the plasma membrane. Synthesis, uptake and efflux of cholesterol are regulated by a variety of protein-lipid and protein-protein interactions...

Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

Directory of Open Access Journals (Sweden)

Kexin Zhao

2017-05-01

Full Text Available Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs by Niemann-Pick C1 (NPC1. However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles.

Cholesterol modulates the cellular localization of Orai1 channels and its disposition among membrane domains.

Science.gov (United States)

Bohórquez-Hernández, A; Gratton, Enrico; Pacheco, Jonathan; Asanov, Alexander; Vaca, Luis

2017-12-01

Store Operated Calcium Entry (SOCE) is one of the most important mechanisms for calcium mobilization in to the cell. Two main proteins sustain SOCE: STIM1 that acts as the calcium sensor in the endoplasmic reticulum (ER) and Orai1 responsible for calcium influx upon depletion of ER. There are many studies indicating that SOCE is modulated by the cholesterol content of the plasma membrane (PM). However, a myriad of questions remain unanswered concerning the precise molecular mechanism by which cholesterol modulates SOCE. In the present study we found that reducing PM cholesterol results in the internalization of Orai1 channels, which can be prevented by overexpressing caveolin 1 (Cav1). Furthermore, Cav1 and Orai1 associate upon SOCE activation as revealed by FRET and coimmunoprecipitation assays. The effects of reducing cholesterol were not limited to an increased rate of Orai1 internalization, but also, affects the lateral movement of Orai1, inducing movement in a linear pattern (unobstructed diffusion) opposite to basal cholesterol conditions were most of Orai1 channels moves in a confined space, as assessed by Fluorescence Correlation Spectroscopy, Cav1 overexpression inhibited these alterations maintaining Orai1 into a confined and partially confined movement. These results not only highlight the complex effect of cholesterol regulation on SOCE, but also indicate a direct regulatory effect on Orai1 localization and compartmentalization by this lipid. Copyright © 2017 Elsevier B.V. All rights reserved.

Aerobic Exercise Training Selectively Changes Oxysterol Levels and Metabolism Reducing Cholesterol Accumulation in the Aorta of Dyslipidemic Mice

Directory of Open Access Journals (Sweden)

Guilherme Silva Ferreira

2017-09-01

Full Text Available Background: Oxysterols are bioactive lipids that control cellular cholesterol synthesis, uptake, and exportation besides mediating inflammation and cytotoxicity that modulate the development of atherosclerosis. Aerobic exercise training (AET prevents and regresses atherosclerosis by the improvement of lipid metabolism, reverse cholesterol transport (RCT and antioxidant defenses in the arterial wall. We investigated in dyslipidemic mice the role of a 6-week AET program in the content of plasma and aortic arch cholesterol and oxysterols, the expression of genes related to cholesterol flux and the effect of the exercise-mimetic AICAR, an AMPK activator, in macrophage oxysterols concentration.Methods: Sixteen-week old male apo E KO mice fed a chow diet were included in the protocol. Animals were trained in a treadmill running, 15 m/min, 5 days/week, for 60 min (T; n = 29. A control group was kept sedentary (S; n = 32. Plasma lipids and glucose were determined by enzymatic techniques and glucometer, respectively. Cholesterol and oxysterols in aortic arch and macrophages were measured by gas chromatography/mass spectrometry. The expression of genes involved in lipid metabolism was determined by RT-qPCR. The effect of AMPK in oxysterols metabolism was determined in J774 macrophages treated with 0.25 mM AICAR.Results: Body weight and plasma TC, TG, HDL-c, glucose, and oxysterols were similar between groups. As compared to S group, AET enhanced 7β-hydroxycholesterol (70% and reduced cholesterol (32% in aorta. In addition, exercise increased Cyp27a1 (54%, Cd36 (75%, Cat (70%, Prkaa1 (40%, and Prkaa2 (51% mRNA. In macrophages, the activation of AMPK followed by incubation with HDL2 increased Abca1 (52% and Cd36 (220% and decrease Prkaa1 (19%, Cyp27a1 (47% and 7α-hydroxycholesterol level.Conclusion: AET increases 7β-hydroxycholesterol in the aortic arch of dyslipidemic mice, which is related to the enhanced expression of Cd36. In addition, the increase

The influence of saponins on cell membrane cholesterol.

Science.gov (United States)

Böttger, Stefan; Melzig, Matthias F

2013-11-15

We studied the influence of structurally different saponins on the cholesterol content of cellular membranes. Therefore a cell culture model using ECV-304 urinary bladder carcinoma cells was developed. To measure the cholesterol content we used radiolabeled (3)H-cholesterol which is chemically and physiologically identical to natural cholesterol. The cells were pre-incubated with (3)H-cholesterol and after a medium change, they were treated with saponins to assess a saponin-induced cholesterol liberation from the cell membrane. In another experiment the cells were pre-incubated with saponins and after a medium change, they were treated with (3)H-cholesterol to assess a saponin-induced inhibition of cholesterol uptake into the cell membrane. Furthermore, the membrane toxicity of all applied saponins was analyzed using extracellular LDH quantification and the general cytotoxicity was analyzed using a colorimetric MTT-assay and DNA quantification. Our results revealed a correlation between membrane toxicity and general cytotoxicity. We also compared the results from the experiments on the saponin-induced cholesterol liberation as well as the saponin-induced inhibition of cholesterol uptake with the membrane toxicity. A significant reduction in the cell membrane cholesterol content was noted for those saponins who showed membrane toxicity (IC50 saponins either liberated (3)H-cholesterol from intact cell membranes or blocked the integration of supplemented (3)H-cholesterol into the cell membrane. Saponins with little influence on the cell membrane (IC50 >100 μM) insignificantly altered the cell membrane cholesterol content. The results suggested that the general cytotoxicity of saponins is mainly dependent on their membrane toxicity and that the membrane toxicity might be caused by the loss of cholesterol from the cell membrane. We also analyzed the influence of a significantly membrane toxic saponin on the cholesterol content of intracellular membranes such as those

Differential Membrane Dipolar Orientation Induced by Acute and Chronic Cholesterol Depletion.

Science.gov (United States)

Sarkar, Parijat; Chakraborty, Hirak; Chattopadhyay, Amitabha

2017-06-30

Cholesterol plays a crucial role in cell membrane organization, dynamics and function. Depletion of cholesterol represents a popular approach to explore cholesterol-sensitivity of membrane proteins. An emerging body of literature shows that the consequence of membrane cholesterol depletion often depends on the actual process (acute or chronic), although the molecular mechanism underlying the difference is not clear. Acute depletion, using cyclodextrin-type carriers, is faster relative to chronic depletion, in which inhibitors of cholesterol biosynthesis are used. With the overall goal of addressing molecular differences underlying these processes, we monitored membrane dipole potential under conditions of acute and chronic cholesterol depletion in CHO-K1 cells, using a voltage-sensitive fluorescent dye in dual wavelength ratiometric mode. Our results show that the observed membrane dipole potential exhibits difference under acute and chronic cholesterol depletion conditions, even when cholesterol content was identical. To the best of our knowledge, these results provide, for the first time, molecular insight highlighting differences in dipolar reorganization in these processes. A comprehensive understanding of processes in which membrane cholesterol gets modulated would provide novel insight in its interaction with membrane proteins and receptors, thereby allowing us to understand the role of cholesterol in cellular physiology associated with health and disease.

Synthesis and live-cell imaging of fluorescent sterols for analysis of intracellular cholesterol transport

DEFF Research Database (Denmark)

Modzel, Maciej; Lund, Frederik W.; Wüstner, Daniel

2017-01-01

Cellular cholesterol homeostasis relies on precise control of the sterol content of organelle membranes. Obtaining insight into cholesterol trafficking pathways and kinetics by live-cell imaging relies on two conditions. First, one needs to develop suitable analogs that resemble cholesterol...... as closely as possible with respect to their biophysical and biochemical properties. Second, the cholesterol analogs should have good fluorescence properties. This interferes, however, often with the first requirement, such that the imaging instrumentation must be optimized to collect photons from suboptimal...... fluorophores, but good cholesterol mimics, such as the intrinsically fluorescent sterols, cholestatrienol (CTL) or dehydroergosterol (DHE). CTL differs from cholesterol only in having two additional double bonds in the ring system, which is why it is slightly fluorescent in the ultraviolet (UV). In the first...

Cholesterol regulates the endoplasmic reticulum exit of the major membrane protein P0 required for peripheral myelin compaction.

Science.gov (United States)

Saher, Gesine; Quintes, Susanne; Möbius, Wiebke; Wehr, Michael C; Krämer-Albers, Eva-Maria; Brügger, Britta; Nave, Klaus-Armin

2009-05-13

Rapid impulse conduction requires electrical insulation of axons by myelin, a cholesterol-rich extension of the glial cell membrane with a characteristic composition of proteins and lipids. Mutations in several myelin protein genes cause endoplasmic reticulum (ER) retention and disease, presumably attributable to failure of misfolded proteins to pass the ER quality control. Because many myelin proteins partition into cholesterol-rich membrane rafts, their interaction with cholesterol could potentially be part of the ER quality control system. Here, we provide in vitro and in vivo evidence that the major peripheral myelin protein P0 requires cholesterol for exiting the ER and reaching the myelin compartment. Cholesterol dependency of P0 trafficking in heterologous cells is mediated by a cholesterol recognition/interaction amino acid consensus (CRAC) motif. Mutant mice lacking cholesterol biosynthesis in Schwann cells suffer from severe hypomyelination with numerous uncompacted myelin stretches. This demonstrates that high-level cholesterol coordinates P0 export with myelin membrane synthesis, which is required for the correct stoichiometry of myelin components and for myelin compaction.

Regulation of alpha1 Na/K-ATPase expression by cholesterol.

Science.gov (United States)

Chen, Yiliang; Li, Xin; Ye, Qiqi; Tian, Jiang; Jing, Runming; Xie, Zijian

2011-04-29

We have reported that α1 Na/K-ATPase regulates the trafficking of caveolin-1 and consequently alters cholesterol distribution in the plasma membrane. Here, we report the reciprocal regulation of α1 Na/K-ATPase by cholesterol. Acute exposure of LLC-PK1 cells to methyl β-cyclodextrin led to parallel decreases in cellular cholesterol and the expression of α1 Na/K-ATPase. Cholesterol repletion fully reversed the effect of methyl β-cyclodextrin. Moreover, inhibition of intracellular cholesterol trafficking to the plasma membrane by compound U18666A had the same effect on α1 Na/K-ATPase. Similarly, the expression of α1, but not α2 and α3, Na/K-ATPase was significantly reduced in the target organs of Niemann-Pick type C mice where the intracellular cholesterol trafficking is blocked. Mechanistically, decreases in the plasma membrane cholesterol activated Src kinase and stimulated the endocytosis and degradation of α1 Na/K-ATPase through Src- and ubiquitination-dependent pathways. Thus, the new findings, taken together with what we have already reported, revealed a previously unrecognized feed-forward mechanism by which cells can utilize the Src-dependent interplay among Na/K-ATPase, caveolin-1, and cholesterol to effectively alter the structure and function of the plasma membrane.

Macrophage mitochondrial damage from StAR transport of 7-hydroperoxycholesterol: implications for oxidative stress-impaired reverse cholesterol transport.

Science.gov (United States)

Korytowski, Witold; Wawak, Katarzyna; Pabisz, Pawel; Schmitt, Jared C; Girotti, Albert W

2014-01-03

StAR family proteins in vascular macrophages participate in reverse cholesterol transport (RCT). We hypothesize that under pathophysiological oxidative stress, StARs will transport not only cholesterol to macrophage mitochondria, but also pro-oxidant cholesterol hydroperoxides (7-OOHs), thereby impairing early-stage RCT. Upon stimulation with dibutyryl-cAMP, RAW264.7 macrophages exhibited a strong time-dependent induction of mitochondrial StarD1 and plasma membrane ABCA1, which exports cholesterol. 7α-OOH uptake by stimulated RAW cell mitochondria (like cholesterol uptake) was strongly reduced by StarD1 knockdown, consistent with StarD1 involvement. Upon uptake by mitochondria, 7α-OOH (but not redox-inactive 7α-OH) triggered lipid peroxidation and membrane depolarization while reducing ABCA1 upregulation. These findings provide strong initial support for our hypothesis. Copyright © 2013. Published by Elsevier B.V.

Cell proliferation in the atherosclerotic plaques of cholesterol-fed rabbits

International Nuclear Information System (INIS)

Cavallero, C.; Tondo, U. di; Mingazinni, P.L.; Nicosia, R.; Pericoli, M.N.; Sarti, P.; Spagnoli, L.G.; Villaschi, S.

1976-01-01

Tritiated thymidine radioautography was employed to study the effect of cortisol and other glucocorticoids on cellular proliferation in the aorta and pulmonary artery of rabbits with cholesterol atherosclerosis. Labelled cell counts showed that glucocorticoids, even after one day and at a relatively low dose, decrease sharply the deoxyribonucleic acid synthesis in the intimal plaques. The hormonal influence on [ 3 H] thymidine uptake seems to be a dose-dependent process. The relative potency of these steroids in inhibiting DNA synthesis in the plaques parallels closely their anti-inflammatory effectiveness. Conversely mineralocorticoids, including aldosterone and deoxycorticosterone, increase the rate of DNA synthesis in the plaques. It is concluded that the anti-atherogenic effect of glucocorticoids on cholesterol-fed rabbits may be due, at least partly, to the inhibitory effect of these steroids on the DNA synthesis of the cellular components of the intimal plaques

Neurosteroids: oligodendrocyte mitochondria convert cholesterol to pregnenolone

International Nuclear Information System (INIS)

Hu, Z.Y.; Bourreau, E.; Jung-Testas, I.; Robel, P.; Baulieu, E.E.

1987-01-01

Oligodendrocyte mitochondria from 21-day-old Sprague-Dawley male rats were incubated with 100 nM [ 3 H]cholesterol. It yielded [ 3 H]pregnenolone at a rate of 2.5 +/- 0.7 and 5-[ 3 H]pregnene-3β,20α-diol at a rate of 2.5 +/- 1.1 pmol per mg of protein per hr. Cultures of glial cells from 19- to 21-day-old fetuses (a mixed population of astrocytes and oligodendrocytes) were incubated for 24 hr with [ 3 H]mevalonolactone. [ 3 H]Cholesterol, [ 3 H]pregnenolone, and 5-[ 3 H]pregnene-3β,20α-diol were characterized in cellular extracts. The formation of the 3 H-labeled steroids was increased by dibutyryl cAMP (0.2 mM) added to the culture medium. The active cholesterol side-chain cleavage mechanism, recently suggested immunohistochemically and already observed in cultures of C6 glioma cells, reinforces the concept of neurosteroids applied to Δ 5 -3β-hydroxysteroids previously isolated from brain

NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis.

Science.gov (United States)

Widenmaier, Scott B; Snyder, Nicole A; Nguyen, Truc B; Arduini, Alessandro; Lee, Grace Y; Arruda, Ana Paula; Saksi, Jani; Bartelt, Alexander; Hotamisligil, Gökhan S

2017-11-16

Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process. We show that Nrf1 directly binds to and specifically senses cholesterol in the ER through a defined domain and that cholesterol regulates Nrf1 turnover, processing, localization, and activity. In Nrf1 deficiency, in vivo cholesterol challenges induce massive hepatic cholesterol accumulation and damage, which is rescued by replacing Nrf1 exogenously. This Nrf1-mediated mechanism involves the suppression of CD36-driven inflammatory signaling and derepression of liver X receptor activity. These findings reveal Nrf1 as a guardian of cholesterol homeostasis and a core component of adaptive responses to excess cellular cholesterol. Copyright © 2017. Published by Elsevier Inc.

C282Y-HFE gene variant affects cholesterol metabolism in human neuroblastoma cells.

Science.gov (United States)

Ali-Rahmani, Fatima; Huang, Michael A; Schengrund, C-L; Connor, James R; Lee, Sang Y

2014-01-01

Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells.

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.

Science.gov (United States)

Chutiwitoonchai, Nopporn; Mano, Takafumi; Kakisaka, Michinori; Sato, Hirotaka; Kondoh, Yasumitsu; Osada, Hiroyuki; Kotani, Osamu; Yokoyama, Masaru; Sato, Hironori; Aida, Yoko

2017-07-01

An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. Copyright © 2017 Elsevier Inc. All rights reserved.

Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1.

Directory of Open Access Journals (Sweden)

Fumin Dong

Full Text Available ATP-binding cassette transporter A1 (ABCA1 plays an essential role in mediating cholesterol efflux to apolipoprotein A-I (apoA-I, a major housekeeping mechanism for cellular cholesterol homeostasis. After initial engagement with ABCA1, apoA-I directly interacts with the plasma membrane to acquire cholesterol. This apoA-I lipidation process is also known to require cellular signaling processes, presumably to support cholesterol trafficking to the plasma membrane. We report here that one of major signaling pathways in mammalian cells, Akt, is also involved. In several cell models that express ABCA1 including macrophages, pancreatic beta cells and hepatocytes, inhibition of Akt increases cholesterol efflux to apoA-I. Importantly, Akt inhibition has little effect on cells expressing non-functional mutant of ABCA1, implicating a specific role of Akt in ABCA1 function. Furthermore, we provide evidence that mTORC1, a major downstream target of Akt, is also a negative regulator of cholesterol efflux. In cells where mTORC1 is constitutively activated due to tuberous sclerosis complex 2 deletion, cholesterol efflux to apoA-I is no longer sensitive to Akt activity. This suggests that Akt suppresses cholesterol efflux through mTORC1 activation. Indeed, inhibition of mTORC1 by rapamycin or Torin-1 promotes cholesterol efflux. On the other hand, autophagy, one of the major pathways of cholesterol trafficking, is increased upon Akt inhibition. Furthermore, Akt inhibition disrupts lipid rafts, which is known to promote cholesterol efflux to apoA-I. We therefore conclude that Akt, through its downstream targets, mTORC1 and hence autophagy, negatively regulates cholesterol efflux to apoA-I.

Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3.

Science.gov (United States)

Bedard, James E J; Purnell, Jennifer D; Ware, Stephanie M

2007-01-15

Missense, frameshift and nonsense mutations in the zinc finger transcription factor ZIC3 cause heterotaxy as well as isolated congenital heart disease. Previously, we developed transactivation and subcellular localization assays to test the function of ZIC3 point mutations. Aberrant cytoplasmic localization suggested that the pathogenesis of ZIC3 mutations results, at least in part, from failure of appropriate cellular trafficking. To further investigate this hypothesis, the nucleocytoplasmic shuttling properties of ZIC3 have been examined. Subcellular localization assays designed to span the entire open-reading frame of wild-type and mutant ZIC3 proteins identified the presence of nucleocytoplasmic transport signals. ZIC3 domain mapping indicates that a relatively large region containing the zinc finger binding sites and a known GLI interacting domain is required for transport to the nucleus. Site-directed mutagenesis of critical residues within two putative nuclear localization signals (NLSs) leads to loss of nuclear localization. No further decrease was observed when both NLS sites were mutated, suggesting that mutation of either NLS site is sufficient for loss of importin-mediated nuclear localization. Additionally, we identify a cryptic CRM-1-dependent nuclear export signal (NES) within ZIC3, and identify a mutation within this region in a patient with heterotaxy. These results provide the first evidence that control of cellular trafficking of ZIC3 is critical for function and suggest a possible mechanism for transcriptional control during left-right patterning. Identification of mutations in mapped NLS or NES domains in heterotaxy patients demonstrates the functional importance of these domains in cardiac morphogenesis and allows for integration of structural analysis with developmental function.

Cholesterol transfer from normal and atherogenic low density lipoproteins to Mycoplasma membranes

International Nuclear Information System (INIS)

Mitschelen, J.J.; St Clair, R.W.; Hester, S.H.

1981-01-01

The purpose of this study was to determine whether the free cholesterol of hypercholesterolemic low density lipoprotein from cholesterol-fed nonhuman primates has a greater potential for surface transfer to cell membranes than does the free cholesterol of normal low density lipoprotein. The low density lipoproteins were isolated from normal and hypercholesterolemic rhesus and cynomolgus monkeys, incubated with membranes from Acholeplasma laidlawii, a mycoplasma species devoid of cholesterol in its membranes, and the mass transfer of free cholesterol determined by measuring membrane cholesterol content. Since these membranes neither synthesize nor esterify cholesterol, nor degrade the protein or cholesterol ester moieties of low density lipoprotein, they are an ideal model with which to study differences in the cholesterol transfer potential of low density lipoprotein independent of the uptake of the intact low density lipoprotein particle. These studies indicate that, even though there are marked differences in the cholesterol composition of normal and hypercholesterolemic low density lipoproteins, this does not result in a greater chemical potential for surface transfer of free cholesterol. Consequently, if a difference in the surface transfer of free cholesterol is responsible for the enhanced ability of hypercholesterolemic low density lipoprotein to promote cellular cholesterol accumulation and, perhaps, also atherosclerosis, it must be the result of differences in the interaction to the hypercholesterolemic low density lipoprotein with the more complicated mammalian cell membranes, rather than differences in the chemical potential for cholesterol transfer

A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis.

Science.gov (United States)

Chua, Ngee Kiat; Howe, Vicky; Jatana, Nidhi; Thukral, Lipi; Brown, Andrew J

2017-12-08

Cholesterol biosynthesis in the endoplasmic reticulum (ER) is tightly controlled by multiple mechanisms to regulate cellular cholesterol levels. Squalene monooxygenase (SM) is the second rate-limiting enzyme in cholesterol biosynthesis and is regulated both transcriptionally and post-translationally. SM undergoes cholesterol-dependent proteasomal degradation when cholesterol is in excess. The first 100 amino acids of SM (designated SM N100) are necessary for this degradative process and represent the shortest cholesterol-regulated degron identified to date. However, the fundamental intrinsic characteristics of this degron remain unknown. In this study, we performed a series of deletions, point mutations, and domain swaps to identify a 12-residue region (residues Gln-62-Leu-73), required for SM cholesterol-mediated turnover. Molecular dynamics and circular dichroism revealed an amphipathic helix within this 12-residue region. Moreover, 70% of the variation in cholesterol regulation was dependent on the hydrophobicity of this region. Of note, the earliest known Doa10 yeast degron, Deg1, also contains an amphipathic helix and exhibits 42% amino acid similarity with SM N100. Mutating SM residues Phe-35/Ser-37/Leu-65/Ile-69 into alanine, based on the key residues in Deg1, blunted SM cholesterol-mediated turnover. Taken together, our results support a model whereby the amphipathic helix in SM N100 attaches reversibly to the ER membrane depending on cholesterol levels; with excess, the helix is ejected and unravels, exposing a hydrophobic patch, which then serves as a degradation signal. Our findings shed new light on the regulation of a key cholesterol synthesis enzyme, highlighting the conservation of critical degron features from yeast to humans. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses.

Science.gov (United States)

Bajimaya, Shringkhala; Frankl, Tünde; Hayashi, Tsuyoshi; Takimoto, Toru

2017-10-01

Cholesterol-rich lipid raft microdomains in the plasma membrane are considered to play a major role in the enveloped virus lifecycle. However, the functional role of cholesterol in assembly, infectivity and stability of respiratory RNA viruses is not fully understood. We previously reported that depletion of cellular cholesterol by cholesterol-reducing agents decreased production of human parainfluenza virus type 1 (hPIV1) particles by inhibiting virus assembly. In this study, we analyzed the role of cholesterol on influenza A virus (IAV) and respiratory syncytial virus (RSV) production. Unlike hPIV1, treatment of human airway cells with the agents did not decrease virus particle production. However, the released virions were less homogeneous in density and unstable. Addition of exogenous cholesterol to the released virions restored virus stability and infectivity. Collectively, these data indicate a critical role of cholesterol in maintaining IAV and RSV membrane structure that is essential for sustaining viral stability and infectivity. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Elaidic Acid on Lipid Metabolism in HepG2 Cells, Investigated by an Integrated Approach of Lipidomics, Transcriptomics and Proteomics

DEFF Research Database (Denmark)

Vendel Nielsen, Lone; Hansen, Toke Peter Krogager; Young, Clifford

2013-01-01

in a combined proteomic, transcriptomic and lipidomic approach. We found many of the proteins responsible for cholesterol synthesis up-regulated together with several proteins involved in the esterification and hepatic import/export of cholesterol. Furthermore, a profound remodeling of the cellular membrane...... occurred at the phospholipid level. Our findings contribute to the explanation on how trans fatty acids from the diet can cause modifications in plasma cholesterol levels by inducing abundance changes in several hepatic proteins and the hepatic membrane composition....

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL Function.

Science.gov (United States)

Millar, Courtney L; Duclos, Quinn; Blesso, Christopher N

2017-03-01

Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their well-documented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function. Based on preclinical studies that used cell culture and rodent models, it appears that many flavonoids (e.g., anthocyanidins, flavonols, and flavone subclasses) influence RCT and HDL function beyond simple HDL cholesterol concentration by regulating cellular cholesterol efflux from macrophages and hepatic paraoxonase 1 expression and activity. In clinical studies, dietary anthocyanin intake is associated with beneficial changes in serum biomarkers related to HDL function in a variety of human populations (e.g., in those who are hyperlipidemic, hypertensive, or diabetic), including increased HDL cholesterol concentration, as well as HDL antioxidant and cholesterol efflux capacities. However, clinical research on HDL functionality is lacking for some flavonoid subclasses (e.g., flavanols, flavones, flavanones, and isoflavones). Although there has been a tremendous effort to develop HDL-targeted drug therapies, more research is warranted on how the intake of foods or specific nutrients affects HDL function. © 2017 American Society for Nutrition.

The membrane as the gatekeeper of infection: Cholesterol in host-pathogen interaction.

Science.gov (United States)

Kumar, G Aditya; Jafurulla, Md; Chattopadhyay, Amitabha

2016-09-01

The cellular plasma membrane serves as a portal for the entry of intracellular pathogens. An essential step for an intracellular pathogen to gain entry into a host cell therefore is to be able to cross the cell membrane. In this review, we highlight the role of host membrane cholesterol in regulating the entry of intracellular pathogens using insights obtained from work on the interaction of Leishmania and Mycobacterium with host cells. The entry of these pathogens is known to be dependent on host membrane cholesterol. Importantly, pathogen entry is inhibited either upon depletion (or complexation), or enrichment of membrane cholesterol. In other words, an optimum level of host membrane cholesterol is necessary for efficient infection by pathogens. In this overall context, we propose a general mechanism, based on cholesterol-induced conformational changes, involving cholesterol binding sites in host cell surface receptors that are implicated in this process. A therapeutic strategy targeting modulation of membrane cholesterol would have the advantage of avoiding the commonly encountered problem of drug resistance in tackling infection by intracellular pathogens. Insights into the role of host membrane cholesterol in pathogen entry would be instrumental in the development of novel therapeutic strategies to effectively tackle intracellular pathogenesis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Influenza A Virus NS1 Protein Promotes Efficient Nuclear Export of Unspliced Viral M1 mRNA.

Science.gov (United States)

Pereira, Carina F; Read, Eliot K C; Wise, Helen M; Amorim, Maria J; Digard, Paul

2017-08-01

Influenza A virus mRNAs are transcribed by the viral RNA-dependent RNA polymerase in the cell nucleus before being exported to the cytoplasm for translation. Segment 7 produces two major transcripts: an unspliced mRNA that encodes the M1 matrix protein and a spliced transcript that encodes the M2 ion channel. Export of both mRNAs is dependent on the cellular NXF1/TAP pathway, but it is unclear how they are recruited to the export machinery or how the intron-containing but unspliced M1 mRNA bypasses the normal quality-control checkpoints. Using fluorescent in situ hybridization to monitor segment 7 mRNA localization, we found that cytoplasmic accumulation of unspliced M1 mRNA was inefficient in the absence of NS1, both in the context of segment 7 RNPs reconstituted by plasmid transfection and in mutant virus-infected cells. This effect was independent of any major effect on steady-state levels of segment 7 mRNA or splicing but corresponded to a ∼5-fold reduction in the accumulation of M1. A similar defect in intronless hemagglutinin (HA) mRNA nuclear export was seen with an NS1 mutant virus. Efficient export of M1 mRNA required both an intact NS1 RNA-binding domain and effector domain. Furthermore, while wild-type NS1 interacted with cellular NXF1 and also increased the interaction of segment 7 mRNA with NXF1, mutant NS1 polypeptides unable to promote mRNA export did neither. Thus, we propose that NS1 facilitates late viral gene expression by acting as an adaptor between viral mRNAs and the cellular nuclear export machinery to promote their nuclear export. IMPORTANCE Influenza A virus is a major pathogen of a wide variety of mammalian and avian species that threatens public health and food security. A fuller understanding of the virus life cycle is important to aid control strategies. The virus has a small genome that encodes relatively few proteins that are often multifunctional. Here, we characterize a new function for the NS1 protein, showing that, as well as

A Novel Corynebacterium glutamicum l-Glutamate Exporter.

Science.gov (United States)

Wang, Yu; Cao, Guoqiang; Xu, Deyu; Fan, Liwen; Wu, Xinyang; Ni, Xiaomeng; Zhao, Shuxin; Zheng, Ping; Sun, Jibin; Ma, Yanhe

2018-03-15

Besides metabolic pathways and regulatory networks, transport systems are also pivotal for cellular metabolism and hyperproduction of biochemicals using microbial cell factories. The identification and characterization of transporters are therefore of great significance for the understanding and engineering of transport reactions. Herein, a novel l-glutamate exporter, MscCG2, which exists extensively in Corynebacterium glutamicum strains but is distinct from the only known l-glutamate exporter, MscCG, was discovered in an industrial l-glutamate-producing C. glutamicum strain. MscCG2 was predicted to possess three transmembrane helices in the N-terminal region and located in the cytoplasmic membrane, which are typical structural characteristics of the mechanosensitive channel of small conductance. MscCG2 has a low amino acid sequence identity (23%) to MscCG and evolved separately from MscCG with four transmembrane helices. Despite the considerable differences between MscCG2 and MscCG in sequence and structure, gene deletion and complementation confirmed that MscCG2 also functioned as an l-glutamate exporter and an osmotic safety valve in C. glutamicum Besides, transcriptional analysis showed that MscCG2 and MscCG genes were transcribed in similar patterns and not induced by l-glutamate-producing conditions. It was also demonstrated that MscCG2-mediated l-glutamate excretion was activated by biotin limitation or penicillin treatment and that constitutive l-glutamate excretion was triggered by a gain-of-function mutation of MscCG2 (A151V). Discovery of MscCG2 will enrich the understanding of bacterial amino acid transport and provide additional targets for exporter engineering. IMPORTANCE The exchange of matter, energy, and information with surroundings is fundamental for cellular metabolism. Therefore, studying transport systems that are essential for these processes is of great significance. Besides, transport systems of bacterial cells are usually related to

Quantitative assessment of sterol traffic in living cells by dual labeling with dehydroergosterol and BODIPY-cholesterol

DEFF Research Database (Denmark)

Wustner, D.; Solanko, L.; Sokol, Olena

2011-01-01

Cholesterol with BODIPY at carbon-24 of the side chain (BCh2) has recently been introduced as new cholesterol probe with superior fluorescence properties. We compare BCh2 with the intrinsically fluorescent dehythoergosterol (DHE), a well-established marker for cholesterol, by introducing simultan......Cholesterol with BODIPY at carbon-24 of the side chain (BCh2) has recently been introduced as new cholesterol probe with superior fluorescence properties. We compare BCh2 with the intrinsically fluorescent dehythoergosterol (DHE), a well-established marker for cholesterol, by introducing...... and followed a stretched exponential decay, while the fluorescence lifetime of BCh2 was comparable in various cellular regions. Our results indicate that BCh2 is suitable for analyzing sterol uptake pathways and inter-organelle sterol flux in living cells. The BODIPY-moiety affects lipid phase preference...

Dietary and biliary cholesterol absorption in rats. Effect of dietary cholesterol level and cholesterol saturation of bile

International Nuclear Information System (INIS)

Wilson, M.D.

1985-01-01

The principal objective of this research was to determine if cholesterol introduced into the duodenum of rats in a micellar form as occurs with bile, is absorbed more efficiently than cholesterol presented in a nonmicellar form, as occurs with dietary cholesterol. Cholesterol absorption was measured during the constant intraduodenal infusion of liquid diets ([ 14 C] cholesterol) and artificial biles ([ 3 H] cholesterol) in thoracic lymph duct cannulated rats. Percentage absorption was calculated by dividing the rate of appearance of radiolabeled cholesterol in lymph by its rate of infusion when lymph cholesterol specific activity was constant. Results provide strong evidence that under certain conditions biliary cholesterol is more efficiently absorbed than is dietary cholesterol, and that this differential must be considered when evaluating the influence of diet or drug therapy on cholesterol absorption

Tap and Dbp5, but not Gag, are involved in DR-mediated nuclear export of unspliced Rous sarcoma virus RNA

International Nuclear Information System (INIS)

LeBlanc, Jason J.; Uddowla, Sabena; Abraham, Benjamin; Clatterbuck, Sarah; Beemon, Karen L.

2007-01-01

All retroviruses must circumvent cellular restrictions on the export of unspliced RNAs from the nucleus. While the unspliced RNA export pathways for HIV and Mason-Pfizer monkey virus are well characterized, that of Rous sarcoma virus (RSV) is not. We have previously reported that the RSV direct repeat (DR) elements are involved in the cytoplasmic accumulation of unspliced viral RNA. Here, using fluorescent in situ hybridization (FISH), we demonstrate that unspliced viral RNAs bearing a single point mutation (G8863C) in the DR exhibit a restricted cellular localization in and around the nucleus. In contrast, wild type unspliced viral RNA had a diffuse localization throughout the nucleus and cytoplasm. Since the RSV Gag protein has a transient localization in the nucleus, we examined the effect of Gag over-expression on a DR-mediated reporter construct. While Gag did not enhance DR-mediated nuclear export, the dominant-negative expression of two cellular export factors, Tap and Dbp5, inhibited expression of the same reporter construct. Furthermore, FISH studies using the dominant-negative Dbp5 demonstrated that unspliced wild type RSV RNA was retained within the nucleus. Taken together, these results further implicate the DR in nuclear RNA export through interactions with Tap and Dbp5

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development

Energy Technology Data Exchange (ETDEWEB)

Chutiwitoonchai, Nopporn; Mano, Takafumi; Kakisaka, Michinori; Sato, Hirotaka [Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Kondoh, Yasumitsu; Osada, Hiroyuki [Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Kotani, Osamu; Yokoyama, Masaru; Sato, Hironori [Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011 (Japan); Aida, Yoko, E-mail: aida@riken.jp [Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)

2017-07-15

An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. - Highlights: •DP2392-E10 inhibits replication of a broad range of influenza A subtypes. •DP2392-E10 inhibits nuclear exports of NP and NEP via their NP-NES3 and NEP-NES2 domains, respectively. •DP2392-E10 is predicted to directly bind CRM1 in the region near the HEAT9 and HEAT10 repeats.

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development

International Nuclear Information System (INIS)

Chutiwitoonchai, Nopporn; Mano, Takafumi; Kakisaka, Michinori; Sato, Hirotaka; Kondoh, Yasumitsu; Osada, Hiroyuki; Kotani, Osamu; Yokoyama, Masaru; Sato, Hironori; Aida, Yoko

2017-01-01

An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. - Highlights: •DP2392-E10 inhibits replication of a broad range of influenza A subtypes. •DP2392-E10 inhibits nuclear exports of NP and NEP via their NP-NES3 and NEP-NES2 domains, respectively. •DP2392-E10 is predicted to directly bind CRM1 in the region near the HEAT9 and HEAT10 repeats.

What's Cholesterol?

Science.gov (United States)

... LDL. Most cholesterol is LDL (low-density lipoprotein) cholesterol. LDL cholesterol is more likely to clog blood vessels because ... Here's a way to remember the difference: the LDL cholesterol is the bad kind, so call it "lousy" ...

Fluorescent Sterols and Cholesteryl Esters as Probes for Intracellular Cholesterol Transport

Science.gov (United States)

Solanko, Katarzyna A.; Modzel, Maciej; Solanko, Lukasz M.; Wüstner, Daniel

2015-01-01

Cholesterol transport between cellular organelles comprised vesicular trafficking and nonvesicular exchange; these processes are often studied by quantitative fluorescence microscopy. A major challenge for using this approach is producing analogs of cholesterol with suitable brightness and structural and chemical properties comparable with those of cholesterol. This review surveys currently used fluorescent sterols with respect to their behavior in model membranes, their photophysical properties, as well as their transport and metabolism in cells. In the first part, several intrinsically fluorescent sterols, such as dehydroergosterol or cholestatrienol, are discussed. These polyene sterols (P-sterols) contain three conjugated double bonds in the steroid ring system, giving them slight fluorescence in ultraviolet light. We discuss the properties of P-sterols relative to cholesterol, outline their chemical synthesis, and explain how to image them in living cells and organisms. In particular, we show that P-sterol esters inserted into low-density lipoprotein can be tracked in the fibroblasts of Niemann–Pick disease using high-resolution deconvolution microscopy. We also describe fluorophore-tagged cholesterol probes, such as BODIPY-, NBD-, Dansyl-, or Pyrene-tagged cholesterol, and eventual esters of these analogs. Finally, we survey the latest developments in the synthesis and use of alkyne cholesterol analogs to be labeled with fluorophores by click chemistry and discuss the potential of all approaches for future applications. PMID:27330304

Cholesterol metabolism: increasingly complex; El metabolismo del colesterol: cada vez mas complejo

Energy Technology Data Exchange (ETDEWEB)

Sanhueza, J.; Valenzuela, R.; Valenzuela, A.

2012-07-01

Cholesterol is an important molecule; it is necessary for the biosynthesis of steroidal hormones, bile salts and to maintain the stability of biological membranes in animal cells. However, its excess is negative and is responsible for the development of many diseases involving the heart and brain, or in the generation of some types of cancer. For these reasons, the cellular cholesterol levels must be finely regulated and therefore, an infinite number of mechanisms participate in this regulation, which undertake the organism as a whole. These mechanisms should begin to operate efficiently from the intake of cholesterol from the diet, its incorporation into the enterocytes, where are involved carriers such as ABC and NCP1 transporters, PDZ structural motif, to name a few. It is also necessary an adequate regulation of circulating cholesterol and once inside the body, there should be a perfect harmony between the addition of cholesterol to various tissues, its metabolic use, the mechanisms of its tissue deposition, and the synthesis of this lipid. From this perspective, this review offers a general view of the molecular mechanisms that allow the regulation of extra and intracellular cholesterol levels. (Author) 82 refs.

Stable assembly of HIV-1 export complexes occurs cotranscriptionally

DEFF Research Database (Denmark)

Nawroth, Isabel; Mueller, Florian; Basyuk, Eugenia

2014-01-01

The HIV-1 Rev protein mediates export of unspliced and singly spliced viral transcripts by binding to the Rev response element (RRE) and recruiting the cellular export factor CRM1. Here, we investigated the recruitment of Rev to the transcription sites of HIV-1 reporters that splice either post......- or cotranscriptionally. In both cases, we observed that Rev localized to the transcription sites of the reporters and recruited CRM1. Rev and CRM1 remained at the reporter transcription sites when cells were treated with the splicing inhibitor Spliceostatin A (SSA), showing that the proteins associate with RNA prior...... to or during early spliceosome assembly. Fluorescence recovery after photobleaching (FRAP) revealed that Rev and CRM1 have similar kinetics as the HIV-1 RNA, indicating that Rev, CRM1, and RRE-containing RNAs are released from the site of transcription in one single export complex. These results suggest...

Inhibiting cancer cell hallmark features through nuclear export inhibition.

Science.gov (United States)

Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

2016-01-01

Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Murine Leukemia Virus Uses TREX Components for Efficient Nuclear Export of Unspliced Viral Transcripts

Directory of Open Access Journals (Sweden)

Toshie Sakuma

2014-03-01

Full Text Available Previously we reported that nuclear export of both unspliced and spliced murine leukemia virus (MLV transcripts depends on the nuclear export factor (NXF1 pathway. Although the mRNA export complex TREX, which contains Aly/REF, UAP56, and the THO complex, is involved in the NXF1-mediated nuclear export of cellular mRNAs, its contribution to the export of MLV mRNA transcripts remains poorly understood. Here, we studied the involvement of TREX components in the export of MLV transcripts. Depletion of UAP56, but not Aly/REF, reduced the level of both unspliced and spliced viral transcripts in the cytoplasm. Interestingly, depletion of THO components, including THOC5 and THOC7, affected only unspliced viral transcripts in the cytoplasm. Moreover, the RNA immunoprecipitation assay showed that only the unspliced viral transcript interacted with THOC5. These results imply that MLV requires UAP56, THOC5 and THOC7, in addition to NXF1, for nuclear export of viral transcripts. Given that naturally intronless mRNAs, but not bulk mRNAs, require THOC5 for nuclear export, it is plausible that THOC5 plays a key role in the export of unspliced MLV transcripts.

