Sample records for apolipoprotein c-i identifies

  1. A prominent large high-density lipoprotein at birth enriched in apolipoprotein C-I identifies a new group of infancts of lower birth weight and younger gestational age

    Energy Technology Data Exchange (ETDEWEB)

    Kwiterovich Jr., Peter O.; Cockrill, Steven L.; Virgil, Donna G.; Garrett, Elizabeth; Otvos, James; Knight-Gibson, Carolyn; Alaupovic, Petar; Forte, Trudy; Farwig, Zachlyn N.; Macfarlane, Ronald D.


    Because low birth weight is associated with adverse cardiovascular risk and death in adults, lipoprotein heterogeneity at birth was studied. A prominent, large high-density lipoprotein (HDL) subclass enriched in apolipoprotein C-I (apoC-I) was found in 19 percent of infants, who had significantly lower birth weights and younger gestational ages and distinctly different lipoprotein profiles than infants with undetectable, possible or probable amounts of apoC-I-enriched HDL. An elevated amount of an apoC-I-enriched HDL identifies a new group of low birth weight infants.

  2. Human apolipoprotein C-I expression in mice impairs learning and memory functions

    NARCIS (Netherlands)

    Abildayeva, Karlygash; Berbee, Jimmy F. P.; Blokland, Arjan; Jansen, Paula J.; Hoek, Frans J.; Meijer, Onno; Luetjohann, Dieter; Gautier, Thomas; Pillot, Thierry; De Vente, Jan; Havekes, Louis M.; Ramaekers, Frans C. S.; Kuipers, Folkert; Rensen, Patrick C. N.; Mulder, Monique


    The H2 allele of APOC I, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hi

  3. Human apolipoprotein C-I expression in mice impairs learning and memory functions

    NARCIS (Netherlands)

    Abildayeva, K.; Berbée, J.F.P.; Blokland, A.; Jansen, P.J.; Hoek, F.J.; Meijer, O.; Lütjohann, D.; Gautier, T.; Pillot, T.; Vente,; Havekes, L.M.; Ramaekers, F.C.S.; Kuipers, F.; Rensen, P.C.N.; Mulder, M.


    The H2 allele of APOC1, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hip


    Institute of Scientific and Technical Information of China (English)

    王克勤; 吕新跃; 吴钢; 薛红; 陈保生


    A rabbit anti-serum to tree shrew apolipoprotein C-I (apo C-l) was used to screen an expression cDNA li-braDy constructed by us from tree shrew (TS) liver tissue. Two apo C-I cDNA clones were obtained. The longerone consists of 380 nucleotides, including 21 bp and 95 bp at the 5' and 3' end of the non-translated region srespectively, and a 2 64-bp fragment in an open reading frame encoding 88 amino acids prepropeptide which con-ta-ins 26 amino acids of signal peptide and a mature protein (62 amino acids). Comparing the amino-acid se-quence deduced from this cDNA with those of the published mammalian apo C-Is reveals that it shared some struc-tural similarity with zat, mouse and dog apo C-l, but it had 5 more amino acids than that of human and baboon.The expression of apo C-I mRNA in 8 different tissues were also assayed with Northern blot. The results demonstrat-ed that liver had the highest expression, intestine had much less expression and no expression in other tissues,which is much different from human and other species. This study has laid down a good foundation for further study-ing on the function and the stucture of tree shrew apo C-I gene.``

  5. Effect of Synthetic Truncated Apolipoprotein C-I Peptide on Plasma Lipoprotein Cholesterol in Nonhuman Primates

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    Rampratap S. Kushwaha


    Full Text Available The present studies were conducted to determine whether a synthetic truncated apoC-I peptide that inhibits CETP activity in baboons would raise plasma HDL cholesterol levels in nonhuman primates with low HDL levels. We used 2 cynomolgus monkeys and 3 baboons fed a cholesterol- and fat-enriched diet. In cynomolgus monkeys, we injected synthetic truncated apoC-I inhibitor peptide at a dose of 20 mg/kg and, in baboons, at doses of 10, 15, and 20 mg/kg at weekly intervals. Blood samples were collected 3 times a week and VLDL + LDL and HDL cholesterol concentrations were measured. In cynomolgus monkeys, administration of the inhibitor peptide caused a rapid decrease in VLDL + LDL cholesterol concentrations (30%–60% and an increase in HDL cholesterol concentrations (10%–20%. VLDL + LDL cholesterol concentrations returned to baseline levels in approximately 15 days. In baboons, administration of the synthetic inhibitor peptide caused a decrease in VLDL + LDL cholesterol (20%–60% and an increase in HDL cholesterol (10%–20%. VLDL + LDL cholesterol returned to baseline levels by day 21, whereas HDL cholesterol concentrations remained elevated for up to 26 days. ApoA-I concentrations increased, whereas apoE and triglyceride concentrations decreased. Subcutaneous and intravenous administrations of the inhibitor peptide had similar effects on LDL and HDL cholesterol concentrations. There was no change in body weight, food consumption, or plasma IgG levels of any baboon during the study. These studies suggest that the truncated apoC-I peptide can be used to raise HDL in humans.

  6. The isolation and identification of apolipoprotein C-I in hormone-refractory prostate cancer using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry

    Institute of Scientific and Technical Information of China (English)

    Kaori Yamamoto-Ishikawa; Hiroyoshi Suzuki; Masahiko Nezu; Naoto Kamiya; Takashi Imamoto; Akira Komiya; Kazuyuki Sogawa; Takeshi Tomonaga; Fumio Nomura; Tomohiko Ichikawa


    Androgens play a central role in prostate cancer pathogenesis, and hence most of the patients respond to androgen deprivation therapies. However, patients tend to relapse with aggressive prostate cancer, which has been termed as hormone refractory. To identify the proteins that mediate progression to the hormone-refractory state, we used protein-chip technology for mass profiling of patients' sera. This study included 16 patients with metastatic hormone-refractory prostate cancer who were initially treated with androgen deprivation therapy. Serum samples were collected from each patient at five time points: point A, pre-treatment; point B, at the nadir of the prostate-specific antigen (PSA) level; point C, PSA failure; point D, the early hormone-refractory phase; and point E, the late hormone-refractory phase. Using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, we performed protein mass profiling of the patients' sera and identified a 6 640-Da peak that increased with disease progression. Target proteins were partially purified, and by amino acid sequencing the peak was identified as a fragment of apolipoprotein C-I (ApoC-I). Serum ApoC-I protein levels increased with disease progression. On immunohistochemical analysis, the ApoC-I protein was found localized to the cytoplasm of the hormone-refractory cancer cells. In this study, we showed an increase in serum ApoC-I protein levels in prostate cancer patients during their progression to the hormone-refractory state, which suggests that ApoC-I protein is related to progression of prostate cancer. However, as the exact role of ApoC-I in prostate cancer pathogenesis is unclear, further research is required.

  7. Apolipoprotein A5: A newly identified gene impacting plasmatriglyceride levels in humans and mice

    Energy Technology Data Exchange (ETDEWEB)

    Pennacchio, Len A.; Rubin, Edward M.


    Apolipoprotein A5 (APOA5) is a newly described member of theapolipoprotein gene family whose initial discovery arose from comparativesequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functionalstudies in mice indicated that alteration in the level of APOA5significantly impacted plasma triglyceride concentrations. Miceover-expressing human APOA5 displayed significantly reducedtriglycerides, while mice lacking apoA5 had a large increase in thislipid parameter. Studies in humans have also suggested an important rolefor APOA5 in determining plasma triglyceride concentrations. In theseexperiments, polymorphisms in the human gene were found to define severalcommon haplotypes that were associated with significant changes intriglyceride concentrations in multiple populations. Several separateclinical studies have provided consistent and strong support for theeffect with 24 percent of Caucasians, 35 percent of African-Americans and53 percent of Hispanics carrying APOA5 haplotypes associated withincreased plasma triglyceride levels. In summary, APOA5 represents anewly discovered gene involved in triglyceride metabolism in both humansand mice whose mechanism of action remains to be deciphered.

  8. Apolipoprotein CI knock-out mice display impaired memory functions

    NARCIS (Netherlands)

    Berbée, J.F.P.; Abildayeva, K.; Blokland, A.; Jansen, P.J.; Lütjohann, D.; Gautier, T.; Sijbrands, E.; Prickaerts, J.; Hadfoune, M.; Ramaekers, F.C.S.; Kuipers, F.; Rensen, P.C.N.


    The e4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer's disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that the H2

  9. Apolipoprotein CI Knock-Out Mice Display Impaired Memory Functions

    NARCIS (Netherlands)

    Berbee, Jimmy F. P.; Vanmierlo, Tim; Abildayeva, Karlygash; Blokland, Arjan; Jansen, Paula J.; Luetjohann, Dieter; Gautier, Thomas; Sijbrands, Eric; Prickaerts, Jos; Hadfoune, M'hamed; Ramaekers, Frans C. S.; Kuipers, Folkert; Rensen, Patrick C. N.; Mulder, Monique


    The epsilon 4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer's disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that

  10. Apolipoprotein M

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Dahlbäck, B; Nielsen, L B


    ApoM is a novel apolipoprotein mainly present in high-density lipoprotein (HDL). It belongs to the lipocalin protein superfamily and may bind a small but so far unknown lipophilic ligand. It is secreted without cleavage of its hydrophobic signal peptide, which probably anchors apoM...... in the phospholipid moiety of plasma lipoproteins. Recent studies suggest that apoM may affect HDL metabolism and have anti-atherogenic functions. The subfraction of human HDL that contains apoM therefore protects LDL from oxidation and mediates cholesterol efflux more efficiently then HDL without apoM. In addition...... to hepatocytes, apoM is highly expressed in kidney proximal tubule cells. Recent data suggest that apoM is secreted into the pre-urine from the tubule cells but is normally taken up again in a megalin-dependent fashion. Further studies of mice with genetically modified apoM expression will be essential...