Increased expression of RXRα in dementia: an early harbinger for the cholesterol dyshomeostasis?

Directory of Open Access Journals (Sweden)

Katsel Pavel

2010-09-01

Full Text Available Abstract Background Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1 and ApoE. Results In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRα, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRα expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions. Conclusions These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD.

Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content.

Directory of Open Access Journals (Sweden)

Hanna Appelqvist

Full Text Available Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1 protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2, which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determineD the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems.

Science.gov (United States)

Girotti, Albert W; Korytowski, Witold

2017-12-01

Cholesterol is like other unsaturated lipids in being susceptible to peroxidative degradation upon exposure to strong oxidants like hydroxyl radical or peroxynitrite generated under conditions of oxidative stress. In the eukaryotic cell plasma membrane, where most of the cellular cholesterol resides, peroxidation leads to membrane structural and functional damage from which pathological states may arise. In low density lipoprotein, cholesterol and phospholipid peroxidation have long been associated with atherogenesis. Among the many intermediates/products of cholesterol oxidation, hydroperoxide species (ChOOHs) have a number of different fates and deserve special attention. These fates include (a) damage-enhancement via iron-catalyzed one-electron reduction, (b) damage containment via two-electron reduction, and (c) inter-membrane, inter-lipoprotein, and membrane-lipoprotein translocation, which allows dissemination of one-electron damage or off-site suppression thereof depending on antioxidant location and capacity. In addition, ChOOHs can serve as reliable and conveniently detected mechanistic reporters of free radical-mediated reactions vs. non-radical (e.g., singlet oxygen)-mediated reactions. Iron-stimulated peroxidation of cholesterol and other lipids underlies a newly discovered form of regulated cell death called ferroptosis. These and other deleterious consequences of radical-mediated lipid peroxidation will be discussed in this review.

Nuclear Export Signal Masking Regulates HIV-1 Rev Trafficking and Viral RNA Nuclear Export.

Science.gov (United States)

Behrens, Ryan T; Aligeti, Mounavya; Pocock, Ginger M; Higgins, Christina A; Sherer, Nathan M

2017-02-01

HIV-1's Rev protein forms a homo-oligomeric adaptor complex linking viral RNAs to the cellular CRM1/Ran-GTP nuclear export machinery through the activity of Rev's prototypical leucine-rich nuclear export signal (NES). In this study, we used a functional fluorescently tagged Rev fusion protein as a platform to study the effects of modulating Rev NES identity, number, position, or strength on Rev subcellular trafficking, viral RNA nuclear export, and infectious virion production. We found that Rev activity was remarkably tolerant of diverse NES sequences, including supraphysiological NES (SNES) peptides that otherwise arrest CRM1 transport complexes at nuclear pores. Rev's ability to tolerate a SNES was both position and multimerization dependent, an observation consistent with a model wherein Rev self-association acts to transiently mask the NES peptide(s), thereby biasing Rev's trafficking into the nucleus. Combined imaging and functional assays also indicated that NES masking underpins Rev's well-known tendency to accumulate at the nucleolus, as well as Rev's capacity to activate optimal levels of late viral gene expression. We propose that Rev multimerization and NES masking regulates Rev's trafficking to and retention within the nucleus even prior to RNA binding. HIV-1 infects more than 34 million people worldwide causing >1 million deaths per year. Infectious virion production is activated by the essential viral Rev protein that mediates nuclear export of intron-bearing late-stage viral mRNAs. Rev's shuttling into and out of the nucleus is regulated by the antagonistic activities of both a peptide-encoded N-terminal nuclear localization signal and C-terminal nuclear export signal (NES). How Rev and related viral proteins balance strong import and export activities in order to achieve optimal levels of viral gene expression is incompletely understood. We provide evidence that multimerization provides a mechanism by which Rev transiently masks its NES peptide

An innovative method to selectively ablate cholesterol esters from an arteriosclerotic region of the arterial wall using a free-electron laser

International Nuclear Information System (INIS)

Awazu, K.; Nagai, A.; Tomimasu, T.; Aizawa, K.

1998-01-01

The selective removal of cholesterol esters accumulated in the intra-cellular or extra-cellular spaces has clinical significance. In the present work we investigate the removal of cholesterol esters by using a free electron laser (FEL) in an arteriosclerotic region. Thin films of cholesteryl oleate and albumin, and the cross-section of a rabbit artery were placed on an inverted microscope stage and the changes caused by the FEL irradiation of 5.75 and 6.1 μm with 1.5-3 mW in average were monitored continuously by a CCD camera in real time. FEL irradiation at a wavelength of 5.75 μm, which is a stretching vibrational mode of the ester, was able to ablate cholesterol esters without affecting albumin and that it can also remove cholesterol esters from rabbits' arteriosclerotic arterial walls. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

Influenza polymerase encoding mRNAs utilize atypical mRNA nuclear export.

Science.gov (United States)

Larsen, Sean; Bui, Steven; Perez, Veronica; Mohammad, Adeba; Medina-Ramirez, Hilario; Newcomb, Laura L

2014-08-28

Influenza is a segmented negative strand RNA virus. Each RNA segment is encapsulated by influenza nucleoprotein and bound by the viral RNA dependent RNA polymerase (RdRP) to form viral ribonucleoproteins responsible for RNA synthesis in the nucleus of the host cell. Influenza transcription results in spliced mRNAs (M2 and NS2), intron-containing mRNAs (M1 and NS1), and intron-less mRNAs (HA, NA, NP, PB1, PB2, and PA), all of which undergo nuclear export into the cytoplasm for translation. Most cellular mRNA nuclear export is Nxf1-mediated, while select mRNAs utilize Crm1. Here we inhibited Nxf1 and Crm1 nuclear export prior to infection with influenza A/Udorn/307/1972(H3N2) virus and analyzed influenza intron-less mRNAs using cellular fractionation and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We examined direct interaction between Nxf1 and influenza intron-less mRNAs using immuno purification of Nxf1 and RT-PCR of associated RNA. Inhibition of Nxf1 resulted in less influenza intron-less mRNA export into the cytoplasm for HA and NA influenza mRNAs in both human embryonic kidney cell line (293 T) and human lung adenocarcinoma epithelial cell line (A549). However, in 293 T cells no change was observed for mRNAs encoding the components of the viral ribonucleoproteins; NP, PA, PB1, and PB2, while in A549 cells, only PA, PB1, and PB2 mRNAs, encoding the RdRP, remained unaffected; NP mRNA was reduced in the cytoplasm. In A549 cells NP, NA, HA, mRNAs were found associated with Nxf1 but PA, PB1, and PB2 mRNAs were not. Crm1 inhibition also resulted in no significant difference in PA, PB1, and PB2 mRNA nuclear export. These results further confirm Nxf1-mediated nuclear export is functional during the influenza life cycle and hijacked for select influenza mRNA nuclear export. We reveal a cell type difference for Nxf1-mediated nuclear export of influenza NP mRNA, a reminder that cell type can influence molecular mechanisms. Importantly, we

Human immunodeficiency virus impairs reverse cholesterol transport from macrophages.

Directory of Open Access Journals (Sweden)

Zahedi Mujawar

2006-10-01

Full Text Available Several steps of HIV-1 replication critically depend on cholesterol. HIV infection is associated with profound changes in lipid and lipoprotein metabolism and an increased risk of coronary artery disease. Whereas numerous studies have investigated the role of anti-HIV drugs in lipodystrophy and dyslipidemia, the effects of HIV infection on cellular cholesterol metabolism remain uncharacterized. Here, we demonstrate that HIV-1 impairs ATP-binding cassette transporter A1 (ABCA1-dependent cholesterol efflux from human macrophages, a condition previously shown to be highly atherogenic. In HIV-1-infected cells, this effect was mediated by Nef. Transfection of murine macrophages with Nef impaired cholesterol efflux from these cells. At least two mechanisms were found to be responsible for this phenomenon: first, HIV infection and transfection with Nef induced post-transcriptional down-regulation of ABCA1; and second, Nef caused redistribution of ABCA1 to the plasma membrane and inhibited internalization of apolipoprotein A-I. Binding of Nef to ABCA1 was required for down-regulation and redistribution of ABCA1. HIV-infected and Nef-transfected macrophages accumulated substantial amounts of lipids, thus resembling foam cells. The contribution of HIV-infected macrophages to the pathogenesis of atherosclerosis was supported by the presence of HIV-positive foam cells in atherosclerotic plaques of HIV-infected patients. Stimulation of cholesterol efflux from macrophages significantly reduced infectivity of the virions produced by these cells, and this effect correlated with a decreased amount of virion-associated cholesterol, suggesting that impairment of cholesterol efflux is essential to ensure proper cholesterol content in nascent HIV particles. These results reveal a previously unrecognized dysregulation of intracellular lipid metabolism in HIV-infected macrophages and identify Nef and ABCA1 as the key players responsible for this effect. Our findings

What Is Cholesterol?

Science.gov (United States)

... of Cholesterol There are two main types of cholesterol: LDL and HDL. The cholesterol blood test tells how much of each kind you have. Most cholesterol is LDL (low-density lipoprotein) cholesterol. This type is most ...

Cellular Localization and Trafficking of the Human ABCG1 Transporter

Science.gov (United States)

Neufeld, Edward B.; O’Brien, Katherine; Walts, Avram D.; Stonik, John A.; Demosky, Steven J.; Malide, Daniela; Combs, Christian A.; Remaley, Alan T.

2014-01-01

We have developed a suitable heterologous cell expression system to study the localization, trafficking, and site(s) of function of the human ABCG1 transporter. Increased plasma membrane (PM) and late endosomal (LE) cholesterol generated by ABCG1 was removed by lipoproteins and liposomes, but not apoA-I. Delivery of ABCG1 to the PM and LE was required for ABCG1-mediated cellular cholesterol efflux. ABCG1 LEs frequently contacted the PM, providing a collisional mechanism for transfer of ABCG1-mobilized cholesterol, similar to ABCG1-mediated PM cholesterol efflux to lipoproteins. ABCG1-mobilized LE cholesterol also trafficked to the PM by a non-vesicular pathway. Transfer of ABCG1-mobilized cholesterol from the cytoplasmic face of LEs to the PM and concomitant removal of cholesterol from the outer leaflet of the PM bilayer by extracellular acceptors suggests that ABCG1 mobilizes cholesterol on both sides of the lipid bilayer for removal by acceptors. ABCG1 increased uptake of HDL into LEs, consistent with a potential ABCG1-mediated cholesterol efflux pathway involving HDL resecretion. Thus, ABCG1 at the PM mobilizes PM cholesterol and ABCG1 in LE/LYS generates mobile pools of cholesterol that can traffic by both vesicular and non-vesicular pathways to the PM where it can also be transferred to extracellular acceptors with a lipid surface. PMID:25405320

Reference intervals for serum total cholesterol, HDL cholesterol and ...

African Journals Online (AJOL)

Reference intervals of total cholesterol, HDL cholesterol and non-HDL cholesterol concentrations were determined on 309 blood donors from an urban and peri-urban population of Botswana. Using non-parametric methods to establish 2.5th and 97.5th percentiles of the distribution, the intervals were: total cholesterol 2.16 ...

Cholesterol-lowing effect of taurine in HepG2 cell.

Science.gov (United States)

Guo, Junxia; Gao, Ya; Cao, Xuelian; Zhang, Jing; Chen, Wen

2017-03-16

A number of studies indicate that taurine promotes cholesterol conversion to bile acids by upregulating CYP7A1 gene expression. Few in vitro studies are concerned the concentration change of cholesterol and its product of bile acids, and the molecular mechanism of CYP7A1 induction by taurine. The levels of intracellular total cholesterol (TC), free cholesterol (FC), cholesterol ester (EC), total bile acids (TBA) and medium TBA were determined after HepG2 cells were cultured for 24/48 h in DMEM supplemented with taurine at the final concentrations of 1/10/20 mM respectively. The protein expressions of CYP7A1, MEK1/2, c-Jun, p-c-Jun and HNF-4α were detected. Taurine significantly reduced cellular TC and FC in dose -and time-dependent ways, and obviously increased intracellular/medium TBA and CYP7A1 expressions. There was no change in c-Jun expression, but the protein expressions of MEK1/2 and p-c-Jun were increased at 24 h and inhibited at 48 h by 20 mM taurine while HNF4α was induced after both of the 24 h and 48 h treatment. Taurine could enhance CYP7A1 expression by inducing HNF4α and inhibiting MEK1/2 and p-c-Jun expressions to promote intracellular cholesterol metabolism.

Impact of Silver and Iron Nanoparticle Exposure on Cholesterol Uptake by Macrophages

Directory of Open Access Journals (Sweden)

Jonathan H. Shannahan

2015-01-01

Full Text Available Macrophages are central to the development of atherosclerosis by absorbing lipids, promoting inflammation, and increasing plaque deposition. Nanoparticles (NPs are becoming increasingly common in biomedical applications thereby increasing exposure to the immune and vascular systems. This project investigated the influence of NPs on macrophage function and specifically cholesterol uptake. Macrophages were exposed to 20 nm silver NPs (AgNPs, 110 nm AgNPs, or 20 nm Fe3O4 NPs for 2 h and NP uptake, cytotoxicity, and subsequent uptake of fluorescently labeled cholesterol were assessed. Macrophage uptake of NPs did not induce cytotoxicity at concentrations utilized (25 μg/mL; however, macrophage exposure to 20 nm AgNPs reduced subsequent uptake of cholesterol. Further, we assessed the impact of a cholesterol-rich environment on macrophage function following NP exposure. In these sets of experiments, macrophages internalized NPs, exhibited no cytotoxicity, and altered cholesterol uptake. Alterations in the expression of scavenger receptor-B1 following NP exposure, which likely influences cholesterol uptake, were observed. Overall, NPs alter cholesterol uptake, which may have implications in the progression of vascular or immune mediated diseases. Therefore, for the safe development of NPs for biomedical applications, it is necessary to understand their impact on cellular function and biological interactions in underlying disease environments.

Quantitative comparison of the efficacy of various compounds in lowering intracellular cholesterol levels in Niemann-Pick type C fibroblasts.

Directory of Open Access Journals (Sweden)

Zachary T Wehrmann

Full Text Available Niemann-Pick Type C disease (NPC is a lethal, autosomal recessive disorder caused by mutations in the NPC1 and NPC2 cholesterol transport proteins. NPC's hallmark symptoms include an accumulation of unesterified cholesterol and other lipids in the late endosomal and lysosomal cellular compartments, causing progressive neurodegeneration and death. Although the age of onset may vary in those affected, NPC most often manifests in juveniles, and is usually fatal before adolescence. In this study, we investigated the effects of various drugs, many of which modify the epigenetic control of NPC1/NPC2 gene expression, in lowering the otherwise harmful elevated intracellular cholesterol levels in NPC cells. Our studies utilized a previously described image analysis technique, which allowed us to make quantitative comparisons of the efficacy of these drugs in lowering cholesterol levels in a common NPC1 mutant model. Of the drugs analyzed, several that have been previously studied (vorinostat, panobinostat, and β-cyclodextrin significantly lowered the relative amount of unesterified cellular cholesterol, consistent with earlier observations. In addition, a novel potential treatment, rapamycin, likewise alleviated the NPC phenotype. We also studied combinations of effective compounds with β-cyclodextrin; the addition of β-cyclodextrin significantly enhanced the cholesterol-lowering activity of vorinostat and panobinostat, but had mixed effects with rapamycin. Collectively, these results may provide a basis for the eventual development of improved NPC therapies.

Nuclear export of human hepatitis B virus core protein and pregenomic RNA depends on the cellular NXF1-p15 machinery.

Science.gov (United States)

Yang, Ching-Chun; Huang, Er-Yi; Li, Hung-Cheng; Su, Pei-Yi; Shih, Chiaho

2014-01-01

Hepatitis B virus (HBV) core protein (HBc) can shuttle between nucleus and cytoplasm. Cytoplasm-predominant HBc is clinically associated with severe liver inflammation. Previously, we found that HBc arginine-rich domain (ARD) can associate with a host factor NXF1 (TAP) by coimmunoprecipitation. It is well known that NXF1-p15 heterodimer can serve as a major export receptor of nuclear mRNA as a ribonucleoprotein complex (RNP). In the NXF1-p15 pathway, TREX (transcription/export) complex plays an important role in coupling nuclear pre-mRNA processing with mRNA export in mammalian cells. Here, we tested the hypothesis whether HBc and HBV specific RNA can be exported via the TREX and NXF1-p15 mediated pathway. We demonstrated here that HBc can physically and specifically associate with TREX components, and the NXF1-p15 export receptor by coimmunoprecipitation. Accumulation of HBc protein in the nucleus can be induced by the interference with TREX and NXF1-p15 mediated RNA export machinery. HBV transcripts encodes a non-spliced 3.5 kb pregenomic RNA (pgRNA) which can serve as a template for reverse transcription. Cytoplasmic HBV pgRNA appeared to be reduced by siRNA treatment specific for the NXF1-p15 complex by quantitative RT-qPCR and Northern blot analyses. This result suggests that the pgRNA was also exported via the NXF1-p15 machinery. We entertain the hypothesis that HBc protein can be exported as an RNP cargo via the mRNA export pathway by hijacking the TREX and NXF1-p15 complex. In our current and previous studies, HBc is not required for pgRNA accumulation in the cytoplasm. Furthermore, HBc ARD can mediate nuclear export of a chimeric protein containing HBc ARD in a pgRNA-independent manner. Taken together, it suggests that while both pgRNA and HBc protein exports are dependent on NXF1-p15, they are using the same export machinery in a manner independent of each other.

Export Margins, Price and Quantity of Belarus’s Export Growth

Directory of Open Access Journals (Sweden)

Otamurodov Shavkat

2017-03-01

Full Text Available This paper examines the sources of Belarus’s export growth and decomposes export growth into extensive and intensive margins. This study also aims to determine export margins for intermediate and final goods and to determine the price and quantity components of the intensive export margin. In order to achieve the desired objectives, we use two methods for decomposing export growth, the count method and the export shares method. We analyse Belarus's export growth using export data at the HS-6 digit level for the 2004-2014 period. Our results show that Belarus's exports grew mainly due to growth in the price margin during the studied period 2004-2014. However, the extensive margin was important in export growth to some extent. Comparing the growth rate across final and intermediate goods reveals that although the share of final products in Belarus’s exports is not very big (18.9% in 2014, the average annual growth in exports of final products is higher than that of intermediate goods. Our investigation also shows that Belarus produces a wide range of commodities, but the share of the most of these commodities is not large; its exports depend on a restricted range of commodities. Moreover, most of the commodities are exported to Russia and Ukraine. Our results give us reason to assume that finding new markets for their new products is one of the main challenges for developing countries wishing to increase their exports by an extensive margin. This has important implications for how policy makers promote the trade and diversification of exports.

Intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts

International Nuclear Information System (INIS)

Liscum, L.; Ruggiero, R.M.; Faust, J.R.

1989-01-01

Niemann-Pick disease type C (NPC) is characterized by substantial intracellular accumulation of unesterified cholesterol. The accumulation of unesterified cholesterol in NPC fibroblasts cultured with low density lipoprotein (LDL) appears to result from the inability of LDL to stimulate cholesterol esterification in addition to impaired LDL-mediated downregulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in cholesterol transport in NPC cells has been inferred from previous studies, no experiments have been reported that measure the intracellular movement of LDL-cholesterol specifically. We have used four approaches to assess intracellular cholesterol transport in normal and NPC cells and have determined the following: (a) mevinolin-inhibited NPC cells are defective in using LDL-cholesterol for growth. However, exogenously added mevalonate restores cell growth equally in normal and NPC cells; (b) the transport of LDL-derived [3H]cholesterol to the plasma membrane is slower in NPC cells, while the rate of appearance of [3H]acetate-derived, endogenously synthesized [3H]cholesterol at the plasma membrane is the same for normal and NPC cells; (c) in NPC cells, LDL-derived [3H]cholesterol accumulates in lysosomes to higher levels than normal, resulting in defective movement to other cell membranes; and (d) incubation of cells with LDL causes an increase in cholesterol content of NPC lysosomes that is threefold greater than that observed in normal lysosomes. Our results indicate that a cholesterol transport defect exists in NPC that is specific for LDL-derived cholesterol

MILD CHOLESTEROL DEPLETION REDUCES AMYLOID-β PRODUCTION BY IMPAIRING APP TRAFFICKING TO THE CELL SURFACE

Science.gov (United States)

Guardia-Laguarta, Cristina; Coma, Mireia; Pera, Marta; Clarimón, Jordi; Sereno, Lidia; Agulló, José M.; Molina-Porcel, Laura; Gallardo, Eduard; Deng, Amy; Berezovska, Oksana; Hyman, Bradley T.; Blesa, Rafael; Gómez-Isla, Teresa; Lleó, Alberto

2009-01-01

It has been suggested that cellular cholesterol levels can modulate the metabolism of the amyloid precursor protein (APP) but the underlying mechanism remains controversial. In the current study, we investigate in detail the relationship between cholesterol reduction, APP processing and γ-secretase function in cell culture studies. We found that mild membrane cholesterol reduction led to a decrease in Aβ40 and Aβ42 in different cell types. We did not detect changes in APP intracellular domain or Notch intracellular domain generation. Western blot analyses showed a cholesterol-dependent decrease in the APP C-terminal fragments and cell surface APP. Finally, we applied a fluorescence resonance energy transfer (FRET)-based technique to study APP-Presenilin 1 (PS1) interactions and lipid rafts in intact cells. Our data indicate that cholesterol depletion reduces association of APP into lipid rafts and disrupts APP-PS1 interaction. Taken together, our results suggest that mild membrane cholesterol reduction impacts the cleavage of APP upstream of γ-secretase and appears to be mediated by changes in APP trafficking and partitioning into lipid rafts. PMID:19457132

The cholesterol space of the rat; L'espace cholesterol du rat

Energy Technology Data Exchange (ETDEWEB)

Chevallier, F [Commissariat a l' Energie Atomique, Saclay (France).Centre d' Etudes Nucleaires

1959-07-01

The experiments consisted in feeding daily to rats the same mass of radioactive cholesterol, over variable time intervals. From the evolution of the specific radioactivity of cholesterol carbon-14 in the organs as a function of time, information relative to the transport of cholesterol in the organism may be obtained. 1) The cholesterol space, defined as the group of molecules capable of being transferred from the organs into the serum and vice versa, represents at the most 50 per cent of the total cholesterol of the adult rat. 2) The incessant interchange between the tissual and the serum cholesterol renews entirely or for the most part the cholesterol molecules contained in the following organs: spleen, heart, adipose tissue, suprarenal glands, lungs, bone marrow, liver, erythrocytes. For a second group of organs: skin, testicles, kidneys, colon, bones, muscles, only a fraction of their cholesterol is renewable by this process. No transfer can be detected at the level of the brain. 3) The relative speeds of the various means of appearance (absorption, synthesis) and disappearance (excretion, transformation) of the cholesterol from its space are such that a stationary isotopic state is established around the eighth day, when the animal absorbs 5 milligrams of radioactive cholesterol daily. (author) [French] Les experiences ont consiste a faire ingerer quotidiennement une meme masse de cholesterol radioactif a des rats, durant des laps de temps variables. L'evolution de la radioactivite specifique du carbone-14 du cholesterol des organes en fonction du temps permet d'obtenir des renseignements relatifs au transport du cholesterol dans l'organisme. 1) L'espace cholesterol defini comme l'ensemble des molecules susceptibles d'etre transferees des organes dans le serum, et vice-versa, represente au plus 50 pour cent du cholesterol total du rat adulte. 2) Le va et vient incessant entre le cholesterol tissulaire et le cholesterol serique renouvelle en totalite ou en

Organizing export strategies.

OpenAIRE

G. Lojacono; M. Venzin

2014-01-01

The article unfolds as follows: after a brief introduction on the relevance of international trade and the characteristics of export strategies, we describe four distinct archetypes: export manager, centralistic export developer, export skimmer, integrated export developer.

Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXRα signalling pathway in oxLDL-loaded macrophages.

Science.gov (United States)

Xu, Xiaoyang; Zhang, Aolin; Halquist, Matthew S; Yuan, Xinxu; Henderson, Scott C; Dewey, William L; Li, Pin-Lan; Li, Ningjun; Zhang, Fan

2017-02-01

Statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, are the first-line medications prescribed for the prevention and treatment of coronary artery diseases. The efficacy of statins has been attributed not only to their systemic cholesterol-lowering actions but also to their pleiotropic effects that are unrelated to cholesterol reduction. These pleiotropic effects have been increasingly recognized as essential in statins therapy. This study was designed to investigate the pleiotropic actions of simvastatin, one of the most commonly prescribed statins, on macrophage cholesterol homeostasis with a focus on lysosomal free cholesterol egression. With simultaneous nile red and filipin staining, analysis of confocal/multi-photon imaging demonstrated that simvastatin markedly attenuated unesterified (free) cholesterol buildup in macrophages loaded with oxidized low-density lipoprotein but had little effect in reducing the sizes of cholesteryl ester-containing lipid droplets; the reduction in free cholesterol was mainly attributed to decreases in lysosome-compartmentalized cholesterol. Functionally, the egression of free cholesterol from lysosomes attenuated pro-inflammatory cytokine secretion. It was determined that the reduction of lysosomal free cholesterol buildup by simvastatin was due to the up-regulation of Niemann-Pick C1 (NPC1), a lysosomal residing cholesterol transporter. Moreover, the enhanced enzymatic production of 7-hydroxycholesterol by cytochrome P450 7A1 and the subsequent activation of liver X receptor α underscored the up-regulation of NPC1. These findings reveal a novel pleiotropic effect of simvastatin in affecting lysosomal cholesterol efflux in macrophages and the associated significance in the treatment of atherosclerosis. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

OpenAIRE

Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-01-01

2-Hydroxy-propyl-?-cyclodextrin (HP?CD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HP?CD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (e...

Export spillovers

DEFF Research Database (Denmark)

Choquette, Eliane; Meinen, Philipp

2015-01-01

This paper studies the importance of export spillovers in a firm's decision to enter specific export markets and extends the current state of the literature by assessing different mechanisms through which they may occur, namely (i) labour movement, (ii) intra-industry spillovers and (iii) inter......-industry linkages. We do so by exploiting a unique data set covering the universe of manufacturing firms in Denmark for the period 1995–2006 which combines transaction-level export data, firm accounting data, employer–employee linked data and information from yearly input–output tables. We corroborate...... the literature on export spillovers by presenting robust evidence of destination-specific export spillovers. The results suggest that labour mobility as well as intra- and inter-industry linkages (backward linkages) are important channels for export spillovers, while presenting heterogeneous effects across firms...

Cholesterol testing and results

Science.gov (United States)

... your cholesterol is in this normal range. LDL (Bad) Cholesterol LDL cholesterol is sometimes called "bad" cholesterol. ... to 3.3 mmol/l) are desired. VLDL (Bad) Cholesterol VLDL contains the highest amount of triglycerides. ...

Cholesterol Facts and Statistics

Science.gov (United States)

... Managing High Cholesterol Cholesterol-lowering Medicine High Cholesterol Statistics and Maps High Cholesterol Facts High Cholesterol Maps ... Deo R, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart ...

Structure-function relationships in reconstituted HDL: Focus on antioxidative activity and cholesterol efflux capacity.

Science.gov (United States)

Cukier, Alexandre M O; Therond, Patrice; Didichenko, Svetlana A; Guillas, Isabelle; Chapman, M John; Wright, Samuel D; Kontush, Anatol

2017-09-01

High-density lipoprotein (HDL) contains multiple components that endow it with biological activities. Apolipoprotein A-I (apoA-I) and surface phospholipids contribute to these activities; however, structure-function relationships in HDL particles remain incompletely characterised. Reconstituted HDLs (rHDLs) were prepared from apoA-I and soy phosphatidylcholine (PC) at molar ratios of 1:50, 1:100 and 1:150. Oxidative status of apoA-I was varied using controlled oxidation of Met112 residue. HDL-mediated inactivation of PC hydroperoxides (PCOOH) derived from mildly pre-oxidized low-density lipoprotein (LDL) was evaluated by HPLC with chemiluminescent detection in HDL+LDL mixtures and re-isolated LDL. Cellular cholesterol efflux was characterised in RAW264.7 macrophages. rHDL inactivated LDL-derived PCOOH in a dose- and time-dependent manner. The capacity of rHDL to both inactivate PCOOH and efflux cholesterol via ATP-binding cassette transporter A1 (ABCA1) increased with increasing apoA-I/PC ratio proportionally to the apoA-I content in rHDL. Controlled oxidation of apoA-I Met112 gradually decreased PCOOH-inactivating capacity of rHDL but increased ABCA1-mediated cellular cholesterol efflux. Increasing apoA-I content in rHDL enhanced its antioxidative activity towards oxidized LDL and cholesterol efflux capacity via ABCA1, whereas oxidation of apoA-I Met112 decreased the antioxidative activity but increased the cholesterol efflux. These findings provide important considerations in the design of future HDL therapeutics. Non-standard abbreviations and acronyms: AAPH, 2,2'-azobis(-amidinopropane) dihydrochloride; ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; BHT, butylated hydroxytoluene; CV, cardiovascular; EDTA, ethylenediaminetetraacetic acid; HDL-C, high-density lipoprotein cholesterol; LOOH, lipid hydroperoxides; Met(O), methionine sulfoxide; Met112, methionine 112 residue; Met86, methionine 86 residue; oxLDL, oxidized low

Role of UBIAD1 in Intracellular Cholesterol Metabolism and Vascular Cell Calcification.

Directory of Open Access Journals (Sweden)

Sha Liu

the Golgi marker in HUVSMCs. In conclusion, high intracellular cholesterol content contributes to phosphate-induced vascular cell differentiation and calcification. UBIAD1 or menaquinone-4 could decrease vascular cell differentiation and calcification, probably via its potent role of inversely modulating cellular cholesterol.

Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells.

Science.gov (United States)

Geoghegan, Vincent; Stainton, Kirsty; Rainey, Stephanie M; Ant, Thomas H; Dowle, Adam A; Larson, Tony; Hester, Svenja; Charles, Philip D; Thomas, Benjamin; Sinkins, Steven P

2017-09-13

Wolbachia are intracellular maternally inherited bacteria that can spread through insect populations and block virus transmission by mosquitoes, providing an important approach to dengue control. To better understand the mechanisms of virus inhibition, we here perform proteomic quantification of the effects of Wolbachia in Aedes aegypti mosquito cells and midgut. Perturbations are observed in vesicular trafficking, lipid metabolism and in the endoplasmic reticulum that could impact viral entry and replication. Wolbachia-infected cells display a differential cholesterol profile, including elevated levels of esterified cholesterol, that is consistent with perturbed intracellular cholesterol trafficking. Cyclodextrins have been shown to reverse lipid accumulation defects in cells with disrupted cholesterol homeostasis. Treatment of Wolbachia-infected Ae. aegypti cells with 2-hydroxypropyl-β-cyclodextrin restores dengue replication in Wolbachia-carrying cells, suggesting dengue is inhibited in Wolbachia-infected cells by localised cholesterol accumulation. These results demonstrate parallels between the cellular Wolbachia viral inhibition phenotype and lipid storage genetic disorders. Wolbachia infection of mosquitoes can block dengue virus infection and is tested in field trials, but the mechanism of action is unclear. Using proteomics, Geoghegan et al. here identify effects of Wolbachia on cholesterol homeostasis and dengue virus replication in Aedes aegypti.

Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations.

Science.gov (United States)

Dotson, Rachel J; Smith, Casey R; Bueche, Kristina; Angles, Gary; Pias, Sally C

2017-06-06

Cholesterol is widely known to alter the physical properties and permeability of membranes. Several prior works have implicated cell membrane cholesterol as a barrier to tissue oxygenation, yet a good deal remains to be explained with regard to the mechanism and magnitude of the effect. We use molecular dynamics simulations to provide atomic-resolution insight into the influence of cholesterol on oxygen diffusion across and within the membrane. Our simulations show strong overall agreement with published experimental data, reproducing the shapes of experimental oximetry curves with high accuracy. We calculate the upper-limit transmembrane oxygen permeability of a 1-palmitoyl,2-oleoylphosphatidylcholine phospholipid bilayer to be 52 ± 2 cm/s, close to the permeability of a water layer of the same thickness. With addition of cholesterol, the permeability decreases somewhat, reaching 40 ± 2 cm/s at the near-saturating level of 62.5 mol % cholesterol and 10 ± 2 cm/s in a 100% cholesterol mimic of the experimentally observed noncrystalline cholesterol bilayer domain. These reductions in permeability can only be biologically consequential in contexts where the diffusional path of oxygen is not water dominated. In our simulations, cholesterol reduces the overall solubility of oxygen within the membrane but enhances the oxygen transport parameter (solubility-diffusion product) near the membrane center. Given relatively low barriers to passing from membrane to membrane, our findings support hydrophobic channeling within membranes as a means of cellular and tissue-level oxygen transport. In such a membrane-dominated diffusional scheme, the influence of cholesterol on oxygen permeability is large enough to warrant further attention. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The Effects of Altered Membrane Cholesterol Levels on Sodium Pump Activity in Subclinical Hypothyroidism

Directory of Open Access Journals (Sweden)

Suparna Roy

2017-02-01

Full Text Available BackgroundMetabolic dysfunctions characteristic of overt hypothyroidism (OH start at the early stage of subclinical hypothyroidism (SCH. Na+/K+-ATPase (the sodium pump is a transmembrane enzyme that plays a vital role in cellular activities in combination with membrane lipids. We evaluated the effects of early changes in thyroid hormone and membrane cholesterol on sodium pump activity in SCH and OH patients.MethodsIn 32 SCH patients, 35 OH patients, and 34 euthyroid patients, sodium pump activity and cholesterol levels in red blood cell membranes were measured. Serum thyroxine (T4 and thyroid stimulating hormone (TSH levels were measured using enzyme-linked immunosorbent assays. Differences in their mean values were analysed using post hoc analysis of variance. We assessed the dependence of the sodium pump on other metabolites by multiple regression analysis.ResultsSodium pump activity and membrane cholesterol were lower in both hypothyroid groups than in control group, OH group exhibiting lower values than SCH group. In SCH group, sodium pump activity showed a significant direct dependence on membrane cholesterol with an inverse relationship with serum TSH levels. In OH group, sodium pump activity depended directly on membrane cholesterol and serum T4 levels. No dependence on serum cholesterol was observed in either case.ConclusionDespite the presence of elevated serum cholesterol in hypothyroidism, membrane cholesterol contributed significantly to maintain sodium pump activity in the cells. A critical reduction in membrane cholesterol levels heralds compromised enzyme activity, even in the early stage of hypothyroidism, and this can be predicted by elevated TSH levels alone, without any evident clinical manifestations.

Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans

NARCIS (Netherlands)

Brunham, Liam R.; Tietjen, Ian; Bochem, Andrea E.; Singaraja, Roshni R.; Franchini, Patrick L.; Radomski, Chris; Mattice, Maryanne; Legendre, Annick; Hovingh, G. Kees; Kastelein, John J. P.; Hayden, Michael R.

2011-01-01

The scavenger receptor class B, member 1 (SR-BI), is a key cellular receptor for high-density lipoprotein (HDL) in mice, but its relevance to human physiology has not been well established. Recently a family was reported with a mutation in the gene encoding SR-BI and high HDL cholesterol (HDL-C).

LDL Receptor-Related Protein-1 (LRP1 Regulates Cholesterol Accumulation in Macrophages.

Directory of Open Access Journals (Sweden)

Anna P Lillis

Full Text Available Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the in vivo contribution of the LDL receptor-related protein 1 (LRP1 to this process is not known [corrected]. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR-deficient background (macLRP1-/-. After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp+/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis.

Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

KAUST Repository

Mandal, Pritam; Noutsi, Bakiza Kamal; Chaieb, Saharoui

2016-01-01

to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration

Protein export through the bacterial flagellar type III export pathway.

Science.gov (United States)

Minamino, Tohru

2014-08-01

For construction of the bacterial flagellum, which is responsible for bacterial motility, the flagellar type III export apparatus utilizes both ATP and proton motive force across the cytoplasmic membrane and exports flagellar proteins from the cytoplasm to the distal end of the nascent structure. The export apparatus consists of a membrane-embedded export gate made of FlhA, FlhB, FliO, FliP, FliQ, and FliR and a water-soluble ATPase ring complex consisting of FliH, FliI, and FliJ. FlgN, FliS, and FliT act as substrate-specific chaperones that do not only protect their cognate substrates from degradation and aggregation in the cytoplasm but also efficiently transfer the substrates to the export apparatus. The ATPase ring complex facilitates the initial entry of the substrates into the narrow pore of the export gate. The export gate by itself is a proton-protein antiporter that uses the two components of proton motive force, the electric potential difference and the proton concentration difference, for different steps of the export process. A specific interaction of FlhA with FliJ located in the center of the ATPase ring complex allows the export gate to efficiently use proton motive force to drive protein export. The ATPase ring complex couples ATP binding and hydrolysis to its assembly-disassembly cycle for rapid and efficient protein export cycle. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. © 2013 Elsevier B.V. All rights reserved.

The Effect of Export Tax on Indonesia’s Cocoa Export Competitiveness

OpenAIRE

Rifin, Amzul; Nauly, Dahlia

2013-01-01

The government of Indonesia implemented an export tax policy on cocoa beans since April 2010 in order to develop cocoa processing industry. The objective of this article is to analyze the effect of export tax on Indonesia’s cocoa export competitiveness. The results indicate that with the implementation of export tax, cocoa export product composition shift from cocoa beans to processed cocoa products. On the other hand, Indonesia’s cocoa export growth is lower than the growth of cocoa world de...

High blood cholesterol levels

Science.gov (United States)

Cholesterol - high; Lipid disorders; Hyperlipoproteinemia; Hyperlipidemia; Dyslipidemia; Hypercholesterolemia ... There are many types of cholesterol. The ones talked about most are: ... lipoprotein (HDL) cholesterol -- often called "good" cholesterol ...

Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study

KAUST Repository

Mandal, Pritam

2016-06-01

Cholesterol is crucial to the mechanical properties of cell membranes that are important to cells’ behavior. Its depletion from the cell membranes could be dramatic. Among cyclodextrins (CDs), methyl beta cyclodextrin (MβCD) is the most efficient to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MβCD. While the removal of cholesterol by MβCD depends on the cholesterol concentration in most mixed lipid monolayers, it does not depend very much on the concentration of cholesterol in C16-Cer/Chol monolayers. The surface pressure decay during depletion were described by a stretched exponential that suggested that the cholesterol molecules are unable to diffuse laterally and behave like static traps for the MβCD molecules. Cholesterol depletion causes morphology changes of domains but these disrupted monolayers domains seem to reform even when cholesterol level was low.

Cholesterol IQ Quiz

Science.gov (United States)

... Artery Disease Venous Thromboembolism Aortic Aneurysm More Cholesterol IQ Quiz Updated:Jul 5,2017 Begin the quiz ... What Your Cholesterol Levels Mean Common Misconceptions Cholesterol IQ Quiz • HDL, LDL, and Triglycerides • Causes of High ...

The dynamin chemical inhibitor dynasore impairs cholesterol trafficking and sterol-sensitive genes transcription in human HeLa cells and macrophages.

Directory of Open Access Journals (Sweden)

Emmanuelle Girard

Full Text Available Intracellular transport of cholesterol contributes to the regulation of cellular cholesterol homeostasis by mechanisms that are yet poorly defined. In this study, we characterized the impact of dynasore, a recently described drug that specifically inhibits the enzymatic activity of dynamin, a GTPase regulating receptor endocytosis and cholesterol trafficking. Dynasore strongly inhibited the uptake of low-density lipoprotein (LDL in HeLa cells, and to a lower extent in human macrophages. In both cell types, dynasore treatment led to the abnormal accumulation of LDL and free cholesterol (FC within the endolysosomal network. The measure of cholesterol esters (CE further showed that the delivery of regulatory cholesterol to the endoplasmic reticulum (ER was deficient. This resulted in the inhibition of the transcriptional control of the three major sterol-sensitive genes, sterol-regulatory element binding protein 2 (SREBP-2, 3-hydroxy-3-methyl-coenzymeA reductase (HMGCoAR, and low-density lipoprotein receptor (LDLR. The sequestration of cholesterol in the endolysosomal compartment impaired both the active and passive cholesterol efflux in HMDM. Our data further illustrate the importance of membrane trafficking in cholesterol homeostasis and validate dynasore as a new pharmacological tool to study the intracellular transport of cholesterol.

Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions.

Science.gov (United States)

Hallikainen, Maarit; Simonen, Piia; Gylling, Helena

2014-04-27

The efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non-cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols. We collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas-liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method. The results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker. Serum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol

LDL: The "Bad" Cholesterol

Science.gov (United States)

... There are two main types of cholesterol: LDL (bad) cholesterol and HDL (good) cholesterol: LDL stands for low-density lipoproteins. It is called the "bad" cholesterol because a high LDL level leads to ...

Home-Use Tests - Cholesterol

Science.gov (United States)

... Medical Procedures In Vitro Diagnostics Home Use Tests Cholesterol Share Tweet Linkedin Pin it More sharing options ... a home-use test kit to measure total cholesterol. What cholesterol is: Cholesterol is a fat (lipid) ...

The Human ABCG1 Transporter Mobilizes Plasma Membrane and Late Endosomal Non-Sphingomyelin-Associated-Cholesterol for Efflux and Esterification

Directory of Open Access Journals (Sweden)

Edward B. Neufeld

2014-12-01

Full Text Available We have previously shown that GFP-tagged human ABCG1 on the plasma membrane (PM and in late endosomes (LE mobilizes sterol on both sides of the membrane lipid bilayer, thereby increasing cellular cholesterol efflux to lipid surfaces. In the present study, we examined ABCG1-induced changes in membrane cholesterol distribution, organization, and mobility. ABCG1-GFP expression increased the amount of mobile, non-sphingomyelin(SM-associated cholesterol at the PM and LE, but not the amount of SM-associated-cholesterol or SM. ABCG1-mobilized non-SM-associated-cholesterol rapidly cycled between the PM and LE and effluxed from the PM to extracellular acceptors, or, relocated to intracellular sites of esterification. ABCG1 increased detergent-soluble pools of PM and LE cholesterol, generated detergent-resistant, non-SM-associated PM cholesterol, and increased resistance to both amphotericin B-induced (cholesterol-mediated and lysenin-induced (SM-mediated cytolysis, consistent with altered organization of both PM cholesterol and SM. ABCG1 itself resided in detergent-soluble membrane domains. We propose that PM and LE ABCG1 residing at the phase boundary between ordered (Lo and disordered (Ld membrane lipid domains alters SM and cholesterol organization thereby increasing cholesterol flux between Lo and Ld, and hence, the amount of cholesterol available for removal by acceptors on either side of the membrane bilayer for either efflux or esterification.

Curcumin-loaded chitosan-cholesterol micelles: evaluation in monolayers and 3D cancer spheroid model.

Science.gov (United States)

Muddineti, Omkara Swami; Kumari, Preeti; Ray, Eupa; Ghosh, Balaram; Biswas, Swati

2017-06-02

To improve the bioavailability and anticancer potential of curcumin by using a cholesterol-conjugated chitosan micelle. Methods & methods: Cholesterol was conjugated to chitosan (15 kDa) to form self-assembled micelles, which loaded curcumin. Physicochemical characterization and formulation optimization of the drug-loaded micelles (curcumin-loaded chitosan-cholesterol micelles [C-CCM]) were performed. In vitro cellular uptake and viability of C-CCM were investigated in melanoma and breast cancer cell lines. The antitumor efficacy was evaluated in 3D lung cancer spheroid model. The optimized C-CCM had size of approximately 162 nm with loading efficiency of approximately 36%. C-CCM was taken up efficiently by the cells, and it reduced cancer cell viability significantly compared with free curcumin. C-CCM enhanced the antitumor efficacy in spheroids, suggesting that C-CCM could be used as an effective chemotherapy in cancer.

Localization and role of NPC1L1 in cholesterol absorption in human intestine.

Science.gov (United States)

Sané, Alain Théophile; Sinnett, Daniel; Delvin, Edgard; Bendayan, Moise; Marcil, Valérie; Ménard, Daniel; Beaulieu, Jean-François; Levy, Emile

2006-10-01

Recent studies have documented the presence of Niemann-Pick C1-Like 1 (NPC1L1) in the small intestine and its capacity to transport cholesterol in mice and rats. The current investigation was undertaken to explore the localization and function of NPC1L1 in human enterocytes. Cell fractionation experiments revealed an NPC1L1 association with apical membrane of the enterocyte in human jejunum. Signal was also detected in lysosomes, endosomes, and mitochondria. Confirmation of cellular NPC1L1 distribution was obtained by immunocytochemistry. Knockdown of NPC1L1 caused a decline in the ability of Caco-2 cells to capture micellar [(14)C]free cholesterol. Furthermore, this NPC1L1 suppression resulted in increased and decreased mRNA levels and activity of HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and of ACAT, the key enzyme in cholesterol esterification, respectively. An increase was also noted in the transcriptional factor sterol-regulatory element binding protein that modulates cholesterol homeostasis. Efforts were devoted to define the impact of NPC1L1 knockdown on other mediators of cholesterol uptake. RT-PCR evidence is presented to show the significant decrease in the levels of scavenger receptor class B type I (SR-BI) with no changes in ABCA1, ABCG5, and cluster determinant 36 in NPC1L1-deficient Caco-2 cells. Together, our data suggest that NPC1L1 contributes to intestinal cholesterol homeostasis and possibly cooperates with SR-BI to mediate cholesterol absorption in humans.

Circulating PCSK9 affects serum LDL and cholesterol levels more than SREBP-2 expression.

Science.gov (United States)

Mohammadi, Asghar; Shabani, Mohamad; Naseri, Faezeh; Hosseni, Bita; Soltanmohammadi, Elham; Piran, Sadegh; Najafi, Mohammad

2017-07-01

Cholesterol homeostasis is dependent upon the sterol regulatory element binding protein 2 (SREBP-2) regulatory system and the functioning of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9). Many studies have also reported that low density lipoprotein receptor (LDLR) levels in cellular membranes are related to the functioning of these proteins. The aim of this study was to investigate the association of lipid profiles with circulating PCSK9 protein values and SREBP-2 expression levels in normal subjects. The study involved 120 randomly chosen healthy subjects. Their lipid profiles were measured using routine laboratory techniques, and the plasma PCSK9 protein and SREBP-2 expression levels were determined by ELISA and real time quantitative PCR methods, respectively. A statistical analysis was carried out using a statistical software package. Linear regression analyses showed a significant correlation between total cholesterol and PCSK9 (3.54 ± 1.31 ng/mL), as well as between total cholesterol and SREBP-2 (0.1-35.38) (p = 0.002 and p = 0.02, respectively). Furthermore, multiple regression analyses showed strict correlations between PCSK9 and cholesterol-related parameters especially the total cholesterol/HDL-C ratio (β = 3.53, p = 0.001). There was no significant correlation between circulating PCSK9 and SREBP-2 expression levels (r = 1.2, p = 0.3). The study results revealed that serum cholesterol-related parameters are strictly associated with plasma PCSK9 values, suggesting that PCSK9 function has a greater effect on serum total cholesterol levels than SREBP-2 expression does. Furthermore, the total cholesterol/HDL-C ratio was a better indicator for evaluating PCSK9 level than total cholesterol.

Composition of Exports and Export Performance of Eurozone Countries

NARCIS (Netherlands)

Wierts, P.J.; Kerkhoff, H.; de Haan, J.

2014-01-01

This article investigates to what extent the composition of exports is related to the export performance of eurozone countries using a data set on exports from the oldest eurozone countries to their top 20 trade partners for the period 1988-2009. The results suggest that a higher share of high

Renewable energy export network

International Nuclear Information System (INIS)

Anon

2000-01-01

A Renewable Energy Exporters Network (REEN) has recently been established, following a meeting of renewable energy exporters and government agencies on 30 October 2000. REEN will assist the Australian renewable energy industry to take advantage of the opportunities offered by the burgeoning global market for renewable energy goods and services. Recent estimates of the significant potential global growth is renewable energy demand have reinforced the industry and Government's view that, in the medium to long-term, growth in the Australian renewable energy industry will largely depend on capturing export market share. Expanding the export market was identified as a crucial component in the Renewable Energy Action Agenda, developed jointly by industry and Government and released in June 2000. It was estimated that, for the industry to achieve its vision of sales of $4 billion per year by 2010, exports would need to comprise approximately 50% of the forecast growth in sales. As such, the need for a specific export strategy for the Australian renewable energy industry was recognised in the Action Agenda, and the establishment of the REEN is one of the first initiatives undertaken as part of the Renewable Energy Export Strategy. The REEN comprises approximately 50 export-ready renewable energy companies, the Department of Industry, Science and Resources, Austrade, and Stage Government agencies such as NSW's Sustainable Energy Development Authority. The Export Network will operate electronically, with face-to-face meetings held as appropriate. The Department of Industry, Science and Resources will facilitate the Export Network and has published a website at www.isr.gov.au/industry/reen. The site includes: a members directory; a discussion forum; information on opportunities to showcase Australian renewable; energy products and services; and Iinks to sites containing information that may be useful to renewable energy exporters. Other actions that are being undertaken as

Exploring in vivo cholesterol-mediated interactions between activated EGF receptors in plasma membrane with single-molecule optical tracking

International Nuclear Information System (INIS)

Lin, Chien Y.; Huang, Jung Y.; Lo, Leu-Wei

2016-01-01

The first step in many cellular signaling processes occurs at various types of receptors in the plasma membrane. Membrane cholesterol can alter these signaling pathways of living cells. However, the process in which the interaction of activated receptors is modulated by cholesterol remains unclear. In this study, we measured single-molecule optical trajectories of epidermal growth factor receptors moving in the plasma membranes of two cancerous cell lines and one normal endothelial cell line. A stochastic model was developed and applied to identify critical information from single-molecule trajectories. We discovered that unliganded epidermal growth factor receptors may reside nearby cholesterol-riched regions of the plasma membrane and can move into these lipid domains when subjected to ligand binding. The amount of membrane cholesterol considerably affects the stability of correlated motion of activated epidermal growth factor receptors. Our results provide single-molecule evidence of membrane cholesterol in regulating signaling receptors. Because the three cell lines used for this study are quite diverse, our results may be useful to shed light on the mechanism of cholesterol-mediated interaction between activated receptors in live cells

Cholesterol Transport Revisited : A New Turbo Mechanism to Drive Cholesterol Excretion

NARCIS (Netherlands)

de Boer, Jan Freark; Kuipers, Folkert; Groen, Albert K.

A fine-tuned balance between cholesterol uptake and excretion by the body is pivotal to maintain health and to remain free from the deleterious consequences of cholesterol accumulation such as cardiovascular disease. The pathways involved in intracellular and extracellular cholesterol transport are

Cholesterol (image)

Science.gov (United States)

Cholesterol is a soft, waxy substance that is present in all parts of the body including the ... and obtained from animal products in the diet. Cholesterol is manufactured in the liver and is needed ...

Viral MicroRNAs Repress the Cholesterol Pathway, and 25-Hydroxycholesterol Inhibits Infection.

Science.gov (United States)

Serquiña, Anna K P; Kambach, Diane M; Sarker, Ontara; Ziegelbauer, Joseph M

2017-07-11

From various screens, we found that Kaposi's sarcoma-associated herpesvirus (KSHV) viral microRNAs (miRNAs) target several enzymes in the mevalonate/cholesterol pathway. 3-Hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR [a rate-limiting step in the mevalonate pathway]), and farnesyl-diphosphate farnesyltransferase 1 (FDFT1 [a committed step in the cholesterol branch]) are repressed by multiple KSHV miRNAs. Transfection of viral miRNA mimics in primary endothelial cells (human umbilical vein endothelial cells [HUVECs]) is sufficient to reduce intracellular cholesterol levels; however, small interfering RNAs (siRNAs) targeting only HMGCS1 did not reduce cholesterol levels. This suggests that multiple targets are needed to perturb this tightly regulated pathway. We also report here that cholesterol levels were decreased in de novo -infected HUVECs after 7 days. This reduction is at least partially due to viral miRNAs, since the mutant form of KSHV lacking 10 of the 12 miRNA genes had increased cholesterol compared to wild-type infections. We hypothesized that KSHV is downregulating cholesterol to suppress the antiviral response by a modified form of cholesterol, 25-hydroxycholesterol (25HC). We found that the cholesterol 25-hydroxylase (CH25H) gene, which is responsible for generating 25HC, had increased expression in de novo -infected HUVECs but was strongly suppressed in long-term latently infected cell lines. We found that 25HC inhibits KSHV infection when added exogenously prior to de novo infection. In conclusion, we found that multiple KSHV viral miRNAs target enzymes in the mevalonate pathway to modulate cholesterol in infected cells during latency. This repression of cholesterol levels could potentially be beneficial to viral infection by decreasing the levels of 25HC. IMPORTANCE A subset of viruses express unique microRNAs (miRNAs), which act like cellular miRNAs to generally repress host gene

CHITINASE-B FROM SERRATIA-MARCESCENS-BJL200 IS EXPORTED TO THE PERIPLASM WITHOUT PROCESSING

NARCIS (Netherlands)

BRURBERG, MB; EIJSINK, VGH; HAANDRIKMAN, AJ; VENEMA, G; NES, IF

A gene encoding a chitinase from Serratia marcescens BJL200 was cloned and expressed in Escherichia coli and S. marcescens. Nucleotide sequencing revealed an open reading frame encoding a 55.5 kDa protein of 499 amino acids without a typical signal peptide for export. The cellular localization of

Exporting and Productivity

DEFF Research Database (Denmark)

Newman, Carol; Rand, John; Tarp, Finn

2017-01-01

different policy stance than typical in Africa. This is especially so in promoting export-oriented industry. If learning by exporting is a key driver of progress, then a fundamental reason for Africa's lack of transformation is likely to be the low policy priority given to export promotion in the past....... To enlarge the body of empirical evidence, we use an extensive 2005–2012 firm-level panel data set from Vietnam and separate out productivity effects of exporting due to self-selection. This allows us to conclude that firms actually learn by exporting. We also examine how this learning takes place. Our...... findings suggest that productivity gains are associated with moving to larger scale for foreign-owned firms with little evidence of subsequent learning on export markets. We find strong evidence to suggest that private domestic firms learn and accumulate knowledge from export markets with learning...

Distinct Paths for Basic Amino Acid Export in Escherichia coli: YbjE (LysO) Mediates Export of L-Lysine.

Science.gov (United States)

Pathania, Amit; Sardesai, Abhijit A

2015-06-15

In Escherichia coli, argO encodes an exporter for L-arginine (Arg) and its toxic analogue canavanine (CAN), and its transcriptional activation and repression, by Arg and L-lysine (Lys), respectively, are mediated by the regulator ArgP. Accordingly argO and argP mutants are CAN supersensitive (CAN(ss)). We report the identification of ybjE as a gene encoding a predicted inner membrane protein that mediates export of Lys, and our results confirm the previous identification with a different approach of YbjE as a Lys exporter, reported by Ueda and coworkers (T. Ueda, Y. Nakai, Y. Gunji, R. Takikawa, and Y. Joe, U.S. patents 7,629,142 B2 [December 2009] and 8,383,363 B1 [February 2013] and European patent 1,664,318 B1 [September 2009]). ybjE was isolated as a multicopy suppressor of the CAN(ss) phenotype of a strain lacking ArgO. The absence of YbjE did not confer a CAN(ss) phenotype but instead conferred hypersensitivity to the lysine antimetabolite thialysine and led to growth inhibition by the dipeptide lysylalanine, which is associated with elevated cellular Lys content. YbjE overproduction resulted in Lys excretion and syntrophic cross-feeding of a Lys auxotroph. Constitutive overexpression of argO promoted Lys cross-feeding that is indicative of a latent Lys export potential of ArgO. Arg modestly repressed ybjE transcription in an ArgR-dependent manner, and ArgR displayed Arg-sensitive binding to the ybjE promoter region in vitro. Our studies suggest that the reciprocal repression of argO and ybjE, respectively, by Lys and Arg confers the specificity for basic amino acid export by distinct paths and that such cross-repression contributes to maintenance of cytoplasmic Arg/Lys balance. We propose that YbjE be redesignated LysO. This work ascribes a lysine export function to the product of the ybjE gene of Escherichia coli, leading to a physiological scenario wherein two proteins, ArgO and YbjE, perform the task of separately exporting arginine and lysine

Cholesterol Test

Science.gov (United States)

... artery disease. Other names for a cholesterol test: Lipid profile, Lipid panel What is it used for? If you ... Clinic [Internet]. Mayo Foundation for Medical Education and Research; c1998-2017.Cholesterol Test: Overview; 2016 Jan 12 [ ...

Endogenous cholesterol synthesis, fecal steroid excretion and serum lanosterol in subjects with high or low response of serum cholesterol to dietary cholesterol

NARCIS (Netherlands)

Beynen, A.C.; Katan, M.B.; Gent, van C.M.

1986-01-01

In this study we addressed the question whether hypo- and hyper-responders to dietary cholesterol differ with regard to the flexibility of endogenous cholesterol synthesis after changes in cholesterol intake. Whole-body cholesterol synthesis was measured as faecal excretion of neutral steroids and

Export strategy

DEFF Research Database (Denmark)

Knudsen, Thorbjørn; Koed Madsen, Tage

2002-01-01

It is argued here that traditional export strategy research (encompassing the study of internationalization processes and export performance) is characterized by weak theoretical foundations and could benefit from a reorientation towards a dynamic capabilities perspective (DCP). We seek to draw...... on insights from DCP in order to devise a theoretical basis that could enrich export strategy research. Although our development of DCP insights builds on previous work, it also adds a crucial distinction between knowledge stocks and informational architecture. Changes in architecture are of greater...... importance. Following this elaboration of the dynamic capabilities perspective, we outline some implications and guidelines for future export strategy research....

Macrophage cholesterol efflux correlates with lipoprotein subclass distribution and risk of obstructive coronary artery disease in patients undergoing coronary angiography

Directory of Open Access Journals (Sweden)

Kremer Werner

2009-04-01

Full Text Available Abstract Background Studies in patients with low HDL have suggested that impaired cellular cholesterol efflux is a heritable phenotype increasing atherosclerosis risk. Less is known about the association of macrophage cholesterol efflux with lipid profiles and CAD risk in normolipidemic subjects. We have therefore measured macrophage cholesterol efflux in142 normolipidemic subjects undergoing coronary angiography. Methods Monocytes isolated from blood samples of patients scheduled for cardiac catheterization were differentiated into macrophages over seven days. Isotopic cholesterol efflux to exogenously added apolipoprotein A-I and HDL2 was measured. Quantitative cholesterol efflux from macrophages was correlated with lipoprotein subclass distribution in plasma from the same individuals measured by NMR-spectroscopy of lipids and with the extent of coronary artery disease seen on coronary angiography. Results Macrophage cholesterol efflux was positively correlated with particle concentration of smaller HDL and LDL particles but not with total plasma concentrations of HDL or LDL-cholesterol. We observed an inverse relationship between macrophage cholesterol efflux and the concntration of larger and triglyceride rich particles (VLDL, chylomicrons. Subjects with significant stenosis on coronary angiography had lower cholesterol efflux from macrophages compared to individuals without significant stenosis (adjusted p = 0.02. Conclusion Macrophage cholesterol efflux is inversely correlated with lipoprotein particle size and risk of CAD.

Effect of the combinations between pea proteins and soluble fibres on cholesterolaemia and cholesterol metabolism in rats.

Science.gov (United States)

Parolini, Cinzia; Manzini, Stefano; Busnelli, Marco; Rigamonti, Elena; Marchesi, Marta; Diani, Erika; Sirtori, Cesare R; Chiesa, Giulia

2013-10-01

Many functional foods and dietary supplements have been reported to be beneficial for the management of dyslipidaemia, one of the major risk factors for CVD. Soluble fibres and legume proteins are known to be a safe and practical approach for cholesterol reduction. The present study aimed at investigating the hypocholesterolaemic effect of the combinations of these bioactive vegetable ingredients and their possible effects on the expression of genes regulating cholesterol homeostasis. A total of six groups of twelve rats each were fed, for 28 d, Nath's hypercholesterolaemic diets, differing in protein and fibre sources, being, respectively, casein and cellulose (control), pea proteins and cellulose (pea), casein and oat fibres (oat), casein and apple pectin (pectin), pea proteins and oat fibres (pea+oat) and pea proteins and apple pectin (pea+pectin). Administration of each vegetable-containing diet was associated with lower total cholesterol concentrations compared with the control. The combinations (pea+oat and pea+pectin) were more efficacious than fibres alone in modulating cholesterolaemia ( - 53 and - 54%, respectively, at 28 d; Ppea proteins, a lower hepatic cholesterol content (Ppea proteins and oat fibres or apple pectin are extremely effective in lowering plasma cholesterol concentrations in rats and affect cellular cholesterol homeostasis by up-regulating genes involved in hepatic cholesterol turnover.

The Export Administration Act of 1979 and Computer Exports to China

National Research Council Canada - National Science Library

Perez, Elizabeth

2002-01-01

.... The statute that regulates computer exports, the Export Administration Act of 1979 (EAA79), has been interpreted both strictly and loosely by policymakers, executive agencies, and export control regimes...

Perceived impediments to export involvement among small and medium sized firms : non-exporters perspective

Directory of Open Access Journals (Sweden)

Mercy Mpinganjira

2011-12-01

Full Text Available Purpose: The main purpose of this paper is to examine perceived impediments to export involvement among non-exporting small and medium sized firms (SME's in Malawi. The study also examines levels of interest in exporting among the firms. Problem investigated: Many countries have programs aimed at promoting export involvement among SME's. Despite this, most SME's continue to ignore exporting as a viable business strategy. Information on perceived impediments to export involvement especially from the non-exporters' perspective is often lacking hence the need for this study. Methodology: Data was collected from 80 owner managers of non-exporting SME's. A structured questionnaire was the main instrument used to collect data. Personal interviews were also held with managers for the purposes of probing their answers to the questions in the questionnaire. Statistical Package for Social Science (SPSS version 18 was used to analyse the quantitative data obtained from use of the structured questionnaire. Qualitative data obtained through personal interviews was analysed used thematic analysis. Findings: The findings of the study showed significant levels of interest in exporting among the firms. The majority of the owner managers indicated willingness to exploit export opportunities that may be readily available to them. The findings however showed that just over half of the respondents had discussed or investigated the possibility of exporting before. On impediments to exporting, the findings showed that managers perceive many factors as important impediments to their firm's involvement in exporting. The top two most important impediments were internal to the firm and related to human resource issues. They included insufficient knowledge about export opportunities and lack of personnel knowledgeable in exporting. Originality and value of the research: A review of literature shows that most export promotion studies tend to focus more on issues relating to

Intestinal cholesterol transport: Measuring cholesterol absorption and its reverse

NARCIS (Netherlands)

Jakulj, L.

2013-01-01

Intestinal cholesterol transport might serve as an attractive future target for cardiovascular disease reduction, provided that underlying molecular mechanisms are more extensively elucidated, combined with improved techniques to measure changes in cholesterol fluxes and their possible

Correlations-Adjusted Export Market Diversification

OpenAIRE

Jung Joo La

2011-01-01

This paper introduces new export market diversification indices incorporated with correlations of business cycles among export partners to identify the actual effects of export market diversification on export instability. Three existing export market diversification indices reflect the dispersion level in terms of the number of export partners and their export shares, without a clear control for correlations among export earnings from export partners. In addition, they are underestimated or ...

Biogenesis of plasma membrane cholesterol

International Nuclear Information System (INIS)

Lange, Y.

1986-01-01

A striking feature of the molecular organization of eukaryotic cells is the singular enrichment of their plasma membranes in sterols. The authors studies are directed at elucidating the mechanisms underlying this inhomogeneous disposition. Cholesterol oxidase catalyzes the oxidation of plasma membrane cholesterol in intact cells, leaving intracellular cholesterol pools untouched. With this technique, the plasma membrane was shown to contain 95% of the unesterified cholesterol of cultured human fibroblasts. Cholesterol synthesized from [ 3 H] acetate moved to the plasma membrane with a half-time of 1 h at 37 0 C. They used equilibrium gradient centrifugation of homogenates of biosynthetically labeled, cholesterol oxidase treated cells to examine the distribution of newly synthesized sterols among intracellular pools. Surprisingly, lanosterol, a major precursor of cholesterol, and intracellular cholesterol both peaked at much lower buoyant density than did 3-hydroxy-3-methylglutaryl-CoA reductase. This suggests that cholesterol biosynthesis is not taken to completion in the endoplasmic reticulum. The cholesterol in the buoyant fraction eventually moved to the plasma membrane. Digitonin treatment increased the density of the newly synthesized cholesterol fractions, indicating that nascent cholesterol in transit is associated with cholesterol-rich membranes. The authors are testing the hypothesis that the pathway of cholesterol biosynthesis is spatially organized in various intracellular membranes such that the sequence of biosynthetic steps both concentrates the sterol and conveys it to the plasma membrane

The effect of dietary phytosphingosine on cholesterol levels and insulin sensitivity in subjects with the metabolic syndrome

NARCIS (Netherlands)

Snel, M.; Sleddering, M.A.; Pijl, H.; Nieuwenhuizen, W.F.; Frölich, M.; Havekes, L.M.; Romijn, J.A.; Jazet, I.M.

2010-01-01

Background: Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity.Objective:To study the effect of dietary

Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

Science.gov (United States)

Alvarez, Monica I; Glover, Luke C; Luo, Peter; Wang, Liuyang; Theusch, Elizabeth; Oehlers, Stefan H; Walton, Eric M; Tram, Trinh Thi Bich; Kuang, Yu-Lin; Rotter, Jerome I; McClean, Colleen M; Chinh, Nguyen Tran; Medina, Marisa W; Tobin, David M; Dunstan, Sarah J; Ko, Dennis C

2017-09-12

Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi ( S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.

Cholesterol homeostasis in two commonly used human prostate cancer cell-lines, LNCaP and PC-3.

Directory of Open Access Journals (Sweden)

James Robert Krycer

2009-12-01

Full Text Available Recently, there has been renewed interest in the link between cholesterol and prostate cancer. It has been previously reported that in vitro, prostate cancer cells lack sterol-mediated feedback regulation of the major transcription factor in cholesterol homeostasis, sterol-regulatory element binding protein 2 (SREBP-2. This could explain the accumulation of cholesterol observed in clinical prostate cancers. Consequently, perturbed feedback regulation to increased sterol levels has become a pervasive concept in the prostate cancer setting. Here, we aimed to explore this in greater depth.After altering the cellular cholesterol status in LNCaP and PC-3 prostate cancer cells, we examined SREBP-2 processing, downstream effects on promoter activity and expression of SREBP-2 target genes, and functional activity (low-density lipoprotein uptake, cholesterol synthesis. In doing so, we observed that LNCaP and PC-3 cells were sensitive to increased sterol levels. In contrast, lowering cholesterol levels via statin treatment generated a greater response in LNCaP cells than PC-3 cells. This highlighted an important difference between these cell-lines: basal SREBP-2 activity appeared to be higher in PC-3 cells, reducing sensitivity to decreased cholesterol levels.Thus, prostate cancer cells are sensitive to changing sterol levels in vitro, but the extent of this regulation differs between prostate cancer cell-lines. These results shed new light on the regulation of cholesterol metabolism in two commonly used prostate cancer cell-lines, and emphasize the importance of establishing whether or not cholesterol homeostasis is perturbed in prostate cancer in vivo.

[Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion].

Science.gov (United States)

Blanchard, Claire; Moreau, François; Cariou, Bertrand; Le May, Cédric

2014-10-01

The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti-atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases. © 2014 médecine/sciences – Inserm.

Synthesis and validation of novel cholesterol-based fluorescent lipids designed to observe the cellular trafficking of cationic liposomes.

Science.gov (United States)

Kim, Bieong-Kil; Seu, Young-Bae; Choi, Jong-Soo; Park, Jong-Won; Doh, Kyung-Oh

2015-09-15

Cholesterol-based fluorescent lipids with ether linker were synthesized using NBD (Chol-E-NBD) or Rhodamine B (Chol-E-Rh), and the usefulnesses as fluorescent probes for tracing cholesterol-based liposomes were validated. The fluorescent intensities of liposomes containing these modified lipids were measured and observed under a microscope. Neither compound interfered with the expression of GFP plasmid, and live cell images were obtained without interferences. Changes in the fluorescent intensity of liposomes containing Chol-E-NBD were followed by flow cytometry for up to 24h. These fluorescent lipids could be useful probes for trafficking of cationic liposome-mediated gene delivery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Camphene, a plant-derived monoterpene, reduces plasma cholesterol and triglycerides in hyperlipidemic rats independently of HMG-CoA reductase activity.

Directory of Open Access Journals (Sweden)

Ioanna Vallianou

Full Text Available Central to the pathology of coronary heart disease is the accumulation of lipids, cholesterol and triglycerides, within the intima of arterial blood vessels. The search for drugs to treat dislipidemia, remains a major pharmaceutical focus. In this study, we evaluated the hypolipidemic properties of the essential oil from Chios mastic gum (MGO.The hypolipidemic effect of MGO was investigated in naïve as well as in rats susceptible to detergent-induced hyperlipidemia. Serum cholesterol and triglycerides were determined using commercial kits. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A reductase activity was measured in HepG2 cell extracts using a radioactive assay; cellular cholesterol and cholesterol esters were assessed using gas chromatography. MGO administration into naïve rats resulted in a dose-dependent reduction in the constitutive synthesis of serum cholesterol and triglycerides. In hyperlipidemic rats, MGO treatment had also a strong hypolipidemic effect. By testing various components of MGO, we show for the first time that the hypolipidemic action is associated with camphene. Administration of camphene at a dose of 30 µg/gr of body weight in hyperlipidemic rats resulted in a 54.5% reduction of total cholesterol (p<0.001, 54% of Low Density Lipoprotein (LDL-cholesterol (p<0.001 and 34.5% of triglycerides (p<0.001. Treatment of HepG2 cells with camphene led to a decrease in cellular cholesterol content to the same extend as mevinolin, a known HMG-CoA reductase inhibitor. The hypolipidemic action of camphene is independent of HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins.Given the critical role that the control of hyperlipidemia plays in cardiovascular disease, the results of our study provide insights into the use of camphene as an alternative lipid lowering agent and merits further evaluation.

Camphene, a Plant-Derived Monoterpene, Reduces Plasma Cholesterol and Triglycerides in Hyperlipidemic Rats Independently of HMG-CoA Reductase Activity

Science.gov (United States)

Vallianou, Ioanna; Peroulis, Nikolaos; Pantazis, Panayotis; Hadzopoulou-Cladaras, Margarita

2011-01-01

Background Central to the pathology of coronary heart disease is the accumulation of lipids, cholesterol and triglycerides, within the intima of arterial blood vessels. The search for drugs to treat dislipidemia, remains a major pharmaceutical focus. In this study, we evaluated the hypolipidemic properties of the essential oil from Chios mastic gum (MGO). Methodology/Principal Findings The hypolipidemic effect of MGO was investigated in naïve as well as in rats susceptible to detergent-induced hyperlipidemia. Serum cholesterol and triglycerides were determined using commercial kits. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity was measured in HepG2 cell extracts using a radioactive assay; cellular cholesterol and cholesterol esters were assessed using gas chromatography. MGO administration into naïve rats resulted in a dose-dependent reduction in the constitutive synthesis of serum cholesterol and triglycerides. In hyperlipidemic rats, MGO treatment had also a strong hypolipidemic effect. By testing various components of MGO, we show for the first time that the hypolipidemic action is associated with camphene. Administration of camphene at a dose of 30 µg/gr of body weight in hyperlipidemic rats resulted in a 54.5% reduction of total cholesterol (p<0.001), 54% of Low Density Lipoprotein (LDL)-cholesterol (p<0.001) and 34.5% of triglycerides (p<0.001). Treatment of HepG2 cells with camphene led to a decrease in cellular cholesterol content to the same extend as mevinolin, a known HMG-CoA reductase inhibitor. The hypolipidemic action of camphene is independent of HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins. Conclusions Given the critical role that the control of hyperlipidemia plays in cardiovascular disease, the results of our study provide insights into the use of camphene as an alternative lipid lowering agent

Nuclear Factor 90, a cellular dsRNA binding protein inhibits the HIV Rev-export function

Directory of Open Access Journals (Sweden)

St-Laurent Georges

2006-11-01

Full Text Available Abstract Background The HIV Rev protein is known to facilitate export of incompletely spliced and unspliced viral transcripts to the cytoplasm, a necessary step in virus life cycle. The Rev-mediated nucleo-cytoplasmic transport of nascent viral transcripts, dependents on interaction of Rev with the RRE RNA structural element present in the target RNAs. The C-terminal variant of dsRNA-binding nuclear protein 90 (NF90ctv has been shown to markedly attenuate viral replication in stably transduced HIV-1 target cell line. Here we examined a mechanism of interference of viral life cycle involving Rev-NF90ctv interaction. Results Since Rev:RRE complex formations depend on protein:RNA and protein:protein interactions, we investigated whether the expression of NF90ctv might interfere with Rev-mediated export of RRE-containing transcripts. When HeLa cells expressed both NF90ctv and Rev protein, we observed that NF90ctv inhibited the Rev-mediated RNA transport. In particular, three regions of NF90ctv protein are involved in blocking Rev function. Moreover, interaction of NF90ctv with the RRE RNA resulted in the expression of a reporter protein coding sequences linked to the RRE structure. Moreover, Rev influenced the subcellular localization of NF90ctv, and this process is leptomycin B sensitive. Conclusion The dsRNA binding protein, NF90ctv competes with HIV Rev function at two levels, by competitive protein:protein interaction involving Rev binding to specific domains of NF90ctv, as well as by its binding to the RRE-RNA structure. Our results are consistent with a model of Rev-mediated HIV-1 RNA export that envisions Rev-multimerization, a process interrupted by NF90ctv.

The effect of dietary phytosphingosine on cholesterol levels and insulin sensitivity in subjects with the metabolic syndrome

NARCIS (Netherlands)

Snel, M.; Sleddering, M. A.; Pijl, H.; Nieuwenhuizen, W. F.; Frölich, M.; Havekes, L. M.; Romijn, J. A.; Jazet, I. M.

2010-01-01

Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity. To study the effect of dietary supplementation with PS on

Intracellular cholesterol-binding proteins enhance HDL-mediated cholesterol uptake in cultured primary mouse hepatocytes.

Science.gov (United States)

Storey, Stephen M; McIntosh, Avery L; Huang, Huan; Landrock, Kerstin K; Martin, Gregory G; Landrock, Danilo; Payne, H Ross; Atshaves, Barbara P; Kier, Ann B; Schroeder, Friedhelm

2012-04-15

A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L-FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD-95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2/SCP-x/L-FABP null

Adropin: An endocrine link between the biological clock and cholesterol homeostasis

Directory of Open Access Journals (Sweden)

Sarbani Ghoshal

2018-02-01

�/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism. Keywords: Cholesterol, LDL, Cardiovascular disease, Obesity, Adropin, Sex

Exporter Price Premia?

DEFF Research Database (Denmark)

Jäkel, Ina Charlotte; Sørensen, Allan

This paper provides new evidence on manufacturing firms' output prices: in Denmark, on average, exported varieties are sold at a lower price (i.e. a negative exporter price premium) relative to only domestically sold varieties. This finding stands in sharp contrast to previous studies, which have...... found positive exporter price premia. We also document that the exporter price premium varies substantially across products (both in terms of sign and magnitude). We show that in a standard heterogeneous firms model with heterogeneity in quality as well as production efficiency there is indeed no clear......-cut prediction on the sign of the exporter price premium. However, the model unambiguously predicts a negative exporter price premium in terms of quality-adjusted prices, i.e. prices per unit of quality. This prediction is broadly borne out in the Danish data: while the magnitude of the premium varies across...

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

NARCIS (Netherlands)

Schonewille, Marleen; de Boer, Jan Freark; Mele, Laura; Wolters, Henk; Bloks, Vincent W.; Wolters, Justina C.; Kuivenhoven, Jan A.; Tietge, Uwe J. F.; Brufau, Gemma; Groen, Albert K.

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

NARCIS (Netherlands)

Schonewille, Marleen; de Boer, Jan Freark; Mele, Laura; Wolters, Henk; Bloks, Vincent W.; Wolters, Justina C.; Kuivenhoven, Jan A.; Tietge, Uwe J. F.; Brufau, Gemma; Groen, Albert K.

2016-01-01

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we

Dietary cholesterol from eggs increases the ratio of total cholesterol to high-density lipoprotein cholesterol in humans : a meta-analysis

NARCIS (Netherlands)

Weggemans, R.M.; Zock, P.L.; Katan, M.B.

2001-01-01

Several epidemiologic studies found no effect of egg consumption on the risk of coronary heart disease. It is possible that the adverse effect of eggs on LDL-cholesterol is offset by their favorable effect on HDL cholesterol. Objective: The objective was to review the effect of dietary cholesterol

76 FR 66693 - President's Export Council: Meeting of the President's Export Council

Science.gov (United States)

2011-10-27

.... ACTION: Notice of an open meeting. SUMMARY: The President's Export Council will hold a meeting to discuss.... exports, jobs, and growth. DATES: November 16, 2011 at 9:30 a.m. (ET) ADDRESSES: The President's Export... on December 20, 1973 to advise the President on matters relating to U.S. export trade and report to...

76 FR 9550 - President's Export Council: Meeting of the President's Export Council

Science.gov (United States)

2011-02-18

.... ACTION: Notice of an open meeting. SUMMARY: The President's Export Council will hold a meeting to discuss.... exports, jobs, and growth. DATES: March 11, 2011 at 9:30 a.m. (ET). ADDRESSES: The President's Export... on December 20, 1973 to advise the President on matters relating to U.S. export trade and report to...

Cholesterol - what to ask your doctor

Science.gov (United States)

... your doctor; What to ask your doctor about cholesterol ... What is my cholesterol level? What should my cholesterol level be? What are HDL ("good") cholesterol and LDL ("bad") cholesterol? Does my cholesterol ...

Common Misconceptions about Cholesterol

Science.gov (United States)

... Venous Thromboembolism Aortic Aneurysm More Common Misconceptions about Cholesterol Updated:Jan 29,2018 How much do you ... are some common misconceptions — and the truth. High cholesterol isn’t a concern for children. High cholesterol ...

From blood to gut: Direct secretion of cholesterol via transintestinal cholesterol efflux

NARCIS (Netherlands)

Vrins, Carlos L. J.

2010-01-01

The reverse cholesterol transport pathway (RCT) is the focus of many cholesterol lowering therapies By way of this pathway, excess cholesterol is collected from peripheral tissues and delivered back to the liver and gastrointestinal tract for excretion from the body For a long time this removal via

Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole.

Directory of Open Access Journals (Sweden)

Aurélie Fougère

2016-11-01

Full Text Available Many variant proteins encoded by Plasmodium-specific multigene families are exported into red blood cells (RBC. P. falciparum-specific variant proteins encoded by the var, stevor and rifin multigene families are exported onto the surface of infected red blood cells (iRBC and mediate interactions between iRBC and host cells resulting in tissue sequestration and rosetting. However, the precise function of most other Plasmodium multigene families encoding exported proteins is unknown. To understand the role of RBC-exported proteins of rodent malaria parasites (RMP we analysed the expression and cellular location by fluorescent-tagging of members of the pir, fam-a and fam-b multigene families. Furthermore, we performed phylogenetic analyses of the fam-a and fam-b multigene families, which indicate that both families have a history of functional differentiation unique to RMP. We demonstrate for all three families that expression of family members in iRBC is not mutually exclusive. Most tagged proteins were transported into the iRBC cytoplasm but not onto the iRBC plasma membrane, indicating that they are unlikely to play a direct role in iRBC-host cell interactions. Unexpectedly, most family members are also expressed during the liver stage, where they are transported into the parasitophorous vacuole. This suggests that these protein families promote parasite development in both the liver and blood, either by supporting parasite development within hepatocytes and erythrocytes and/or by manipulating the host immune response. Indeed, in the case of Fam-A, which have a steroidogenic acute regulatory-related lipid transfer (START domain, we found that several family members can transfer phosphatidylcholine in vitro. These observations indicate that these proteins may transport (host phosphatidylcholine for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites.