  11. Apolipoprotein M

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Nielsen, Lars Bo


    Purpose of review: The review will address the potential roles of apolipoprotein M (apoM) as a carrier protein and modulator of sphingosine-1-phosphate (S1P) bioactivity. Recent findings: Recombinant apoM can bind small lipids such as retinoic acid, oxidized phospholipids, and S1P. Thus......, the effects of apoM may be pleiotrophic. The S1P binding ability of apoM has biological impact. ApoM-bound S1P can activate S1P1 receptors on endothelial cells and deficiency of apoM abolishes the presence of S1P in HDL. In mice, the lack of apoM causes dysfunctional endothelial barrier function in the lungs....... In humans, sepsis that is characterized by impaired endothelial function is associated with low plasma apoM. Summary: Plasma apoM is mainly bound to HDL. The roles of apoM in atherosclerosis and lipoprotein metabolism have been given much attention. New in the field is the discovery of apoM as a chaperone...

  12. Apolipoprotein M

    Directory of Open Access Journals (Sweden)

    Nilsson-Ehle Peter


    Full Text Available Abstract Apolipoprotein M (apoM is a 26-kDa protein that is mainly associated with high-density lipoprotein (HDL in human plasma, with a small proportion present in triglyceride-rich lipoproteins (TGRLP and low-density lipoproteins (LDL. Human apoM gene is located in p21.31 on chromosome 6 (chromosome 17, in mouse. Human apoM cDNA (734 base pairs encodes 188-amino acid residue-long protein. It belongs to lipocalin protein superfamily. Human tissue expression array study indicates that apoM is only expressed in liver and in kidney and small amounts are found in fetal liver and kidney. In situ apoM mRNA hybridization demonstrates that apoM is exclusively expressed in the hepatocytes and in the tubule epithelial cells in kidney. Expression of apoM could be regulated by platelet activating factor (PAF, transforming growth factors (TGF, insulin-like growth factor (IGF and leptin in vivo and/or in vitro. It has been demonstrated that apoM expression is dramatically decreased in apoA-I deficient mouse. Hepatocyte nuclear factor-1α (HNF-1α is an activator of apoM gene promoter. Deficiency of HNF-1α mouse shows lack of apoM expression. Mutations in HNF-1α (MODY3 have reduced serum apoM levels. Expression of apoM is significantly decreased in leptin deficient (ob/ob mouse or leptin receptor deficient (db/db mouse. ApoM concentration in plasma is positively correlated to leptin level in obese subjects. These may suggest that apoM is related to the initiation and progression of MODY3 and/or obesity.

  13. Apolipoprotein E gene polymorphisms as risk factors for carotid atherosclerosis

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    Zurnić Irena


    Full Text Available Background/Aim. Atherosclerosis is still the leading cause of death in Western world. Development of atherosclerotic plaque involves accumulation of inflammatory cells, lipids, smooth muscle cells and extracellular matrix proteins in the intima of the vascular wall. Apolipoprotein E participates in the transport of exogenous cholesterol, endogenouly synthesized lipids and triglycerides in the organism. Apolipoprotein E gene has been identified as one of the candidate genes for atherosclerosis. Previous studies in different populations have clearly implicated apolipoprotein E genetic variation (ε polymorphisms as a major modulator of low density lipoprotein cholesterol levels. Data considering apolipoprotein E polymorphisms in relation to carotid atherosclerosis gave results that are not in full compliance. The aim of present study was to investigate the apolipoprotein E polymorphisms in association with carotid plaque presence, apolipoprotein E and lipid serum levels in patients with carotid atherosclerosis from Serbia. Methods. The study group enrolled 495 participants: 285 controls and 210 consecutive patients with carotid atherosclerosis who underwent carotid endarterectomy. Genotyping of apolipoprotein E polymorphisms were done using polymerase chain reaction and restriction fragment length polymorphism methods. Results. Patients had significantly decreased frequency of the ε2 allele compared to controls. Patients who carry at least one ε2 allele had a significantly higher level of serum apolipoprotein E and significantly lower low density lipoprotein cholesterol levels compared to those who do not carry this allele. Conclusion. Our results suggest protective effect of apolipoprotein E ε2 allele on susceptibility for carotid plaque presence as well as low density lipoprotein cholesterol lowering effect in Serbian patients with carotid atherosclerosis. Further research of multiple gene and environmental factors that contribute to the

  14. Clinical chemistry of common apolipoprotein E isoforms

    NARCIS (Netherlands)

    Brouwer, DAJ; vanDoormaal, JJ; Muskiet, FAJ


    Apolipoprotein E plays a central role in clearance of lipoprotein remnants by serving as a ligand for low-density lipoprotein and apolipoprotein E receptors. Three common alleles (apolipoprotein E(2), E(3) and E(4)) give rise to six phenotypes. Apolipoprotein E(3) is the ancestral form. Common apoli

  15. Role of apolipoprotein CI in lipid metabolism and bacterial sepsis

    NARCIS (Netherlands)

    Berbée, Jimmy Fransiscus Paulus


    The research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1¬-transgenic and apoc1-/- mice, we were able to identify apoCI as a potent inhibitor of triglyceride hydro

  16. Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma

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    Xianglan eYao


    Full Text Available New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR and goblet cell hyperplasia is mediated by low density lipoprotein (LDL receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130 to 149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE-/- mice. These findings identified the apolipoprotein E - LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease.

  17. C.I.M.E. Summer School

    CERN Document Server


    The C.I.M.E. session on Mathematical Problems in Semiconductor Physics, was addressed to researchers with a strong interest in the mathematical aspects of the theory of carrier transport in semiconductor devices. The subjects covered include hydrodynamical models for semiconductors based on the maximum entropy principle of extended thermodynamics, mathematical theory of drift-diffusion equations with applications, and the methods of asymptotic analysis.

  18. C.I.M.E. Summer School

    CERN Document Server

    Behrend, Kai; Tarasov, Vitaly; Tian, Gang; Quantum Cohomology


    The book gathers the lectures given at the C.I.M.E. summer school "Quantum Cohomology" held in Cetraro (Italy) from June 30th to July 8th, 1997. The lectures and the subsequent updating cover a large spectrum of the subject on the field, from the algebro-geometric point of view, to the symplectic approach, including recent developments of string-branes theories and q-hypergeometric functions.

  19. Apolipoprotein M - a new biomarker in sepsis

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Nielsen, Lars Bo


    Care Kumaraswamy and colleagues have investigated whether plasma apolipoprotein M (apoM) is affected during different grades of sepsis, septic shock and systemic inflammatory response syndrome. Interestingly, plasma apoM was significantly decreased in all groups of patients with a relationship...... to severity of disease. This identifies apoM as a potential new biomarker in sepsis. It also underscores the possibility that altered high-density lipoprotein in sepsis patients can affect the course of disease. Thus, since apoM is the carrier of Sphingosine-1-P (S1P), a molecule with great influence...... on vascular barrier function, the study presented raises the interest and relevance for further studies of apoM and S1P in relation to sepsis and inflammation....

  20. C.I.M.E. Summer School

    CERN Document Server


    The C.I.M.E. session on Dynamical Systems, held in Cetraro (Italy), June 19-26, 2000, focused on the latest developments in several important areas in dynamical systems, with full development and historical context. The lectures of Chow and Mallet-Paret focus on the area of lattice differential systems, the lectures of Conto and Galleotti treat the classical problem of classification of orbits for two-dimensional autonomous systems with polynomial right sides, the lectures of Nussbaum focus on applications of fixed point theorems to the problem of limiting profiles for the solutions of singular perturbations of delay differential equations, and the lectures of Johnson and Mantellini deal with the existence of periodic and quasi-periodic orbits to non-autonomous systems. The volume will be of interest to researchers and graduate students working in these areas. .

  1. Cloning and characterization of a novel apolipoprotein gene, apolipoprotein AV, in tree shrews. (United States)

    Li, Guoping; Luo, Huairong; Sun, Guotao; Wu, Guisheng; Wu, Gang; Wang, Yan; Man, Yong; Wang, Shu; Li, Jian; Chen, Baosheng


    Apolipoprotein AV (apoAV) modulates plasma triglyceride levels, which is an independent risk factor for cardiovascular disease. ApoAV is also involved in atherosclerosis lesion formation. In order to systematically evaluate the apolipoprotein-related gene profile in tree shrew, a model for its insusceptibility to atherosclerosis, we performed apoAV cloning and characterization. The full-length cDNA of apoAV was identified using SMART-RACE. ApoAV cDNA sequence revealed two transcripts, 1,948 and 1,397 base pairs, due to alternative polyadenylation. These two transcripts share the same open reading frame (ORF), which encodes a 369-amino acid protein with high identity to human apoAV (75 %), including a 23-amino acid N-terminal signal peptide. ApoAV is expressed exclusively in the liver. Mature apoAV was expressed in E. coli BL21(DE3) and purified by Ni-chelated resin. Lipoprotein lipase activity was significantly stimulated by this recombinant protein. The full-length ORF of apoAV was cloned into pDsRed-monomer-N1 vector with a red fluorescent protein tag and was primarily localized in cytoplasm of hepG2 cells. The successful cloning, expression and localization of apoAV in tree shrew has laid down the foundation for further investigation on its structure and functions.

  2. Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease

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    Perelas Apostolos


    Full Text Available Abstract Background Visceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center. Methods 35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay: apolipoprotein A-I (apoAI, apolipoprotein A-II (apoAII, apolipoprotein B (apoB, apolipoprotein C-II (apoCII, apolipoprotein C-III (apoCIII and apolipoprotein E (apoE. Results MFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI. Conclusions Our study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No

  3. Diagnosis and treatment of apolipoprotein B dyslipoproteinemias.

    NARCIS (Netherlands)

    Sniderman, A.; Couture, P.; Graaf, J. de


    Conventionally, atherogenic dyslipidemias have been defined by elevated levels of triglyceride and/or LDL cholesterol. However, cholesterol and triglycerides are not metabolically and physically independent entities. Rather, they are constituents of the atherogenic apolipoprotein B (apoB) particles,

  4. Polymorphisms in apolipoprotein B and risk of ischemic stroke

    DEFF Research Database (Denmark)

    Benn, Marianne; Nordestgaard, Børge G; Jensen, Jan Skov;


    Apolipoprotein B levels associate with risk of ischemic stroke. APOB polymorphisms may influence levels of apolipoprotein B and low-density lipoprotein (LDL), but whether they associate with risk of ischemic stroke is unknown.......Apolipoprotein B levels associate with risk of ischemic stroke. APOB polymorphisms may influence levels of apolipoprotein B and low-density lipoprotein (LDL), but whether they associate with risk of ischemic stroke is unknown....