Covalent immobilization of cholesterol esterase and cholesterol oxidase on polyaniline films for application to cholesterol biosensor

Energy Technology Data Exchange (ETDEWEB)

Singh, Suman [Biomolecular Electronics and Conducting Polymer Research Group, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Solanki, Pratima R. [Biomolecular Electronics and Conducting Polymer Research Group, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Pandey, M.K. [Biomolecular Electronics and Conducting Polymer Research Group, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India); Malhotra, B.D. [Biomolecular Electronics and Conducting Polymer Research Group, National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi-110012 (India)]. E-mail: bansi@mail.nplindia.ernet.in

2006-05-24

Cholesterol esterase (ChEt) and cholesterol oxidase (ChOx) have been covalently immobilized on electrochemically prepared polyaniline (PANI) films. These PANI/ChEt/ChOx enzyme films have been characterized using UV-visible, Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). Electrochemical behavior of these films has been studied using cyclic voltammetry (CV) and amperometric techniques, respectively. The PANI/ChEt/ChOx enzyme films show broad oxidation peak from 0.2 to 0.5 V. These PANI/ChEt/ChOx biosensing electrodes have a response time of about 40 s, linearity from 50 to 500 mg/dl of cholesterol oleate concentration. These PANI/ChEt/ChOx films are thermally stable up to 46 deg. C. This polyaniline based cholesterol biosensor has optimum pH in the range of 6.5-7.5, sensitivity as 7.5 x 10{sup -4} nA/mg dl and a lifetime of about 6 weeks.

The major cellular sterol regulatory pathway is required for Andes virus infection.

Directory of Open Access Journals (Sweden)

Josiah Petersen

2014-02-01

Full Text Available The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV. Host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. To identify cellular requirements for ANDV infection, we performed two parallel genetic screens. Analysis of a large library of insertionally mutagenized human haploid cells and a siRNA genomic screen converged on components (SREBP-2, SCAP, S1P and S2P of the sterol regulatory pathway as critically important for infection by ANDV. The significance of this pathway was confirmed using functionally deficient cells, TALEN-mediated gene disruption, RNA interference and pharmacologic inhibition. Disruption of sterol regulatory complex function impaired ANDV internalization without affecting virus binding. Pharmacologic manipulation of cholesterol levels demonstrated that ANDV entry is sensitive to changes in cellular cholesterol and raises the possibility that clinically approved regulators of sterol synthesis may prove useful for combating ANDV infection.

Competition between ergosterol and cholesterol in sterol uptake and intracellular trafficking in the yeast Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Valachovic, M.; Hronska, L.; Hapala, I.

1998-01-01

The fate of internal cholesterol was evaluated in cells grown under various conditions with respect to the amount and the nature of sterols supplemented to the cells. Steryl esters accumulate in stationary phase-yeast cells and they are rapidly hydrolyzed in cells during exponential growth or ergosterol depletion. Cholesterol and other 'unnatural' sterols are esterified more efficiently that native ergosterol and it was speculated that esterification could protect cellular membranes from accumulation of these less optimal sterols. We tested this idea by monitoring the mobility of 14 C-cholesterol between free and esterified fractions in cell supplemented with cholesterol or ergosterol. It was found that cells grown on cholesterol to the stationary phase accumulated up to 80 % of label in the steryl ester fraction. Subsequent growth in sterol-free media caused sterol-depletion of plasma membrane and induced hydrolysis of 14 C- cholesteryl esters and accumulation of the label in free membranous sterol pool.Supplementation of cells with external sterols resulted in a shift in sterol trafficking and in a new accumulation of 14 C-cholesteryl esters. This indicates that the absence of an efficient proof-reading mechanism in plasma membrane that would be able to remove preferentially cholesterol from the free sterol pool in plasma membrane to steryl esters in lipidic particles. The mobility of cholesterol molecules in non-growing cells wa negligible suggesting that active growth or membrane proliferation are required for shifts of sterol molecules between these pools. (authors)

Canadian solar export market study. Export policy recommendations

Energy Technology Data Exchange (ETDEWEB)

1983-11-01

This report outlines policies and recommendations on the export of Canadian solar equipment and technology, with a view toward stimulating the domestic solar industry. The current picture is of an industry which is relatively small, operates in a competitive domestic market with low profit margins, and needs assistance in order to break into the world market. A number of recommendations are therefore made on the main thrust of industry and government solar export development activities. An export development program is described which includes a strategy of concentrating on a limited number of product lines, namely: low-temperature solar heating systems for recreational applications, integrated residential water heating systems, prepackaged commercial water heating systems, and industrial pre-heat systems. It is also recommended that this strategy be directed only at a limited number of target countries where the market justifies such activity. Market research, international cooperation agreements, promotional services, and proper export organization are also needed.

Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease.

Science.gov (United States)

Krawczyk, Marcin; Lütjohann, Dieter; Schirin-Sokhan, Ramin; Villarroel, Luis; Nervi, Flavio; Pimentel, Fernando; Lammert, Frank; Miquel, Juan Francisco

2012-05-01

In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol

Ceruloplasmin Oxidation, a Feature of Parkinson's Disease CSF, Inhibits Ferroxidase Activity and Promotes Cellular Iron Retention

KAUST Repository

Olivieri, S.; Conti, A.; Iannaccone, S.; Cannistraci, C. V.; Campanella, A.; Barbariga, M.; Codazzi, F.; Pelizzoni, I.; Magnani, G.; Pesca, M.; Franciotta, D.; Cappa, S. F.; Alessio, M.

2011-01-01

Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative

Inter-cellular transport of ran GTPase.

Directory of Open Access Journals (Sweden)

Deepak Khuperkar

Full Text Available Ran, a member of the Ras-GTPase superfamily, has a well-established role in regulating the transport of macromolecules across the nuclear envelope (NE. Ran has also been implicated in mitosis, cell cycle progression, and NE formation. Over-expression of Ran is associated with various cancers, although the molecular mechanism underlying this phenomenon is unclear. Serendipitously, we found that Ran possesses the ability to move from cell-to-cell when transiently expressed in mammalian cells. Moreover, we show that the inter-cellular transport of Ran is GTP-dependent. Importantly, Ran displays a similar distribution pattern in the recipient cells as that in the donor cell and co-localizes with the Ran binding protein Nup358 (also called RanBP2. Interestingly, leptomycin B, an inhibitor of CRM1-mediated export, or siRNA mediated depletion of CRM1, significantly impaired the inter-cellular transport of Ran, suggesting a function for CRM1 in this process. These novel findings indicate a possible role for Ran beyond nucleo-cytoplasmic transport, with potential implications in inter-cellular communication and cancers.

Cholesterol and ocular pathologies: focus on the role of cholesterol-24S-hydroxylase in cholesterol homeostasis

Directory of Open Access Journals (Sweden)

Fourgeux Cynthia

2015-03-01

Full Text Available The retina is responsible for coding the light stimulus into a nervous signal that is transferred to the brain via the optic nerve. The retina is formed by the association of the neurosensory retina and the retinal pigment epithelium that is supported by Bruch’s membrane. Both the physical and metabolic associations between these partners are crucial for the functioning of the retina, by means of nutrient intake and removal of the cell and metabolic debris from the retina. Dysequilibrium are involved in the aging processes and pathologies such as age-related macular degeneration, the leading cause of visual loss after the age of 50 years in Western countries. The retina is composed of several populations of cells including glia that is involved in cholesterol biosynthesis. Cholesterol is the main sterol in the retina. It is present as free form in cells and as esters in Bruch’s membrane. Accumulation of cholesteryl esters has been associated with aging of the retina and impairment of the retinal function. Under dietary influence and in situ synthesized, the metabolism of cholesterol is regulated by cell interactions, including neurons and glia via cholesterol-24S-hydroxylase. Several pathophysiological associations with cholesterol and its metabolism can be suggested, especially in relation to glaucoma and age-related macular degeneration.

An exporter's checklist

International Nuclear Information System (INIS)

Englot, P.

1995-01-01

The benefits of exporting goods and services was discussed. The article listed a summary of issues which could be referred to to assist with the development of an effective plan to export. Some issues to consider were: (1) analysis of the export market, such as political and cultural issues, local legislation, competition, infrastructure, transportation and logistics, (2) internal issues, such as people, equipment, capital, time, understanding of the risks, relocation and identification of all costs, (3) sources of support such as banks, government and transporters, (4) development of a solid payment plan. It was concluded that exporting was not for the faint-hearted. It can be expensive, and time consuming, however, if approached in the right spirit it could be highly rewarding. As a rule of thumb, the probability of success was said to be directly related to the amount of effort put into the preparatory phase. Potential exporters were reminded of the very strong infrastructure that exists in Canada to promote and support export initiatives, including all levels of government, financial institutions, freight forwarders and innumerable consultant/specialists

Renewables and exports: how Export Credit Agencies could help develop markets

International Nuclear Information System (INIS)

Volpi, G.; Salter, L.

2002-01-01

Future export markets for renewable energies have enormous potential, yet business-as-usual investment trends will not achieve that potential, write Giulio Volpi and Liam Salter. They examine the role that Export Credit Agencies - which have provided essential support for exports in the conventional energy business - could play in aiding the renewables sector, characterized as it is by small- and medium-sized enterprises. This new role will require certain reforms - but without those reforms the Export Credit Agencies will simply not be providing relevant services to new technologies and new market players. (author)

Export Taxes under Bertrand Duopoly

OpenAIRE

David Collie; Roger Clarke

2006-01-01

This article analyses export taxes in a Bertrand duopoly with product differentiation, where a home and a foreign firm both export to a third-country market. It is shown that the maximum-revenue export tax always exceeds the optimum-welfare export tax. In a Nash equilibrium in export taxes, the country with the low cost firm imposes the largest export tax. The results under Bertrand duopoly are compared with those under Cournot duopoly. It is shown that the absolute value of the export subsid...

Myokit: A simple interface to cardiac cellular electrophysiology.

Science.gov (United States)

Clerx, Michael; Collins, Pieter; de Lange, Enno; Volders, Paul G A

2016-01-01

Myokit is a new powerful and versatile software tool for modeling and simulation of cardiac cellular electrophysiology. Myokit consists of an easy-to-read modeling language, a graphical user interface, single and multi-cell simulation engines and a library of advanced analysis tools accessible through a Python interface. Models can be loaded from Myokit's native file format or imported from CellML. Model export is provided to C, MATLAB, CellML, CUDA and OpenCL. Patch-clamp data can be imported and used to estimate model parameters. In this paper, we review existing tools to simulate the cardiac cellular action potential to find that current tools do not cater specifically to model development and that there is a gap between easy-to-use but limited software and powerful tools that require strong programming skills from their users. We then describe Myokit's capabilities, focusing on its model description language, simulation engines and import/export facilities in detail. Using three examples, we show how Myokit can be used for clinically relevant investigations, multi-model testing and parameter estimation in Markov models, all with minimal programming effort from the user. This way, Myokit bridges a gap between performance, versatility and user-friendliness. Copyright © 2015 Elsevier Ltd. All rights reserved.

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high-cholesterol-fed rats.

Science.gov (United States)

Murakami, Shigeru; Fujita, Michiko; Nakamura, Masakazu; Sakono, Masanobu; Nishizono, Shoko; Sato, Masao; Imaizumi, Katsumi; Mori, Mari; Fukuda, Nobuhiro

2016-03-01

This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high-cholesterol-fed rats. Male Sprague-Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high-cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high-cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine-treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine-conjugated bile acids by 61% and decreased glycine-conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine-conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, by three- and two-fold, respectively. Taurine also decreased the enzymatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine-conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels. © 2016 John Wiley & Sons Australia, Ltd.

Effect of the unfolded protein response on ER protein export: a potential new mechanism to relieve ER stress.

Science.gov (United States)

Shaheen, Alaa

2018-05-05

The unfolded protein response (UPR) is an adaptive cellular response that aims to relieve endoplasmic reticulum (ER) stress via several mechanisms, including inhibition of protein synthesis and enhancement of protein folding and degradation. There is a controversy over the effect of the UPR on ER protein export. While some investigators suggested that ER export is inhibited during ER stress, others suggested the opposite. In this article, their conflicting studies are analyzed and compared in attempt to solve this controversy. The UPR appears indeed to enhance ER export, possibly via multiple mechanisms. However, another factor, which is the integrity of the folding machinery/environment inside ER, determines whether ER export will appear increased or decreased during experimentation. Also, different methods of stress induction appear to have different effects on ER export. Thus, improvement of ER export may represent a new mechanism by which the UPR alleviates ER stress. This may help researchers to understand how the UPR works inside cells and how to manipulate it to alter cell fate during stress, either to promote cell survival or death. This may open up new approaches for the treatment of ER stress-related diseases.

The role of serum non-cholesterol sterols as surrogate markers of absolute cholesterol synthesis and absorption.

Science.gov (United States)

Miettinen, T A; Gylling, H; Nissinen, M J

2011-10-01

To study the whole-body cholesterol metabolism in man, cholesterol synthesis and absorption need to be measured. Because of the complicated methods of the measurements, new approaches were developed including the analysis of serum non-cholesterol sterols. In current lipidologic papers and even in intervention studies, serum non-cholesterol sterols are frequently used as surrogate markers of cholesterol metabolism without any validation to the absolute metabolic variables. The present review compares serum non-cholesterol sterols with absolute measurements of cholesterol synthesis and absorption in published papers to find out whether the serum markers are valid indicators of cholesterol metabolism in various conditions. During statin treatment, during interventions of dietary fat, and in type 2 diabetes the relative and absolute variables of cholesterol synthesis and absorption were frequently but not constantly correlated with each other. In some occasions, especially in subjects with apolipoprotein E3/4 and E4/4 phenotypes, the relative metabolic markers were even more sensitive than the absolute ones to reflect changes in cholesterol metabolism during dietary interventions. Even in general population at very high absorption the homeostasis of cholesterol metabolism is disturbed damaging the validity of the serum markers. It is worth using several instead of only one precursor and absorption sterol marker for making conclusions of altered synthesis or absorption of cholesterol, and even then the presence of at least some absolute measurement is valuable. During consumption of plant sterol-enriched diets and in situations of interfered cholesterol homeostasis the relative markers do not adequately reflect cholesterol metabolism. Accordingly, the validity of the relative markers of cholesterol metabolism should not be considered as self-evident. Copyright © 2011 Elsevier B.V. All rights reserved.

Steady-state oxidation of cholesterol catalyzed by cholesterol oxidase in lipid bilayer membranes on platinum electrodes

International Nuclear Information System (INIS)

Bokoch, Michael P.; Devadoss, Anando; Palencsar, Mariela S.; Burgess, James D.

2004-01-01

Cholesterol oxidase is immobilized in electrode-supported lipid bilayer membranes. Platinum electrodes are initially modified with a self-assembled monolayer of thiolipid. A vesicle fusion method is used to deposit an outer leaflet of phospholipids onto the thiolipid monolayer forming a thiolipid/lipid bilayer membrane on the electrode surface. Cholesterol oxidase spontaneously inserts into the electrode-supported lipid bilayer membrane from solution and is consequently immobilized to the electrode surface. Cholesterol partitions into the membrane from buffer solutions containing cyclodextrin. Cholesterol oxidase catalyzes the oxidation of cholesterol by molecular oxygen, forming hydrogen peroxide as a product. Amperometric detection of hydrogen peroxide for continuous solution flow experiments are presented, where flow was alternated between cholesterol solution and buffer containing no cholesterol. Steady-state anodic currents were observed during exposures of cholesterol solutions ranging in concentration from 10 to 1000 μM. These data are consistent with the Michaelis-Menten kinetic model for oxidation of cholesterol as catalyzed by cholesterol oxidase immobilized in the lipid bilayer membrane. The cholesterol detection limit is below 1 μM for cholesterol solution prepared in buffered cyclodextrin. The response of the electrodes to low density lipoprotein solutions is increased upon addition of cyclodextrin. Evidence for adsorption of low density lipoprotein to the electrode surface is presented

Isotope dilution/mass spectrometry of serum cholesterol with [3,4-13C]cholesterol: proposed definitive method

International Nuclear Information System (INIS)

Pelletier, O.; Wright, L.A.; Breckenridge, W.C.

1987-01-01

We describe a new gas-chromatographic/mass-spectrometric (GC/MS) isotope-dilution method for determination of serum cholesterol. The method has been fully optimized and documented to provide the high accuracy and precision expected for a Definitive Method. In the presence of [3,4- 13 C]cholesterol, cholesteryl esters in serum are hydrolyzed under optimum conditions and the entire cholesterol pool is extracted and derivatized to silyl ethers. The cholesterol derivatives are resolved from other sterols by gas-liquid chromatography on a fused silica column, and selected ions characteristic of cholesterol and the [3,4- 13 C]cholesterol are monitored with a GC/MS quandrupole system. We estimated the cholesterol content of samples by bracketing each sample with standards of comparable cholesterol concentration that also contained the [3,4- 13 C]cholesterol. The procedure was highly reproducible (CV less than 0.5%), better accuracy and precision being obtained with [3,4- 13 C]cholesterol than with heptadeuterated cholesterol. Mean values per gram of dry serum for one serum pool assayed by this method and that of the National Bureau of Standards differed by 0.5%. We conclude that the method satisfies the criteria for a Definitive Method

Cholesterol - drug treatment

Science.gov (United States)

... this page: //medlineplus.gov/ency/patientinstructions/000314.htm Cholesterol - drug treatment To use the sharing features on ... treatment; Hardening of the arteries - statin Statins for Cholesterol Statins reduce your risk of heart disease, stroke, ...

Free cholesterol and cholesterol esters in bovine oocytes: Implications in survival and membrane raft organization after cryopreservation.

Directory of Open Access Journals (Sweden)

Jorgelina Buschiazzo

Full Text Available Part of the damage caused by cryopreservation of mammalian oocytes occurs at the plasma membrane. The addition of cholesterol to cell membranes as a strategy to make it more tolerant to cryopreservation has been little addressed in oocytes. In order to increase the survival of bovine oocytes after cryopreservation, we proposed not only to increase cholesterol level of oocyte membranes before vitrification but also to remove the added cholesterol after warming, thus recovering its original level. Results from our study showed that modulation of membrane cholesterol by methyl-β-cyclodextrin (MβCD did not affect the apoptotic status of oocytes and improved viability after vitrification yielding levels of apoptosis closer to those of fresh oocytes. Fluorometric measurements based on an enzyme-coupled reaction that detects both free cholesterol (membrane and cholesteryl esters (stored in lipid droplets, revealed that oocytes and cumulus cells present different levels of cholesterol depending on the seasonal period. Variations at membrane cholesterol level of oocytes were enough to account for the differences found in total cholesterol. Differences found in total cholesterol of cumulus cells were explained by the differences found in both the content of membrane cholesterol and of cholesterol esters. Cholesterol was incorporated into the oocyte plasma membrane as evidenced by comparative labeling of a fluorescent cholesterol. Oocytes and cumulus cells increased membrane cholesterol after incubation with MβCD/cholesterol and recovered their original level after cholesterol removal, regardless of the season. Finally, we evaluated the effect of vitrification on the putative raft molecule GM1. Cholesterol modulation also preserved membrane organization by maintaining ganglioside level at the plasma membrane. Results suggest a distinctive cholesterol metabolic status of cumulus-oocyte complexes (COCs among seasons and a dynamic organizational structure

Genetic alterations affecting cholesterol metabolism and human fertility.

Science.gov (United States)

DeAngelis, Anthony M; Roy-O'Reilly, Meaghan; Rodriguez, Annabelle

2014-11-01

Single nucleotide polymorphisms (SNPs) represent genetic variations among individuals in a population. In medicine, these small variations in the DNA sequence may significantly impact an individual's response to certain drugs or influence the risk of developing certain diseases. In the field of reproductive medicine, a significant amount of research has been devoted to identifying polymorphisms which may impact steroidogenesis and fertility. This review discusses current understanding of the effects of genetic variations in cholesterol metabolic pathways on human fertility that bridge novel linkages between cholesterol metabolism and reproductive health. For example, the role of the low-density lipoprotein receptor (LDLR) in cellular metabolism and human reproduction has been well studied, whereas there is now an emerging body of research on the role of the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI) in human lipid metabolism and female reproduction. Identifying and understanding how polymorphisms in the SCARB1 gene or other genes related to lipid metabolism impact human physiology is essential and will play a major role in the development of personalized medicine for improved diagnosis and treatment of infertility. © 2014 by the Society for the Study of Reproduction, Inc.

Cholesterol, sphingolipids, and glycolipids: What do we know about their role in raft-like membranes?

DEFF Research Database (Denmark)

Rog, T.; Vattulainen, I.

2014-01-01

Lipids rafts are considered to be functional nanoscale membrane domains enriched in cholesterol and sphingolipids, characteristic in particular of the external leaflet of cell membranes. Lipids, together with membrane-associated proteins, are therefore considered to form nanoscale units with pote......Lipids rafts are considered to be functional nanoscale membrane domains enriched in cholesterol and sphingolipids, characteristic in particular of the external leaflet of cell membranes. Lipids, together with membrane-associated proteins, are therefore considered to form nanoscale units...... with potential specific functions. Although the understanding of the structure of rafts in living cells is quite limited, the possible functions of rafts are widely discussed in the literature, highlighting their importance in cellular functions. In this review, we discuss the understanding of rafts that has...... emerged based on recent atomistic and coarse-grained molecular dynamics simulation studies on the key lipid raft components, which include cholesterol, sphingolipids, glycolipids, and the proteins interacting with these classes of lipids. The simulation results are compared to experiments when possible...

Examining the role of export competitive advantages on export performance

OpenAIRE

Yeganeh Alimohammadi; Reza Aghamousa; Fataneh Alizadeh Meshkani

2014-01-01

This paper investigates the role of export competitive advantage on export performance in food industry. The proposed study designs a questionnaire in Likert scale and distributes it among 280 randomly selected experts in food industry and Cronbach alpha has been calculated as 0.827. The study has applied factor analysis to find important factors influencing export performance. Kaiser-Meyer-Olkin Measure of Sampling Adequacy and Bartlett's Test of Sphericity have been performed to validate th...

Annexins as organizers of cholesterol- and sphingomyelin-enriched membrane microdomains in Niemann-Pick type C disease.

Science.gov (United States)

Domon, Magdalena; Nasir, Mehmet Nail; Matar, Gladys; Pikula, Slawomir; Besson, Françoise; Bandorowicz-Pikula, Joanna

2012-06-01

Growing evidence suggests that membrane microdomains enriched in cholesterol and sphingomyelin are sites for numerous cellular processes, including signaling, vesicular transport, interaction with pathogens, and viral infection, etc. Recently some members of the annexin family of conserved calcium and membrane-binding proteins have been recognized as cholesterol-interacting molecules and suggested to play a role in the formation, stabilization, and dynamics of membrane microdomains to affect membrane lateral organization and to attract other proteins and signaling molecules onto their territory. Furthermore, annexins were implicated in the interactions between cytosolic and membrane molecules, in the turnover and storage of cholesterol and in various signaling pathways. In this review, we focus on the mechanisms of interaction of annexins with lipid microdomains and the role of annexins in membrane microdomains dynamics including possible participation of the domain-associated forms of annexins in the etiology of human lysosomal storage disease called Niemann-Pick type C disease, related to the abnormal storage of cholesterol in the lysosome-like intracellular compartment. The involvement of annexins and cholesterol/sphingomyelin-enriched membrane microdomains in other pathologies including cardiac dysfunctions, neurodegenerative diseases, obesity, diabetes mellitus, and cancer is likely, but is not supported by substantial experimental observations, and therefore awaits further clarification.

75 FR 47548 - President's Export Council Subcommittee on Export Administration; Notice of Recruitment of...

Science.gov (United States)

2010-08-06

... DEPARTMENT OF COMMERCE Bureau of Industry and Security President's Export Council Subcommittee on Export Administration; Notice of Recruitment of Private-Sector Members SUMMARY: The President's Export... their services. The PECSEA is seeking private-sector members with senior export control expertise and...

Cholesterol autoxidation in phospholipid membrane bilayers

International Nuclear Information System (INIS)

Sevanian, A.; McLeod, L.L.

1987-01-01

Lipid peroxidation in unilamellar liposomes of known cholesterol-phospholipid composition was monitored under conditions of autoxidation or as induced by a superoxide radical generating system, gamma-irradiation or cumene hydroperoxide. Formation of cholesterol oxidation products was indexed to the level of lipid peroxidation. The major cholesterol oxidation products identified were 7-keto-cholesterol, isomeric cholesterol 5,6-epoxides, isomeric 7-hydroperoxides and isomeric 3,7-cholestane diols. Other commonly encountered products included 3,5-cholestadiene-7-one and cholestane-3 beta, 5 alpha, 6 beta-triol. Superoxide-dependent peroxidation required iron and produced a gradual increase in 7-keto-cholesterol and cholesterol epoxides. Cholesterol oxidation was greatest in liposomes containing high proportions of unsaturated phospholipid to cholesterol (4:1 molar ratio), intermediate with low phospholipid to cholesterol ratios (2:1) and least in liposomes prepared with dipalmitoylphosphatidylcholine and cholesterol. This relationship held regardless of the oxidizing conditions used. Cumene hydroperoxide-dependent lipid peroxidation and/or more prolonged oxidations with other oxidizing systems yielded a variety of products where cholesterol-5 beta,6 beta-epoxide, 7-ketocholesterol and the 7-hydroperoxides were most consistently elevated. Oxyradical initiation of lipid peroxidation produced a pattern of cholesterol oxidation products distinguishable from the pattern derived by cumene hydroperoxide-dependent peroxidation

High Cholesterol/Low Cholesterol: Effects in Biological Membranes: A Review.

Science.gov (United States)

Subczynski, Witold K; Pasenkiewicz-Gierula, Marta; Widomska, Justyna; Mainali, Laxman; Raguz, Marija

2017-12-01

Lipid composition determines membrane properties, and cholesterol plays a major role in this determination as it regulates membrane fluidity and permeability, as well as induces the formation of coexisting phases and domains in the membrane. Biological membranes display a very diverse lipid composition, the lateral organization of which plays a crucial role in regulating a variety of membrane functions. We hypothesize that, during biological evolution, membranes with a particular cholesterol content were selected to perform certain functions in the cells of eukaryotic organisms. In this review, we discuss the major membrane properties induced by cholesterol, and their relationship to certain membrane functions.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

Science.gov (United States)

Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; Duross, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-08-01

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1-/-) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1-/- cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.

PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

Science.gov (United States)

Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

2016-01-01

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders. PMID:27572704

Demand Uncertainty: Exporting Delays and Exporting Failures

DEFF Research Database (Denmark)

Nguyen, Daniel Xuyen

2012-01-01

This paper presents a model of trade that explains why firms wait to export and why many exporters fail. Firms face uncertain demands that are only realized after the firm enters the destination. The model retools the timing of the resolution of uncertainty found in models with heterogeneity...... of firm productivity. This retooling addresses several shortcomings. First, the imperfect correlation of demands reconciles the sales variation observed in and across destinations. Second, since demands for the firm's output are correlated across destinations, a firm can use previously realized demands...... to forecast unknown demands in untested destinations. The option to forecast demands causes firms to delay exporting in order to gather more information about foreign demand. Third, since uncertainty is resolved after entry, many firms enter a destination and then exit after learning that they cannot profit...

Remnant cholesterol and ischemic heart disease

DEFF Research Database (Denmark)

Varbo, Anette; Nordestgaard, Børge G

2014-01-01

PURPOSE OF REVIEW: To review recent advances in the field of remnant cholesterol as a contributor to the development of ischemic heart disease (IHD). RECENT FINDINGS: Epidemiologic, mechanistic, and genetic studies all support a role for elevated remnant cholesterol (=cholesterol in triglyceride......-rich lipoproteins) as a contributor to the development of atherosclerosis and IHD. Observational studies show association between elevated remnant cholesterol and IHD, and mechanistic studies show remnant cholesterol accumulation in the arterial wall like LDL-cholesterol (LDL-C) accumulation. Furthermore, large...... genetic studies show evidence of remnant cholesterol as a causal risk factor for IHD independent of HDL-cholesterol levels. Genetic studies also show that elevated remnant cholesterol is associated with low-grade inflammation, whereas elevated LDL-C is not. There are several pharmacologic ways of lowering...

Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses.

Science.gov (United States)

Kaur, Randip; Henriksen-Lacey, Malou; Wilkhu, Jitinder; Devitt, Andrew; Christensen, Dennis; Perrie, Yvonne

2014-01-06

Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses.

ATP binding cassette G1-dependent cholesterol efflux during inflammation.

Science.gov (United States)

de Beer, Maria C; Ji, Ailing; Jahangiri, Anisa; Vaughan, Ashley M; de Beer, Frederick C; van der Westhuyzen, Deneys R; Webb, Nancy R

2011-02-01

ATP binding cassette transporter G1 (ABCG1) mediates the transport of cellular cholesterol to HDL, and it plays a key role in maintaining macrophage cholesterol homeostasis. During inflammation, HDL undergoes substantial remodeling, acquiring lipid changes and serum amyloid A (SAA) as a major apolipoprotein. In the current study, we investigated whether remodeling of HDL that occurs during acute inflammation impacts ABCG1-dependent efflux. Our data indicate that lipid free SAA acts similarly to apolipoprotein A-I (apoA-I) in mediating sequential efflux from ABCA1 and ABCG1. Compared with normal mouse HDL, acute phase (AP) mouse HDL containing SAA exhibited a modest but significant 17% increase in ABCG1-dependent efflux. Interestingly, AP HDL isolated from mice lacking SAA (SAAKO mice) was even more effective in promoting ABCG1 efflux. Hydrolysis with Group IIA secretory phospholipase A(2) (sPLA(2)-IIA) significantly reduced the ability of AP HDL from SAAKO mice to serve as a substrate for ABCG1-mediated cholesterol transfer, indicating that phospholipid (PL) enrichment, and not the presence of SAA, is responsible for alterations in efflux. AP human HDL, which is not PL-enriched, was somewhat less effective in mediating ABCG1-dependent efflux compared with normal human HDL. Our data indicate that inflammatory remodeling of HDL impacts ABCG1-dependent efflux independent of SAA.

Exports of petroleum products, 1987

International Nuclear Information System (INIS)

1988-04-01

A summary is presented of exports of motor gasoline, middle distillate, aviation turbine fuel, heavy fuel oil, and partially processed oil from Canada for the 1987 calendar year. A discussion of petroleum product imports is included in order to put exports in the context of the overall trade. Exports of the above petroleum products averaged 22,200 m 3 /d in 1987, up 15% from 1986 levels. Exports of middle distillates and aviation fuel had the largest gains in 1987. Export prices for light petroleum products stayed relatively close to USA spot prices. The heavy fuel oil price was below the New York spot price in the beginning of 1987 but remained close for the rest of the year. Canada's petroleum products exports were made to 5 countries while imports came from at least 13 countries. The USA remained Canada's largest trading partner in petroleum products. Exports to Japan and the Far East rose ca 60% over 1986. Product outturns for export were 9% of total Canadian refinery throughput. Exports of aviation turbine fuel from Ontario began in April 1987. The top single exporter in Canada was Irving Oil Ltd. with 2,485,000 m 3 . Irving was also the top exporter in 1986. 11 figs., 4 tabs

The future of Russian gas exports

International Nuclear Information System (INIS)

Rodiononv, Alexander; Krasheninnikov, Yuri; Panin, Sergei

1999-12-01

Contains Executive Summary and Chapters on: Introduction; The structure of Russian gas exports; Exports to Europe; Exports to Turkey/Middle East; Exports to Asia/Pacific Rim; FSU gas exports; Regulations for exporting gas from Russia; Equipment and services. (Author)

Engineering the lipid layer of lipid-PLGA hybrid nanoparticles for enhanced in vitro cellular uptake and improved stability.

Science.gov (United States)

Hu, Yun; Hoerle, Reece; Ehrich, Marion; Zhang, Chenming

2015-12-01

Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid-PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long-term storage. However, stabilized hybrid structures of high cholesterol content tended to fuse with each other during storage, resulting in significant size increase and lowered cellular uptake. Additional experiments demonstrated that PEGylation of NPs could effectively minimize fusion-caused size increase after long term storage, leading to improved cellular uptake, although excessive PEGylation will not be beneficial and led to reduced improvement. This paper reports the engineering of the lipid layer that encloses a polymeric nanoparticle, which can be used as a carrier for drug and vaccine molecules for targeted delivery. We demonstrated that the concentration of cholesterol is critical for the stability and uptake of the hybrid nanoparticles by dendritic cells, a targeted cell for the delivery of immune effector molecules. However, we found that hybrid nanoparticles with high cholesterol concentration tend to fuse during storage resulting in larger particles with decreased cellular uptake. This problem is

Nuclear export controls

International Nuclear Information System (INIS)

Thorne, C.E.

1999-01-01

One approach to describing the multilateral nuclear export controls is to do it according to time. This led to an interesting discovery, i.e. multilateral export controls have been defined by four distinct periods, the forst two of abut five years each, the second two about twice as long. These time periods have another interesting property. The two suppliers groups, which we will discuss in detail, have alternated in dominance over nearly thirty years. After describing the historical developments, the status of the present situation in multilateral nuclear export controls is examined, with the strengths and weaknesses. The future of multilateral nuclear export controls and possible ways that might be taken are considered

75 FR 70905 - President's Export Council: Meeting of the President's Export Council

Science.gov (United States)

2010-11-19

.... ACTION: Notice of an open meeting. SUMMARY: The President's Export Council will hold a meeting to discuss.... exports, jobs, and growth. DATES: December 9, 2010 at 9 a.m. (EST). ADDRESSES: The President's Export... trade and report to the President on its activities and on its recommendations for expanding U.S...

Cloning, expression, and enzymatic activity evaluation of cholesterol oxidase gene isolated from a native Rhodococcus sp.

Directory of Open Access Journals (Sweden)

Hamed Esmaeil Lashgarian

2016-10-01

Full Text Available Cholesterol oxidase (CHO is one of the valuable enzymes that play an important role in: measurement of serum cholesterol, food industry as a biocatalyst and agriculture as a biological larvicide. This enzyme was produced by several bacterial strains. Wild type enzyme produced by Rhodococcus sp. secret two forms of CHO enzyme: extra cellular and membrane bound type which its amount is low and unstable. The goal of the study was cloning, expression, and enzymatic activity evaluation of cholesterol oxidase gene isolated from a native Rhodococcus sp. CHO gene was isolated from native bacteria and cloned into pET23a. In the next step, the construct was expressed in E.coli BL21 and induced by different concentration of IPTG ranges from 0.1 - 0.9 mM. This gene contains 1642 bp and encodes a protein consists of 533 amino acids. It has about 96 % homology with CHO gene isolated from Rhodococcus equi. The high expression was obtained in 0.5 mM concentration of IPTG after 4 hour induction. This recombinant enzyme had a molecular weight of 55 kDa, that secretion of intra cellular type is much more than extracellular form. The optimum pH and temperature conditions for the recombinant enzyme were 7.5 and 45°C, respectively. CHO enzyme obtained from Rhodococcus sp. is a cheap enzyme with medical and industrial applications that can be produced easily and purified in large scale with simple methods.

Angiogenin activates phospholipase C and elicits a rapid incorporation of fatty acid into cholesterol esters in vascular smooth muscle cells

International Nuclear Information System (INIS)

Moore, F.; Riordan, J.F.

1990-01-01

Angiogenin activates the phosphoinositide-specific phospholipase C (PLC) in cultured rat aortic smooth muscle cells to yield a transient (30 s) peak of 1,2-diacylglycerol (DG) and inositol trisphosphate. Within 1 min, the DG level falls below that of the control and remains so for at least 20 min. A transient increase in monoacylglycerol indicates that depletion of DG may be the consequence of hydrolysis by DG lipase. In addition to these changes in second messengers, a rapid increase in incorporating of radiolabeled tracer into cellular cholesterol esters is observed. Stimulated cholesterol ester labeling is inhibited by preincubation with either the DG lipase inhibitor RHC 80267 or the acyl coenzyme A:cholesterol acyltransferase inhibitor Sandoz 58035. Cells prelabeled with [ 3 H]arachidonate show a sustained increase in labeling of cholesterol esters following exposure to angiogenin. In contrast, cells prelabeled with [ 3 H]oleate show only a transient elevation that returns to the basal level by 5 min. This suggests initial cholesterol esterification by oleate followed by arachidonate that is released by stimulation of the PLC/DG lipase pathway

Monocytes of patients with familial hypercholesterolemia show alterations in cholesterol metabolism

Directory of Open Access Journals (Sweden)

Soufi Muhidien

2008-11-01

Full Text Available Abstract Background Elevated plasma cholesterol promotes the formation of atherosclerotic lesions in which monocyte-derived lipid-laden macrophages are frequently found. To analyze, if circulating monocytes already show increased lipid content and differences in lipoprotein metabolism, we compared monocytes from patients with Familial Hypercholesterolemia (FH with those from healthy individuals. Methods Cholesterol and oxidized cholesterol metabolite serum levels of FH and of healthy, gender/age matched control subjects were measured by combined gas chromatography – mass spectroscopy. Monocytes from patients with FH and from healthy subjects were isolated by antibody-assisted density centrifugation. Gene expression profiles of isolated monocytes were measured using Affymetrix HG-U 133 Plus 2.0 microarrays. We compared monocyte gene expression profiles from FH patients with healthy controls using a Welch T-test with correction for multiple testing (p Results Using microarray analysis we found in FH patients a significant up-regulation of 1,617 genes and a down-regulation of 701 genes compared to monocytes from healthy individuals. These include genes of proteins that are involved in the uptake, biosynthesis, disposition, and cellular efflux of cholesterol. In addition, plasma from FH patients contains elevated amounts of sterols and oxysterols. An increased uptake of oxidized as well as of native LDL by FH monocytes combined with a down-regulation of NPC1 and ABCA1 explains the lipid accumulation observed in these cells. Conclusion Our data demonstrate that circulating FH monocytes show differences in cell physiology that may contribute to the early onset of atherosclerosis in this disease.

SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer

Directory of Open Access Journals (Sweden)

Jorge L. Gutierrez-Pajares

2016-10-01

Full Text Available Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI, which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI’s function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies.

Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus

DEFF Research Database (Denmark)

von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael

2013-01-01

The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from...... Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing....... Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance...

Bile acid sequestrants for cholesterol

Science.gov (United States)

... ency/patientinstructions/000787.htm Bile acid sequestrants for cholesterol To use the sharing features on this page, ... are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can stick ...

to HDL-cholesterol functionality

Directory of Open Access Journals (Sweden)

Malara Marzena

2016-05-01

Full Text Available The purpose of this study was to analyse the scientific evidence concerning the effects of two enzymes – paraoxonase 1 and myeloperoxidase – on the functions of HDL-cholesterol. It is well documented that disturbed circulating lipoproteins (a high total and high LDL-cholesterol, and low HDL-cholesterol bring about atherosclerosis and an increased risk of cardiovascular disease (CVD which is recognised as the main cause of death all around the world. In consequence, numerous studies have focused on procedures which will improve the plasma lipoproteins profile by decreasing the total cholesterol and the LDL-cholesterol (LDL-C and increasing the HDL-cholesterol (HDL-C. However, the anti-atherogenic role of HDL-C has been challenged in studies showing that genetically elevated HDL-cholesterol does not offer protection against CVD. Moreover, it has been found that raising the circulating HDL-cholesterol fails to reduce atherosclerosis. The doubts concerning the protective role of HDL-C have been supported by in vitro studies which indicate that the HDL-C from patients with atherosclerosis does not have a protective action, but does stimulate inflammation and free radical synthesis. The above data suggests that HDL-C, commonly recognised as protective against atherosclerosis, in some circumstances becomes pro-atherogenic, and is thus dysfunctional. Our review focuses on two enzymes – paraoxonase 1 (PON1 and myeloperoxidase (MPO – which markedly affect the properties of HDL-C and contribute to its anti – or pro-atherogenic activity. Moreover, the effects of the diet and physical activity on PON1 and MPO are summarised with respect to the HDL-C functionality.

Effect of dietary cholesterol and plant sterol consumption on plasma lipid responsiveness and cholesterol trafficking in healthy individuals.

Science.gov (United States)

Alphonse, Peter A S; Ramprasath, Vanu; Jones, Peter J H

2017-01-01

Dietary cholesterol and plant sterols differentially modulate cholesterol kinetics and circulating cholesterol. Understanding how healthy individuals with their inherent variabilities in cholesterol trafficking respond to such dietary sterols will aid in improving strategies for effective cholesterol lowering and alleviation of CVD risk. The objectives of this study were to assess plasma lipid responsiveness to dietary cholesterol v. plant sterol consumption, and to determine the response in rates of cholesterol absorption and synthesis to each sterol using stable isotope approaches in healthy individuals. A randomised, double-blinded, crossover, placebo-controlled clinical trial (n 49) with three treatment phases of 4-week duration were conducted in a Manitoba Hutterite population. During each phase, participants consumed one of the three treatments as a milkshake containing 600 mg/d dietary cholesterol, 2 g/d plant sterols or a control after breakfast meal. Plasma lipid profile was determined and cholesterol absorption and synthesis were measured by oral administration of [3, 4-13C] cholesterol and 2H-labelled water, respectively. Dietary cholesterol consumption increased total (0·16 (sem 0·06) mmol/l, P=0·0179) and HDL-cholesterol (0·08 (sem 0·03) mmol/l, P=0·0216) concentrations with no changes in cholesterol absorption or synthesis. Plant sterol consumption failed to reduce LDL-cholesterol concentrations despite showing a reduction (6 %, P=0·0004) in cholesterol absorption. An over-compensatory reciprocal increase in cholesterol synthesis (36 %, P=0·0026) corresponding to a small reduction in absorption was observed with plant sterol consumption, possibly resulting in reduced LDL-cholesterol lowering efficacy of plant sterols. These data suggest that inter-individual variability in cholesterol trafficking mechanisms may profoundly impact plasma lipid responses to dietary sterols in healthy individuals.