  5. Apical secretion of apolipoproteins from enterocytes

    DEFF Research Database (Denmark)

    Danielsen, E M; Hansen, Gert Helge; Poulsen, Mona Dam


    Synthesis and secretion of apolipoproteins in pig small intestine was studied by pulse-chase labeling of jejunal segments, kept in organ culture. Apo A-1 and apo B-48 were the two major proteins released, constituting 25 and 10%, respectively, of the total amount of labeled protein in the mucosal...... that enterocytes release most of their newly made free apo A-1 and a significant portion of apo B-48 by exocytosis via the brush border membrane into the intestinal lumen. Fat absorption reduced apolipoprotein secretion to the medium and induced the formation of chylomicrons, containing apo A-1 at their surface......-side medium where they appeared with a t1/2 of 50-60 min. Using tissue from fasting animals, > 85% of newly synthesized apo A-1 and about one third of apo B-48 was released to the mucosal-side medium. Newly synthesized apolipoprotein that remained associated with the intestinal segment accumulated...

  6. Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor ROR alpha

    Energy Technology Data Exchange (ETDEWEB)

    Genoux, Annelise; Dehondt, Helene; Helleboid-Chapman, Audrey; Duhem, Christian; Hum, Dean W.; Martin, Genevieve; Pennacchio, Len; Staels, Bart; Fruchart-Najib, Jamila; Fruchart, Jean-Charles


    Apolipoprotein A5 has recently been identified as a crucial determinant of plasma triglyceride levels. Our results showed that RORa up-regulates human APOA5 but has no effect on mouse apoa5 promoter. These data suggest an additional important physiological role for RORa in the regulation of genes involved in plasma triglyceride homeostasis in human and probably in the development of atherosclerosis

  7. DNA damage in isolated rat hepatocytes exposed to C.I. pigment orange 5 and C.I. pigment yellow 12 by the alkaline comet assay

    DEFF Research Database (Denmark)

    Møller, P; Wallin, Håkan; Grunnet, N;


    The induction of DNA damage by commonly used printing ink pigments, C.I. pigment orange 5 (C.I. 12075) and C.I. pigment yellow 12 (C.I. 21090), was investigated in freshly isolated rat hepatocytes with the comet assay. C.I. pigment yellow 12 is a 3,3'-dichlorobenzidine-based diarylide pigment, an...

  8. Rat apolipoprotein A-IV metabolism

    NARCIS (Netherlands)

    G.M. Dallinga-Thie (Geesje)


    textabstractEarlier studies by Van 't Hoeft et al. (85, 160), in our laboratory, mainly focussed upon the catabolism of HDL apolipoproteins A-I and E. They found that the kidneys were an important organ involved in the catabolism of these proteins together with the liver. The present thesis mainly d

  9. Altered small-world anatomical networks in Apolipoprotein-E4 (ApoE4) carriers using MRI. (United States)

    Goryawala, Mohammed; Zhou, Qi; Duara, Ranjan; Loewenstein, David; Cabrerizo, Mercedes; Barker, Warren; Adjouadi, Malek


    Apolipoprotein E (ApoE) gene and primarily its allele e4 have been identified as a risk factor for Alzheimer's disease (AD). The prevalence of the gene in 25-30% in the population makes it essential to estimate its role in neuroregulation and its impact on distributed brain networks. In this study, we provide computational neuroanatomy based interpretation of large-scale and small-world cortical networks in cognitive normal (CN) subjects with differing Apolipoprotein-E4 (ApoE4) gene expression. We estimated large-scale anatomical networks from cortical thickness measurements derived from magnetic resonance imaging in 147 CN subjects explored in relation to ApoE4 genotype (e4+ carriers (n=41) versus e4- non-carriers (n=106)). Brain networks were constructed by thresholding cortical thickness correlation matrices of 68 bilateral regions of the brain analyzed using well-established graph theoretical approaches. Compared to ApoE4 non-carriers, carriers showed increased interregional correlation coefficients in regions like precentral, superior frontal and inferior temporal regions. Interestingly most of the altered connections were intra-hemispheric limited primarily to the right hemisphere. Furthermore, ApoE4 carriers demonstrated abnormal small-world architecture in the cortical networks with increased clustering coefficient and path lengths as compared to non-carrier, suggesting a less optimal topological organization. Additionally non-carriers demonstrated higher betweenness in regions such as middle temporal, para-hippocampal gyrus, posterior cingulate and insula of the default mode network (DMN), also seen in subjects with AD and mild cognitive impairment (MCI). The results suggest that the complex morphological cortical connectivity patterns are altered in ApoE4 carriers as compared to non-carriers, providing evidence for disruption of integrity in large-scale anatomical brain networks.

  10. Observations and modelling of CO and [C i] in protoplanetary disks. First detections of [C i] and constraints on the carbon abundance (United States)

    Kama, M.; Bruderer, S.; Carney, M.; Hogerheijde, M.; van Dishoeck, E. F.; Fedele, D.; Baryshev, A.; Boland, W.; Güsten, R.; Aikutalp, A.; Choi, Y.; Endo, A.; Frieswijk, W.; Karska, A.; Klaassen, P.; Koumpia, E.; Kristensen, L.; Leurini, S.; Nagy, Z.; Perez Beaupuits, J.-P.; Risacher, C.; van der Marel, N.; van Kempen, T. A.; van Weeren, R. J.; Wyrowski, F.; Yıldız, U. A.


    Context. The gas-solid budget of carbon in protoplanetary disks is related to the composition of the cores and atmospheres of the planets forming in them. The principal gas-phase carbon carriers CO, C0, and C+ can now be observed regularly in disks. Aims: The gas-phase carbon abundance in disks has thus far not been well characterized observationally. We obtain new constraints on the [C]/[H] ratio in a large sample of disks, and compile an overview of the strength of [C i] and warm CO emission. Methods: We carried out a survey of the CO 6-5 line and the [C i] 1-0 and 2-1 lines towards 37 disks with the APEX telescope, and supplemented it with [C ii] data from the literature. The data are interpreted using a grid of models produced with the DALI disk code. We also investigate how well the gas-phase carbon abundance can be determined in light of parameter uncertainties. Results: The CO 6-5 line is detected in 13 out of 33 sources, [C i] 1-0 in 6 out of 12, and [C i] 2-1 in 1 out of 33. With separate deep integrations, the first unambiguous detections of the [C i] 1-0 line in disks are obtained, in TW Hya and HD 100546. Conclusions: Gas-phase carbon abundance reductions of a factor of 5-10 or more can be identified robustly based on CO and [C i] detections, assuming reasonable constraints on other parameters. The atomic carbon detection towards TW Hya confirms a factor of 100 reduction of [C]/[H]gas in that disk, while the data are consistent with an ISM-like carbon abundance for HD 100546. In addition, BP Tau, T Cha, HD 139614, HD 141569, and HD 100453 are either carbon-depleted or gas-poor disks. The low [C i] 2-1 detection rates in the survey mostly reflect insufficient sensitivity for T Tauri disks. The Herbig Ae/Be disks with CO and [C ii] upper limits below the models are debris-disk-like systems. An increase in sensitivity of roughly order of magnitude compared to our survey is required to obtain useful constraints on the gas-phase [C]/[H] ratio in most of the

  11. Plasma proteome changes in cardiovascular disease patients: novel isoforms of apolipoprotein A1

    Directory of Open Access Journals (Sweden)

    Oravec Milan


    Full Text Available Abstract Background The aim of this proteomic study was to look for changes taking place in plasma proteomes of patients with acute myocardial infarction (AMI, unstable angina pectoris (UAP, and stable angina pectoris (SAP. Methods Depleted plasma proteins were separated by 2D SDS-PAGE (pI 4-7, and proteomes were compared using Progenesis SameSpots statistical software. Proteins were identified by nanoLC-MS/MS. Proteins were quantified using commercial kits. Apolipoprotein A1 was studied using 1D and 2D SDS-PAGE, together with western blotting. Results Reciprocal comparison revealed 46 unique, significantly different spots; proteins in 34 spots were successfully identified and corresponded to 38 different proteins. Discrete comparisons of patient groups showed 45, 41, and 8 significantly different spots when AMI, UAP, and SAP were compared with the control group. On the basis of our proteomic data, plasma levels of two of them, alpha-1 microglobulin and vitamin D-binding protein, were determined. The data, however, failed to prove the proteins to be suitable markers or risk factors in the studied groups. The plasma level and isoform representation of apolipoprotein A1 were also estimated. Using 1D and 2D SDS-PAGE, together with western blotting, we observed extra high-molecular weight apolipoprotein A1 fractions presented only in the patient groups, indicating that the novel high-molecular weight isoforms of apolipoprotein A1 may be potential new markers or possible risk factors of cardiovascular disease. Conclusion The reported data show plasma proteome changes in patients with AMI, UAP, and SAP. We propose some apolipoprotein A1 fractions as a possible new disease-associated marker of cardiovascular disorders.

  12. Direct Transcriptional Effects of Apolipoprotein E. (United States)

    Theendakara, Veena; Peters-Libeu, Clare A; Spilman, Patricia; Poksay, Karen S; Bredesen, Dale E; Rao, Rammohan V


    A major unanswered question in biology and medicine is the mechanism by which the product of the apolipoprotein E ε4 allele, the lipid-binding protein apolipoprotein E4 (ApoE4), plays a pivotal role in processes as disparate as Alzheimer's disease (AD; in which it is the single most important genetic risk factor), atherosclerotic cardiovascular disease, Lewy body dementia, hominid evolution, and inflammation. Using a combination of neural cell lines, skin fibroblasts from AD patients, and ApoE targeted replacement mouse brains, we show in the present report that ApoE4 undergoes nuclear translocation, binds double-stranded DNA with high affinity (low nanomolar), and functions as a transcription factor. Using chromatin immunoprecipitation and high-throughput DNA sequencing, our results indicate that the ApoE4 DNA binding sites include ∼1700 gene promoter regions. The genes associated with these promoters provide new insight into the mechanism by which AD risk is conferred by ApoE4, because they include genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, aging, and insulin resistance, all processes that have been implicated in AD pathogenesis. Significance statement: This study shows for the first time that apolipoprotein E4 binds DNA with high affinity and that its binding sites include 1700 promoter regions that include genes associated with neurotrophins, programmed cell death, synaptic function, sirtuins and aging, and insulin resistance, all processes that have been implicated in Alzheimer's disease pathogenesis.

  13. Apolipoprotein A-IV inhibits AgRP/NPY neurons and activates POMC neurons in the arcuate nucleus (United States)

    Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However the mechanisms underlying its anorexigenic effects remain to be identified. We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and ne...

  14. Cloning and characterization of an apolipoprotein C2 promoter in the mouse central nervous system

    Institute of Scientific and Technical Information of China (English)

    Zhaoyang Li; Bing Du; Shengyang Li; Xiangchuan Lv; Shenglai Zhou; Yang Yu; Wei Wang; Zhihong Zheng


    Apolipoprotein C2 is an important member of the apolipoprotein C family, and is a potent activator of lipoprotein lipase. In the central nervous system, apolipoprotein C2 plays an important role in the catabolism of triglyceride-rich lipoproteins. Studies into the exact regulatory mechanism of mouse apolipoprotein C2 expression have not been reported. In this study, seven luciferase expression vectors, which contained potential mouse apolipoprotein C2 gene promoters, were constructed and co-transfected with pRL-TK into HEK293T cells to investigate apolipoprotein C2 promoter activity. Luciferase assays indicated that the apolipoprotein C2 promoter region was mainly located in the +104 bp to +470 bp region. The activity of the different lengths of apolipoprotein C2 promoter region varied. This staggered negative-positive-negative arrangement indicates the complex regulation of apolipoprotein C2 expression and provides important clues for elucidating the regulatory mechanism of apolipoprotein C2 gene transcription.

  15. Specificity determinants in the interaction of apolipoprotein(a) kringles with tetranectin and LDL

    DEFF Research Database (Denmark)

    Caterer, Nigel R; Graversen, Jonas Heilskov; Jacobsen, Christian


    Lipoprotein(a) is composed of low density lipoprotein and apolipoprotein(a). Apolipoprotein(a) has evolved from plasminogen and contains 10 different plasminogen kringle 4 homologous domains [KIV(1-110)]. Previous studies indicated that lipoprotein(a) non-covalently binds the N-terminal region...... was similar to that of plasminogen kringle 4 to tetranectin. Only KIV(7) bound to LDL. In order to identify the residues responsible for the difference in specificity between KIV(7) and KIV(10), a number of surface-exposed residues located around the lysine binding clefts were exchanged. Ligand binding...... analysis of these derivatives showed that Y62, and to a minor extent W32 and E56, of KIV(7) are important for LDL binding to KIV(7), whereas R32 and D56 of KIV(10) are required for tetranectin binding of KIV(10)....

  16. The signal peptide anchors apolipoprotein M in plasma lipoproteins and prevents rapid clearance of apolipoprotein M from plasma

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Ahnström, Josefin; Axler, Olof


    Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic alpha-helixes and beta-sheets. Plasma apolipoprotein (apo) M lacks an external amphipathic motif but, nevertheless, is exclusively associated with lipoproteins......M(Q22A)-Tg mice (transgenic mice)) and compared them with mice expressing wild-type human apoM (apoM-Tg mice). The substitution of the amino acid glutamine 22 with alanine in apoM(Q22A) results in secretion of human apoM without a signal peptide. The human apoM mRNA level in liver and the amount...

  17. The common polymorphism of apolipoprotein E

    DEFF Research Database (Denmark)

    Gerdes, Ulrik


    Apolipoprotein E (apoE) has important functions in systemic and local lipid transport, but also has other functions. The gene (APOE) shows a common polymorphism with three alleles--APOE*2, APOE*3, and APOE*4. Their frequencies vary substantially around the world, but APOE*3 is the most common alm...... is associated with varying risk of cardiovascular disease and Alzheimer's disease, but other interesting aspects may emerge in the future....... from only 10-15% in southern Europe to 40-50% in the north. The gradient may be a trace of the demic expansion of agriculture that began about 10,000 years ago, but it may also reflect the possibility that APOE*4 carriers are less likely to develop vitamin D deficiency. The common APOE polymorphism...

  18. Independent effects of apolipoprotein AV and apolipoprotein CIII on plasma triglyceride concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Baroukh, Nadine N.; Bauge, Eric; Akiyama, Jennifer; Chang, Jessie; Fruchart, Jean-Charles; Rubin, Edward M.; Fruchart, Jamila; Pennacchio, Len A.


    Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered triglycerides. To overcome these confounding factors and address their relationship, we generated independent lines of mice that either over-expressed (''double transgenic'') or completely lacked (''double knockout'') both apolipoprotein genes. We report that both ''double transgenic'' and ''double knockout'' mice display intermedia tetriglyceride concentrations compared to over-expression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the ''double transgenic'' mice are approximately 500-fold lower than human ApoCIII levels, supporting Apo

  19. Interactions of metals and Apolipoprotein E in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    He eXu


    Full Text Available Alzheimer’s disease (AD is the most common form of dementia, which is characterized by the neuropathological accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs. Clinically, patients will endure a gradual erosion of memory and other higher order cognitive functions. Whilst the underlying etiology of the disease remains to be definitively identified, a body of work has developed over the last two decades demonstrating that AD plasma/serum and brain are characterized by a dyshomeostasis in a number of metal ions. Furthermore, these metals (such as zinc, copper and iron play roles in the regulation of the levels AD-related proteins, including the amyloid precursor protein (APP and tau. It is becoming apparent that metals also interact with other proteins, including apolipoprotein E (ApoE. The Apolipoprotein E gene (APOE is critically associated with AD, with APOE4 representing the strongest genetic risk factor for the development of late-onset AD whereas APOE2 appears to have a protective role. In this review we will summarize the evidence supporting a role for metals in the function of Apolipoprotein E (ApoE and its consequent role in the pathogenesis of AD.

  20. Amyloid-β colocalizes with apolipoprotein B in absorptive cells of the small intestine

    Directory of Open Access Journals (Sweden)

    Dhaliwal Satvinder S


    Full Text Available Abstract Background Amyloid-β is recognized as the major constituent of senile plaque found in subjects with Alzheimer's disease. However, there is increasing evidence that in a physiological context amyloid-β may serve as regulating apolipoprotein, primarily of the triglyceride enriched lipoproteins. To consider this hypothesis further, this study utilized an in vivo immunological approach to explore in lipogenic tissue whether amyloid-β colocalizes with nascent triglyceride-rich lipoproteins. Results In murine absorptive epithelial cells of the small intestine, amyloid-β had remarkable colocalization with chylomicrons (Manders overlap coefficient = 0.73 ± 0.03 (SEM, the latter identified as immunoreactive apolipoprotein B. A diet enriched in saturated fats doubled the abundance of both amyloid-β and apo B and increased the overlap coefficient of the two proteins (0.87 ± 0.02. However, there was no evidence that abundance of the two proteins was interdependent within the enterocytes (Pearson's Coefficient Conclusion The findings of this study are consistent with the possibility that amyloid-β is secreted by enterocytes as an apolipoprotein component of chylomicrons. However, secretion of amyloid-β appears to be independent of chylomicron biogenesis.

  1. Abundance of atomic carbon /C I/ in dense interstellar clouds (United States)

    Phillips, T. G.; Huggins, P. J.


    The abundance of interstellar neutral atomic carbon is investigated by means of its ground state fine-structure line emission at 492 GHz using the 91.5 cm telescope of NASAs Kuiper Airborne Observatory. Atomic carbon is found to be very abundant in dense interstellar molecular clouds with column densities of about 10 to the 19th per sq cm. Because the observations have considerably greater column densities than current theories of carbon chemistry, it is suggested that the physical conditions of these clouds are not as simple as assumed in the models. Various situations are discussed which would lead to large C I abundances, including the possibility that the chemical lifetimes of the clouds are relatively short.

  2. The effects of ginger on fasting blood sugar, hemoglobin a1c, apolipoprotein B, apolipoprotein a-I and malondialdehyde in type 2 diabetic patients. (United States)

    Khandouzi, Nafiseh; Shidfar, Farzad; Rajab, Asadollah; Rahideh, Tayebeh; Hosseini, Payam; Mir Taheri, Mohsen


    Diabetes mellitus is the most common endocrine disorder, causes many complications such as micro- and macro-vascular diseases. Anti-diabetic, hypolipidemic and anti-oxidative properties of ginger have been noticed in several researches. The present study was conducted to investigate the effects of ginger on fasting blood sugar, Hemoglobin A1c, apolipoprotein B, apolipoprotein A-I, and malondialdehyde in type 2 diabetic patients. In a randomized, double-blind, placebo-controlled, clinical trial, a total of 41 type 2 diabetic patients randomly were assigned to ginger or placebo groups (22 in ginger group and 19 in control group), received 2 g/day of ginger powder supplement or lactose as placebo for 12 weeks. The serum concentrations of fasting blood sugar, Hemoglobin A1c, apolipoprotein B, apolipoprotein A-I and malondialdehyde were analyzed before and after the intervention. Ginger supplementation significantly reduced the levels of fasting blood sugar, hemoglobin A1c, apolipoprotein B, apolipoprotein B/apolipoprotein A-I and malondialdehyde in ginger group in comparison to baseline, as well as control group, while it increased the level of apolipoprotein A-I (pginger powder supplement can improves fasting blood sugar, hemoglobin A1c, apolipoprotein B, apolipoprotein A-I, apolipoprotein B/apolipoprotein A-I and malondialdehyde in type 2 diabetic patients. So it may have a role in alleviating the risk of some chronic complications of diabetes.