Lack of Abcg1 results in decreased plasma HDL cholesterol levels and increased biliary cholesterol secretion in mice fed a high cholesterol diet

NARCIS (Netherlands)

Wiersma, Harmen; Nijstad, Niels; de Boer, Jan Freark; Out, Ruud; Hogewerf, Wytse; Van Berkel, Theo J.; Kuipers, Folkert; Tietge, Uwe J. F.

Objective: The ATP Binding Cassette transporter G1 (ABCG1) has been implicated in cholesterol efflux towards HDL and reverse cholesterol transport (RCT). Biliary cholesterol secretion is considered as an important step in RCT. The aim of the present study was to determine the consequences of Abcg1

Sulforaphane Protects against High Cholesterol-Induced Mitochondrial Bioenergetics Impairments, Inflammation, and Oxidative Stress and Preserves Pancreatic β-Cells Function

Directory of Open Access Journals (Sweden)

Catalina Carrasco-Pozo

2017-01-01

Full Text Available Cholesterol plays an important role in inducing pancreatic β-cell dysfunction, leading to an impaired insulin secretory response to glucose. This study aimed to determine the protective effects of sulforaphane, a natural isothiocyanate Nrf2-inducer, against cholesterol-induced pancreatic β-cells dysfunction, through molecular and cellular mechanisms involving mitochondrial bioenergetics. Sulforaphane prevented cholesterol-induced alterations in the coupling efficiency of mitochondrial respiration, improving ATP turnover and spare capacity, and averted the impairment of the electron flow at complexes I, II, and IV. Sulforaphane also attenuated the cholesterol-induced activation of the NFκB pathway, normalizing the expression of pro- and anti-inflammatory cytokines. In addition, it also inhibited the decrease in sirtuin 1 expression and greatly increased Pgc-1α expression in Min6 cells. Sulforaphane increased the expression of antioxidant enzymes downstream of the Nrf2 pathway and prevented lipid peroxidation induced by cholesterol. The antioxidant and anti-inflammatory properties of sulforaphane and its ability to protect and improve mitochondrial bioenergetic function contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction. Our data provide a scientifically tested foundation upon which sulforaphane can be developed as nutraceutical to preserve β-cell function and eventually control hyperglycemia.

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge.

Science.gov (United States)

Mc Auley, Mark T; Mooney, Kathleen M

2017-07-01

The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our

19 CFR 351.402 - Calculation of export price and constructed export price; reimbursement of antidumping and...

Science.gov (United States)

2010-04-01

... Export Price, Constructed Export Price, Fair Value, and Normal Value § 351.402 Calculation of export... (date of final determination of sales at less than fair value). (3) Presumption. The Secretary may...) Introduction. In order to establish export price, constructed export price, and normal value, the Secretary...

HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events

NARCIS (Netherlands)

Barter, Philip; Gotto, Antonio M.; LaRosa, John C.; Maroni, Jaman; Szarek, Michael; Grundy, Scott M.; Kastelein, John J. P.; Bittner, Vera; Fruchart, Jean-Charles

2007-01-01

BACKGROUND: High-density lipoprotein (HDL) cholesterol levels are a strong inverse predictor of cardiovascular events. However, it is not clear whether this association is maintained at very low levels of low-density lipoprotein (LDL) cholesterol. METHODS: A post hoc analysis of the recently

Ezetimibe Increases Endogenous Cholesterol Excretion in Humans.

Science.gov (United States)

Lin, Xiaobo; Racette, Susan B; Ma, Lina; Wallendorf, Michael; Ostlund, Richard E

2017-05-01

Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool. In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d 7 in a lipid emulsion and dietary cholesterol with cholesterol-d 5 and sitostanol-d 4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30±4.3% (SE, P <0.0001) and low-density lipoprotein cholesterol 19.8±1.9% ( P =0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6±12.2% ( P <0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7±14.3% ( P <0.0001), whereas plasma cholesterol turnover rose 26.2±3.6% ( P =0.0096). Fecal bile acids were unchanged. Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758. © 2017 American Heart Association, Inc.

The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells.

Directory of Open Access Journals (Sweden)

Keith Cha

Full Text Available The Ran GTPase activating protein RanGAP1 plays an essential role in nuclear transport by stimulating RanGTP hydrolysis in the cytoplasmic compartment. In mammalian cells, unmodified RanGAP1 is predominantly cytoplasmic, whereas modification by small ubiquitin-related modifier protein (SUMO targets RanGAP1 to the cytoplasmic filaments of nuclear pore complex (NPC. Although RanGAP1 contains nine putative nuclear export signals and a nuclear localization signal, little is known if RanGAP1 shuttles between the nuclear and cytoplasmic compartments and how its primary localization in the cytoplasm and at the NPC is regulated. Here we show that inhibition of CRM1-mediated nuclear export using RNAi-knockdown of CRM1 and inactivation of CRM1 by leptomycin B (LMB results in nuclear accumulation of RanGAP1. LMB treatment induced a more robust redistribution of RanGAP1 from the cytoplasm to the nucleoplasm compared to CRM1 RNAi and also uniquely triggered a decrease or loss of RanGAP1 localization at the NPC, suggesting that LMB treatment is more effective in inhibiting CRM1-mediated nuclear export of RanGAP1. Our time-course analysis of LMB treatment reveals that the NPC-associated RanGAP1 is much more slowly redistributed to the nucleoplasm than the cytoplasmic RanGAP1. Furthermore, LMB-induced nuclear accumulation of RanGAP1 is positively correlated with an increase in levels of SUMO-modified RanGAP1, suggesting that SUMOylation of RanGAP1 may mainly take place in the nucleoplasm. Lastly, we demonstrate that the nuclear localization signal at the C-terminus of RanGAP1 is required for its nuclear accumulation in cells treated with LMB. Taken together, our results elucidate that RanGAP1 is actively transported between the nuclear and cytoplasmic compartments, and that the cytoplasmic and NPC localization of RanGAP1 is dependent on CRM1-mediated nuclear export.

Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development.

Directory of Open Access Journals (Sweden)

Anita M Quintana

Full Text Available There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf, but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.

In situ probing of cholesterol in astrocytes at the single-cell level using laser desorption ionization mass spectrometric imaging with colloidal silver.

Science.gov (United States)

Perdian, D C; Cha, Sangwon; Oh, Jisun; Sakaguchi, Donald S; Yeung, Edward S; Lee, Young Jin

2010-04-30

Mass spectrometric imaging has been utilized to localize individual astrocytes and to obtain cholesterol populations at the single-cell level in laser desorption ionization (LDI) with colloidal silver. The silver ion adduct of membrane-bound cholesterol was monitored to detect individual cells. Good correlation between mass spectrometric and optical images at different cell densities indicates the ability to perform single-cell studies of cholesterol abundance. The feasibility of quantification is confirmed by the agreement between the LDI-MS ion signals and the results from a traditional enzymatic fluorometric assay. We propose that this approach could be an effective tool to study chemical populations at the cellular level. Published in 2010 by John Wiley & Sons, Ltd.

Trapping crystal nucleation of cholesterol monohydrate

DEFF Research Database (Denmark)

Solomonov, I.; Weygand, M.J.; Kjær, K.

2005-01-01

Crystalline nucleation of cholesterol at the air-water interface has been studied via grazing incidence x-ray diffraction using synchrotron radiation. The various stages of cholesterol molecular assembly from monolayer to three bilayers incorporating interleaving hydrogen-bonded water layers......, at least initially, an intralayer cholesterol rearrangement in a single-crystal-to-single-crystal transition. The preferred nucleation of the monoclinic phase of cholesterol . H2O followed by transformation to the stable monohydrate phase may be associated with an energetically more stable cholesterol...... bilayer arrangement of the former and a more favorable hydrogen-bonding arrangement of the latter. The relevance of this nucleation process of cholesterol monohydrate to pathological crystallization of cholesterol from cell biomembranes is discussed....

Characterization of placental cholesterol transport

DEFF Research Database (Denmark)

Lindegaard, Marie L; Wassif, Christopher A; Vaisman, Boris

2008-01-01

Patients with Smith-Lemli-Opitz syndrome (SLOS) are born with multiple congenital abnormalities. Postnatal cholesterol supplementation is provided; however, it cannot correct developmental malformations due to in utero cholesterol deficit. Increased transport of cholesterol from maternal to fetal...... circulation might attenuate congenital malformations. The cholesterol transporters Abca1, Abcg1, and Sr-b1 are present in placenta; however, their potential role in placental transport remains undetermined. In mice, expression analyses showed that Abca1 and Abcg1 transcripts increased 2-3-fold between...... embryonic days 13.5 and 18.5 in placental tissue; whereas, Sr-b1 expression decreased. To examine the functional role of Abca1, Abcg1 and Sr-b1 we measured the maternal-fetal transfer of (14)C-cholesterol in corresponding mutant embryos. Disruption of either Abca1 or Sr-b1 decreased cholesterol transfer...

Increased hepatic cholesterol esterification with essential fatty acid deficiency (EFAD): relationship to plasma lipoprotein (LP) cholesterol content

International Nuclear Information System (INIS)

Ney, D.M.; Ziboh, V.A.; Schneeman, B.O.

1986-01-01

EFAD in the rat is associated with hepatic accumulation of esterified cholesterol and altered distribution of cholesterol between plasma and hepatic tissue. Little is known regarding the impact of EFAD on LP composition. To determine the relationship between hepatic cholesterol esterification and plasma lP composition in control (C) and EFAD male Wistar rats, the authors induced EFAD with continuous intragastric (IG) infusion of EFA-free solutions containing 3.5% of calories as triolein for 7 and 14 days. C animals received IG infusion of solutions containing 3.5% of calories as linoleic acid. Data in the EFAD groups reveal: (i) marked decreases in hepatic EFAs and increases in monoenoic acids; (ii) progressive increases in hepatic content of triglyceride and esterified cholesterol with 7 and 14 days of feeding; (iii) assay of acyl CoA:cholesterol acyltransferase activity in hepatic tissue using 14 C-cholesterol demonstrates an increase in hepatic cholesterol esterification when compared to C animals. Increased hepatic cholesterol esterification correlates with elevated levels of esterified cholesterol in plasma VLDL and HDL particles. These data indicate that the elevated levels of cholesterol esters in LP particles is due, at least in part, to increased hepatic cholesterol esterification with EFAD

Superstar Exporters: An Empirical Investigation of Strategic Interactions in Danish Export Markets

DEFF Research Database (Denmark)

Ciliberto, Federico; Jäkel, Ina Charlotte

, product and destination. We also obtain detailed information on applied, preferential tariff protection from the MAcMap-HS6 database. We find evidence of strong negative competitive effects of entry: in the absence of strategic competitive effects, firms would be 54.3 percentage points more likely...... to export to a given market. Next, we run two counterfactual exercises. We show that failing to account for the strategic interaction among superstar exporters leads to: (i) overstating the probability that firms would start exporting to a market following tariff elimination by 8 percentage points; and, (ii......) overstating the probability that firms would stop exporting to a market if tariffs were imposed by 7.5 percentage points. We also show that competitive effects vary across export markets and competitors. This heterogeneity in the competitive effects implies that there exist multiple equilibria, both...

76 FR 11756 - Action Affecting Export Privileges; Ali Amirnazmi; Order Denying Export Privileges

Science.gov (United States)

2011-03-03

... DEPARTMENT OF COMMERCE Bureau of Industry and Security Action Affecting Export Privileges; Ali Amirnazmi; Order Denying Export Privileges In the Matter of: Ali Amirnazmi, Register 63302-066, FCI... release and forfeit $81,277.37. Section 766.25 of the Export Administration Regulations (``EAR'' or...

Export diversification in Uganda : developments in non-traditional agricultural exports

NARCIS (Netherlands)

Dijkstra, T.

2001-01-01

Over the last two decades agricultural export diversification has been pushed as an economic development strategy for sub-Saharan Africa. This paper looks at Uganda, where nontraditional agricultural export commodities have been (re)-introduced since Museveni came to power in 1986. The most

Nuclear localization signal regulates porcine circovirus type 2 capsid protein nuclear export through phosphorylation.

Science.gov (United States)

Hou, Qiang; Hou, Shaohua; Chen, Qing; Jia, Hong; Xin, Ting; Jiang, Yitong; Guo, Xiaoyu; Zhu, Hongfei

2018-02-15

The open reading frame 2 (ORF2) of Porcine circovirus type 2 (PCV2) encodes the major Capsid (Cap) protein, which self-assembles into virus-like particle (VLP) of similar morphology to the PCV2 virion and accumulates in the nucleus through the N-terminal arginine-rich nuclear localization signal (NLS). In this study, PCV2 Cap protein and its derivates were expressed via the baculovirus expression system, and the cellular localization of the recombinant proteins were investigated using anti-Cap mAb by imaging flow cytometry. Analysis of subcellular localization of Cap protein and its variants demonstrated that NLS mediated Cap protein nuclear export as well as nuclear import, and a phosphorylation site (S17) was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the NLS domain to regulate Cap protein nuclear export. Phosphorylation of NLS regulating the PCV2 Cap protein nuclear export was also demonstrated in PK15 cells by fluorescence microscopy. Moreover, the influence of Rep and Rep' protein on Cap protein subcellular localization was investigated in PK15 cells. Phosphorylation of NLS regulating Cap protein nuclear export provides more detailed knowledge of the PCV2 viral life cycle. Copyright © 2018 Elsevier B.V. All rights reserved.

Recovery and purification of cholesterol from cholesterol-β-cyclodextrin inclusion complex using ultrasound-assisted extraction.

Science.gov (United States)

Li, Yong; Chen, Youliang; Li, Hua

2017-01-01

Response surface methodology was used to optimize ultrasound-assisted ethanol extraction (UAE) of cholesterol from cholesterol-β-cyclodextrin (C-β-CD) inclusion complex prepared from duck yolk oil. The best extraction conditions were solvent-solid ratio 10mL/g, ultrasonic power 251W, extraction temperature 56°C and sonication time 36min. Under these conditions, the highest cholesterol extraction yield and cholesterol content obtained 98.12±0.25% and 43.38±0.61mg/g inclusion complex, respectively. As compared with Reflux extraction and Soxhlet extraction, the UAE was more efficient and economical. To increase the purity of crude cholesterol extraction, silica gel column chromatography and crystallization were carried out. Finally, cholesterol was obtained at 95.1% purity, 71.7% recovery and 22.0% yield. Copyright © 2016 Elsevier B.V. All rights reserved.

Cholesterol Medicines: MedlinePlus Health Topic

Science.gov (United States)

... heart diseases . There are two main types of cholesterol. LDL is the "bad" cholesterol. A high LDL level leads to a buildup of cholesterol in ... 75 years old, you have diabetes, and your LDL cholesterol level is 70 mg/dL or higher You ...

The cholesterol space of the rat

International Nuclear Information System (INIS)

Chevallier, F.

1959-01-01

The experiments consisted in feeding daily to rats the same mass of radioactive cholesterol, over variable time intervals. From the evolution of the specific radioactivity of cholesterol carbon-14 in the organs as a function of time, information relative to the transport of cholesterol in the organism may be obtained. 1) The cholesterol space, defined as the group of molecules capable of being transferred from the organs into the serum and vice versa, represents at the most 50 per cent of the total cholesterol of the adult rat. 2) The incessant interchange between the tissual and the serum cholesterol renews entirely or for the most part the cholesterol molecules contained in the following organs: spleen, heart, adipose tissue, suprarenal glands, lungs, bone marrow, liver, erythrocytes. For a second group of organs: skin, testicles, kidneys, colon, bones, muscles, only a fraction of their cholesterol is renewable by this process. No transfer can be detected at the level of the brain. 3) The relative speeds of the various means of appearance (absorption, synthesis) and disappearance (excretion, transformation) of the cholesterol from its space are such that a stationary isotopic state is established around the eighth day, when the animal absorbs 5 milligrams of radioactive cholesterol daily. (author) [fr

Cholesterol Absorption and Synthesis in Vegetarians and Omnivores.

Science.gov (United States)

Lütjohann, Dieter; Meyer, Sven; von Bergmann, Klaus; Stellaard, Frans

2018-03-01

Vegetarian diets are considered health-promoting; however, a plasma cholesterol lowering effect is not always observed. We investigate the link between vegetarian-diet-induced alterations in cholesterol metabolism. We study male and female omnivores, lacto-ovo vegetarians, lacto vegetarians, and vegans. Cholesterol intake, absorption, and fecal sterol excretion are measured as well as plasma concentrations of cholesterol and noncholesterol sterols. These serve as markers for cholesterol absorption, synthesis, and catabolism. The biliary cholesterol secretion rate is estimated. Flux data are related to body weight. Individual vegetarian diet groups are statistically compared to the omnivore group. Lacto vegetarians absorb 44% less dietary cholesterol, synthesized 22% more cholesterol, and show no differences in plasma total and LDL cholesterol. Vegan subjects absorb 90% less dietary cholesterol, synthesized 35% more cholesterol, and have a similar plasma total cholesterol, but a 13% lower plasma LDL cholesterol. No diet-related differences in biliary cholesterol secretion and absorption are observed. Total cholesterol absorption is lower only in vegans. Total cholesterol input is similar under all vegetarian diets. Unaltered biliary cholesterol secretion and higher cholesterol synthesis blunt the lowered dietary cholesterol intake in vegetarians. LDL cholesterol is significantly lower only in vegans. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Exports of crude oil, 1988

International Nuclear Information System (INIS)

1989-06-01

Effective June 1, 1985, licensing and charging of oil exports ended. The Board now issues export orders specifying neither volumes nor prices and covering an exportation period of up to 1 year for light crude oil and up to 2 years for heavy crude oil, available on request to both Canadian and foreign companies. The Board has assumed a monitoring role, and export prices and volumes are reported monthly by exporters. This annual report provides a review of the volumes and prices associated with the supply and disposition of Canadian crude oil during 1988. Highlights are given with detailed information on prices, both internationally, in Canada, and the Chicago posted price by light or heavy crude, and on volumes including capacity and disposition in both domestic and export markets. A short description of the import market is included. Comparisons are made with the previous year. Export volumes of light crude oil in 1988 increased by 13% to average 50,200 m 3 /d. Export volumes of heavy crude also increased by ca 13% to 62,600 m 3 /d. 15 figs., 2 tabs

Relative variations of gut microbiota in disordered cholesterol metabolism caused by high-cholesterol diet and host genetics.

Science.gov (United States)

Bo, Tao; Shao, Shanshan; Wu, Dongming; Niu, Shaona; Zhao, Jiajun; Gao, Ling

2017-08-01

Recent studies performed provide mechanistic insight into effects of the microbiota on cholesterol metabolism, but less focus was given to how cholesterol impacts the gut microbiota. In this study, ApoE -/- Sprague Dawley (SD) rats and their wild-type counterparts (n = 12) were, respectively, allocated for two dietary condition groups (normal chow and high-cholesterol diet). Total 16S rDNA of fecal samples were extracted and sequenced by high-throughput sequencing to determine differences in microbiome composition. Data were collected and performed diversity analysis and phylogenetic analysis. The influence of cholesterol on gut microbiota was discussed by using cholesterol dietary treatment as exogenous cholesterol disorder factor and genetic modification as endogenous metabolic disorder factor. Relative microbial variations were compared to illustrate the causality and correlation of cholesterol and gut microbiota. It turned out comparing to genetically modified rats, exogenous cholesterol intake may play more effective role in changing gut microbiota profile, although the serum cholesterol level of genetically modified rats was even higher. Relative abundance of some representative species showed that the discrepancies due to dietary variation were more obvious, whereas some low abundance species changed because of genetic disorders. Our results partially demonstrated that gut microbiota are relatively more sensitive to dietary variation. Nevertheless, considering the important effect of bacteria in cholesterol metabolism, the influence to gut flora by "genetically caused cholesterol disorder" cannot be overlooked. Manipulation of gut microbiota might be an effective target for preventing cholesterol-related metabolic disorders. © 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

In vitro fatty acid enrichment of macrophages alters inflammatory response and net cholesterol accumulation

Science.gov (United States)

Wang, Shu; Wu, Dayong; Lamon-Fava, Stefania; Matthan, Nirupa R.; Honda, Kaori L.; Lichtenstein, Alice H.

2010-01-01

Dietary long-chain PUFA, both n-3 and n-6, have unique benefits with respect to CVD risk. The aim of the present study was to determine the mechanisms by which n-3 PUFA (EPA, DHA) and n-6 PUFA (linoleic acid (LA), arachidonic acid (AA)) relative to SFA (myristic acid (MA), palmitic acid (PA)) alter markers of inflammation and cholesterol accumulation in macrophages (MΦ). Cells treated with AA and EPA elicited significantly less inflammatory response than control cells or those treated with MA, PA and LA, with intermediate effects for DHA, as indicated by lower levels of mRNA and secretion of TNFα, IL-6 and monocyte chemoattractant protein-1. Differences in cholesterol accumulation after exposure to minimally modified LDL were modest. AA and EPA resulted in significantly lower MΦ scavenger receptor 1 mRNA levels relative to control or MA-, PA-, LA- and DHA-treated cells, and ATP-binding cassette A1 mRNA levels relative to control or MA-, PA- and LA-treated cells. These data suggest changes in the rate of bidirectional cellular cholesterol flux. In summary, individual long-chain PUFA have differential effects on inflammatory response and markers of cholesterol flux in MΦ which are not related to the n position of the first double bond, chain length or degree of saturation. PMID:19660150

Cholesterol and related sterols autoxidation.

Science.gov (United States)

Zerbinati, Chiara; Iuliano, Luigi

2017-10-01

Cholesterol is a unique lipid molecule providing the building block for membranes, hormones, vitamin D and bile acid synthesis. Metabolism of cholesterol involves several enzymes acting on the sterol nucleus or the isooctyl tail. In the recent years, research interest has been focused on oxysterols, cholesterol derivatives generated by the addition of oxygen to the cholesterol backbone. Oxysterols can be produced enzymatically or by autoxidation. Autoxidation of cholesterol proceeds through type I or type II mechanisms. Type I autoxidation is initiated by free radical species, such as those arising from the superoxide/hydrogen peroxide/hydroxyl radical system. Type II autoxidation occurs stoichiometrically by non-radical highly reactive oxygen species such as singlet oxygen, HOCl, and ozone. The vulnerability of cholesterol towards high reactive species has raised considerable interest for mechanistic studies and for the potential biological activity of oxysterols, as well as for the use of oxysterols as biomarkers for the non-invasive study of oxidative stress in vivo. Copyright © 2017. Published by Elsevier Inc.

Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin

DEFF Research Database (Denmark)

Klausen, Thomas Kjaer; Hougaard, Charlotte; Hoffmann, Else K

2006-01-01

swollen cells, this reduction was prevented by cholesterol depletion, which also increased isotonic Rho activity. Thrombin, which stimulates Rho and causes actin polymerization, potentiated VRAC in modestly swollen cells. VRAC activity was unaffected by inclusion of a water-soluble PtdIns(4,5)P(2......) analogue or a PtdIns(4,5)P(2)-blocking antibody in the pipette, or neomycin treatment to sequester PtdIns(4,5)P(2). It is suggested that in ELA cells, F-actin and Rho-Rho kinase modulate VRAC magnitude and activation rate, respectively, and that cholesterol depletion potentiates VRAC at least in part......The mechanisms controlling the volume-regulated anion current (VRAC) are incompletely elucidated. Here, we investigate the modulation of VRAC by cellular cholesterol and the potential involvement of F-actin, Rho, Rho kinase, and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P(2...

Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content

Science.gov (United States)

Mundy, Dorothy I.; Li, Wei Ping; Luby-Phelps, Katherine; Anderson, Richard G. W.

2012-01-01

Caveolin-1 is an integral membrane protein of plasma membrane caveolae. Here we report that caveolin-1 collects at the cytosolic surface of lysosomal membranes when cells are serum starved. This is due to an elevation of the intralysosomal pH, since ionophores and proton pump inhibitors that dissipate the lysosomal pH gradient also trapped caveolin-1 on late endosome/lysosomes. Accumulation is both saturable and reversible. At least a portion of the caveolin-1 goes to the plasma membrane upon reversal. Several studies suggest that caveolin-1 is involved in cholesterol transport within the cell. Strikingly, we find that blocking cholesterol export from lysosomes with progesterone or U18666A or treating cells with low concentrations of cyclodextrin also caused caveolin-1 to accumulate on late endosome/lysosomal membranes. Under these conditions, however, live-cell imaging shows cavicles actively docking with lysosomes, suggesting that these structures might be involved in delivering caveolin-1. Targeting of caveolin-1 to late endosome/lysosomes is not observed normally, and the degradation rate of caveolin-1 is not altered by any of these conditions, indicating that caveolin-1 accumulation is not a consequence of blocked degradation. We conclude that caveolin-1 normally traffics to and from the cytoplasmic surface of lysosomes during intracellular cholesterol trafficking. PMID:22238363

Quebec's electricity exports

International Nuclear Information System (INIS)

Averyt, W.F.

1992-01-01

In 1987 Hydro-Quebec exported over 16 TWh to New England and New York and it plans to export 3,500 MW of firm power, not interruptible, by the early 2000s. It estimates that the northeast US market has an additional potential of 9,000 MW. The export market has become more difficult than anticipated. The federal/state regulatory framework for electricity generation was changing - it encouraged small scale generation, cogeneration and conservation which decreased demand. Demand for power imports has also been influenced by pricing judgements and avoided costs. Environmental concerns and Native protest have become increasingly important factors affecting future export sales and hence the proposed James Bay developments. Regulatory changes affecting supply and pricing, concerns about continental impacts, about further development of electrical sources together with Native requirements will further complicate the Quebec-US electricity trade. (author)

High Cholesterol in Children and Teens

Science.gov (United States)

... dairy products. The body needs some cholesterol to work properly. But if your child or teen has high cholesterol (too much cholesterol in the blood), he or she has a higher risk of coronary artery disease and other heart diseases. What causes high cholesterol in children and teens? Three main ...

Exports and Job Training

OpenAIRE

Bastos, Paulo; Silva, Joana; Proenca, Rafael

2016-01-01

This paper examines whether export participation matters for job training. The paper draws on longitudinal worker-firm data for Brazilian manufacturing, linked with detailed records on training activity from the main provider. The analysis uses industry-specific exchange rate movements to generate exogenous variation in export status at the firm-level. The findings indicate that export par...

Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages.

Science.gov (United States)

Park, Sin-Hye; Paek, Ji Hun; Shin, Daekeun; Lee, Jae-Yong; Lim, Soon Sung; Kang, Young-Hee

2015-04-01

The cellular accumulation of cholesterol is critical in the development and progression of atherosclerosis. ATP-binding cassette (ABC) transporters play an essential role in mediating the efflux of excess cholesterol. In the current study, we investigated whether purple Perilla frutescens extracts (PPE) at a non-toxic concentration of 1-10 µg/ml stimulate the induction of the ABC transporters, ABCA1 and ABCG1, and cholesterol efflux from lipid-laden J774A.1 murine macrophages exposed to 50 ng/ml oxidized low-density lipoprotein (LDL). Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects. Our results revealed that treatment with oxidized LDL for 24 h led to the accumulation of lipid droplets in the macrophages. PPE suppressed the oxidized LDL-induced foam cell formation by blocking the induction of scavenger receptor B1. However, PPE promoted the induction of the ABC transporters, ABCA1 and ABCG1, and subsequently accelerated cholesterol efflux from the lipid-loaded macrophages. The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect. PPE did not induce LXRα and PPARγ expression per se, but enhanced their expression in the macrophages exposed to oxidized LDL. α-asarone was isolated from PPE and characterized as a major component enhancing the induction of ABCA1 and ABCG1 in macrophages exposed to oxidized LDL. α-asarone, but not β-asarone was effective in attenuating foam cell formation and enhancing cholesterol efflux, revealing an isomeric difference in their activity. The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export.

Science.gov (United States)

Boehringer, Ashley; Garcia-Mansfield, Krystine; Singh, Gurkaran; Bakkar, Nadine; Pirrotte, Patrick; Bowser, Robert

2017-11-06

Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.

Histone deacetylase inhibition decreases cholesterol levels in neuronal cells by modulating key genes in cholesterol synthesis, uptake and efflux.

Directory of Open Access Journals (Sweden)

Maria João Nunes

Full Text Available Cholesterol is an essential component of the central nervous system and increasing evidence suggests an association between brain cholesterol metabolism dysfunction and the onset of neurodegenerative disorders. Interestingly, histone deacetylase inhibitors (HDACi such as trichostatin A (TSA are emerging as promising therapeutic approaches in neurodegenerative diseases, but their effect on brain cholesterol metabolism is poorly understood. We have previously demonstrated that HDACi up-regulate CYP46A1 gene transcription, a key enzyme in neuronal cholesterol homeostasis. In this study, TSA was shown to modulate the transcription of other genes involved in cholesterol metabolism in human neuroblastoma cells, namely by up-regulating genes that control cholesterol efflux and down-regulating genes involved in cholesterol synthesis and uptake, thus leading to an overall decrease in total cholesterol content. Furthermore, co-treatment with the amphipathic drug U18666A that can mimic the intracellular cholesterol accumulation observed in cells of Niemman-Pick type C patients, revealed that TSA can ameliorate the phenotype induced by pathological cholesterol accumulation, by restoring the expression of key genes involved in cholesterol synthesis, uptake and efflux and promoting lysosomal cholesterol redistribution. These results clarify the role of TSA in the modulation of neuronal cholesterol metabolism at the transcriptional level, and emphasize the idea of HDAC inhibition as a promising therapeutic tool in neurodegenerative disorders with impaired cholesterol metabolism.

Examining the role of export competitive advantages on export performance

Directory of Open Access Journals (Sweden)

Yeganeh Alimohammadi

2014-04-01

Full Text Available This paper investigates the role of export competitive advantage on export performance in food industry. The proposed study designs a questionnaire in Likert scale and distributes it among 280 randomly selected experts in food industry and Cronbach alpha has been calculated as 0.827. The study has applied factor analysis to find important factors influencing export performance. Kaiser-Meyer-Olkin Measure of Sampling Adequacy and Bartlett's Test of Sphericity have been performed to validate the results and they both validated the questionnaire. The results of the survey have determined six effective groups including product development, e-commerce, marketing planning, organizational performance, competitiveness and supply chain management.

Export incentives, exchange rate policy and export growth in Turkey

NARCIS (Netherlands)

van Wijnbergen, S.J.G.; Arslan, I.

1993-01-01

The driving forces behind the Turkish export miracle, and in fact its very existence, have remained a matter of debate We show there was a boom. As to contributing factors, import growth in the Middle East in excess of import growth elsewhere made a negative contribution. On exports to non-oil

Exports of petroleum products, 1988

International Nuclear Information System (INIS)

1989-04-01

A summary is presented of exports of motor gasoline, middle distillate, aviation turbine fuel, heavy fuel oil, and partially processed oil from Canada for the 1988 calendar year. A discussion of petroleum product imports is included in order to put exports in the context of the overall trade. Exports of the above petroleum products averaged 32,000 m 3 /d in 1988, up 44% from 1987 levels. Each product except aviation fuel registered increases in export volumes, which reached the highest total volume of the decade. The main reason for the large increase was the first full year of production from the export-directed refinery at Come By Chance, Newfoundland. Export prices for light petroleum products stayed relatively close to USA spot prices. The heavy fuel oil price was mostly above the USA east coast spot price during 1988. Attractive prices on the USA east coast resulted in a few cargoes of middle distillate and motor gasoline shipped from British Columbia. Petroleum products imports came from 12 countries; Quebec had the largest volume of imports in 1988. The USA remained Canada's largest trading partner in petroleum products. Western exporters view the Far East as an ongoing important market. The top single exporter in Canada was Newfoundland Processing, with 32% of the total export volume. 12 figs., 3 tabs

Controlling Cholesterol with Statins

Science.gov (United States)

... For Consumers Home For Consumers Consumer Updates Controlling Cholesterol with Statins Share Tweet Linkedin Pin it More ... not, the following tips can help keep your cholesterol in check: Talk with your healthcare provider about ...

Promoting exports in the energy technology area; Foerderung des Exports im Bereich der Energietechnologien

Energy Technology Data Exchange (ETDEWEB)

Iten, R.; Oettli, B. [Infras, Zuerich (Switzerland); Jochem, E.; Mannsbart, W. [Fraunhofer Institut Systemtechnik und Innovationsforschung, Karlsruhe (Germany)

2001-07-01

This report for the Swiss Federal Office of Energy (SFOE) examines the position of Switzerland as a leader in the investment goods markets for energy-efficiency products and for technologies for using renewable forms of energy. The report quotes figures for exports in these areas and discusses the difficulty of extracting useful data on these products from normal statistical data. Analyses made by a group of experts from the export-oriented technology field, energy service providers and representatives of export promotion institutions are presented and figures are quoted for various product categories. Factors promoting the competitiveness of Swiss products are discussed as well as those impeding it. An analysis of export potential is presented and measures to promote export are discussed. The report also discusses the aids and promotion activities that are considered necessary by companies in the field and the macro-economic perspectives of increased export promotion.

The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

Directory of Open Access Journals (Sweden)

Frans Stellaard

2017-01-01

Full Text Available The cholesterol balance procedure allows the calculation of cholesterol synthesis based on the assumption that loss of endogenous cholesterol via fecal excretion and bile acid synthesis is compensated by de novo synthesis. Under ezetimibe therapy hepatic cholesterol is diminished which can be compensated by hepatic de novo synthesis and hepatic extraction of plasma cholesterol. The plasma lathosterol concentration corrected for total cholesterol concentration (R_Lath as a marker of de novo cholesterol synthesis is increased during ezetimibe treatment but unchanged under treatment with ezetimibe and simvastatin. Cholesterol balance derived synthesis data increase during both therapies. We hypothesize the following. (1 The cholesterol balance data must be applied to the hepatobiliary cholesterol pool. (2 The calculated cholesterol synthesis value is the sum of hepatic de novo synthesis and the net plasma—liver cholesterol exchange rate. (3 The reduced rate of biliary cholesterol absorption is the major trigger for the regulation of hepatic cholesterol metabolism under ezetimibe treatment. Supportive experimental and literature data are presented that describe changes of cholesterol fluxes under ezetimibe, statin, and combined treatments in omnivores and vegans, link plasma R_Lath to liver function, and define hepatic de novo synthesis as target for regulation of synthesis. An ezetimibe dependent direct hepatic drug effect cannot be excluded.

Nanoscale Membrane Domain Formation Driven by Cholesterol

DEFF Research Database (Denmark)

Javanainen, Matti; Martinez-Seara, Hector; Vattulainen, Ilpo

2017-01-01

Biological membranes generate specific functions through compartmentalized regions such as cholesterol-enriched membrane nanodomains that host selected proteins. Despite the biological significance of nanodomains, details on their structure remain elusive. They cannot be observed via microscopic...... dipalmitoylphosphatidylcholine and cholesterol - the "minimal standard" for nanodomain formation. The simulations reveal how cholesterol drives the formation of fluid cholesterol-rich nanodomains hosting hexagonally packed cholesterol-poor lipid nanoclusters, both of which show registration between the membrane leaflets....... The complex nanodomain substructure forms when cholesterol positions itself in the domain boundary region. Here cholesterol can also readily flip-flop across the membrane. Most importantly, replacing cholesterol with a sterol characterized by a less asymmetric ring region impairs the emergence of nanodomains...

Preparation of cholesterol oxidase nanoparticles and their application in amperometric determination of cholesterol

Energy Technology Data Exchange (ETDEWEB)

Chawla, Sheetal; Rawal, Rachna; Sonia; Ramrati; Pundir, C. S., E-mail: pundircs@rediffmail.com [M. D. University, Department of Biochemistry (India)

2013-09-15

The nanoparticle (NP) aggregates of commercial cholesterol oxidase (ChOx) were prepared by desolvation method. The formation and characterization of ChOxNP aggregates were studied by transmission electron microscopy and scanning electron microscopy. NP aggregates were more stable, active and had a higher shelf life than that of free enzyme. An amperometric cholesterol biosensor was constructed by immobilizing ChOxNPs onto Au electrode. The biosensor showed optimum response within 8 s at pH 6.0 and 35 Degree-Sign C, when polarized at +0.27 V versus Ag/AgCl. The biosensor possesses high sensitivity and measures cholesterol concentrations as low as 1.56 mg/dl. The working linear range was 12.5-700 mg/dl for cholesterol. The biosensor was evaluated and employed for measurement of total cholesterol in human serum. The enzyme electrode lost 50 % of its initial activity during its regular use for 180 times over a period of 90 days when stored in 0.1 M sodium phosphate buffer, pH 7.0 at 4 Degree-Sign C.

Preparation of cholesterol oxidase nanoparticles and their application in amperometric determination of cholesterol

International Nuclear Information System (INIS)

Chawla, Sheetal; Rawal, Rachna; Sonia; Ramrati; Pundir, C. S.

2013-01-01

The nanoparticle (NP) aggregates of commercial cholesterol oxidase (ChOx) were prepared by desolvation method. The formation and characterization of ChOxNP aggregates were studied by transmission electron microscopy and scanning electron microscopy. NP aggregates were more stable, active and had a higher shelf life than that of free enzyme. An amperometric cholesterol biosensor was constructed by immobilizing ChOxNPs onto Au electrode. The biosensor showed optimum response within 8 s at pH 6.0 and 35 °C, when polarized at +0.27 V versus Ag/AgCl. The biosensor possesses high sensitivity and measures cholesterol concentrations as low as 1.56 mg/dl. The working linear range was 12.5–700 mg/dl for cholesterol. The biosensor was evaluated and employed for measurement of total cholesterol in human serum. The enzyme electrode lost 50 % of its initial activity during its regular use for 180 times over a period of 90 days when stored in 0.1 M sodium phosphate buffer, pH 7.0 at 4 °C

Programmed cell death in the marine cyanobacterium Trichodesmium mediates carbon and nitrogen export

Science.gov (United States)

Bar-Zeev, Edo; Avishay, Itamar; Bidle, Kay D; Berman-Frank, Ilana

2013-01-01

The extent of carbon (C) and nitrogen (N) export to the deep ocean depends upon the efficacy of the biological pump that transports primary production to depth, thereby preventing its recycling in the upper photic zone. The dinitrogen-fixing (diazotrophic) Trichodesmium spp. contributes significantly to oceanic C and N cycling by forming extensive blooms in nutrient-poor tropical and subtropical regions. These massive blooms generally collapse several days after forming, but the cellular mechanism responsible, along with the magnitude of associated C and N export processes, are as yet unknown. Here, we used a custom-made, 2-m high water column to simulate a natural bloom and to specifically test and quantify whether the programmed cell death (PCD) of Trichodesmium mechanistically regulates increased vertical flux of C and N. Our findings demonstrate that extremely rapid development and abrupt, PCD-induced demise (within 2–3 days) of Trichodesmium blooms lead to greatly elevated excretions of transparent exopolymers and a massive downward pulse of particulate organic matter. Our results mechanistically link autocatalytic PCD and bloom collapse to quantitative C and N export fluxes, suggesting that PCD may have an impact on the biological pump efficiency in the oceans. PMID:23887173

Canada's reactor exports

International Nuclear Information System (INIS)

Morrison, R.W.

1981-01-01

A brief sketch of the development of Canada's nuclear exports is presented and some of the factors which influence the ability to export reactors have been identified. The potential market for CANDUs is small and will develop slowly. The competition will be tough. There are few good prospects for immediate export orders in the next two or three years. Nonetheless there are reasonable opportunities for CANDU exports, especially in the mid-to-late 1980s. Such sales could be of great benefit to Canada and could do much to sustain the domestic nuclear industry. Apart from its excellent economic and technical performance, the main attraction of the CANDU seems to be the autonomy it confers on purchasing countries, the effectiveness with which the associated technology can be transferred, and the diversification it offers to countries which wish to reduce their dependence on the major industrial suppliers. Each sales opportunity is unique, and marketing strategy will have to be tailored to the customer's needs. Over the next decade, the factors susceptible to Canadian government action which are most likely to influence CANDU exports will be the political commitment of the government to those reactor exports, the performance established by the four 600 MWe CANDUs now nearing completion, the continuing successful operation of the nuclear program in Ontario, and the co-ordination of the different components of Canada's nuclear program (AECL, nuclear industry, utilities, and government) in putting forth a coherent marketing effort and following through with effective project management

Intracellular transport of cholesterol in mammalian cells

International Nuclear Information System (INIS)

Brasaemle, D.L.

1989-01-01

The erythrocyte was selected as a simple cell for the study of transbilayer movement of cholesterol. Cholesterol oxidase was used to measure the distribution of [ 3 H]cholesterol across the erythrocyte membrane. Cholesterol oxidase was also used to estimate the rate of transport of low density lipoprotein (LDL) cholesterol to the plasma membrane of cultured Chinese hamster ovary (CHO) fibroblasts; the half-time of this process was 42 minutes. The rate of transport of LDL cholesterol to the plasma membrane was confirmed by a second procedure using amphotericin B. Amphotericin B was also used to estimate the rate of transport of endogenously synthesized cholesterol to the plasma membrane of CHO cells. New methodology was developed including improvements of the previously published cholesterol oxidase assay for plasma membrane cholesterol. A new method for detecting transport of cholesterol to the plasma membrane in cultured cells was developed using amphotericin B. Preliminary studies investigated the use of fluorescent polyenes, pimaricin and etruscomycin, as probes for plasma membrane cholesterol in transport studies. Finally, a modification of a previously published cell staining protocol yielded a simple, quantitative assay for cell growth

Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

International Nuclear Information System (INIS)

Luo, Di-xian; Xia, Cheng-lai; Li, Jun-mu; Xiong, Yan; Yuan, Hao-yu; TANG, Zhen-Wang; Zeng, Yixin; Liao, Duan-fang

2010-01-01

Research highlights: → Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. → Static pressure induces SREBP-1 activation. → Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. → Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. → Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different static pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 ± 2.8 mg/g, 31.8 ± 0.7 mg/g, 92.3 ± 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 ± 9.4 mg/g, 235.9 ± 3.0 mg/g, 386.7 ± 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were upregulated. Conclusion: Static

Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

Energy Technology Data Exchange (ETDEWEB)

Luo, Di-xian, E-mail: luodixian_2@163.com [Department of Pharmacology, School of Pharmaceutics, Central South University, Changsha 410083, Hunan (China); Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); First People' s Hospital of Chenzhou City, Chenzhou 423000, Hunan (China); Xia, Cheng-lai [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Department of Pharmacy, Third Affiliated Hospital Medical College of Guangzhou, Guangzhou 510150, Guangdong (China); Li, Jun-mu [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Xiong, Yan [Department of Pharmacology, School of Pharmaceutics, Central South University, Changsha 410083, Hunan (China); Yuan, Hao-yu [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Lusong Center for Disease Control and Prevention, Zhuzhou 412000, Hunan (China); TANG, Zhen-Wang; Zeng, Yixin [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Liao, Duan-fang, E-mail: dfliao66@yahoo.com.cn [Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang 421001, Hunan (China); Department of Traditional Chinese Diagnostics, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 420108, Hunan (China)

2010-12-03

Research highlights: {yields} Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. {yields} Static pressure induces SREBP-1 activation. {yields} Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. {yields} Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. {yields} Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different static pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 {+-} 2.8 mg/g, 31.8 {+-} 0.7 mg/g, 92.3 {+-} 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 {+-} 9.4 mg/g, 235.9 {+-} 3.0 mg/g, 386.7 {+-} 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were

Learning by Exporting

DEFF Research Database (Denmark)

Cruz, Antonio; Newman, Carol; Rand, John

2017-01-01

In this article, we analyse the learning-by-exporting (LBE) hypothesis in the Mozambican context. Due to the presence of the ‘Born-Global’ phenomenon among exporters, we address the endogeneity introduced by self-selection, combining a generalised Blinder–Oaxaca approach with results from...

Learning by Exporting

DEFF Research Database (Denmark)

Cruz, Antonio; Newman, Carol; Rand, John

2017-01-01

In this article, we analyse the learning-by-exporting (LBE) hypothesis in the Mozambican context. Due to the presence of the ‘Born-Global’ phenomenon among exporters, we address the endogeneity introduced by self-selection, combining a generalised Blinder–Oaxaca approach with results from traditi...

Effect of Processing Methods on Cholesterol Contents and Cholesterol Oxides Formation in Some Dairy Products

International Nuclear Information System (INIS)

AlRowaily, Meshref A

2008-01-01

The effects of pasteurization, boiling, microwaving, processing and storage of milk and some locally produced dairy products on cholesterol contents and cholesterol oxides formation were studied and evaluated. The 7-ketocholesterol were not detected (ND) in all raw milk samples. On the contrary, heating of milk led to formation of cholesterol oxidation products (COPs), mostly, 7- ketocholesterol in different quantities. No significant effect of heating of milk on cholesterol level was observed with the exception of the ultra-high temperature (UHT) milk prepared from milk powder heated at 140 + - 1.0 degree C for 4 sec showed the highest value of 7-ketocholesterol (80.97 mgg-1), followed by microwave heated milk for 5 min (31.29 mgg-1), whereas the lowest value was in milk pasteurized at 85 + - 1.0 degree C for 16 sec (3.125 mgg-1). Commercial storage showed no significant effect on cholesterol and 7-ketocholestrol but lowered cholesterol concentration and increased 7-ketocholestrol level of UHT reconstituted milk. Cholesterol content of both yogurt and labaneh strained by centrifugal separator showed significant decrease while 7-ketochostrol level was increased significantly with refrigerated storage. The findings are discussed in the context with the results of previous similar studies. (author)

Cholesterol in unusual places

Energy Technology Data Exchange (ETDEWEB)

Kucerka, N; Nieh, M P; Marquardt, D; Harroun, T A; Wassail, S R; Katsaras, J, E-mail: John.Katsaras@nrc.gc.ca, E-mail: Norbert.Kucerka@nrc.gc.ca

2010-11-01

Cholesterol is an essential component of mammalian cells, and is required for building and maintaining cell membranes, regulating their fluidity, and possibly acting as an antioxidant. Cholesterol has also been implicated in cell signaling processes, where it has been suggested that it triggers the formation of lipid rafts in the plasma membrane. Aside from cholesterol's physiological roles, what is also becoming clear is its poor affinity for lipids with unsaturated fatty acids as opposed to saturated lipids, such as sphingomyelin with which it forms rafts. We previously reported the location of cholesterol in membranes with varying degrees of acyl chain unsaturation as determined by neutron diffraction studies (Harroun et al 2006 Biochemistry 45, 1227; Harroun et al 2008 Biochemistry 47, 7090). In bilayers composed of phosphatidylcholine (PC) molecules with a saturated acyl chain at the sn-1 position or a monounsaturated acyl chain at both sn-1 and sn-2 positions, cholesterol was found in its much-accepted 'upright' position. However, in dipolyunsaturated 1,2-diarachidonyl phosphatidylcholine (20:4-20:4PC) membranes the molecule was found sequestered in the center of the bilayers. In further experiments, mixing l-palmitoyl-2-oleoyl phosphatidylcholine (16:0-18:1 PC) with 20:4-20:4PC resulted in cholesterol reverting to its upright orientation at approximately 40 mol% 16:0-18:1 PC. Interestingly, the same effect was achieved with only 5 mol% 1,2-dimyristoyl phosphatidylchoile (14:0-14:0PC).

Cholesterol in unusual places

International Nuclear Information System (INIS)

Kucerka, N; Nieh, M P; Marquardt, D; Harroun, T A; Wassail, S R; Katsaras, J

2010-01-01

Cholesterol is an essential component of mammalian cells, and is required for building and maintaining cell membranes, regulating their fluidity, and possibly acting as an antioxidant. Cholesterol has also been implicated in cell signaling processes, where it has been suggested that it triggers the formation of lipid rafts in the plasma membrane. Aside from cholesterol's physiological roles, what is also becoming clear is its poor affinity for lipids with unsaturated fatty acids as opposed to saturated lipids, such as sphingomyelin with which it forms rafts. We previously reported the location of cholesterol in membranes with varying degrees of acyl chain unsaturation as determined by neutron diffraction studies (Harroun et al 2006 Biochemistry 45, 1227; Harroun et al 2008 Biochemistry 47, 7090). In bilayers composed of phosphatidylcholine (PC) molecules with a saturated acyl chain at the sn-1 position or a monounsaturated acyl chain at both sn-1 and sn-2 positions, cholesterol was found in its much-accepted 'upright' position. However, in dipolyunsaturated 1,2-diarachidonyl phosphatidylcholine (20:4-20:4PC) membranes the molecule was found sequestered in the center of the bilayers. In further experiments, mixing l-palmitoyl-2-oleoyl phosphatidylcholine (16:0-18:1 PC) with 20:4-20:4PC resulted in cholesterol reverting to its upright orientation at approximately 40 mol% 16:0-18:1 PC. Interestingly, the same effect was achieved with only 5 mol% 1,2-dimyristoyl phosphatidylchoile (14:0-14:0PC).

[Cholesterol reducing food certainly is useful].

Science.gov (United States)

Stalenhoef, A F

1997-12-27

The effect of a low-cholesterol diet in open intervention studies depends in the long run on motivation, knowledge and dedication. The mean decrease of the serum cholesterol level is 10% (range: 0-20). Epidemiological and cohort studies clearly prove a connection between the intake of saturated fat, the serum cholesterol level and the risk of coronary heart disease and death. High-fat food slows down the clearance of the degradation products rich in cholesterol which appear in the blood after a meal and which are highly atherogenic (these products are not found at a fasting cholesterol assay). Cholesterol-reducing nutrition has additional useful effects, for instance on the blood pressure and the coagulation. The recommendations for healthy, low-cholesterol nutrition for the population as a whole apply particularly to patients with a high risk of coronary heart disease. Although advice given to individuals often has a disappointing effect, influencing the life pattern should be included in the strategy to reduce the risk of coronary heart disease.

Hierarchical protein export mechanism of the bacterial flagellar type III protein export apparatus.

Science.gov (United States)

Minamino, Tohru

2018-06-01

The bacterial flagellum is supramolecular motility machinery consisting of the basal body, the hook and the filament. Flagellar proteins are translocated across the cytoplasmic membrane via a type III protein export apparatus, diffuse down the central channel of the growing structure and assemble at the distal end. Flagellar assembly begins with the basal body, followed by the hook and finally the filament. The completion of hook assembly is the most important morphological checkpoint of the sequential flagellar assembly process. When the hook reaches its mature length of about 55 nm in Salmonella enterica, the type III protein export apparatus switches export specificity from proteins required for the structure and assembly of the hook to those responsible for filament assembly, thereby terminating hook assembly and initiating filament assembly. Three flagellar proteins, namely FliK, FlhB and FlhA, are responsible for this substrate specificity switching. Upon completion of the switching event, interactions among FlhA, the cytoplasmic ATPase complex and flagellar type III export chaperones establish the assembly order of the filament at the hook tip. Here, we describe our current understanding of a hierarchical protein export mechanism used in flagellar type III protein export.

Estimating the contribution of strong daily export events to total pollutant export from the United States in summer

Science.gov (United States)

Fang, Yuanyuan; Fiore, Arlene M.; Horowitz, Larry W.; Gnanadesikan, Anand; Levy, Hiram; Hu, Yongtao; Russell, Armistead G.

2009-12-01

While the export of pollutants from the United States exhibits notable variability from day to day and is often considered to be "episodic," the contribution of strong daily export events to total export has not been quantified. We use carbon monoxide (CO) as a tracer of anthropogenic pollutants in the Model of OZone And Related Tracers (MOZART) to estimate this contribution. We first identify the major export pathway from the United States to be through the northeast boundary (24-48°N along 67.5°W and 80-67.5°W along 48°N), and then analyze 15 summers of daily CO export fluxes through this boundary. These daily CO export fluxes have a nearly Gaussian distribution with a mean of 1100 Gg CO day-1 and a standard deviation of 490 Gg CO day-1. To focus on the synoptic variability, we define a "synoptic background" export flux equal to the 15 day moving average export flux and classify strong export days according to their fluxes relative to this background. As expected from Gaussian statistics, 16% of summer days are "strong export days," classified as those days when the CO export flux exceeds the synoptic background by one standard deviation or more. Strong export days contributes 25% to the total export, a value determined by the relative standard deviation of the CO flux distribution. Regressing the anomalies of the CO export flux through the northeast U.S. boundary relative to the synoptic background on the daily anomalies in the surface pressure field (also relative to a 15 day running mean) suggests that strong daily export fluxes are correlated with passages of midlatitude cyclones over the Gulf of Saint Lawrence. The associated cyclonic circulation and Warm Conveyor Belts (WCBs) that lift surface pollutants over the northeastern United States have been shown previously to be associated with long-range transport events. Comparison with observations from the 2004 INTEX-NA field campaign confirms that our model captures the observed enhancements in CO outflow

Markups and Firm-Level Export Status

DEFF Research Database (Denmark)

De Loecker, Jan; Warzynski, Frederic

and export behavior using plant-level data. We find that i) markups are estimated significantly higher when controlling for unobserved productivity, ii) exporters charge on average higher markups and iii) firms' markups increase (decrease) upon export entry (exit).We see these findings as a first step...... in opening up the productivity-export black box, and provide a potential explanation for the big measured productivity premia for firms entering export markets....

Foreign Direct Investment and Electronics Exports: Exploratory Empirical Evidence from Malaysia's Top Five Electronics Exports

OpenAIRE

Tuck Cheong Tang; Koi Nyen Wong

2007-01-01

The foreign direct investment (FDI) has contributed significantly to Malaysia's electronics exports as well as the growth and development of the electronics industry as a result of the export-oriented industrialization initiatives undertaken since 1970s. The aim of this study is to explore the causation between FDI and electronics exports by using Malaysia''s top five electronics exports by SITC (Standard International Trade Classification) product groups. The findings show a bi-directional c...

Indonesian coal export potential

International Nuclear Information System (INIS)

Millsteed, Ch.; Jolly, L.; Stuart, R.

1993-01-01

Indonesia's coal mining sector is expanding rapidly. Much of the increase in coal production since the mid-1980s has been exported. Indonesian coal mining companies have large expansion programs and continuing strong export growth is projected for the remainder of the 1990s. The low mining costs of indonesian coal, together with proximity to Asian markets, mean that Indonesia is well placed to compete strongly with other thermal coal exporters and win market share in the large and expanding thermal coal market in Asia. However, there is significant uncertainty about the likely future level of Indonesia's exportable surplus of coal. The government's planned expansion in coal fired power generation could constrain export growth, while the ability of producers to meet projected output levels is uncertain. The purpose in this article is to review coal supply and demand developments in Indonesia and, taking account of the key determining factors, to estimate the level of coal exports from Indonesia to the year 2000. This time frame has been chosen because all currently committed mine developments are expected to be on stream by 2000 and because it is difficult to project domestic demand for coal beyond that year. 29 refs., 8 tabs., 7 figs

Nuclear export controls - Closing the gaps

International Nuclear Information System (INIS)

Schmidt, Fritz W.

2005-01-01

Concerns over a nuclear 'black market' have focused international attention on the effectiveness of nuclear export controls. IAEA Director General Mohamed ElBaradei has stated that the emergence of a multinational illicit network demonstrated the inadequacy of the present export control system, that international cooperation on export controls lay on informal arrangements that were not only not binding but also limited in membership, and that export control information was not systematically shared with the IAEA. This criticism, often heard on the political level, does not really do justice to the work of export control groups. The emergence of a multinational illicit network does not necessarily prove failures in export control systems. Criminal activities, by definition, try to circumvent existing rules and regulations, or they exploit the absence of such rules on State level. To fight such individual cases is not so much a task of regular export control systems, whose function lies primarily in establishing standards and procedures for export controls on State level, but rather the task for intelligence services and their international cooperation. The basis of the export control regime is the Nuclear Non-Proliferation Treaty (NPT). Export controls can - and do - play an important role in fostering this universality goal by demanding the implementation of internationally agreed security standards in recipient countries before export licenses are granted. Drawn from the deliberations in the NPT conferences, the current standards to be demanded as conditions of supply are the following: Safeguards, Physical Protection, National export control provisions. According to the NPT system, export controls require IAEA verification in the recipient country. In addition, export controls enable States to provide information to the IAEA on exports and imports as required by the Additional Protocol. The 2005 NPT Review Conference will be an opportunity to review developments

The expression of cholesterol metabolism genes in monocytes from HIV-infected subjects suggests intracellular cholesterol accumulation.

Science.gov (United States)

Feeney, Eoin R; McAuley, Nuala; O'Halloran, Jane A; Rock, Clare; Low, Justin; Satchell, Claudette S; Lambert, John S; Sheehan, Gerald J; Mallon, Patrick W G

2013-02-15

Human immunodeficiency virus (HIV) infection is associated with increased cardiovascular risk and reduced high-density lipoprotein cholesterol (HDL-c). In vitro, HIV impairs monocyte-macrophage cholesterol efflux, a major determinant of circulating HDL-c, by increasing ABCA1 degradation, with compensatory upregulation of ABCA1 messenger RNA (mRNA). We examined expression of genes involved in cholesterol uptake, metabolism, and efflux in monocytes from 22 HIV-positive subjects on antiretroviral therapy (ART-Treated), 30 untreated HIV-positive subjects (ART-Naive), and 22 HIV-negative controls (HIV-Neg). HDL-c was lower and expression of ABCA1 mRNA was higher in ART-Naive subjects than in both ART-Treated and HIV-Neg subjects (both P ART-Treated and ART-Naive subjects than in HIV-Neg controls. In vivo, increased monocyte ABCA1 expression in untreated HIV-infected patients and normalization of ABCA1 expression with virological suppression by ART supports direct HIV-induced impairment of cholesterol efflux previously demonstrated in vitro. However, decreased expression of cholesterol sensing, uptake, and synthesis genes in both untreated and treated HIV infection suggests that both HIV and ART affect monocyte cholesterol metabolism in a pattern consistent with accumulation of intramonocyte cholesterol.

Identification of an exported heat shock protein 70 in Plasmodium falciparum

Directory of Open Access Journals (Sweden)

Grover Manish

2013-01-01

Full Text Available Host cell remodelling is a hallmark of malaria pathogenesis. It involves protein folding, unfolding and trafficking events and thus participation of chaperones such as Hsp70s and Hsp40s is well speculated. Until recently, only Hsp40s were thought to be the sole representative of the parasite chaperones in the exportome. However, based on the re-annotated Plasmodium falciparum genome sequence, a putative candidate for exported Hsp70 has been reported, which otherwise was known to be a pseudogene. We raised a specific antiserum against a C-terminal peptide uniquely present in PfHsp70-x. Immunoblotting and immunofluorescence-based approaches in combination with sub-cellular fractionation by saponin and streptolysin-O have been taken to determine the expression and localization of PfHsp70-x in infected erythrocyte. The re-annotated sequence of PfHsp70-x reveals it to be a functional protein with an endoplasmic reticulum signal peptide. It gets maximally expressed at the schizont stage of intra-erythrocytic life cycle. Majority of the protein localizes to the parasitophorous vacuole and some of it gets exported to the erythrocyte compartment where it associates with Maurer’s clefts. The identification of an exported parasite Hsp70 chaperone presents us with the fact that the parasite has evolved customized chaperones which might be playing crucial roles in aspects of trafficking and host cell remodelling.

A Study on Improvement of Export Control law's understanding for nuclear control items' exporters in Rep. of Korea

International Nuclear Information System (INIS)

Lim, Dong Hyuk; Choi, Sun Do; Yang, Seung Hyo

2011-01-01

According to export of UAE commercial reactor and JRTR(Jordan Research and Training Reactor) in 2009, Korea's international prestige has enhanced and it has been more important for researcher in charge of export control to understand and carry out duties on export control by obeying Nuclear Suppliers Group(NSG) Guidelines. Currently, the NSG tries to prevent the proliferation of nuclear weapons by harmonising export control systems of participating countries in relation to trade with nuclear commodities and nuclear-related dual-use materials, equipment, software and technology. In addition, through the implementation of two sets of Guidelines for nuclear exports and nuclear-related exports, the NSG aims to ensure that nuclear trade for peaceful purposes does not contribute to the proliferation of nuclear weapons or other nuclear explosive devices, and that international trade and cooperation in the nuclear field is not hindered unjustly in the process. However, there is still not a little confusion of export businesses owing to lack of understanding of nuclear items in Korea. Therefore, by correctly understanding export control systems, permits and licenses, ITT and persistingly communicating with export businesses, Researchers in charge of export control are able to eliminate confusion of production businesses regarding export and establish a export control culture

Phases definition in marketing export process

OpenAIRE

Rajković Dragan; Kokić Miljko

2004-01-01

The result of export marketing process depends on its five phases. The first phase-revision of export capacities, inner view on advantages and defects of company concerning export possibilities. The second phase-identification of export strategy market penetration. The forth phase-preparing for the marketing campaign (action). The fifth phase-carrying out the above mentioned activities. This study shows the structure and contents of the mentioned phases. At the end, export marketing analyzed ...

Determinants of Short-Term Export Performance in Pakistan

OpenAIRE

Subhani, Muhammad Imtiaz; Osman, Ms.Amber; Habib, Sukaina

2010-01-01

This research investigates the interdependency between independent (Increase of pricing strategy adaptation, Increase of export intensity, Firm's commitment to exporting, Export market development, Export market competition, Past Pricing Strategy Adaptation, Past Export Performance Satisfaction, Past Export Intensity, Export market distance) and dependent variables (i.e. Expected Short-Term Export Performance improvement) of export performance. The framework is tested via a survey through que...

7 CFR 923.15 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 923.15 Section 923.15 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... IN WASHINGTON Order Regulating Handling Definitions § 923.15 Export. Export means to ship cherries...

7 CFR 958.14 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 958.14 Section 958.14 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... IN IDAHO, AND MALHEUR COUNTY, OREGON Order Regulating Handling Definitions § 958.14 Export. Export...

Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

Directory of Open Access Journals (Sweden)

Ye J

2016-08-01

Full Text Available Jun Ye,1,2 Xuejun Xia,1,2 Wujun Dong,1,2 Huazhen Hao,1,2 Luhua Meng,1,2 Yanfang Yang,1,2 Renyun Wang,1,2 Yuanfeng Lyu,3 Yuling Liu1,2 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 3School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: There is no effective clinical therapy for triple-negative breast cancers (TNBCs, which have high low-density lipoprotein (LDL requirements and express relatively high levels of LDL receptors (LDLRs on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel–cholesterol complex (PTX-CH Emul was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231 and non-TNBC (MCF7 cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native

27 CFR 28.30 - Export status.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Export status. 28.30... Export status. (a) Distilled spirits and wines manufactured, produced, bottled in bottles packed in... such purposes are considered to be exported. Export status is not acquired until application on Form...

76 FR 54193 - Fiscal Year 2012 Veterinary Import/Export, Diagnostic Services, and Export Certification for...

Science.gov (United States)

2011-08-31

...] Fiscal Year 2012 Veterinary Import/Export, Diagnostic Services, and Export Certification for Plants and.... SUMMARY: This notice pertains to user fees charged for Veterinary Services animal quarantine and other..., organisms, and vectors; for certain veterinary diagnostic services; and for export certification of plants...

Interactions between an anticancer drug - edelfosine - and cholesterol in Langmuir monolayers

International Nuclear Information System (INIS)

Wiecek, Agata; Dynarowicz-Latka, Patrycja; Minones, J.; Conde, Olga; Casas, Matilde

2008-01-01

Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, abbr. Et-18-OCH 3 ) is a new generation anticancer drug based on a phospholipids-like structure. Since its mechanism of action is believed to be related to the lipids of cellular membrane, we have investigated the interactions between edelfosine and main mammalian sterol: cholesterol, using the Langmuir monolayer technique. The interactions have been analyzed by comparing the experimental curves with theoretical ones, obtained basing on the additivity rule. The observed contraction together with negative deviations from ideality observed on the mean molecular area (A 12 ) vs film composition plots proves the existence of strong attractive forces between edelfosine and cholesterol, which have been quantified with the excess free energy of mixing (ΔG exc ) values, calculated from the surface pressure-area isotherms datapoints. The most negative values of ΔG exc have been found for the mixture of equimolar composition, proving its highest thermodynamic stability and the existence of the strongest interactions between film components. Thus, it has been postulated that at the surface edelfosine and cholesterol form stable complexes of 1:1 stoichiometry. The analysis of the collapse pressure values for the investigated mixed monolayers proves that films of edelfosine mole fraction ≤ 0.5 are miscible within the whole range of surface pressures, while monolayers richer in edelfosine mix in the pressure region below ca. 37.6 mN/m, which corresponds to the collapse of pure edelfosine monolayer. At this very surface pressure, edelfosine is expelled from the mixed monolayer and the remaining film is composed by surface complexes of high stability. The hypothesis of complex formation explains the results performed in vitro on cell cultures, indicating that the increase of cholesterol content significantly reduces the uptake of edelfosine

Cholesterol trafficking and raft-like membrane domain composition mediate scavenger receptor class B type 1-dependent lipid sensing in intestinal epithelial cells.

Science.gov (United States)

Morel, Etienne; Ghezzal, Sara; Lucchi, Géraldine; Truntzer, Caroline; Pais de Barros, Jean-Paul; Simon-Plas, Françoise; Demignot, Sylvie; Mineo, Chieko; Shaul, Philip W; Leturque, Armelle; Rousset, Monique; Carrière, Véronique

2018-02-01

Scavenger receptor Class B type 1 (SR-B1) is a lipid transporter and sensor. In intestinal epithelial cells, SR-B1-dependent lipid sensing is associated with SR-B1 recruitment in raft-like/ detergent-resistant membrane domains and interaction of its C-terminal transmembrane domain with plasma membrane cholesterol. To clarify the initiating events occurring during lipid sensing by SR-B1, we analyzed cholesterol trafficking and raft-like domain composition in intestinal epithelial cells expressing wild-type SR-B1 or the mutated form SR-B1-Q445A, defective in membrane cholesterol binding and signal initiation. These features of SR-B1 were found to influence both apical cholesterol efflux and intracellular cholesterol trafficking from plasma membrane to lipid droplets, and the lipid composition of raft-like domains. Lipidomic analysis revealed likely participation of d18:0/16:0 sphingomyelin and 16:0/0:0 lysophosphatidylethanolamine in lipid sensing by SR-B1. Proteomic analysis identified proteins, whose abundance changed in raft-like domains during lipid sensing, and these included molecules linked to lipid raft dynamics and signal transduction. These findings provide new insights into the role of SR-B1 in cellular cholesterol homeostasis and suggest molecular links between SR-B1-dependent lipid sensing and cell cholesterol and lipid droplet dynamics. Copyright © 2017 Elsevier B.V. All rights reserved.

RNA Export through the NPC in Eukaryotes.

Science.gov (United States)

Okamura, Masumi; Inose, Haruko; Masuda, Seiji

2015-03-20

In eukaryotic cells, RNAs are transcribed in the nucleus and exported to the cytoplasm through the nuclear pore complex. The RNA molecules that are exported from the nucleus into the cytoplasm include messenger RNAs (mRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), micro RNAs (miRNAs), and viral mRNAs. Each RNA is transported by a specific nuclear export receptor. It is believed that most of the mRNAs are exported by Nxf1 (Mex67 in yeast), whereas rRNAs, snRNAs, and a certain subset of mRNAs are exported in a Crm1/Xpo1-dependent manner. tRNAs and miRNAs are exported by Xpot and Xpo5. However, multiple export receptors are involved in the export of some RNAs, such as 60S ribosomal subunit. In addition to these export receptors, some adapter proteins are required to export RNAs. The RNA export system of eukaryotic cells is also used by several types of RNA virus that depend on the machineries of the host cell in the nucleus for replication of their genome, therefore this review describes the RNA export system of two representative viruses. We also discuss the NPC anchoring-dependent mRNA export factors that directly recruit specific genes to the NPC.

7 CFR 945.14 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 945.14 Section 945.14 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... COUNTIES IN IDAHO, AND MALHEUR COUNTY, OREGON Order Regulating Handling Definitions § 945.14 Export. Export...

7 CFR 948.17 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 948.17 Section 948.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... Regulating Handling Definitions § 948.17 Export. Export means the shipment of potatoes to any destination...

7 CFR 915.12 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 915.12 Section 915.12 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... Regulating Handling Definitions § 915.12 Export. Export means to ship avocados to any destination which is...

7 CFR 922.15 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 922.15 Section 922.15 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... WASHINGTON Order Regulating Handling Definitions § 922.15 Export. Export means to ship apricots beyond the...

7 CFR 946.15 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 946.15 Section 946.15 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... Regulating Handling Definitions § 946.15 Export. Export means shipment of potatoes beyond the boundaries of...

7 CFR 966.18 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 966.18 Section 966.18 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... Handling Definitions § 966.18 Export. Export means shipment of tomatoes beyond the boundaries of the 48...

7 CFR 924.15 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 924.15 Section 924.15 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... WASHINGTON AND IN UMATILLA COUNTY, OREGON Order Regulating Handling Definitions § 924.15 Export. Export means...

7 CFR 947.17 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 947.17 Section 947.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... Definitions § 947.17 Export. Export means shipment of potatoes beyond the boundaries of continental United...

Niacin to Boost Your HDL "Good" Cholesterol

Science.gov (United States)

Niacin can boost 'good' cholesterol Niacin is a B vitamin that may raise your HDL ("good") cholesterol. But side effects might outweigh benefits for most ... been used to increase high-density lipoprotein (HDL) cholesterol — the "good" cholesterol that helps remove low-density ...

Nanomolar Cellular Antisense Activity of Peptide Nucleic Acid (PNA) Cholic Acid ("Umbrella") and Cholesterol Conjugates Delivered by Cationic Lipids

DEFF Research Database (Denmark)

Shiraishi, Takehiko; Nielsen, Peter E

2012-01-01

of cholesterol and cholic acid ("umbrella") derivatives of splice correction antisense PNA oligomers. While the conjugates alone were practically inactive up to 1 µM, their activity was dramatically improved when delivered by a cationic lipid transfection agent (LipofectAMINE2000). In particular, PNAs...

The nucleolus directly regulates p53 export and degradation.

Science.gov (United States)

Boyd, Mark T; Vlatkovic, Nikolina; Rubbi, Carlos P

2011-09-05

The correlation between stress-induced nucleolar disruption and abrogation of p53 degradation is evident after a wide variety of cellular stresses. This link may be caused by steps in p53 regulation occurring in nucleoli, as suggested by some biochemical evidence. Alternatively, nucleolar disruption also causes redistribution of nucleolar proteins, potentially altering their interactions with p53 and/or MDM2. This raises the fundamental question of whether the nucleolus controls p53 directly, i.e., as a site where p53 regulatory processes occur, or indirectly, i.e., by determining the cellular localization of p53/MDM2-interacting factors. In this work, transport experiments based on heterokaryons, photobleaching, and micronucleation demonstrate that p53 regulatory events are directly regulated by nucleoli and are dependent on intact nucleolar structure and function. Subcellular fractionation and nucleolar isolation revealed a distribution of ubiquitylated p53 that supports these findings. In addition, our results indicate that p53 is exported by two pathways: one stress sensitive and one stress insensitive, the latter being regulated by activities present in the nucleolus.

Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function.

Science.gov (United States)

Lopez, Adam M; Jones, Ryan Dale; Repa, Joyce J; Turley, Stephen D

2018-06-07

Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase 1 (SOAT1) or sterol O-acyltransferase 2 (SOAT2) in various cell types, and lecithin cholesterol acyltransferase (LCAT) in plasma. Esterified cholesterol (EC) and triacylglycerol (TAG) contained in lipoproteins cleared from the circulation via receptor-mediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase (LAL) within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C2 (NPC2) and Niemann-Pick C1 (NPC1), unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7 wk-old mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1:SOAT2 double knockouts, compared to their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma ALT and AST activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency.

Coal exports still growing

International Nuclear Information System (INIS)

Blain, M.

1998-01-01

It is shown that the swings and roundabouts of the Asian economic shake out and Australian dollar devaluation are starting to work their way through the Australian export coal market. Perhaps somewhat surprisingly, at this stage the results are not proving to be as bad as were at first predicted by some market watchers. Export revenue and tonnages are up 12% for the year to July 98. Coal exports totaling $9.5 billion left Australia's shores in the 12 months confirming coal as Australia's single largest export revenue earner. Sales volumes in the present financial year are still increasing, the market being driven by steadily increasing Asian demand for steaming coal from places like Korea, Malaysia, Thailand and the Philippines

Localization of the placental BCRP/ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity.

Science.gov (United States)

Szilagyi, John T; Vetrano, Anna M; Laskin, Jeffrey D; Aleksunes, Lauren M

2017-07-01

The breast cancer resistance protein (BCRP/ABCG2) is an efflux transporter in the placental barrier. By transporting chemicals from the fetal to the maternal circulation, BCRP limits fetal exposure to a range of drugs, toxicants, and endobiotics such as bile acids and hormones. The purpose of the present studies was to 1) determine whether BCRP localizes to highly-ordered, cholesterol-rich lipid raft microdomains in placenta microvillous membranes, and 2) determine the impact of cholesterol on BCRP-mediated placental transport in vitro. BCRP expression was analyzed in lipid rafts isolated from placentas from healthy, term pregnancies and BeWo trophoblasts by density gradient ultracentrifugation. BeWo cells were also tested for their ability to efflux BCRP substrates after treatment with the cholesterol sequestrant methyl-β-cyclodextrin (MβCD, 5 mM, 1 h) or the cholesterol synthesis inhibitor pravastatin (200 μM, 48 h). BCRP was found to co-localize with lipid raft proteins in detergent-resistant, lipid raft-containing fractions from placental microvillous membranes and BeWo cells. Treatment of BeWo cells with MβCD redistributed BCRP protein into higher density non-lipid raft fractions. Repletion of the cells with cholesterol restored BCRP localization to lipid raft-containing fractions. Treatment of BeWo cells with MβCD or pravastatin increased cellular retention of two BCRP substrates, the fluorescent dye Hoechst 33342 and the mycotoxin zearalenone. Repletion with cholesterol restored BCRP transporter activity. Taken together, these data demonstrate that cholesterol may play a critical role in the post-translational regulation of BCRP in placental lipid rafts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Export of radiopharmaceuticals and establishment of export base of cyclotron

International Nuclear Information System (INIS)

Jung, Kyungil; Kim, Youngsik

2006-01-01

Sam young Unit ech has seized an opportunity to advance into the radiopharmaceuticals market through successful transfer of radiopharmaceuticals manufacturing technology and medical cyclotron, an original technology in nuclear medicine that is the core of less developed areas in nuclear-related fields. The company has continued to push for research development and establishment of market base through industry-academia-research center cooperation with an aim to complement relatively less developed domestic technology and market than in advanced countries, and is making efforts to establish export base in the overseas market based on stabilized supply in the domestic market. As for radiopharmaceuticals, the company is exporting Tc-99m generator to Vietnam, Thailand and the Philippines and preparing itself to export manufacture facilities for Tc-99m generator to Syria and Kazakhstan. In addition, it plans to export 13Mev Cyclotron that has been commercialized after being developed in the domestic market to the U. S. The company plans to grow up to play a pivotal role in the domestic RT area by conducting proactive business activities with an aim to revitalize the domestic market and further domestic original technologies and products in the global market

7 CFR 959.18 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export. 959.18 Section 959.18 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and... Handling Definitions § 959.18 Export. Export means to ship onions to any destination which is not within...

NEW APPROACHES TO EXPORT COMPETITIVENESS

Directory of Open Access Journals (Sweden)

Alina Petronela NEGREA

2015-04-01

Full Text Available The economic literature and the political discourse typically look at international competitiveness mainly by the means of export market shares. However, globalisation, production fragmentation and the growing importance of global value chains (GVCs increasingly challenge traditional approaches of export competitiveness and call for a more accurate and disaggregated level of analysis. Due to the growing fragmentation of production, a country exports now include a significant amount of imports of intermediate goods which are part of the export value. In this case, a simple analysis of the evolution of exports can distort the international competitive position of a country. The article suggests a new approach based on the value-added content of international trade measured by means of global value chain analysis.

Phases definition in marketing export process

Directory of Open Access Journals (Sweden)

Rajković Dragan

2004-01-01

Full Text Available The result of export marketing process depends on its five phases. The first phase-revision of export capacities, inner view on advantages and defects of company concerning export possibilities. The second phase-identification of export strategy market penetration. The forth phase-preparing for the marketing campaign (action. The fifth phase-carrying out the above mentioned activities. This study shows the structure and contents of the mentioned phases. At the end, export marketing analyzed DPV is given as the example.

Intestinal cholesterol secretion : future clinical implications

NARCIS (Netherlands)

Jakulj, L.; Besseling, J.; Stroes, E. S. G.; Groen, A. K.

2013-01-01

Together with the liver, the intestine serves as a homeostatic organ in cholesterol metabolism. Recent evidence has substantiated the pivotal role of the intestine in reverse cholesterol transport (RCT). RCT is a fundamental antiatherogenic pathway, mediating the removal of cholesterol from tissues

Intestinal cholesterol secretion: future clinical implications

NARCIS (Netherlands)

Jakulj, L.; Besseling, J.; Stroes, E. S. G.; Groen, A. K.

2013-01-01

Together with the liver, the intestine serves as a homeostatic organ in cholesterol metabolism. Recent evidence has substantiated the pivotal role of the intestine in reverse cholesterol transport (RCT). RCT is a fundamental antiatherogenic pathway, mediating the removal of cholesterol from tissues

DIETARY-CHOLESTEROL INDUCED DOWN-REGULATION OF INTESTINAL 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE-ACTIVITY IS DIMINISHED IN RABBITS WITH HYPERRESPONSE OF SERUM-CHOLESTEROL TO DIETARY-CHOLESTEROL

NARCIS (Netherlands)

MEIJER, GW; SMIT, MJ; VANDERPALEN, JGP; KUIPERS, F; VONK, RJ; VANZUTPHEN, BFM; BEYNEN, AC

Key enzymes of cholesterol metabolism were studied in two inbred strains of rabbits with hyper- or hyporesponse of serum cholesterol to dietary cholesterol. Baseline 3-hydroxy-3-methylglutaryl (HMG)CoA reductase activity in liver was similar in hypo- and hyperresponders, but that in intestine was

Dietary cholesterol and fats at a young age : do they influence cholesterol metabolism in adult life?

NARCIS (Netherlands)

Temmerman, A.M.; Vonk, R.J.; Niezen-Koning, K.; Berger, R.; Fernandes, J.

1989-01-01

The effects of dietary cholesterol and fats on cholesterol metabolism later in life were studied in Mongolian gerbils. Three groups were given a basic diet with soybean oil, palm kernel oil amounting to 8.75% (w/w), or the basic diet only. In three other groups, cholesterol (0.05%) was added to the

Imaging appearances of cholesterol pneumonia

International Nuclear Information System (INIS)

Miao Yanwei; Zhang Jingwen; Wu Jianlin; Zhou Yong; Li Mingwu; Lei Zhen; Shi Lifu

2006-01-01

Objection: To analyze the imaging appearances of cholesterol pneumonia. Methods We retrospectively analyzed the X-ray and CT findings of 3 patients with cholesterol pneumonia confirmed pathologically and reviewed correlative literature. Results: Lesions similar to mass were found in X-ray and CT imaging of three cases. Two of them appeared cavity with fluid-level and one showed multiple ring enhancement after CT contrast. The course of disease was very. long and it had no respond to antibiotic therapy. Amounts of foam cells rich in cholesterol crystal were detected in pathological examination. Conclusions: Cholesterol pneumonia is a rare chronic pulmonary idiopathic disease, and the radiological findings can do some help to its diagnosis. (authors)

Firm-level volatility and exports

NARCIS (Netherlands)

Vannoorenberghe, G.C.L.

2012-01-01

This paper shows that the share of exports in the total sales of a firm has a positive and substantial impact on the volatility of its sales. Decomposing the volatility of sales of exporters between their domestic and export markets, I show using an identification strategy based on a firm-specific

The anatomy of China's export growth

OpenAIRE

Amiti, Mary; Freund, Caroline

2008-01-01

Decomposing China's real export growth, of over 500 percent since 1992, reveals a number of interesting findings. First, China's export structure changed dramatically, with growing export shares in electronics and machinery and a decline in agriculture and apparel. Second, despite the shift into these more sophisticated products, the skill content of China's manufacturing exports remained ...