  3. Apolipoprotein M promotes mobilization of cellular cholesterol in vivo

    DEFF Research Database (Denmark)

    Elsøe, Sara; Christoffersen, Christina; Luchoomun, Jayraz


    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....

  4. Polimorfisme Gen Apolipoprotein E Pada Penderita Sindrom Down Trisomi 21

    Directory of Open Access Journals (Sweden)

    Malinda Meinapuri


    mengkonfirmasi hasil penelitian ini.Kata kunci: Sindrom Down, Polimorfisme, Apolipoprotein E.AbstractBackgrounds :Down syndrome is an abnormal chromosomal condition, characterized by the presence of all (trisomy 21 or part (such as due to translocations of a third copy of chromosome 21. Apolipoprotein E (APOE is a polymorphic protein coded by a gene located on the long arm (q of chromosome 19, positioning at 13.2 (19q13.2. Polymorphism of APOE gene is related with the increasing of allele ε4’s frequency thus cause obstruction in neuron ramification and development. In previous study, Down Syndrome groups are having different type of APOE gene compared with control. That why it can be considered as one of the caused premature aging of brain. Methods : This is a case control study to observe the difference of distribution and frequency of APOE gene allele and genotype in Down Syndrome Trysomi 21 compared to control. Down Syndrome and control samples was taken as secondary data from Center for Biomedical Research (CEBIOR Semarang Indonesia. DNA extraction was done by using the commonly used salting out method in CEBIOR Semarang Indonesia. Subsequently polimorphism of APOE gene analysis has been done by using PCR and RFLP.Result : Thirty three samples were Down Syndrom patients, consist of 18 male and 15 female. Thirty three samples are control, consist of 18 male and 15 female. Both groups were having the highest frequency of allele ε3 compared to allele ε2 and ε4. In Down Syndrome, frequency of ε4 allele was found in 4 samples (6,1% while allele ε2 was found in 8 samples (12,1%. Genotype ε3/ε3 were the highest frequency on both group compared to the other. In Down Syndrome group identified ε2/ε4 genotype in 4 samples (12,1% and ε2/ε2 genotype in 2 samples (6,1%.Conclusion : There is slight difference distribution of APOE gene allele and genotype in Down Syndrome Trysomi 21 compared to control. More samples should be analyzed to confirm this finding

  5. Apolipoprotein D Internalization Is a Basigin-dependent Mechanism. (United States)

    Najyb, Ouafa; Brissette, Louise; Rassart, Eric


    Apolipoprotein D (apoD), a member of the lipocalin family, is a 29-kDa secreted glycoprotein that binds and transports small lipophilic molecules. Expressed in several tissues, apoD is up-regulated under different stress stimuli and in a variety of pathologies. Numerous studies have revealed that overexpression of apoD led to neuroprotection in various mouse models of acute stress and neurodegeneration. This multifunctional protein is internalized in several cells types, but the specific internalization mechanism remains unknown. In this study, we demonstrate that the internalization of apoD involves a specific cell surface receptor in 293T cells, identified as the transmembrane glycoprotein basigin (BSG, CD147); more particularly, its low glycosylated form. Our results show that internalized apoD colocalizes with BSG into vesicular compartments. Down-regulation of BSG disrupted the internalization of apoD in cells. In contrast, overexpression of basigin in SH-5YSY cells, which poorly express BSG, restored the uptake of apoD. Cyclophilin A, a known ligand of BSG, competitively reduced apoD internalization, confirming that BSG is a key player in the apoD internalization process. In summary, our results demonstrate that basigin is very likely the apoD receptor and provide additional clues on the mechanisms involved in apoD-mediated functions, including neuroprotection.

  6. DMPD: Regulation of endogenous apolipoprotein E secretion by macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18388328 Regulation of endogenous apolipoprotein E secretion by macrophages. Kockx M, Jessup...328 Title Regulation of endogenous apolipoprotein E secretion by macrophages. Authors Kockx M, Jessup

  7. Molecular basis of the apolipoprotein H (beta 2-glycoprotein I) protein polymorphism

    DEFF Research Database (Denmark)

    Sanghera, Dharambir K; Kristensen, Torsten; Hamman, Richard F


    Apolipoprotein H (apoH, protein; APOH, gene) is considered to be an essential cofactor for the binding of certain antiphospholipid autoantibodies to anionic phospholipids. APOH exhibits a genetically determined structural polymorphism due to the presence of three common alleles (APOH*1, APOH*2...... and its distribution in three large U.S. population samples comprising 661 non-Hispanic whites, 444 Hispanics and 422 blacks. By direct DNA sequencing of PCR amplified fragments corresponding to the eight APOH exons, we identified two missense mutations that correspond to the APOH*1 and APOH*3W alleles...

  8. Apolipoprotein E: Risk factor for Alzheimer disease

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, M.S.; Thibodeau, S.N.; Tangalos, E.G.; Petersen, R.C.; Kokmen, E.; Smith, G.E.; Schaid, D.J.; Ivnik, R.J. (Mayo Clinic, Rochester, MN (United States))


    The apolipoprotein E gene (APOE) has three common alleles (E2, E3, and E4) that determine six genotypes in the general population. In this study, the authors examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-E4 allele. They show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-E4/E3 genotype being the most common in the AD group and the APOE-E3/E3 being the most common in the control group. In the AD group, homozygosity for E4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two E4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-E4, was 3.6 (05% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-E4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). The data, which are in agreement with recent reports, suggest that the APOE-E4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population. 30 refs., 5 tabs.

  9. Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4

    NARCIS (Netherlands)

    Mulder, M.; Ravid, R.; Kloet, J.E.R. de; Haasdijk, E.D.; Julk, J.; Boom, J. van der; Havekes, L.M.


    Apolipoprotein E4 (apoE4) has been identified as a major risk factor for Alzheimer disease (AD). Previously it has been reported that levels of apoE are reduced in cerebrospinal fluid (CSF) of AD patients. Because it is known that apoE4 affectss plasma lipid metabolism we examined whether the presen

  10. Immunolocalization of cubilin, megalin, apolipoprotein J, and apolipoprotein A-I in the uterus and oviduct. (United States)

    Argraves, W Scott; Morales, Carlos R


    Spermatozoa maturation and capacitation occurring in the male and female reproductive tracts, respectively, involves the remodeling of the spermatozoa plasma membrane. Apolipoprotein J (apoJ) and apolipoprotein A-I (apoA-I) have been implicated in the process of lipid exchange from the spermatozoa plasma membrane to epithelial cells lining the male reproductive tract. Evidence suggests that this process is mediated by the cooperative action of the endocytic lipoprotein receptors megalin and cubilin, which are expressed at the apical surface of absorptive epithelia in various tissues, including the efferent ducts and epididymis. Here, we investigated the possibility that these receptors and their lipid-binding ligands, apoJ and apoA-I, might function similarly in the female reproductive tract. We show that megalin and cubilin are expressed in the uterine epithelium at all stages of the estrous cycle, maximally during estrous and metestrous stages. In the oviduct, there is pronounced expression of both megalin and cubilin in the nonciliated cells of the proximal oviduct and epithelial cells of the distal oviduct, particularly during estrous and metestrous stages. In both uterine and oviduct epithelial cells, megalin and cubilin were located on the apical regions of the cells, consistent with a distribution at the cell surface and in endosomes. ApoJ and apoA-I were both detected in apical regions of uterine and oviduct epithelial cells. Secretory cells of the uterine glands were found to express apoJ and apoA-I suggesting that the glands are a site of synthesis for both proteins. In summary, our findings indicate that megalin and cubilin function within the female reproductive tract, possibly mediating uterine and oviduct epithelial cell endocytosis of apoJ/apoA-I-lipid complexes and thus playing a role in lipid efflux from the sperm plasma membrane, a major initiator of capacitation.

  11. Apolipoprotein E and its role in aging and survival. (United States)

    Bonomini, Francesca; Filippini, Francesca; Hayek, Tony; Aviram, Michael; Keidar, Shlomo; Rodella, Luigi F; Coleman, Raymond; Rezzani, Rita


    The study of biological aging has seen spectacular progress in the last decade and markers are increasingly employed for understanding physiological processes that change with age. Recently, it has been demonstrated that apolipoprotein E (apoE) has a major impact on longevity, but its mechanisms are still not fully understood. ApoE-deficient (E(o)) mice have proved to be a very popular model for studying spontaneous hypercholesterolemia and the subsequent development of atherosclerotic lesions, but only limited data are available with regard to aging and aging changes. We used this murine model to better characterize the involvement of apoE in aging and to evaluate its role in the maintenance of normal organ morphology. Our results show that E(0) mice at different ages (6, 12, 20 weeks old) developed age-dependent morphological and biochemical alterations, including fibrosis (newly formed collagen), pro-inflammatory cytokine (IL-6 and iNOS), lipofuscin accumulation, and decrease of antioxidant enzymes (superoxide dismutase and catalase) in several organs (kidney, liver and heart). It is significant that the observed degenerative findings in E(0) mice at different ages (6, 12, 20 weeks old) were not identified in control mice (C57BL), at 6, 12 and 20 weeks of age. Consequently, since these mice showed enzymatic and structural alterations, normally linked to the age, such as increase of lipofuscin, pro-inflammatory cytokines and decrease of antioxidant enzymes, we can conclude that apoE is a useful player in studies of longevity and age-related diseases, such as inflammatory status and atherosclerosis that are known risk factors for functional decline and early mortality. Moreover, it is possible that apoE may also play a role in other pathological conditions including, for example, cancer, rheumatoid arthritis and macular degeneration.

  12. Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

    NARCIS (Netherlands)

    Dallinga-Thie, GM; Van Tol, A; Hattori, H; van Vark-van de Zee, LC; Jansen, H; Sijbrands, EJG


    Aims/hypothesis: Variation in the human apolipoprotein (APO) A5 gene (APOA5) is associated with elevated plasma triglycerides. However, data on the exact role of plasma concentrations of APOA5 in human triglyceride homeostasis are lacking. In the present study, we estimated plasma APOA5 levels in pa

  13. Human placenta secretes apolipoprotein B-100-containing lipoproteins

    DEFF Research Database (Denmark)

    Munk-Madsen, Eva; Lindegaard, Marie Louise Skakkebæk; Andersen, Claus B


    Supply of lipids from the mother is essential for fetal growth and development. In mice, disruption of yolk sac cell secretion of apolipoprotein (apo) B-containing lipoproteins results in embryonic lethality. In humans, the yolk sac is vestigial. Nutritional functions are instead established very...... of lipid transfer from the mother to the developing fetus....