E-business and small Ghanaian exporters

DEFF Research Database (Denmark)

Hinson, Robert; Sørensen, Olav Jull

2006-01-01

The arfticle aims to investigate the relationship between export intensity and e-business adoption in Ghana. No clear relationship is found among exporters of non-traditional items.......The arfticle aims to investigate the relationship between export intensity and e-business adoption in Ghana. No clear relationship is found among exporters of non-traditional items....

Markups and Firm-Level Export Status

DEFF Research Database (Denmark)

De Loecker, Jan; Warzynski, Frederic

We derive an estimating equation to estimate markups using the insight of Hall (1986) and the control function approach of Olley and Pakes (1996). We rely on our method to explore the relationship between markups and export behavior using plant-level data. We find significantly higher markups when...... we control for unobserved productivity shocks. Furthermore, we find significant higher markups for exporting firms and present new evidence on markup-export status dynamics. More specifically, we find that firms' markups significantly increase (decrease) after entering (exiting) export markets. We...... see these results as a first step in opening up the productivity-export black box, and provide a potential explanation for the big measured productivity premia for firms entering export markets....

75 FR 44761 - Export Trade Certificate of Review

Science.gov (United States)

2010-07-29

... sales prices and/or minimum target sales prices, and other terms of sales in the Export Markets... canned salmon in the Export Markets, selling strategies for the Export Markets, sales for the Export... described below for the following Export Trade and Export Markets: Export Trade Products Shelf stable non...

Import-Export Business Plan

OpenAIRE

Asad, Muhammad

2014-01-01

Import export businesses, also known as international trading, are one of the hottest commercial trends of this decade. Since the owner of an import export enterprise, can work as a distributor by focusing on exporting and importing goods and services that cannot be obtained on national soil. With a rapidly growing population of about 150 million, Pakistan is a major country, recognized by the international community, and is one of the most important actors in the Islamic world. Based on its ...

Model of OSBP-Mediated Cholesterol Supply to Aichi Virus RNA Replication Sites Involving Protein-Protein Interactions among Viral Proteins, ACBD3, OSBP, VAP-A/B, and SAC1.

Science.gov (United States)

Ishikawa-Sasaki, Kumiko; Nagashima, Shigeo; Taniguchi, Koki; Sasaki, Jun

2018-04-15

Positive-strand RNA viruses, including picornaviruses, utilize cellular machinery for genome replication. Previously, we reported that each of the 2B, 2BC, 2C, 3A, and 3AB proteins of Aichi virus (AiV), a picornavirus, forms a complex with the Golgi apparatus protein ACBD3 and phosphatidylinositol 4-kinase IIIβ (PI4KB) at viral RNA replication sites (replication organelles [ROs]), enhancing PI4KB-dependent phosphatidylinositol 4-phosphate (PI4P) production. Here, we demonstrate AiV hijacking of the cellular cholesterol transport system involving oxysterol-binding protein (OSBP), a PI4P-binding cholesterol transfer protein. AiV RNA replication was inhibited by silencing cellular proteins known to be components of this pathway, OSBP, the ER membrane proteins VAPA and VAPB (VAP-A/B), the PI4P-phosphatase SAC1, and PI-transfer protein β. OSBP, VAP-A/B, and SAC1 were present at RNA replication sites. We also found various previously unknown interactions among the AiV proteins (2B, 2BC, 2C, 3A, and 3AB), ACBD3, OSBP, VAP-A/B, and SAC1, and the interactions were suggested to be involved in recruiting the component proteins to AiV ROs. Importantly, the OSBP-2B interaction enabled PI4P-independent recruitment of OSBP to AiV ROs, indicating preferential recruitment of OSBP among PI4P-binding proteins. Protein-protein interaction-based OSBP recruitment has not been reported for other picornaviruses. Cholesterol was accumulated at AiV ROs, and inhibition of OSBP-mediated cholesterol transfer impaired cholesterol accumulation and AiV RNA replication. Electron microscopy showed that AiV-induced vesicle-like structures were close to ER membranes. Altogether, we conclude that AiV directly recruits the cholesterol transport machinery through protein-protein interactions, resulting in formation of membrane contact sites between the ER and AiV ROs and cholesterol supply to the ROs. IMPORTANCE Positive-strand RNA viruses utilize host pathways to modulate the lipid composition of

7 CFR 51.912 - Export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 2 2010-01-01 2010-01-01 false Export. 51.912 Section 51.912 Agriculture Regulations... Standards for Grades of Table Grapes (European or Vinifera Type) 1 Definitions § 51.912 Export. When designated as Export, grapes shall be packed with any of the customary protective materials such as cushions...

The Chinese Export Displacement Effect Revisited

DEFF Research Database (Denmark)

Elleby, Christian; Yu, Wusheng; Yu, Qian

China’s global export share has increased dramatically over the past decades. This development has prompted an empirical literature on whether Chinese exports displace those originated from elsewhere in various destination markets. In this paper we focus on the growth of China’s exports to the East...... African Community (EAC) countries and show how it has affected exports from the European Union (EU) to the EAC. Our main contribution to the literature on the displacement effect of Chinese exports is a set of total and relative displacement estimates based on different specifications of the gravity model...... where we control for country-year fixed effects so as to avoid the “gold medal mistake” of not accounting for time varying “multilateral resistance”. Our findings do not support the hypothesis that Chinese exports have displaced exports from other countries in general. Nor do they support the hypothesis...

Exploitative Learning by Exporting

DEFF Research Database (Denmark)

Golovko, Elena; Lopes Bento, Cindy; Sofka, Wolfgang

Decisions on entering foreign markets are among the most challenging but also potentially rewarding strategy choices managers can make. In this study, we examine the effect of export entry on the firm investment decisions in two activities associated with learning about new technologies...... and learning about new markets ? R&D investments and marketing investments, in search of novel insights into the content and process underlying learning by exporting. We draw from organizational learning theory for predicting changes in both R&D and marketing investment patterns that accompany firm entry......, it is predominantly the marketing-related investment decisions associated with starting to export that lead to increases in firm productivity. We conclude that learning-by-exporting might be more properly characterized as ?learning about and exploiting new markets? rather than ?learning about new technologies...

Understanding China's renewable energy technology exports

International Nuclear Information System (INIS)

Liu, Jialu; Goldstein, Don

2013-01-01

China became a major player in renewable energy (RE) technology during the 2000s. Chinese solar PV cell and module makers quickly dominated global sales in that industry, while the country's wind turbine producers became poised for significant exports after capturing their rapidly growing home market. In countries like the US, Chinese RE technology strength has been met with claims of excessive governmental support of exports. This study examines to what extent Chinese firms' solar PV and wind technology successes have been enabled by policy supports, and whether those policies appear to have been driven by broader goals versus RE export promotion per se. The evidence suggests that governmental policy toward both wind and solar originated in a push for export-competitive Chinese companies. But the specifics differed substantially due to the particular requirements of building technological capabilities in each: export readiness necessitated substantial support for domestic installation of wind but not solar PV power. The findings also suggest that as the decade of the 2000s progressed, environmental goals played an increasing role alongside export promotion in motivating and shaping Chinese RE technology policies. - Highlights: ► Export policy in the rise of Chinese renewable energy technologies is studied. ► Policy supported wind turbine firms' capabilities via domestic uptake, not exports. ► Pre-2009 solar module exports enjoyed, but did not depend on, export subsidies. ► Renewables development also fit wider technology and environmental policy goals.

22 CFR 120.17 - Export.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Export. 120.17 Section 120.17 Foreign Relations DEPARTMENT OF STATE INTERNATIONAL TRAFFIC IN ARMS REGULATIONS PURPOSE AND DEFINITIONS § 120.17 Export. (a) Export means: (1) Sending or taking a defense article out of the United States in any manner, except by...

Gly[14]-humanin inhibits ox-LDL uptake and stimulates cholesterol efflux in macrophage-derived foam cells.

Science.gov (United States)

Zhu, Wa-Wa; Wang, Shu-Rong; Liu, Zhi-Hua; Cao, Yong-Jun; Wang, Fen; Wang, Jing; Liu, Chun-Feng; Xie, Ying; Xie, Ying; Zhang, Yan-Lin

2017-01-01

Foam cell formation, which is caused by imbalanced cholesterol influx and efflux by macrophages, plays a vital role in the occurrence and development of atherosclerosis. Humanin (HN), a mitochondria-derived peptide, can prevent the production of reactive oxygen species and death of human aortic endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL) and has a protective effect on patients with in early atherosclerosis. However, the effects of HN on the regulation of cholesterol metabolism in RAW 264.7 macrophages are still unknown. This study was designed to investigate the role of [Gly14]-humanin (HNG) in lipid uptake and cholesterol efflux in RAW 264.7 macrophages. Flow cytometry and live cell imaging results showed that HNG reduced Dil-ox-LDL accumulation in the RAW 264.7 macrophages. A similar result was obtained for lipid accumulation by measuring cellular cholesterol content. Western blot analysis showed that ox-LDL treatment upregulated not only the protein expression of CD36 and LOX-1, which mediate ox-LDL endocytosis, but also ATP-binding cassette (ABC) transporter A1 and ABCG1, which mediate ox-LDL exflux. HNG pretreatment inhibited the upregulation of CD36 and LOX-1 levels, prompting the upregulation of ABCA1 and ABCG1 levels induced by ox-LDL. Therefore we concluded that HNG could inhibit ox-LDL-induced macrophage-derived foam cell formation, which occurs because of a decrease in lipid uptake and an increase in cholesterol efflux from macrophage cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Cholesterol depletion induces dynamic confinement of the G-protein coupled serotonin(1A) receptor in the plasma membrane of living cells.

Science.gov (United States)

Pucadyil, Thomas J; Chattopadhyay, Amitabha

2007-03-01

Cholesterol is an essential constituent of eukaryotic membranes and plays a crucial role in membrane organization, dynamics, function, and sorting. It is often found distributed non-randomly in domains or pools in biological and model membranes and is thought to contribute to a segregated distribution of membrane constituents. Signal transduction events mediated by seven transmembrane domain G-protein coupled receptors (GPCRs) are the primary means by which cells communicate with and respond to their external environment. We analyzed the role of cholesterol in the plasma membrane organization of the G-protein coupled serotonin(1A) receptor by fluorescence recovery after photobleaching (FRAP) measurements with varying bleach spot sizes. Our results show that lateral diffusion parameters of serotonin(1A) receptors in normal cells are consistent with models describing diffusion of molecules in a homogenous membrane. Interestingly, these characteristics are altered in cholesterol-depleted cells in a manner that is consistent with dynamic confinement of serotonin(1A) receptors in the plasma membrane. Importantly, analysis of ligand binding and downstream signaling of the serotonin(1A) receptor suggests that receptor function is affected in a significantly different manner when intact cells or isolated membranes are depleted of cholesterol. These results assume significance in the context of interpreting effects of cholesterol depletion on diffusion characteristics of membrane proteins in particular, and cholesterol-dependent cellular processes in general.

BRAZILIAN EXPORTS OF MANUFACTURED WOOD

Directory of Open Access Journals (Sweden)

Rafael de Azevedo Calderon

2010-08-01

Full Text Available The present work deals with the Brazilian exports of sawnwood of non-coniferous, veneer sheets and plywood, from 1961 to 2002. The data regarding the three studied products, sawnwood of non-coniferous, veneer sheets and plywood, were joined through the method of Fisher so that an econometric evaluation of the market of the three products could be carried out. Supply and demand models of the Brazilian exports were specified. The results were satisfactory and they match with the literature. The supply of exports presented a positive answer in relation to the exporter's remuneration, to the production, to the use of the installed capacity (cycles of domestic economical activity and to the tendency, and negative in relation to the internal demand. The demand for the Brazilian exports was influenced positively by the world income, participation index and tendency, and negatively for the relative price. The low elasticity-price of the found demand can have implications in the conservation of the Brazilian forest resources because the exporters can increase the prices, reduce the amounts and still increase the incomes.

7 CFR 1488.9 - Evidence of export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Evidence of export. 1488.9 Section 1488.9 Agriculture... Export Sales of Agricultural Commodities From Private Stocks Under CCC Export Credit Sales Program (GSM-5) Documents Required for Financing § 1488.9 Evidence of export. (a) If the commodity is exported by rail or...

Guide to software export

CERN Document Server

Philips, Roger A

2014-01-01

An ideal reference source for CEOs, marketing and sales managers, sales consultants, and students of international marketing, Guide to Software Export provides a step-by-step approach to initiating or expanding international software sales. It teaches you how to examine critically your candidate product for exportability; how to find distributors, agents, and resellers abroad; how to identify the best distribution structure for export; and much, much more!Not content with providing just the guidelines for setting up, expanding, and managing your international sales channels, Guide to Software

Phytosterol glycosides reduce cholesterol absorption in humans

Science.gov (United States)

Lin, Xiaobo; Ma, Lina; Racette, Susan B.; Anderson Spearie, Catherine L.; Ostlund, Richard E.

2009-01-01

Dietary phytosterols inhibit intestinal cholesterol absorption and regulate whole body cholesterol excretion and balance. However, they are biochemically heterogeneous and a portion is glycosylated in some foods with unknown effects on biological activity. We tested the hypothesis that phytosterol glycosides reduce cholesterol absorption in humans. Phytosterol glycosides were extracted and purified from soy lecithin in a novel two-step process. Cholesterol absorption was measured in a series of three single-meal tests given at intervals of 2 wk to each of 11 healthy subjects. In a randomized crossover design, participants received ∼300 mg of added phytosterols in the form of phytosterol glycosides or phytosterol esters, or placebo in a test breakfast also containing 30 mg cholesterol-d7. Cholesterol absorption was estimated by mass spectrometry of plasma cholesterol-d7 enrichment 4–5 days after each test. Compared with the placebo test, phytosterol glycosides reduced cholesterol absorption by 37.6 ± 4.8% (P lecithin are bioactive in humans and should be included in methods of phytosterol analysis and tables of food phytosterol content. PMID:19246636

Potassium-doped carbon nanotubes toward the direct electrochemistry of cholesterol oxidase and its application in highly sensitive cholesterol biosensor

Energy Technology Data Exchange (ETDEWEB)

Li Xiaorong [State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China); Xu Jingjuan, E-mail: xujj@nju.edu.cn [State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China); Chen Hongyuan [State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China)

2011-10-30

We demonstrate herein a newly developed serum total cholesterol biosensor by using the direct electron transfer of cholesterol oxidase (ChOx), which is based on the immobilization of cholesterol oxidase and cholesterol esterase (ChEt) on potassium-doped multi-walled carbon nanotubes (KMWNTs) modified electrodes. The KMWNTs accelerate the electron transfer from electrode surface to the immobilized ChOx, achieving the direct electrochemistry of ChOx and maintaining its bioactivity. As a new platform in cholesterol analysis, the resulting electrode (ChOx/KMWNTs/GCE) exhibits a sensitive response to free cholesterol, with a linear range of 0.050-16.0 {mu}mol L{sup -1} and a detection limit of 5.0 nmol L{sup -1} (S/N = 3). Coimmobilization of ChEt and ChOx (ChEt/ChOx/KMWNTs/GCE) allows the determination of both free cholesterol and esterified cholesterol. The resulting biosensor shows the same linear range of 0.050-16.0 {mu}mol L{sup -1} for free cholesterol and cholesteryl oleate, with the detection limit of 10.0 and 12.0 nmol L{sup -1} (S/N = 3), respectively. The concentrations of total (free and esterified) cholesterol in human serum samples, determined by using the techniques developed in the present study, are in good agreement with those determined by the well-established techniques using the spectrophotometry.

Notice to exporters on products prohibited from export (nuclear material, equipment and large nuclear units)

International Nuclear Information System (INIS)

1988-01-01

In order to ensure that the policy to avoid the proliferation of nuclear weapons is complied with, the French Administration applies stricter controls over the export of certain sensitive products, materials and equipment. To this effect, lists of such products, materials and equipment are published in the form of Notices to exporters and periodically revised. This Notice repeals and replaces the previous Notice published in the Official Gazette of 21 January 1986. Annex I contains the list of materials whose export is subject to nuclear non-proliferation controls. Annex II lists the equipment whose export is subject to the same controls. Annex III includes the list of large nuclear units for which an application for prior approval of export must be submitted to the Administrations concerned. (NEA) [fr

78 FR 12719 - President's Export Council: Meeting of the President's Export Council

Science.gov (United States)

2013-02-25

... deliberate on recommendations related to promoting the expansion of U.S. exports. Topics may include the Administration's ``Doing Business in Africa'' campaign, the need for nominations to the U.S. Export- Import Bank.../pec ) without change, including any business or personal information provided such as names, addresses...

Identification of essential sequences for cellular localization in BRMS1 metastasis suppressor.

Directory of Open Access Journals (Sweden)

José Rivera

Full Text Available BACKGROUND: Breast cancer metastasis suppressor 1 (BRMS1 reduces the number and the size of secondary tumours in a mouse model without affecting the growth of the primary foci upon its re-expression. Knockdown of BRMS1 expression associates with metastasis. The molecular details on BRMS1 mechanism of action include its ability to function as a transcriptional co-repressor and consistently BRMS1 has been described as a predominantly nuclear protein. Since cellular distribution could represent a potential mechanism of regulation, we wanted to characterize BRMS1 sequence motifs that might regulate its cellular distribution. According to its amino acids sequence, BRMS1 contain two putative nuclear localization signals, however none of them has been proved to work so far. METHODOLOGY/PRINCIPAL FINDINGS: By using well known in vivo assays to detect both nuclear import and export signal, we have characterized, in the present study, one functional nuclear localisation signal as necessary and sufficient to promote nuclear transport. Additionally, the outcome of a directed yeast two-hybrid assay identify importin alpha6 as a specific partner of BRMS1 thus speculating that BRMS1 nuclear import could be specifically mediated by the reported nuclear transporter. Besides, the combination of a computational searching approach along the utilization of a nuclear export assay, identified a functional motif within the BRMS1 sequence responsible for its nuclear export, that resulted not affected by the highly specific CRM1 inhibitor Leptomycin-B. Interspecies heterokaryon assay demonstrate the capability of BRMS1 to shuttle between the nuclear and cytosolic compartments CONCLUSIONS/SIGNIFICANCE: Our results show for the first time that BRMS1 contains both nuclear import and export signals enabling its nucleo-cytoplasmic shuttling. These findings contributes new data for the understanding of the BRMS1 functions and allow us to speculate that this phenomenon could

Export performance and investment in R&D

DEFF Research Database (Denmark)

Smith, Valdemar; Madsen, Erik Strøjer; Dilling-Hansen, Mogens

2002-01-01

This paper analyses the role of R&D in the export behaviour of Danish firms. Export behaviour is defined as the export intensity and the likelihood of a firm being an exporter. In the theoretical part of the paper it is argued that export and being R&D active are endogenous with respect to each...... other, and an empirical model is formulated in order to estimate which factors affect the firm's export. It is argued that besides R&D, firm size, wages and a number of other firm-specific factors controlling for risks are highly important for the export performance. In the empirical part of the paper...... the model is tested on a sample of 3,500 Danish firms. Using a FIML estimation form in order to deal with endogeneity problems between the R&D and export decisions of the firms, the computation clearly verifies the theoretical model put forward. Moreover, R&D is an important factor for being an exporting...

Do R&D Investments Affect Export Performance?

DEFF Research Database (Denmark)

Smith, Valdemar; Madsen, Erik Strøjer; Dilling-Hansen, Mogens

2002-01-01

This paper analyses the role of R&D in the export behaviour of Danish firms. Export behaviour is defined as the export intensity and the likelihood of a firm being an exporter. In the theoretical part of the paper it is argued that export and being R&D active are endogenous with respect to each...... other, and an empirical model is formulated in order to estimate which factors affect the firm's export. It is argued that besides R&D, firm size, wages and a number of other firm-specific factors controlling for risks are highly important for the export performance. In the empirical part of the paper...... the model is tested on a sample of 3,500 Danish firms. Using a FIML estimation form in order to deal with endogeneity problems between the R&D and export decisions of the firms, the computation clearly verifies the theoretical model put forward. Moreover, R&D is an important factor for being an exporting...

Export Controls: Controls Over the Export Licensing Process for Chemical and Biological Items

National Research Council Canada - National Science Library

2005-01-01

.... foreign policy should read this report. The report discusses the effectiveness of the DoD review process for export license applications and updates to Federal export regulations to prevent the proliferation of items that could pose...

Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

Directory of Open Access Journals (Sweden)

Fabian Arenas

2017-11-01

Full Text Available Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD, however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.

Cholesterol asymmetry in synaptic plasma membranes.

Science.gov (United States)

Wood, W Gibson; Igbavboa, Urule; Müller, Walter E; Eckert, Gunter P

2011-03-01

Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. A common characteristic of these membrane domains is their association with cholesterol. Lipid rafts and caveolae are examples of cholesterol enriched domains, which have attracted keen interest. However, two other important cholesterol domains are the exofacial and cytofacial leaflets of the plasma membrane. The two leaflets that make up the bilayer differ in their fluidity, electrical charge, lipid distribution, and active sites of certain proteins. The synaptic plasma membrane (SPM) cytofacial leaflet contains over 85% of the total SPM cholesterol as compared with the exofacial leaflet. This asymmetric distribution of cholesterol is not fixed or immobile but can be modified by different conditions in vivo: (i) chronic ethanol consumption; (ii) statins; (iii) aging; and (iv) apoE isoform. Several potential candidates have been proposed as mechanisms involved in regulation of SPM cholesterol asymmetry: apoE, low-density lipoprotein receptor, sterol carrier protein-2, fatty acid binding proteins, polyunsaturated fatty acids, P-glycoprotein and caveolin-1. This review examines cholesterol asymmetry in SPM, potential mechanisms of regulation and impact on membrane structure and function. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Dairy products and plasma cholesterol levels

Directory of Open Access Journals (Sweden)

Lena Ohlsson

2010-08-01

Full Text Available Cholesterol synthesized in the body or ingested is an essential lipid component for human survival from our earliest life. Newborns ingest about 3–4 times the amount per body weight through mother's milk compared to the dietary intake of adults. A birth level of 1.7 mmol/L plasma total cholesterol will increase to 4–4.5 mmol/L during the nursing period and continue to increase from adulthood around 40% throughout life. Coronary artery disease and other metabolic disorders are strongly associated with low-density lipoprotein (LDL and high-density lipoprotein (HDL cholesterol as well as triacylglycerol concentration. Milk fat contains a broad range of fatty acids and some have a negative impact on the cholesterol rich lipoproteins. The saturated fatty acids (SFAs, such as palmitic acid (C16:0, myristic acid (C14:0, and lauric acid (C12:0, increase total plasma cholesterol, especially LDL, and constitute 11.3 g/L of bovine milk, which is 44.8% of total fatty acid in milk fat. Replacement of dairy SFA and trans-fatty acids with polyunsaturated fatty acids decreases plasma cholesterol, especially LDL cholesterol, and is associated with a reduced risk of cardiovascular disease. Available data shows different effects on lipoproteins for different dairy products and there is uncertainty as to the impact a reasonable intake amount of dairy items has on cardiovascular risk. The aim of this review is to elucidate the effect of milk components and dairy products on total cholesterol, LDL, HDL, and the LDL/HDL quotients. Based on eight recent randomized controlled trials of parallel or cross-over design and recent reviews it can be concluded that replacement of saturated fat mainly (but not exclusively derived from high-fat dairy products with low-fat dairy products lowers LDL/HDL cholesterol and total/HDL cholesterol ratios. Whey, dairy fractions enriched in polar lipids, and techniques such as fermentation, or fortification of cows feeding can be used

The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity.

Science.gov (United States)

Sag, Duygu; Cekic, Caglar; Wu, Runpei; Linden, Joel; Hedrick, Catherine C

2015-02-27

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Here we demonstrate a role of ABCG1 as a mediator of tumour immunity. Abcg1(-/-) mice have dramatically suppressed subcutaneous MB49-bladder carcinoma and B16-melanoma growth and prolonged survival. We show that reduced tumour growth in Abcg1(-/-) mice is myeloid cell intrinsic and is associated with a phenotypic shift of the macrophages from a tumour-promoting M2 to a tumour-fighting M1 within the tumour. Abcg1(-/-) macrophages exhibit an intrinsic bias towards M1 polarization with increased NF-κB activation and direct cytotoxicity for tumour cells in vitro. Overall, our study demonstrates that the absence of ABCG1 inhibits tumour growth through modulation of macrophage function within the tumour, and illustrates a link between cholesterol homeostasis and cancer.

Can non-cholesterol sterols and lipoprotein subclasses distribution predict different patterns of cholesterol metabolism and statin therapy response?

Science.gov (United States)

Gojkovic, Tamara; Vladimirov, Sandra; Spasojevic-Kalimanovska, Vesna; Zeljkovic, Aleksandra; Vekic, Jelena; Kalimanovska-Ostric, Dimitra; Djuricic, Ivana; Sobajic, Sladjana; Jelic-Ivanovic, Zorana

2017-03-01

Cholesterol homeostasis disorders may cause dyslipidemia, atherosclerosis progression and coronary artery disease (CAD) development. Evaluation of non-cholesterol sterols (NCSs) as synthesis and absorption markers, and lipoprotein particles quality may indicate the dyslipidemia early development. This study investigates associations of different cholesterol homeostasis patterns with low-density (LDL) and high-density lipoproteins (HDL) subclasses distribution in statin-treated and statin-untreated CAD patients, and potential use of aforementioned markers for CAD treatment optimization. The study included 78 CAD patients (47 statin-untreated and 31 statin-treated) and 31 controls (CG). NCSs concentrations were quantified using gas chromatography- flame ionization detection (GC-FID). Lipoprotein subclasses were separated by gradient gel electrophoresis. In patients, cholesterol-synthesis markers were significantly higher comparing to CG. Cholesterol-synthesis markers were inversely associated with LDL size in all groups. For cholesterol homeostasis estimation, each group was divided to good and/or poor synthetizers and/or absorbers according to desmosterol and β-sitosterol median values. In CG, participants with reduced cholesterol absorption, the relative proportion of small, dense LDL was higher in those with increased cholesterol synthesis compared to those with reduced synthesis (p<0.01). LDL I fraction was significantly higher in poor synthetizers/poor absorbers subgroup compared to poor synthetizers/good absorbers (p<0.01), and good synthetizers/poor absorbers (p<0.01). Statin-treated patients with increased cholesterol absorption had increased proportion of LDL IVB (p<0.05). The results suggest the existence of different lipoprotein abnormalities according to various patterns of cholesterol homeostasis. Desmosterol/β-sitosterol ratio could be used for estimating individual propensity toward dyslipidemia development and direct the future treatment.

Mevinolin-induced changes in cholesterol synthesis and protein glycosylation in lymphocytes of hypercholesterolemics

International Nuclear Information System (INIS)

Goel, V.; Premkumar, N.D.; Ramachandran, C.K.; Melnykovych, G.; Dujovne, C.A.

1987-01-01

Mevinolin (lovastatin, MVN), a potent competitive inhibitor of HMG CoA reductase (HMGR), has proven to be an effective hypolipidemic agent in patients with non-homozygous primary hypercholesterolemia. Since inhibition of HMGR can also reduce the synthesis of non-sterol mevalonate products such as dolichols, it was of interest to examine the dolichol-mediated cellular reactions in MVN-treated patients. Blood was collected from patients after various durations of MVN therapy. Peripheral lymphocytes were isolated using Ficoll-Paque gradient. The cells were suspended in RPMI-1640 medium and pulsed in the presence of 14 C-2-acetate or 3 H-mannose for 30 min. At the end of incubation the radioactivity recovered in non-saponifiable fraction ( 14 C) or TCA precipitable protein ( 3 H) was measured. Cholesterol synthesis continued to fall gradually and remained low throughout, in direct correlation with falls in plasma LDL cholesterol levels. Incorporation of mannose into protein fraction was reduced by the 1st month of therapy, remained low until the 7th month and recovered by the 10th month while on MVN. In summary, MVN appears to reduce cholesterol synthesis continuously but its inhibitory effect on glycosylation seems to be overcome after prolonged therapy. This escape effect could result from a rebound increase in HMGR in response to its competitive inhibition by MVN

Competitiveness, export control and export promotion of dual-use goods. European and German balancing exercises

International Nuclear Information System (INIS)

Feldmann, Ulrike

2014-01-01

The EU Commission Communication of 24 April 2014 to the Council and the European Parliament ''The review of export control policy: Ensuring Security and Competitiveness in a changing world'' as well as the increasingly number of inquiries and applications to the German Federal Government (e.g. the rejection of Hermes guarantees and state funding of nuclear export and termination of bilateral cooperation in the field of nuclear technologies) once again reason to discuss the current tension between the principle of free movement of goods, competitiveness and export promotion on the one hand and the export control on the other.

Impaired cholesterol esterification in primary brain cultures of the lysosomal cholesterol storage disorder (LCSD) mouse mutant

International Nuclear Information System (INIS)

Patel, S.C.; Suresh, S.; Weintroub, H.; Brady, R.O.; Pentchev, P.G.

1987-01-01

Esterification of cholesterol was investigated in primary neuroglial cultures obtained from newborn lysosomal cholesterol storage disorder (LCSD) mouse mutants. An impairment in 3 H-oleic acid incorporation into cholesteryl esters was demonstrated in cultures of homozygous LCSD brain. Primary cultures derived from other phenotypically normal pups of the carrier breeders esterified cholesterol at normal levels or at levels which were intermediary between normal and deficient indicating a phenotypic expression of the LCSD heterozygote genotype. These observations on LCSD mutant brain cells indicate that the defect in cholesterol esterification is closely related to the primary genetic defect and is expressed in neuroglial cells in culture

Synthesis of cholesterol 26. C{sup 14} (1961); Synthese du cholesterol {sup 14}C-26 (1961)

Energy Technology Data Exchange (ETDEWEB)

Herbert, M; Pichat, L [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

1961-07-01

Cholesterol 26 {sup 14}C is synthesized from methylmagnesium iodide {sup 14}C with a 48 per cent overall yield. Cholesterol is purified by chromatography on alumina. The various intermediates of the synthesis are characterized by thin-layer chromatography according to Stahl. (authors) [French] Le cholesterol {sup 14}C-26 est synthetise a partir d'iodure de methyl magnesium {sup 14}C, avec un rendement de 48 pour cent par rapport a l'iodure de methyl {sup 14}C mis en jeu. Le cholesterol est purifie par chromatographie sur alumine. Les intermediaires de la synthese sont caracterises par chromatographie en couche mince, selon Stahl. (auteurs)

Microwave assisted direct saponification for the simultaneous determination of cholesterol and cholesterol oxides in shrimp.

Science.gov (United States)

Souza, Hugo A L; Mariutti, Lilian R B; Bragagnolo, Neura

2017-05-01

A novel microwave-assisted direct saponification method for the simultaneous determination of cholesterol and cholesterol oxides in shrimp was developed and validated. Optimal saponification conditions, determined by means of an experimental design, were achieved using 500mg of sample and 20mL of 1mol/L KOH ethanol solution for 16min at 45°C at maximum power at 200W and magnetic stirring at 120rpm. Higher extraction of cholesterol oxides in a reduced saponification time (∼75 times) was achieved in comparison with the direct cold saponification method. The new method showed low detection (≤0.57μg/mL) and quantification (≤1.73μg/mL) limits, good repeatability (≤10.50% intraday and ≤8.56% interday) and low artifact formation (evaluated by using a deuterated cholesterol-D6 standard). Raw, salted and dried-salted shrimps were successfully analyzed by the validated method. The content of cholesterol oxides increased after salting and decreased after drying. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characteristics of human hypo- and hyperresponders to dietary cholesterol.

Science.gov (United States)

Katan, M B; Beynen, A C

1987-03-01

The characteristics of people whose serum cholesterol level is unusually susceptible to consumption of cholesterol were investigated. Thirty-two volunteers from the general population of Wageningen, the Netherlands, each participated in three controlled dietary trials in 1982. A low-cholesterol diet was fed during the first half and a high-cholesterol diet during the second half of each trial, and the change (response) of serum cholesterol was measured. The responses in the three trials were averaged to give each subject's mean responsiveness. Fecal excretion of cholesterol and its metabolites were measured in the second trial, and body cholesterol synthesis was calculated. Responsiveness showed a positive correlation with serum high density lipoprotein2 (HDL2) cholesterol (r = 0.41, p less than 0.05) and with serum total cholesterol level on a high-cholesterol diet (r = 0.31, p = 0.09). A negative relation was found with habitual cholesterol consumption (r = -0.62, p less than 0.01), with body mass index (r = -0.50, p less than 0.01), and with the rate of endogenous cholesterol synthesis (r = -0.40, p less than 0.05), but not with the reaction of endogenous cholesterol synthesis rate to an increased intake of cholesterol. No relation was found with age, sex, total caloric needs, or the ratio of primary to secondary fecal steroids. Upon multiple regression analysis, only habitual cholesterol intake and serum total and HDL2 cholesterol levels contributed significantly to the explanation of variance in responsiveness. Thus, a low habitual cholesterol intake, a high serum HDL2 cholesterol level, or a low body weight do not make one less susceptible to dietary cholesterol-induced hypercholesterolemia.

Desipramine induces disorder in cholesterol-rich membranes: implications for viral trafficking

Science.gov (United States)

Pakkanen, Kirsi; Salonen, Emppu; Mäkelä, Anna R.; Oker-Blom, Christian; Vattulainen, Ilpo; Vuento, Matti

2009-12-01

In this study, the effect of desipramine (DMI) on phospholipid bilayers and parvoviral entry was elucidated. In atomistic molecular dynamics simulations, DMI was found to introduce disorder in cholesterol-rich phospholipid bilayers. This was manifested by a decrease in the deuterium order parameter SCD as well as an increase in the membrane area. Disordering of the membrane suggested DMI to destabilize cholesterol-rich membrane domains (rafts) in cellular conditions. To relate the raft disrupting ability of DMI with novel biological relevance, we studied the intracellular effect of DMI using canine parvovirus (CPV), a virus known to interact with endosomal membranes and sphingomyelin, as an intracellular probe. DMI was found to cause retention of the virus in intracellular vesicular structures leading to the inhibition of viral proliferation. This implies that DMI has a deleterious effect on the viral traffic. As recycling endosomes and the internal vesicles of multivesicular bodies are known to contain raft components, the effect of desipramine beyond the plasma membrane step could be caused by raft disruption leading to impaired endosomal function and possibly have direct influence on the penetration of the virus through an endosomal membrane.

Desipramine induces disorder in cholesterol-rich membranes: implications for viral trafficking

International Nuclear Information System (INIS)

Pakkanen, Kirsi; Mäkelä, Anna R; Oker-Blom, Christian; Vuento, Matti; Salonen, Emppu; Vattulainen, Ilpo

2009-01-01

In this study, the effect of desipramine (DMI) on phospholipid bilayers and parvoviral entry was elucidated. In atomistic molecular dynamics simulations, DMI was found to introduce disorder in cholesterol-rich phospholipid bilayers. This was manifested by a decrease in the deuterium order parameter S CD as well as an increase in the membrane area. Disordering of the membrane suggested DMI to destabilize cholesterol-rich membrane domains (rafts) in cellular conditions. To relate the raft disrupting ability of DMI with novel biological relevance, we studied the intracellular effect of DMI using canine parvovirus (CPV), a virus known to interact with endosomal membranes and sphingomyelin, as an intracellular probe. DMI was found to cause retention of the virus in intracellular vesicular structures leading to the inhibition of viral proliferation. This implies that DMI has a deleterious effect on the viral traffic. As recycling endosomes and the internal vesicles of multivesicular bodies are known to contain raft components, the effect of desipramine beyond the plasma membrane step could be caused by raft disruption leading to impaired endosomal function and possibly have direct influence on the penetration of the virus through an endosomal membrane

Nitrogen and carbon export from urban areas through removal and export of litterfall

International Nuclear Information System (INIS)

Templer, Pamela H.; Toll, Jonathan W.; Hutyra, Lucy R.; Raciti, Steve M.

2015-01-01

We found that up to 52 ± 17% of residential litterfall carbon (C) and nitrogen (N; 390.6 kg C and 6.5 kg N ha −1  yr −1 ) is exported through yard waste removed from the City of Boston, which is equivalent to more than half of annual N outputs as gas loss (i.e. denitrification) or leaching. Our results show that removing yard waste results in a substantial decrease in N inputs to urban areas, which may offset excess N inputs from atmospheric deposition, fertilizer application and pet waste. However, export of C and N via yard waste removal may create nutrient limitation for some vegetation due to diminished recycling of nutrients. Removal of leaf litter from residential areas disrupts nutrient cycling and residential yard management practices are an important modification to urban biogeochemical cycling, which could contribute to spatial heterogeneity of ecosystems that are either N limited or saturated within urban ecosystems. - Highlights: • We monitored yard waste bags for one complete fall yard waste collection season. • 52% of residential litterfall C and N is exported annually from the City of Boston. • Litterfall export may create nutrient limitation hotspots in urban ecosystems. • C and N export through litterfall collection modifies urban biogeochemical cycling. - Litterfall removal leads to C and N export from urban ecosystems and disrupts nutrient cycling, showing that this activity is an important modification to urban biogeochemical cycling

National Cholesterol Education Month

Centers for Disease Control (CDC) Podcasts

2009-09-01

Do you know your cholesterol numbers? Your doctor can do a simple test to check your cholesterol levels and help you make choices that lower your risk for heart disease and stroke.  Created: 9/1/2009 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 9/9/2009.

Phytosterol glycosides reduce cholesterol absorption in humans.

Science.gov (United States)

Lin, Xiaobo; Ma, Lina; Racette, Susan B; Anderson Spearie, Catherine L; Ostlund, Richard E

2009-04-01

Dietary phytosterols inhibit intestinal cholesterol absorption and regulate whole body cholesterol excretion and balance. However, they are biochemically heterogeneous and a portion is glycosylated in some foods with unknown effects on biological activity. We tested the hypothesis that phytosterol glycosides reduce cholesterol absorption in humans. Phytosterol glycosides were extracted and purified from soy lecithin in a novel two-step process. Cholesterol absorption was measured in a series of three single-meal tests given at intervals of 2 wk to each of 11 healthy subjects. In a randomized crossover design, participants received approximately 300 mg of added phytosterols in the form of phytosterol glycosides or phytosterol esters, or placebo in a test breakfast also containing 30 mg cholesterol-d7. Cholesterol absorption was estimated by mass spectrometry of plasma cholesterol-d7 enrichment 4-5 days after each test. Compared with the placebo test, phytosterol glycosides reduced cholesterol absorption by 37.6+/-4.8% (Pphytosterol esters 30.6+/-3.9% (P=0.0001). These results suggest that natural phytosterol glycosides purified from lecithin are bioactive in humans and should be included in methods of phytosterol analysis and tables of food phytosterol content.

Nuclear exports. Parliamentary control and confidentiality

International Nuclear Information System (INIS)

Feldmann, Ulrike

2015-01-01

With its decision taken on 21. October 2014 (Az.: 2 BvE 5/11) the Federal Constitutional Court (BVerfG) decided during court proceedings between administrative bodies on the scope and limits of the parliamentary right of information. Even though the proceeding did not deal with nuclear exports but arm exports, foreign trade law, however, does not only designate an export licence obligation for military weapons but also for so called dual-use goods meaning goods, which can be used both for friendly as well as for military purposes. The export of these goods requires according to the so-called Dual-Use Regulation (EG) 428/2009 a licence. Annex I category 0 of the regulation (EG) 428/2009 lists a variety of nuclear materials, plants and equipment items for which this licence applies. In the same manner as arm exports, also exports of nuclear dual-use goods are being discussed in a special cabinet committee, the Federal Security Council (BSR), which shall coordinate cross-departmentally the German security and defence policy under consideration of economic interests and which categorises its results, according to the rules of procedure, as confidential. Also legally not regulated but common ''preliminary enquiries'' at the responsible Federal Ministry or rather Federal Office of Economics and Export Control by companies which plan an export and want to affirm the general approval for their export business prior to conclusion of contract take not only place for arm exports but also for nuclear dual-use goods. The decision by the Federal Constitutional Court can be applied to consultations about the authorisation of nuclear dual-use goods.

Topical cholesterol in clofazimine induced ichthyosis

Directory of Open Access Journals (Sweden)

Pandey S

1994-01-01

Full Text Available Topical application of 10% cholesterol in petrolatum significantly (P< 0.05 controlled the development of ichthyosis in 62 patients taking 100 mg clofazimine daily for a period of 3 months. However, topical cholesterol application did not affect the lowering of serum cholesterol induced by oral clofazimine. Probable mechanism of action is being discussed.

Export Variety and Country Productivity

OpenAIRE

Feenstra, Robert; Looi Kee, Hiau

2004-01-01

The authors study the link between export product variety and country productivity based on data from 34 industrial and developing countries, from 1982 to 1997. They measure export product variety by the share of U.S. imports on the set of goods exported by each sampled country relative to the world. It is a theoretically sound index which is consistent with within-country GDP maximization...

Import-push or Export-pull?

DEFF Research Database (Denmark)

Jäkel, Ina Charlotte

2014-01-01

predictions regarding the export market and the role of product differentiation. Empirical results for a sample of Danish manufacturing industries confirm the import- "push" hypothesis as well as the export- "pull" hypothesis, but also reveal differences across industries. The selection effect of trade...... is mainly driven by the "import-push" if product differentiation is high, whereas it is driven by the "export-pull" if goods are homogeneous....

Import-push or Export-pull?

DEFF Research Database (Denmark)

Jäkel, Ina Charlotte

predictions regarding the export market and the role of product differentiation. Empirical results for a sample of Danish manufacturing industries confirm the import-"push" hypothesis as well as the export-"pull" hypothesis, but also reveal differences across industries. The selection effect of trade...... is mainly driven by the "import-push" if product differentiation is high, whereas it is driven by the "export-pull" if goods are homogeneous....

Phytosterol glycosides reduce cholesterol absorption in humans

OpenAIRE

Lin, Xiaobo; Ma, Lina; Racette, Susan B.; Anderson Spearie, Catherine L.; Ostlund, Richard E.

2009-01-01

Dietary phytosterols inhibit intestinal cholesterol absorption and regulate whole body cholesterol excretion and balance. However, they are biochemically heterogeneous and a portion is glycosylated in some foods with unknown effects on biological activity. We tested the hypothesis that phytosterol glycosides reduce cholesterol absorption in humans. Phytosterol glycosides were extracted and purified from soy lecithin in a novel two-step process. Cholesterol absorption was measured in a series ...

Topics in Productivity, Exporting and Outsourced Services

OpenAIRE

Kidder, Matthew Benjamin

2016-01-01

This dissertation is a collection of three empirical studies using the a survey of Chilean Manufactures. The first two chapters of this dissertation evaluates the productivity impact of exporting and service outsourcing. The last chapter evaluates selection mechanisms into exporting.The first chapter examines productivity and exporting. I find that asymmetric responses, between exporters and non-exporters, to changes in the domestic lending rate can cause propensity-score-matching-differen...

Analysis of Cholesterol Trafficking with Fluorescent Probes

DEFF Research Database (Denmark)

Maxfield, Frederick R.; Wustner, Daniel

2012-01-01

Cholesterol plays an important role in determining the biophysical properties of biological membranes, and its concentration is tightly controlled by homeostatic processes. The intracellular transport of cholesterol among organelles is a key part of the homeostatic mechanism, but sterol transport...... that can bind to cholesterol to reveal its distribution in cells. We also discuss the use of intrinsically fluorescent sterols that closely mimic cholesterol, as well as some minimally modified fluorophore-labeled sterols. Methods for imaging these sterols by conventional fluorescence microscopy...... and by multiphoton microscopy are described. Some label-free methods for imaging cholesterol itself are also discussed briefly....

LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals

DEFF Research Database (Denmark)

Haase, Christiane L; Tybjærg-Hansen, Anne; Ali Qayyum, Abbas

2012-01-01

, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis.Results:Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels...... was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies......Background:Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear.Methods:We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants...

Export constraints facing Lesotho-based manufacturing enterprises

Directory of Open Access Journals (Sweden)

Motšelisi C. Mokhethi

2015-07-01

Full Text Available Orientation: Exporting is preferred by many enterprises as the mode of foreign entry as it requires less commitment of organisational resources and offers flexibility of managerial actions. However, enterprises face a number of challenges when attempting to initiate exports or expand their export operations. Research purpose: This study was undertaken to determine the characteristics and composition of export barriers constraining exporting by Lesotho-based manufacturing enterprises. Motivation for the study: Lesotho is faced with low destination diversity and low diversity in export products. Research design, approach and method: Data was collected from 162 Lesotho-based manufacturing enterprises through a self-administered questionnaire. Main findings: In its findings, the study firstly identified international constraints, distribution constraints and financial constraints as factors constraining exporting. Secondly, it was determined that three exporting constraints, all internal to the enterprise and all related to one factor (namely financial constraint hampered exporting. Lastly, the ANOVA results revealed that the perceptions of export constraints differed according to the enterprise characteristics, enterprise size, ownership and type of industry. Contribution/value-add: With the majority of enterprises in this study being identified as micro-enterprises, the government of Lesotho needs to pay particular attention to addressing the export needs of these enterprises in order to enable them to participate in exporting activities − especially considering that they can play a pivotal role in the alleviation of poverty, job creation and economic rejuvenation.

Biliary cholesterol secretion : More than a simple ABC

NARCIS (Netherlands)

Dikkers, Arne; Tietge, Uwe J. F.

2010-01-01

Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease With respect to cardiovascular disease, biliary cholesterol secretion is regarded as the final step for the elimination of cholesterol

The effects of cholesterol on learning and memory.

Science.gov (United States)

Schreurs, Bernard G

2010-07-01

Cholesterol is vital to normal brain function including learning and memory but that involvement is as complex as the synthesis, metabolism and excretion of cholesterol itself. Dietary cholesterol influences learning tasks from water maze to fear conditioning even though cholesterol does not cross the blood brain barrier. Excess cholesterol has many consequences including peripheral pathology that can signal brain via cholesterol metabolites, pro-inflammatory mediators and antioxidant processes. Manipulations of cholesterol within the central nervous system through genetic, pharmacological, or metabolic means circumvent the blood brain barrier and affect learning and memory but often in animals already otherwise compromised. The human literature is no less complex. Cholesterol reduction using statins improves memory in some cases but not others. There is also controversy over statin use to alleviate memory problems in Alzheimer's disease. Correlations of cholesterol and cognitive function are mixed and association studies find some genetic polymorphisms are related to cognitive function but others are not. In sum, the field is in flux with a number of seemingly contradictory results and many complexities. Nevertheless, understanding cholesterol effects on learning and memory is too important to ignore.

Industrialisation, Exports and Employment.

Science.gov (United States)

Sabolo, Yves

1980-01-01

After reviewing trends in industrial production, exports, and employment in the Third World since 1960, the author discusses industrialization strategies based on the local processing of raw materials for export. Such processing has proved to be a major factor in job creation. (Author/SK)

What Are High Blood Cholesterol and Triglycerides?

Science.gov (United States)

... Reduction Cholesterol What Are High Blood Cholesterol and Triglycerides? Cholesterol travels to the body’s cells through the ... doctor about medicines that can help. What are triglycerides? Triglycerides are the most common type of fat ...

Markups and Exporting Behavior

DEFF Research Database (Denmark)

De Loecker, Jan; Warzynski, Frederic Michel Patrick

2012-01-01

In this paper, we develop a method to estimate markups using plant-level production data. Our approach relies on cost minimizing producers and the existence of at least one variable input of production. The suggested empirical framework relies on the estimation of a production function and provides...... estimates of plant- level markups without specifying how firms compete in the product market. We rely on our method to explore the relationship be- tween markups and export behavior. We find that markups are estimated significantly higher when controlling for unobserved productivity; that exporters charge......, on average, higher markups and that markups increase upon export entry....

Photoaffinity labeling with cholesterol analogues precisely maps a cholesterol-binding site in voltage-dependent anion channel-1.

Science.gov (United States)

Budelier, Melissa M; Cheng, Wayland W L; Bergdoll, Lucie; Chen, Zi-Wei; Janetka, James W; Abramson, Jeff; Krishnan, Kathiresan; Mydock-McGrane, Laurel; Covey, Douglas F; Whitelegge, Julian P; Evers, Alex S

2017-06-02

Voltage-dependent anion channel-1 (VDAC1) is a highly regulated β-barrel membrane protein that mediates transport of ions and metabolites between the mitochondria and cytosol of the cell. VDAC1 co-purifies with cholesterol and is functionally regulated by cholesterol, among other endogenous lipids. Molecular modeling studies based on NMR observations have suggested five cholesterol-binding sites in VDAC1, but direct experimental evidence for these sites is lacking. Here, to determine the sites of cholesterol binding, we photolabeled purified mouse VDAC1 (mVDAC1) with photoactivatable cholesterol analogues and analyzed the photolabeled sites with both top-down mass spectrometry (MS), and bottom-up MS paired with a clickable, stable isotope-labeled tag, FLI -tag. Using cholesterol analogues with a diazirine in either the 7 position of the steroid ring (LKM38) or the aliphatic tail (KK174), we mapped a binding pocket in mVDAC1 localized to Thr 83 and Glu 73 , respectively. When Glu 73 was mutated to a glutamine, KK174 no longer photolabeled this residue, but instead labeled the nearby Tyr 62 within this same binding pocket. The combination of analytical strategies employed in this work permits detailed molecular mapping of a cholesterol-binding site in a protein, including an orientation of the sterol within the site. Our work raises the interesting possibility that cholesterol-mediated regulation of VDAC1 may be facilitated through a specific binding site at the functionally important Glu 73 residue. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice

NARCIS (Netherlands)

Bura, Kanwardeep S.; Lord, Caleb; Marshall, Stephanie; McDaniel, Allison; Thomas, Gwyn; Warrier, Manya; Zhang, Jun; Davis, Matthew A.; Sawyer, Janet K.; Shah, Ramesh; Wilson, Martha D.; Dikkers, Arne; Tietge, Uwe J. F.; Collet, Xavier; Rudel, Lawrence L.; Temel, Ryan E.; Brown, J. Mark

Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the non-biliary transintestinal cholesterol efflux (TICE) pathway. Scavenger receptor class B type I (SR-BI) plays a critical role in the classic hepatobiliary route of RCT. However, the role of SR-BI

7 CFR 1493.470 - Evidence of export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Evidence of export. 1493.470 Section 1493.470... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS CCC EXPORT CREDIT GUARANTEE PROGRAMS CCC Supplier Credit Guarantee Program Operations § 1493.470 Evidence of export. (a) Report of export. The...

7 CFR 1493.80 - Evidence of export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Evidence of export. 1493.80 Section 1493.80... OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS CCC EXPORT CREDIT GUARANTEE PROGRAMS CCC Export Credit Guarantee Program (GSM-102) and CCC Intermediate Export Credit Guarantee Program (GSM-103...

Quebec-USA electricity export contracts

International Nuclear Information System (INIS)

Labbe, J.-F.

1993-06-01

Electricity exports from Hydro-Quebec to utilities in the USA significantly affects the economy and environment of Quebec. These exports may be arranged under interconnection agreements to sell excess capacity and production during off-peak periods or under firm sales contracts. Hydro-Quebec exports could also replace power plants that would otherwise be needed in the USA. The economic environment for Hydro-Quebec exports to the USA is reviewed along with the regulatory environment applicable to international trade (General Agreement on Tariffs and Trade, Canada-USA Free Trade Agreement, North American Free Trade Agreement), Quebec (Canadian federal and provincial law), and the USA (federal and state law). A jurisdictional analysis of power export contracts is then presented, citing examples of contracts already signed by Hydro-Quebec with utilities in New York and New England. Contract law and contract provisions are discussed, including common clauses and particular clauses. Suggestions are made for new clauses that would improve the electricity trade. 215 refs., 13 figs., 3 tabs

Second Thoughts on Exporter Productivity

DEFF Research Database (Denmark)

Sørensen, Allan; Schröder, Philipp J.H.

Empirical literature has established a positive link between firm productivity and export status, yet notable exceptions exist. The present paper shows that the underlying theory (Melitz, 2003) is in fact able to accommodate the rule as well as the exception. The fulcrum of the argument is the te......Empirical literature has established a positive link between firm productivity and export status, yet notable exceptions exist. The present paper shows that the underlying theory (Melitz, 2003) is in fact able to accommodate the rule as well as the exception. The fulcrum of the argument...... is the tension between empirical work measuring productivity based on average cost information, and theoretical work representing productivity by marginal cost. In a heterogeneous firms trade model, we compute productivity based on average cost and find that around the export-indifferent firm, exporters...... will be less productive than non-exporters. Furthermore, we show that this effect may feed through at the industry level....

Cholesterol Perturbs Lipid Bilayers Nonuniversally

International Nuclear Information System (INIS)

Pan Jianjun; Mills, Thalia T.; Tristram-Nagle, Stephanie; Nagle, John F.

2008-01-01

Cholesterol is well known to modulate the physical properties of biomembranes. Using modern x-ray scattering methods, we have studied the effects of cholesterol on the bending modulus K C , the thickness D HH , and the orientational order parameter S xray of lipid bilayers. We find that the effects are different for at least three classes of phospholipids characterized by different numbers of saturated hydrocarbon chains. Most strikingly, cholesterol strongly increases K C when both chains of the phospholipid are fully saturated but not at all when there are two monounsaturated chains

Export Failure and its Consequences: Theory and Evidence

OpenAIRE

Mora, Jesse

2015-01-01

The purpose of this dissertation is to argue that exporting is a risky endeavor and that there are consequences to export failure. Exporters pay high fixed costs to enter foreign markets, yet the majority will not export beyond one year. What happens to these exporters after they fail abroad? For these firms, exporting likely resulted in heavy profit losses. Despite this, trade literature often views exporting as a harmless exercise based on a simple cost-benefit analysis of foreign profits. ...

Dietary cholesterol, heart disease risk and cognitive dissonance.

Science.gov (United States)

McNamara, Donald J

2014-05-01

In the 1960s, the thesis that dietary cholesterol contributes to blood cholesterol and heart disease risk was a rational conclusion based on the available science at that time. Fifty years later the research evidence no longer supports this hypothesis yet changing the dietary recommendation to limit dietary cholesterol has been a slow and at times contentious process. The preponderance of the clinical and epidemiological data accumulated since the original dietary cholesterol restrictions were formulated indicate that: (1) dietary cholesterol has a small effect on the plasma cholesterol levels with an increase in the cholesterol content of the LDL particle and an increase in HDL cholesterol, with little effect on the LDL:HDL ratio, a significant indicator of heart disease risk, and (2) the lack of a significant relationship between cholesterol intake and heart disease incidence reported from numerous epidemiological surveys. Over the last decade, many countries and health promotion groups have modified their dietary recommendations to reflect the current evidence and to address a now recognised negative consequence of ineffective dietary cholesterol restrictions (such as inadequate choline intake). In contrast, health promotion groups in some countries appear to suffer from cognitive dissonance and continue to promote an outdated and potentially hazardous dietary recommendation based on an invalidated hypothesis. This review evaluates the evidence for and against dietary cholesterol restrictions and the potential consequences of such restrictions.

Immobilization of cholesterol esterase and cholesterol oxidase onto sol-gel films for application to cholesterol biosensor

International Nuclear Information System (INIS)

Singh, Suman; Singhal, Rahul; Malhotra, B.D.

2007-01-01

Cholesterol oxidase (ChOx) and cholesterol esterase (ChEt) have been covalently immobilized onto tetraethylorthosilicate (TEOS) sol-gel films. The tetraethylorthosilicate sol-gel/ChEt/ChOx enzyme films thus prepared have been characterized using scanning electron microscopic (SEM), UV-vis spectroscopic, Fourier-transform-infrared (FTIR) spectroscopic and amperometric techniques, respectively. The results of photometric measurements carried out on tetraethylorthosilicate sol-gel/ChEt/ChOx reveal thermal stability up to 55 deg. C, response time as 180 s, linearity up to 780 mg dL -1 (12 mM), shelf life of 1 month, detection limit of 12 mg dL -1 and sensitivity as 5.4 x 10 -5 Abs. mg -1 dL -1

75 FR 52929 - President's Export Council: Meeting of the President's Export Council

Science.gov (United States)

2010-08-30

.... ACTION: Notice of an open meeting. SUMMARY: The President's Export Council will hold a meeting to discuss... how to promote U.S. exports, jobs, and growth. DATES: September 16, 2010 at 9:30 a.m. (EDT). ADDRESSES... trade and report to the President on its activities and on its recommendations for expanding U.S...

In Situ and Real-Time SFG Measurements Revealing Organization and Transport of Cholesterol Analogue 6-Ketocholestanol in a Cell Membrane.

Science.gov (United States)

Ma, Sulan; Li, Hongchun; Tian, Kangzhen; Ye, Shuji; Luo, Yi

2014-02-06

Cholesterol organization and transport within a cell membrane are essential for human health and many cellular functions yet remain elusive so far. Using cholesterol analogue 6-ketocholestanol (6-KC) as a model, we have successfully exploited sum frequency generation vibrational spectroscopy (SFG-VS) to track the organization and transport of cholesterol in a membrane by combining achiral-sensitive ssp (ppp) and chiral-sensitive psp polarization measurements. It is found that 6-KC molecules are aligned at the outer leaflet of the DMPC lipid bilayer with a tilt angle of about 10°. 6-KC organizes itself by forming an α-β structure at low 6-KC concentration and most likely a β-β structure at high 6-KC concentration. Among all proposed models, our results favor the so-called umbrella model with formation of a 6-KC cluster. Moreover, we have found that the long anticipated flip-flop motion of 6-KC in the membrane takes time to occur, at least much longer than previously thought. All of these interesting findings indicate that it is critical to explore in situ, real-time, and label-free methodologies to obtain a precise molecular description of cholesterol's behavior in membranes. This study represents the first application of SFG to reveal the cholesterol-lipid interaction mechanism at the molecular level.

Export controls on high technology

Energy Technology Data Exchange (ETDEWEB)

Frank, N.K.

1987-01-01

A overview of the Export Administration Act of 1979 and subsequent regulations and amendments focuses on how licensing requirements and restrictions against boycott affect high technology exports. The purpose of these controls is to limit the export of technology with possible military applications, as well as to advance US foreign policy and protect the economy without imposing too great a restriction on the principles of free trade. Thus, the act encompasses political, economic, and security goals. Problems of predictability arise when embargoes or other controls are imposed for political or foreign policy reasons without regard to economic impacts. Amendments have attempted to streamline the exporting process, particularly in the area of computer and software licensing.

48 CFR 1825.1103-70 - Export control.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Export control. 1825.1103...-70 Export control. (a) Background. (1) NASA contractors and subcontractors are subject to U.S. export... 120 through 130, and the Export Administration Regulations (EAR), 15 CFR parts 730 through 799. The...

7 CFR 927.12 - Export market.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Export market. 927.12 Section 927.12 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Order Regulating Handling Definitions § 927.12 Export market. Export market means any destination which...

7 CFR 35.8 - Date of export.

Science.gov (United States)

2010-01-01

... 7 Agriculture 2 2010-01-01 2010-01-01 false Date of export. 35.8 Section 35.8 Agriculture... Practices), DEPARTMENT OF AGRICULTURE COMMODITY STANDARDS AND STANDARD CONTAINER REGULATIONS EXPORT GRAPES AND PLUMS Definitions § 35.8 Date of export. Date of export means the date of loading on board the...

Estimation of the Impacts of Non-Oil Traditional and NonTraditional Export Sectors on Non-Oil Export of Azerbaijan

Directory of Open Access Journals (Sweden)

Nicat Hagverdiyev

2016-12-01

Full Text Available The significant share of oil sector of the Azerbaijan export portfolio necessitates promotion of non-oil exports. This study analyzes weather the commodities which contain the main share (more than 70% in non-oil export are traditional or non-traditional areas, using the so-called Commodity-specific cumulative export experience function, for the 1995-2015 time frame. Then, the impact of traditional and non-traditional exports on non-oil GDP investigated employing econometric model. The results of the study based on 16 non-oil commodities show that cotton, tobacco, and production of mechanic devices are traditional sectors in non-oil export. The estimation results of the model indicate that both, traditional and non-traditional non-oil export sectors have economically and statistically significant impact on non-oil GDP.

Iran, a gas exporter?

International Nuclear Information System (INIS)

Therme, C.

2008-01-01

The development of the gas sector has not allowed, up to now, Iran to become one of the main gas actors, whether it is on the regional or international market. This under-development of the gas sector finds expression, each winter, through the Iranian incapability to satisfy its domestic demand as well as its exportation commitments to Turkey or Armenia. In this study, the author tries to examine the origins of Iranian difficulties to increase its gas production and to abide by its commitments to export gas to other countries. The possibility of gas exportation from Iran to the European Union is also discussed

The Role of Macrophage Lipophagy in Reverse Cholesterol Transport

Directory of Open Access Journals (Sweden)

Se-Jin Jeong

2017-03-01

Full Text Available Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis.

Cholesterol-induced conformational changes in the sterol-sensing domain of the Scap protein suggest feedback mechanism to control cholesterol synthesis.

Science.gov (United States)

Gao, Yansong; Zhou, Yulian; Goldstein, Joseph L; Brown, Michael S; Radhakrishnan, Arun

2017-05-26

Scap is a polytopic protein of endoplasmic reticulum (ER) membranes that transports sterol regulatory element-binding proteins to the Golgi complex for proteolytic activation. Cholesterol accumulation in ER membranes prevents Scap transport and decreases cholesterol synthesis. Previously, we provided evidence that cholesterol inhibition is initiated when cholesterol binds to loop 1 of Scap, which projects into the ER lumen. Within cells, this binding causes loop 1 to dissociate from loop 7, another luminal Scap loop. However, we have been unable to demonstrate this dissociation when we added cholesterol to isolated complexes of loops 1 and 7. We therefore speculated that the dissociation requires a conformational change in the intervening polytopic sequence separating loops 1 and 7. Here we demonstrate such a change using a protease protection assay in sealed membrane vesicles. In the absence of cholesterol, trypsin or proteinase K cleaved cytosolic loop 4, generating a protected fragment that we visualized with a monoclonal antibody against loop 1. When cholesterol was added to these membranes, cleavage in loop 4 was abolished. Because loop 4 is part of the so-called sterol-sensing domain separating loops 1 and 7, these results support the hypothesis that cholesterol binding to loop 1 alters the conformation of the sterol-sensing domain. They also suggest that this conformational change helps transmit the cholesterol signal from loop 1 to loop 7, thereby allowing separation of the loops and facilitating the feedback inhibition of cholesterol synthesis. These insights suggest a new structural model for cholesterol-mediated regulation of Scap activity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Suppression of cholesterol synthesis in cultured fibroblasts from a patient with homozygous familial hypercholesterolemia by her own low density lipoprotein density fraction. A possible role of apolipoprotein E

NARCIS (Netherlands)

Havekes, L.; Vermeer, B.J.; Wit, E. de

1980-01-01

The suppression of cellular cholesterol synthesis by low density lipoprotein (LDL) from a normal and from a homozygous familial hypercholesterolemic subject was measured on normal fibroblasts and on fibroblasts derived from the same homozygous familial hypercholesterolemic patient. On normal

Nori- and sea spaghetti- but not wakame-restructured pork decrease the hypercholesterolemic and liver proapototic short-term effects of high-dietary cholesterol consumption.

Science.gov (United States)

Schultz Moreira, Adriana R; Benedi, Juana; Bastida, Sara; Sánchez-Reus, Isabel; Sánchez-Muniz, Francisco J

2013-01-01

Restructured pork (RP) enriched in Seaweeds are potential functional foods. The antiapoptotic and hypocholesterolemic effects of consuming cholesterol enriched diets containing Wakame-RP (CW), Nori-RP (CN) and Sea Spaghetti (CS) were tested in a 1-wk study. Groups of six rats per group were fed a mix of 85% AIN-93M rodent-diet containing cholesterol and cholic acid as a cholesterol rising agent plus 15% RP containing alga. These diets were compared to control-RP diets enriched or not in cholesterol (CC and C, respectively). After 1-wk, cholesterol feeding significantly increased liver apoptosis markers which were significantly reduced by CS (cellular cycle DNA, caspase-3, and cytochrome c), CN (caspase-3 and cytochrome c) and CW (caspase-3) diets. CN and CS diets significantly blocked the cholesterolaemic rising effect observed in the CC group but no protective effect was observed in the CW group. Differences in seaweed composition added to RP appear responsible for blocking or not the proapoptotic and hypercholesterolemic effects of high cholesterol-RP consumption; thus, any generalization on seaweed effects or food containing seaweeds must be avoided. Although present results are worthy, future studies are demanded to ascertain the utility of consuming algal-RP as part of usual diets. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

21 CFR 1312.22 - Application for export permit.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Application for export permit. 1312.22 Section... EXPORTATION OF CONTROLLED SUBSTANCES Exportation of Controlled Substances § 1312.22 Application for export permit. (a) An application for a permit to export controlled substances shall be made on DEA Form 161...

19 CFR 10.66 - Articles exported for temporary exhibition and returned; horses exported for horse racing and...

Science.gov (United States)

2010-04-01

... exportation of such articles, an application on Customs Form 4455 (accompanied by an appropriate inventory... 19 Customs Duties 1 2010-04-01 2010-04-01 false Articles exported for temporary exhibition and... ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported for...

Cholesterol metabolism in blood cells of irradiated rats

International Nuclear Information System (INIS)

Novoselova, E.G.; Kulagina, T.P.; Potekhina, N.I.

1985-01-01

Cholesterol metabolism in blood erythrocytes and lymphocytes of irradiated rats has been investigated. It has been found that at all terms and doses of irradiation, a suppression of the synthesis of erythrocyte cholesterol is observed. The increase of cholesterol quantiy in erythrocytes upon total gamma irradiation in the 10 Gr dose possibly is the result of growth of cholesterol transfer from plasma into erythrocyte cells. The study of the cholesterol synthesis in suspension of lymphocytes elminated from peripheral blood of control and irradiated rats has shown that at irradiation doses of 4 and 10 Gr in an hour acivation of cholesterol synthesis in vitro takes places

27 CFR 28.216 - Export marks.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Export marks. 28.216 Section 28.216 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS EXPORTATION OF ALCOHOL Exportation of Wine With Benefit of Drawback § 28.216...

75 FR 12433 - National Export Initiative

Science.gov (United States)

2010-03-16

... Order 13534 of March 11, 2010 National Export Initiative By the authority vested in me as President by... performance will, in turn, create good high-paying jobs. The National Export Initiative (NEI) shall be an Administration initiative to improve conditions that directly affect the private sector's ability to export. The...

Immobilization of cholesterol esterase and cholesterol oxidase onto sol-gel films for application to cholesterol biosensor

Energy Technology Data Exchange (ETDEWEB)

Singh, Suman [Central Mechanical Engineering Research Institute, G. Avenue, Durgapur 713209, West Bengal (India); Singhal, Rahul [Biomolecular Electronics and Conducting Polymer Research Group, National Physical Laboratory, Dr. K.S. Krishnan Marg, New Delhi 110012 (India); Malhotra, B.D. [Biomolecular Electronics and Conducting Polymer Research Group, National Physical Laboratory, Dr. K.S. Krishnan Marg, New Delhi 110012 (India)]. E-mail: bansi.malhotra@gmail.com

2007-01-23

Cholesterol oxidase (ChOx) and cholesterol esterase (ChEt) have been covalently immobilized onto tetraethylorthosilicate (TEOS) sol-gel films. The tetraethylorthosilicate sol-gel/ChEt/ChOx enzyme films thus prepared have been characterized using scanning electron microscopic (SEM), UV-vis spectroscopic, Fourier-transform-infrared (FTIR) spectroscopic and amperometric techniques, respectively. The results of photometric measurements carried out on tetraethylorthosilicate sol-gel/ChEt/ChOx reveal thermal stability up to 55 deg. C, response time as 180 s, linearity up to 780 mg dL{sup -1} (12 mM), shelf life of 1 month, detection limit of 12 mg dL{sup -1} and sensitivity as 5.4 x 10{sup -5} Abs. mg{sup -1} dL{sup -1}.

A Study on Improvement of Export Control law's understanding for nuclear control items' exporters in Rep. of Korea

Energy Technology Data Exchange (ETDEWEB)

Lim, Dong Hyuk; Choi, Sun Do; Yang, Seung Hyo [Korea Institute of Nuclear Nonproliferation and Control, Daejeon (Korea, Republic of)

2011-10-15

According to export of UAE commercial reactor and JRTR(Jordan Research and Training Reactor) in 2009, Korea's international prestige has enhanced and it has been more important for researcher in charge of export control to understand and carry out duties on export control by obeying Nuclear Suppliers Group(NSG) Guidelines. Currently, the NSG tries to prevent the proliferation of nuclear weapons by harmonising export control systems of participating countries in relation to trade with nuclear commodities and nuclear-related dual-use materials, equipment, software and technology. In addition, through the implementation of two sets of Guidelines for nuclear exports and nuclear-related exports, the NSG aims to ensure that nuclear trade for peaceful purposes does not contribute to the proliferation of nuclear weapons or other nuclear explosive devices, and that international trade and cooperation in the nuclear field is not hindered unjustly in the process. However, there is still not a little confusion of export businesses owing to lack of understanding of nuclear items in Korea. Therefore, by correctly understanding export control systems, permits and licenses, ITT and persistingly communicating with export businesses, Researchers in charge of export control are able to eliminate confusion of production businesses regarding export and establish a export control culture

The effects of phytosterols present in natural food matrices on cholesterol metabolism and LDL-cholesterol: a controlled feeding trial.

Science.gov (United States)

Lin, X; Racette, S B; Lefevre, M; Spearie, C A; Most, M; Ma, L; Ostlund, R E

2010-12-01

Extrinsic phytosterols supplemented to the diet reduce intestinal cholesterol absorption and plasma low-density lipoprotein (LDL)-cholesterol. However, little is known about their effects on cholesterol metabolism when given in native, unpurified form and in amounts achievable in the diet. The objective of this investigation was to test the hypothesis that intrinsic phytosterols present in unmodified foods alter whole-body cholesterol metabolism. In all, 20 out of 24 subjects completed a randomized, crossover feeding trial wherein all meals were provided by a metabolic kitchen. Each subject consumed two diets for 4 weeks each. The diets differed in phytosterol content (phytosterol-poor diet, 126 mg phytosterols/2000 kcal; phytosterol-abundant diet, 449 mg phytosterols/2000 kcal), but were otherwise matched for nutrient content. Cholesterol absorption and excretion were determined by gas chromatography/mass spectrometry after oral administration of stable isotopic tracers. The phytosterol-abundant diet resulted in lower cholesterol absorption (54.2±2.2% (95% confidence interval 50.5%, 57.9%) vs 73.2±1.3% (69.5%, 76.9%), Pphytosterol-poor diet. Plasma lathosterol/cholesterol ratio rose by 82% (from 0.71±0.11 (0.41, 0.96) to 1.29±0.14 μg/mg (0.98, 1.53), Pphytosterols at levels present in a healthy diet are biologically active and have large effects on whole-body cholesterol metabolism not reflected in circulating LDL. More work is needed to assess the effects of phytosterol-mediated fecal cholesterol excretion on coronary heart disease risk in humans.

Exports of petroleum products, 1990

International Nuclear Information System (INIS)

1991-04-01

A summary is presented of exports of motor gasoline, middle distillate, aviation turbine fuel, heavy fuel oil, and partially processed oil from Canada for the 1990 calendar year. Exports of the above petroleum products averaged 34,000 m 3 /d in 1990, up 12% from 1989 levels. The increase reflects increased output from the Come By Chance refinery in Newfoundland. Motor gasoline exports increased 35% to 10,500 m 3 /d, reflecting refinery upgrading in eastern Canada. Export prices were generally in line with spot product prices in the USA. Spot prices rose sharply following the Kuwait crisis in August 1990 but fell again in November. The spot price for jet fuel rose more dramatically in that period than for other products, reflecting increased military demand. In winter 1989/90 and during the Kuwait conflict, the export price of heating oil tended to track the USA spot price. Petroleum products imports in 1990 were 18,500 m 3 /d, compared to 21,900 m 3 /d in 1988. Imports were lower partially as a result of higher crude runs in Quebec and a Quebec refinery expansion. Imports of heavy fuel oil in eastern Canada continued to be strong in comparison to the mid-1980s. The top single exporter in 1990, as in 1989, was Newfoundland Processing, with a volume of 4,506,400 m 3 . 13 figs., 5 tabs

Exports of petroleum products, 1989

International Nuclear Information System (INIS)

1990-04-01

A summary is presented of exports of motor gasoline, middle distillate, aviation turbine fuel, heavy fuel oil, and partially processed oil from Canada for the 1989 calendar year. A discussion of petroleum product imports is included in order to put exports in the context of the overall trade. Exports of the above petroleum products averaged 30,400 m 3 /d in 1989, down 5% from 1988 levels. Motor gasoline shipments showed the largest decrease, down 1,500 m 3 to 7,700 m 3 /d. Export prices for light petroleum products stayed relatively close to USA spot prices except in June and July 1989, when attractive prices were obtained for shipments from the prairie provinces. The heavy fuel oil export price was similar to the USA east coast spot price in 1989, except in December. Canada's petroleum products imports in 1989 were 21,600 m 3 /d, compared to 18,400 m 3 /d in 1988. Imports of heavy fuel oil in eastern Canada rose 36% in 1989 because of industries switching from electricity and the high demand for thermal power generation. The USA remained Canada's largest trading partner in petroleum products. The top single exporter in 1989, as in 1988, was Newfoundland Processing, with a volume of 3,484,500 m 3 . 24 figs., 4 tabs

Status of non-HDL-cholesterol and LDL-cholesterol among subjects with and without metabolic syndrome.

Science.gov (United States)

Khan, Sikandar Hayat; Asif, Naveed; Ijaz, Aamir; Manzoor, Syed Mohsin; Niazi, Najumusaquib Khan; Fazal, Nadeem

2018-04-01

To to compare non-high-density lipoprotein and low-density lipoprotein cholesterol among subjects with or without metabolic syndrome, glycation status and nephropathic changes. The comparative cross-sectional study was carried out from Dec 21, 2015, to Nov 15, 2016, at the department of pathology and medicine PNS HAFEEZ and department of chemical pathology and clinical endocrinology (AFIP), and comprised patients of either gender visiting the out-patient department for routine screening. They were evaluated for anthropometric indices, blood pressure and sampled for lipid profile, fasting plasma glucose, glycated haemoglobin, insulin, and urine albumin-to-creatinine ratio. Subjects were segregated based upon presence (Group1) or absence (Group2) of metabolic syndrome based upon criteria of National Cholesterol Education Programme and the International Diabetes Federation. Differences in high and low density lipoprotein cholesterols were calculated between the groups. Of the 229 subjects, 120(52.4%) were women and 109(47.6%) were men. Overall, there were 107(46.7%) subjects in Group 1, and 122(53.3%) in Group 2. Non-high-density lipoprotein cholesterol was significantly different between subjects with and without metabolic syndrome as per both the study criteria (p<0.05 each). . Non-high-density lipoprotein cholesterol levels were higher in subjects with metabolic syndrome.

21 CFR 1312.23 - Issuance of export permit.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Issuance of export permit. 1312.23 Section 1312.23... CONTROLLED SUBSTANCES Exportation of Controlled Substances § 1312.23 Issuance of export permit. (a) The... regulation in § 1312.30 of this part be exported only pursuant to the issuance of an export permit. The...

The Export Promoting Effect of Emigration

DEFF Research Database (Denmark)

Hiller, Sanne

The theoretical claim that ethnic networks encourage trade has found broad empirical support in the literature on migration, business networks and international trade. Ethnic networks matter for the exporting firm, as they exhibit the potential to lower fixed and variable cost of exporting....... This paper provides a first attempt to identify the export-promoting effect of emigration on the firm level. Using detailed Danish firm-level data, we can parsimoniously control for export determinants other than emigration, unobserved heterogeneity at the firm level, as well as for self-selection of firms...... into exporting. Additionally accounting for taste similarity between Denmark and its trade partners, our findings suggest a positive effect of emigration on Danish manufacturing trade within Europe, thereby corroborating preceding studies on aggregate data. Nevertheless, as a novel insight, our analysis reveals...

Manipulation of Host Cholesterol by Obligate Intracellular Bacteria

Directory of Open Access Journals (Sweden)

Dhritiman Samanta

2017-05-01

Full Text Available Cholesterol is a multifunctional lipid that plays important metabolic and structural roles in the eukaryotic cell. Despite having diverse lifestyles, the obligate intracellular bacterial pathogens Chlamydia, Coxiella, Anaplasma, Ehrlichia, and Rickettsia all target cholesterol during host cell colonization as a potential source of membrane, as well as a means to manipulate host cell signaling and trafficking. To promote host cell entry, these pathogens utilize cholesterol-rich microdomains known as lipid rafts, which serve as organizational and functional platforms for host signaling pathways involved in phagocytosis. Once a pathogen gains entrance to the intracellular space, it can manipulate host cholesterol trafficking pathways to access nutrient-rich vesicles or acquire membrane components for the bacteria or bacteria-containing vacuole. To acquire cholesterol, these pathogens specifically target host cholesterol metabolism, uptake, efflux, and storage. In this review, we examine the strategies obligate intracellular bacterial pathogens employ to manipulate cholesterol during host cell colonization. Understanding how obligate intracellular pathogens target and use host cholesterol provides critical insight into the host-pathogen relationship.

[Phytosterols: another way to reduce LDL cholesterol levels].

Science.gov (United States)

Bitzur, Rafael; Cohen, Hofit; Kamari, Yehuda; Harats, Dror

2013-12-01

Phytosterols are sterols found naturally in various oils from plants. Phytosterols compete with cholesterol for a place in the mixed micelles, needed for cholesterol absorption by the small intestine. As a result, cholesterol absorption, either from food or from bile salts is lowered by about 50%, leading to a towering of about 10% of blood cholesterol level, despite an increase in hepatic cholesterol synthesis. This reduction is achieved when phytosterols are given both as monotherapy, and in addition to statin therapy. The average Western diet contains about 400-800 mg of phytosterols per day, while the dose needed for lowering the blood cholesterol level is about 2-3 grams per day. Therefore, for the purpose of reducing blood cholesterol, they should be given either as phytosterol-enriched food or as supplements. The reduction in the level of LDL-choLesterol achieved with phytosterols may reduce the risk of coronary disease by about 25%. Hence, the American Heart Association recommended the consumption of phytosterols, as part of a balanced diet, for towering blood cholesterol levels.

Transport of cholesterol autoxidation products in rabbit lipoproteins

International Nuclear Information System (INIS)

Peng, Shi-Kaung; Phillips, G.A.; Xia, Guang-Zhi; Morin, R.J.

1987-01-01

Radiolabeled pure [4- 14 C] cholesterol was kept at 60 0 C under air to autoxidize for 5 weeks, after which approximately 12% cholesterol oxidation products were formed. The mixture, suspended in gelatin, was given to rabbits by gastric gavage. Rabbits were killed 4, 24 and 48 h after treatment. Cholesterol and its autoxidation products were separated by thin-layer chromatography into 5 fractions and radioactivities of each fraction were measured. Percentages of each fraction of cholesterol oxidation products and cholesterol in the original mixture before administration and in the rabbit sera after administration were similar, suggesting that the rates of absorption of cholesterol oxidation products are not significantly different from that of cholesterol. Lipoproteins were fractioned by ultracentrifugation into VLDL, LDL and HDL. Radioactivities of each fraction in lipoproteins separated by thin layer chromatography showed that fractions containing cholestane-3β, 5α, 6β-triol, 7α- and 7β-hydroxycholesterol and 7-ketocholesterol were more selectively transported in VLDL, whereas most of the 25-hydroxycholesterol was present in LDL. HDL contained only minute amounts of cholesterol oxidation products. 22 refs

HDL cholesterol: atherosclerosis and beyond

NARCIS (Netherlands)

Bochem, A.E.

2013-01-01

Cardiovascular disease (CVD) is the leading cause of death in the Western world. Myocardial infarction and stroke are the result of a compromised blood flow which may result from cholesterol accumulation in the vessel wall due to high plasma levels of LDL cholesterol. High plasma levels of HDL

Cholesterol oxidation products and their biological importance

DEFF Research Database (Denmark)

Kulig, Waldemar; Cwiklik, Lukasz; Jurkiewicz, Piotr

2016-01-01

The main biological cause of oxysterols is the oxidation of cholesterol. They differ from cholesterol by the presence of additional polar groups that are typically hydroxyl, keto, hydroperoxy, epoxy, or carboxyl moieties. Under typical conditions, oxysterol concentration is maintained at a very low...... and precisely regulated level, with an excess of cholesterol. Like cholesterol, many oxysterols are hydrophobic and hence confined to cell membranes. However, small chemical differences between the sterols can significantly affect how they interact with other membrane components, and this in turn can have...

27 CFR 28.223 - Export marks.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Export marks. 28.223... Export marks. In addition to the marks and brands required to be placed on kegs, barrels, cases, crates... “Export” on each container or case before removal for export, for use on vessels or aircraft, or for...