  14. Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke

    DEFF Research Database (Denmark)

    Khan, Tauseef A; Shah, Tina; Prieto, David;


    At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less...


    Energy Technology Data Exchange (ETDEWEB)

    Lo, N.; Bronfman, L. [Departamento de Astronomía, Universidad de Chile, Camino El Observatorio 1515, Las Condes, Santiago, Casilla 36-D (Chile); Cunningham, M. R.; Jones, P. A.; Lowe, V. [School of Physics, University of New South Wales, Sydney, NSW 2052 (Australia); Cortes, P. C. [Joint ALMA Observatory, Santiago (Chile); Simon, R. [Physikalisches Institut, Universität zu Köln, Zülpicher Straße 77, 50937 Köln (Germany); Fissel, L.; Novak, G. [Northwestern University, Center for Interdisciplinary Exploration and Research in Astrophysics (CIERA) and Department of Physics and Astronomy, 2145 Sheridan Road, Evanston, IL 60208 (United States)


    We present the first results of neutral carbon ([C I] {sup 3} P {sub 1}-{sup 3} P {sub 0} at 492 GHz) and carbon monoxide ({sup 13}CO, J = 1-0) mapping in the Vela Molecular Ridge cloud C (VMR-C) and the G333 giant molecular cloud complexes with the NANTEN2 and Mopra telescopes. For the four regions mapped in this work, we find that [C I] has very similar spectral emission profiles to {sup 13}CO, with comparable line widths. We find that [C I] has an opacity of 0.1-1.3 across the mapped region while the [C I]/{sup 13}CO peak brightness temperature ratio is between 0.2 and 0.8. The [C I] column density is an order of magnitude lower than that of {sup 13}CO. The H{sub 2} column density derived from [C I] is comparable to values obtained from {sup 12}CO. Our maps show that C I is preferentially detected in gas with low temperatures (below 20 K), which possibly explains the comparable H{sub 2} column density calculated from both tracers (both C I and {sup 12}CO underestimate column density), as a significant amount of the C I in the warmer gas is likely in the higher energy state transition ([C I] {sup 3} P {sub 2}-{sup 3} P {sub 1} at 810 GHz), and thus it is likely that observations of both the above [C I] transitions are needed in order to recover the total H{sub 2} column density.

  16. Turkish Heart Study: lipids, lipoproteins, and apolipoproteins. (United States)

    Mahley, R W; Palaoğlu, K E; Atak, Z; Dawson-Pepin, J; Langlois, A M; Cheung, V; Onat, H; Fulks, P; Mahley, L L; Vakar, F


    We examined the plasma lipids, lipoproteins, and selected apolipoproteins in approximately 9,000 men and women from six different regions of Turkey with markedly different diets, ranging from an Aegean coast diet high in olive oil (plasma cholesteryl ester fatty acids enriched in monounsaturated fatty acids) to an inland Anatolian diet high in meat and dairy products (plasma cholesteryl esters enriched in saturated fatty acids). The rural population consuming an olive oil-rich diet had the lowest plasma cholesterol levels (men, 149 mg/dl; women, 150 mg/dl). The urban populations of Istanbul and Adana had higher plasma cholesterol levels (men, 202 and 184 mg/dl, respectively; women, 181 and 190 mg/dl, respectively). Affluent men had the highest cholesterol levels (207 mg/dl). The low density lipoprotein (LDL) cholesterol levels tended to parallel the total cholesterol levels (highest for Istanbul men at 136 mg/dl and lowest for Aegean coast men and women at approximately 100 mg/dl). Strikingly, the Turkish people were found to have very low levels of high density lipoprotein (HDL) cholesterol (HDL-C) (mean values for all six regions: men, 34-38 mg/dl; women, 37-45 mg/dl) and total cholesterol/HDL-C ratios that were high (mean values for all six regions: men, 4.5-5.5; women, 3.9-5.0). The low HDL-C levels appear to be caused, at least in part, by a genetic factor. Triglyceride levels also tended to be high in Turkish men (approximately 120-150 mg/dl) and women (approximately 90-110 mg/dl). Thus, even though the total plasma cholesterol levels are not excessively elevated in comparison to those in other populations, the presence of low HDL-C or low HDL-C coupled with mildly elevated triglyceride levels may represent a significant risk factor for heart disease in the Turkish population. Affluence and higher education were associated with higher cholesterol levels. Lack of physical activity, smoking, and alcohol consumption also tended to be associated with a

  17. Apolipoprotein-E forms dimers in human frontal cortex and hippocampus

    Directory of Open Access Journals (Sweden)

    Halliday Glenda M


    Full Text Available Abstract Background Apolipoprotein-E (apoE plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD. ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions. Results In apoE3 homozygous samples, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts. Conclusion The identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.

  18. Opposing effects of apolipoprotein m on catabolism of apolipoprotein B-containing lipoproteins and atherosclerosis

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Pedersen, Tanja Xenia; Gordts, Philip L S M;


    Rationale: Plasma apolipoprotein (apo)M is mainly associated with high-density lipoprotein (HDL). HDL-bound apoM is antiatherogenic in vitro. However, plasma apoM is not associated with coronary heart disease in humans, perhaps because of a positive correlation with plasma low-density lipoprotein...... (LDL). Objective: We explored putative links between apoM and very-low-density (VLDL)/LDL metabolism and the antiatherogenic potential of apoM in vivo. Methods and Results: Plasma apoM was increased approximately 2.1 and approximately 1.5 fold in mice lacking LDL receptors (Ldlr(-/-)) and expressing...... dysfunctional LDL receptor-related protein 1 (Lrp1(n2/n2)), respectively, but was unaffected in apoE-deficient (ApoE(-/-)) mice. Thus, pathways controlling catabolism of VLDL and LDL affect plasma apoM. Overexpression ( approximately 10-fold) of human apoM increased (50% to 70%) and apoM deficiency decreased...

  19. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. (United States)

    Hashimoto, Tadafumi; Serrano-Pozo, Alberto; Hori, Yukiko; Adams, Kenneth W; Takeda, Shuko; Banerji, Adrian Olaf; Mitani, Akinori; Joyner, Daniel; Thyssen, Diana H; Bacskai, Brian J; Frosch, Matthew P; Spires-Jones, Tara L; Finn, Mary Beth; Holtzman, David M; Hyman, Bradley T


    Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.

  20. Apolipoprotein E and its role in aging and survival


    Bonomini, Francesca; Filippini, Francesca; Hayek, Tony; Aviram, Michael; Keidar, Shlomo; F.Rodella, Luigi; Coleman, Raymond; Rezzani, Rita


    Abstract The study of biological aging has seen spectacular progress in the last decade and markers are increasingly employed for understanding physiological processes that change with age. Recently, it has been demonstrated that apolipoprotein E (apoE) has a major impact on longevity, but its mechanisms are still not fully understood. ApoE-deficient (Eo) mice have proved to be a very popular model for studying spontaneous hypercholesterolemia and the subsequent development of athe...

  1. Syndrome: A Comparison with Apolipoprotein Concentrations and Lipid Profile

    Directory of Open Access Journals (Sweden)

    Magdalena Krintus


    Full Text Available Objective. To investigate whether assessment of C-reactive protein (CRP and apolipoproteins, besides the traditional lipid profile, enhances the assessment process for the risk of acute coronary syndrome (ACS. Methods. The study group consisted of 220 consecutive patients admitted to hospital within the first 6 hours from the onset of chest pain. Patients were diagnosed with unstable angina (, non-ST-elevation myocardial infarction (NSTEMI; , or ST-elevation myocardial infarction (STEMI; . ACS patients were compared with 116 healthy volunteers in a case-control study. The serum was assayed on admission for CRP, apolipoproteins ApoAI and ApoB100, and lipid parameters. Results. The highest concentrations of CRP were found in NSTEMI and STEMI, with a median value four-fold higher in ACS patients than in controls (. Only CRP significantly increased the probability of ACS development (adjusted odds ratio for a 1 mg/L increase 1.90; 95% confidence interval [CI] 1.34–2.89 and explained 90% of the variation for ACS development. Similarly, we demonstrated the highest diagnostic accuracy for CRP among all investigated markers (area under the curve 0.80; 95% CI 0.75–0.85. Conclusions. Our study indicates that CRP superiorly to apolipoproteins and lipid profile facilitates the risk stratification for ACS occurrence.

  2. Major lipids, apolipoproteins, and risk of vascular disease

    DEFF Research Database (Denmark)

    Collaboration, Emerging Risk Factors; Di Angelantonio, Emanuele; Sarwar, Nadeem;


    did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.......39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C. CONCLUSION: Lipid...... unclassified strokes. MAIN OUTCOME MEASURES: Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33...

  3. NMR-based metabolomics of urine for the atherosclerotic mouse model using apolipoprotein-E deficient mice. (United States)

    Leo, Gregory C; Darrow, Andrew L


    NMR-based metabolomics of mouse urine was used in conjunction with the traditional staining and imaging of aortas for the characterization of disease advancement, that is, plaque formation in untreated and drug-treated apolipoprotein-E (apoE) knockout mice. The metabolomics approach with multivariate analysis was able to differentiate the captopril-treated from the untreated mice in general agreement with the staining results. Principal component analysis showed a pattern shift in both the drug-treated and untreated samples as a function of time that could possibly be explained as the effect of aging. Allantoin, a marker attributed to captopril treatment was elevated in the drug-treated mice. From partial least squares-discriminant analysis, xanthine and ascorbate were elevated in the untreated mice and were possible markers of plaque formation in the apoE knockout mice. Several additional peaks in the spectra characterizing the study endpoint were found but their respective metabolite identities were unknown.

  4. An Improved Maximum C/I Scheduling Algorithm Combined with HARQ

    Institute of Scientific and Technical Information of China (English)


    It is well known that traffic in downlink will be much greater than that in uplink in 3 G and that beyond. High Speed Downlink Packet Access(HSDPA) is the solution to transmission for high-speed downlink packet service in UMTS, of which Maximum C/I scheduling is one of the important algorithms related to performance enhancement. An improved scheme, Thorough Maximum C/I scheduling algorithm, is presented in this article, in which every transmitted frame has the maximum C/I. The simulation results show that the new Maximum C/I scheme outperforms the conventional scheme in throughput performance and delay performance, and that the FER decreases faster as the maximum number of the retransmission increases.

  5. Extended [C I] and ^{13}CO(5-4) Emission in M17SW

    CERN Document Server

    Howe, J E; Bergin, E A; Chin, G; Erickson, N R; Goldsmith, P F; Harwit, M; Hollenbach, D J; Kaufman, M J; Kleiner, S C; Koch, D G; Neufeld, D A; Patten, B M; Plume, R; Schieder, R; Snell, R L; Stauffer, J R; Tolls, V; Wang, Z; Winnewisser, G; Zhang, Y F; Melnick, G J


    We mapped a 13 by 22 pc region in emission from 492 GHz [C I] and, for the first time, 551 GHz ^{13}CO(5-4) in the giant molecular cloud M17SW, using the Submillimeter Wave Astronomy Satellite. The morphologies of the [C I] and ^{13}CO emission are strikingly similar. The extent and intensity of the [C I] and ^{13}CO(5-4) emission is explained as arising from photodissociation regions on the surfaces of embedded molecular clumps. Modeling of the ^{13}CO(5-4) emission in comparison to ^{13}CO(1-0) indicates a temperature gradient across the cloud, peaking to at least 63 K near the M17 ionization front and decreasing to at least 20 K at the western edge of the cloud. We see no correlation between gas density and column density. The beam-averaged column density of C I in the core is 1x10^{18} cm^-2, and the mean column density ratio N(C I)/N(CO) is about 0.4. The variations of N(C I)/N(CO) with position in M17SW indicate a similar clump size distribution throughout the cloud.

  6. Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. (United States)

    Ganfornina, Maria D; Do Carmo, Sonia; Lora, Jose M; Torres-Schumann, Sonia; Vogel, Marci; Allhorn, Maria; González, Constancio; Bastiani, Michael J; Rassart, Eric; Sanchez, Diego


    Many nervous system pathologies are associated with increased levels of apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila, Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protective potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD overexpression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids.

  7. Apolipoprotein J: A New Predictor and Therapeutic Target in Cardiovascular Disease?

    Institute of Scientific and Technical Information of China (English)

    Ning Yang; Qin Qin


    Objective:To review the functional mechanism of apolipoprotein J (apoJ) in the process of atherosclerosis and the feasibility of apoJ as a therapeutic endpoint.Data Sources:Relevant articles published in English from 1983 to present were selected from PubMed.The terms of"atherosclerosis,apolipoprotein J,clusterin (CLU),oxidative stress,and inflammation" were used for searching.Study Selection:Articles studying the role of apoJ with atherosclerosis and restenosis after injury were reviewed.Articles focusing on the intrinsic determinants of atherosclerosis were selected.The exclusion criteria of articles were that the studies on immunologic vasculitis.Results:ApoJ,involved in numerous physiological process important for lipid transportation and vascular smooth muscle cell differentiation,including apoptotic cell death,cell-cycle regulation,cell adhesion,tissue remodeling,immune system regulation,and oxidative stress,plays a role in the development of clinical atherosclerosis.In the process of relieving atherosclerosis,apoJ can promote cholesterol and phospholipid export from macrophage-foam cells,and exhibit cytoprotective and anti-inflammatory actions by interacting with lots of known inflammatory proteins which may predict the onset of clinical cardiovascular events and may actually play a causal role in mediating atherosclerotic disease such as C-reactive protein,paraoxonase,and leptin.As known as CLU,apoJ has been identified to play central roles in the process of vascular smooth cells migration,adhesion,and proliferation,which can contribute significantly to restenosis after vascular injury.Conclusions:Intense effort and substantial progress have been made to identify the apoJ that relieves atherosclerosis and vascular restenosis after percutaneous coronary intervention.More work is needed to elucidate the exact mechanisms of and the interrelationship between the actions of apoJ and to successfully achieve regression of atherosclerosis by regarding it as a

  8. Identification of two apolipoprotein variants, A-I Karatsu (Tyr 100-->His) and A-I Kurume (His 162-->Gln). (United States)

    Moriyama, K; Sasaki, J; Matsunaga, A; Takada, Y; Kagimoto, M; Arakawa, K


    We identified two apolipoprotein (apo) A-I variants, using isoelectric focusing gel electrophoresis: apo A-I Karatsu, which had a relative charge of +1 compared to normal apo A-I4, and apo A-I Kurume, which had a relative charge of -1. Direct sequence analysis of the PCR-amplified DNA from the proband of apo A-I Karatsu revealed a single substitution of tyrosine (TAC) for histidine (CAC) at position 100. Sequence analysis of apo A-I Kurume revealed a single substitution of histidine (CAT) for glutamine (CAG) at position 162. Probands of these two mutants and limited family study showed no accelerated atherosclerosis.

  9. A Pressure-dependent Model for the Regulation of Lipoprotein Lipase by Apolipoprotein C-II* (United States)

    Meyers, Nathan L.; Larsson, Mikael; Olivecrona, Gunilla; Small, Donald M.


    Apolipoprotein C-II (apoC-II) is the co-factor for lipoprotein lipase (LPL) at the surface of triacylglycerol-rich lipoproteins. LPL hydrolyzes triacylglycerol, which increases local surface pressure as surface area decreases and amphipathic products transiently accumulate at the lipoprotein surface. To understand how apoC-II adapts to these pressure changes, we characterized the behavior of apoC-II at multiple lipid/water interfaces. ApoC-II adsorption to a triacylglycerol/water interface resulted in large increases in surface pressure. ApoC-II was exchangeable at this interface and desorbed on interfacial compressions. These compressions increase surface pressure and mimic the action of LPL. Analysis of gradual compressions showed that apoC-II undergoes a two-step desorption, which indicates that lipid-bound apoC-II can exhibit at least two conformations. We characterized apoC-II at phospholipid/triacylglycerol/water interfaces, which more closely mimic lipoprotein surfaces. ApoC-II had a large exclusion pressure, similar to that of apoC-I and apoC-III. However, apoC-II desorbed at retention pressures higher than those seen with the other apoCs. This suggests that it is unlikely that apoC-I and apoC-III inhibit LPL via displacement of apoC-II from the lipoprotein surface. Upon rapid compressions and re-expansions, re-adsorption of apoC-II increased pressure by lower amounts than its initial adsorption. This indicates that apoC-II removed phospholipid from the interface upon desorption. These results suggest that apoC-II regulates the activity of LPL in a pressure-dependent manner. ApoC-II is provided as a component of triacylglycerol-rich lipoproteins and is the co-factor for LPL as pressure increases. Above its retention pressure, apoC-II desorbs and removes phospholipid. This triggers release of LPL from lipoproteins. PMID:26026161

  10. A Search for AU-Scale C I Structure in the Diffuse ISM (United States)

    Markwardt, Larissa; Meyer, David M.


    We present a multi-epoch, high resolution (R ~ 100,000) study of ultraviolet interstellar C I absorption line profiles taken by the Hubble Space Telescope. The 17 stars of this survey were chosen because each has high resolution spectra taken at least 10 years apart with the same instrument (STIS), grating (E140H), and aperture (0.2"x0.2") thus minimizing the instrumental differences in the multi-epoch comparisons. Given the proper motions and distances of these stars, typically it was possible to observe variances in their C I line profiles which correspond to structure on scales of less than 200 AU. In 16 out of the 17 sightlines no significant differences in C I line profiles between the two epochs were detected (75% of the 68 C I velocity components were measured to vary less than 20% at the 2 σ level). A measurement of ~ 5% of sightlines with variances is consistent with the fraction found recently by McEvoy et al. (2015) in their much larger survey of multi-epoch variance of Na I in optical spectra. However, the sightline toward HD210809 did show significant variance in its C I line profile. The C I absorption arising from both the J = 1 and J = 2 fine-structure states toward this star exhibits variations at an LSR velocity of -37 km/s indicative of C I structure on a scale less than 200 AU. Interestingly, the sky position of HD 210809 corresponds to the edge of an intervening H I shell discovered by Suad et al. (2012) at this same LSR velocity. This connection is consistent with the optical survey of interstellar Na I by Meyer et al. (2015) who found that nearly all of their temporally-varying sightlines involved supernova remnants, H I supershells, or stellar bow shocks.

  11. Influence of apolipoproteins on the association between lipids and insulin sensitivity

    DEFF Research Database (Denmark)

    Baldi, Simona; Bonnet, Fabrice; Laville, Martine;


    We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence.......We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence....

  12. Reduced apolipoprotein glycosylation in patients with the metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Olga V Savinova

    Full Text Available The purpose of this study was to compare the apolipoprotein composition of the three major lipoprotein classes in patients with metabolic syndrome to healthy controls.Very low density (VLDL, intermediate/low density (IDL/LDL, hereafter LDL, and high density lipoproteins (HDL fractions were isolated from plasma of 56 metabolic syndrome subjects and from 14 age-sex matched healthy volunteers. The apolipoprotein content of fractions was analyzed by one-dimensional (1D gel electrophoresis with confirmation by a combination of mass spectrometry and biochemical assays.Metabolic syndrome patients differed from healthy controls in the following ways: (1 total plasma--apoA1 was lower, whereas apoB, apoC2, apoC3, and apoE were higher; (2 VLDL--apoB, apoC3, and apoE were increased; (3 LDL--apoC3 was increased, (4 HDL--associated constitutive serum amyloid A protein (SAA4 was reduced (p<0.05 vs. controls for all. In patients with metabolic syndrome, the most extensively glycosylated (di-sialylated isoform of apoC3 was reduced in VLDL, LDL, and HDL fractions by 17%, 30%, and 25%, respectively (p<0.01 vs. controls for all. Similarly, the glycosylated isoform of apoE was reduced in VLDL, LDL, and HDL fractions by 15%, 26%, and 37% (p<0.01 vs. controls for all. Finally, glycosylated isoform of SAA4 in HDL fraction was 42% lower in patients with metabolic syndrome compared with controls (p<0.001.Patients with metabolic syndrome displayed several changes in plasma apolipoprotein composition consistent with hypertriglyceridemia and low HDL cholesterol levels. Reduced glycosylation of apoC3, apoE and SAA4 are novel findings, the pathophysiological consequences of which remain to be determined.

  13. The Apolipoprotein E Gene, Attention, and Brain Function


    Parasuraman, Raja; Pamela M Greenwood; Sunderland, Trey


    The ɛ4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer’s disease (AD). Changes in components of visuospatial attention with ApoE-ɛ4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ɛ4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE p...

  14. Both serum apolipoprotein B and the apolipoprotein B/apolipoprotein A-I ratio are associated with carotid intima-media thickness.

    Directory of Open Access Journals (Sweden)

    Fei Huang

    Full Text Available BACKGROUND: Previous studies indicated that apolipoprotein measurements predicted cardiovascular disease (CVD risk; however, associations between apolipoproteins and carotid intima-media thickness (CIMT were less explored. METHODOLOGY AND PRINCIPAL FINDINGS: The cross-sectional study included 6069 participants aged 40 years or older with NGT from Shanghai, China. Serum fasting traditional lipids (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG], apoA-I and apoB were assessed. A high-resolution B-mode ultrasonography was performed to measure CIMT. We found CIMT increased progressively across the quartiles of serum apoB (p for trend <0.0001. In logistic regression, concentrations of apoB (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.18-1.36, TC (OR 1.23, 95% CI 1.14-1.32, LDL-C (OR 1.25, 95% CI 1.16-1.34 and TG (OR 1.11, 95% CI 1.04-1.20 were significantly related to elevated CIMT after adjusted for age and sex. Meanwhile, the apoB/apoA-I ratio (OR 1.25, 95% CI 1.17-1.34 related to elevated CIMT. ApoB (OR 1.23, 95% CI 1.00-1.51 and the apoB/apoA-I ratio (OR 1.19, 95% CI 1.04-1.36 remained significantly associated with elevated CIMT, after adjusted for the traditional CVD risk factors including traditional lipids. CONCLUSIONS AND SIGNIFICANCE: There were significant associations between serum apoB, the apoB/apoA-I ratio and elevated CIMT. Serum apoB and the apoB/apoA-I ratio might be independent predictors of early atherosclerosis in NGT.

  15. Apolipoprotein C3 polymorphisms, cognitive function and diabetes in Caribbean origin Hispanics.

    Directory of Open Access Journals (Sweden)

    Caren E Smith

    Full Text Available Apolipoprotein C3 (APOC3 modulates triglyceride metabolism through inhibition of lipoprotein lipase, but is itself regulated by insulin, so that APOC3 represents a potential mechanism by which glucose metabolism may affect lipid metabolism. Unfavorable lipoprotein profiles and impaired glucose metabolism are linked to cognitive decline, and all three conditions may decrease lifespan. Associations between apolipoprotein C3 (APOC3 gene polymorphisms and impaired lipid and glucose metabolism are well-established, but potential connections between APOC3 polymorphisms, cognitive decline and diabetes deserve further attention.We examined whether APOC3 single nucleotide polymorphisms (SNPs m482 (rs2854117 and 3u386 (rs5128 were related to cognitive measures, whether the associations between cognitive differences and genotype were related to metabolic differences, and how diabetes status affected these associations. Study subjects were Hispanics of Caribbean origin (n = 991, aged 45-74 living in the Boston metropolitan area.Cognitive and metabolic measures differed substantially by type II diabetes status. In multivariate regression models, APOC3 m482 AA subjects with diabetes exhibited lower executive function (P = 0.009, Stroop color naming score (P = 0.014 and Stroop color-word score (P = 0.022 compared to AG/GG subjects. APOC3 m482 AA subjects with diabetes exhibited significantly higher glucose (P = 0.032 and total cholesterol (P = 0.028 compared to AG/GG subjects. APOC3 3u386 GC/GG subjects with diabetes exhibited significantly higher triglyceride (P = 0.004, total cholesterol (P = 0.003 and glucose (P = 0.016 compared to CC subjects.In summary, we identified significant associations between APOC3 polymorphisms, impaired cognition and metabolic dysregulation in Caribbean Hispanics with diabetes. Further research investigating these relationships in other populations is warranted.

  16. Apolipoprotein gene involved in lipid metabolism (United States)

    Rubin, Edward; Pennacchio, Len A.


    Methods and materials for studying the effects of a newly identified human gene, APOAV, and the corresponding mouse gene apoAV. The sequences of the genes are given, and transgenic animals which either contain the gene or have the endogenous gene knocked out are described. In addition, single nucleotide polymorphisms (SNPs) in the gene are described and characterized. It is demonstrated that certain SNPs are associated with diseases involving lipids and triglycerides and other metabolic diseases. These SNPs may be used alone or with SNPs from other genes to study individual risk factors. Methods for intervention in lipid diseases, including the screening of drugs to treat lipid-related or diabetic diseases are also disclosed.

  17. Association of apolipoprotein E (RFLP polymorphism with myopia

    Directory of Open Access Journals (Sweden)

    Himabindu P


    Full Text Available BACKGROUND: Myopia or nearsightedness is a spherical error of refraction, whereby the images are focused in front of retina. Eye, being an organ rich in activated oxygen species, requires a high level of antioxidants to protect the unsaturated fatty acids. Apolipoprotein E (APOE is one of the proteins that is produced by Muller cells within the retina and is also endowed with antioxidant properties. Genetic polymorphism of APO E is controlled by three common alleles e3, e2 and e4 and rare e1, e4v at the APOE structural gene locus. Different isoforms of APO E differ in their antioxidant properties, and the e4 allele has lesser ability to combat oxidative stress. AIMS: Myopia being a disease influenced by oxidative stress, the present study was undertaken to find association of myopia with APO E polymorphism. MATERIALS AND METHODS: A total of 187 myopic cases and 192 controls were genotyped for apolipoprotein E polymorphism. RESULTS: In both controls and myopic cases, E3/3 genotype was found to be the most frequent one. There was an increase in E3/4 genotype frequency among male probands, high myopia cases and probands with early age at onset, suggesting that the E3/4 genotype might confer risk for myopia development. CONCLUSION: This association with E3/4 genotype might predispose susceptible individuals to develop high myopia and early onset myopia.

  18. Amphotericin B induced interdigitation of apolipoprotein stabilized nanodisk bilayers

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, T; Weers, P M; Sulchek, T; Hoeprich, P D; Ryan, R O


    Amphotericin B nanodisks (AMB-ND) are ternary complexes of AMB, phospholipid (PL) and apolipoprotein organized as discrete nanometer scale disk-shaped bilayers. In gel filtration chromatography experiments, empty ND lacking AMB elute as a single population of particles with a molecular weight in the range of 200 kDa. AMB-ND formulated at a 4:1 PL:AMB weight ratio, separated into two peaks. Peak 1 eluted at the position of control ND lacking AMB while the second peak, containing all of the AMB present in the original sample, eluted in the void volume. When ND prepared with increased AMB (1:1 phospholipid:AMB molar ratio) were subjected to gel filtration chromatography, an increased proportion of phospholipid and apolipoprotein were recovered in the void volume with the AMB. Prior to gel filtration the AMB-ND sample could be passed through a 0.22 {micro}m filter without loss of AMB while the voided material was lost. Native gel electrophoresis studies corroborated the gel permeation chromatography data. Far UV circular dichroism analyses revealed that apoA-I associated with AMB-ND denatures at a lower guanidine HCl concentration than apoA-I associated with ND lacking AMB. Atomic force microscopy revealed that AMB induces compression of the ND bilayer thickness consistent with bilayer interdigitation, a phenomenon that is likely related to the ability of AMB to induce pore formation in susceptible membranes.

  19. Optimisation for enhanced decolourization and degradation of Reactive Red BS C.I. 111 by Pseudomonas aeruginosa NGKCTS. (United States)

    Sheth, N T; Dave, S R


    Soil samples collected from dye contaminated sites of Vatva, Gujarat, India were studied for the screening and isolation of organisms capable of decolourizing textile dyes. The most efficient isolate, which showed decolourization zone of 48 mm on 300 ppm Reactive Red BS (C.I.111) containing plate, was identified as Pseudomonas aeruginosa. Reactive Red BS (C.I.111) was used as a model dye for the study. The isolated culture exhibited 91% decolourization of 300 ppm dye within 5.5 h over a wide pH range from 5.0 to 10.5 and temperature ranging from 30 to 40 degrees C. The culture was able to decolourize more than 91% of Reactive Red BS under static conditions in presence of either glucose, peptone or yeast extract. Addition of 300 ppm of Reactive Red BS, in each step, in ongoing dye decolourization flask, gave more than 90% decolourization within 2 h corresponding to 136 mg l(-1) h(-1) dye removal rate. The isolate had the ability to decolourize six different reactive dyes tested as well as the actual dye manufacturing industry's effluent. The degradation of the dye was confirmed by HPTLC.

  20. Dyeing PET Textile with C.I. Disperse Red 60 and C.I. Disperse Orange 25 in Supercritical CO2

    Institute of Scientific and Technical Information of China (English)

    LI Zhi-yi; MENG Ting-yu; LIU Xue-wu; XIA Yuan-jing; HU Da-peng


    For a better understanding of the feasibility of supercritical fluid dyeing(SFD)and more available information for the process development,the experiments of dyeing PET textile with C.I.disperse red 60(anthraquinone type)and C.I.disperse orange 25(azo type)in supercritical CO2 were carried out with a high-pressure dyeing apparatus at temperatures from 80 to 130℃ and pressure up to 31 MPa.The effect of operating conditions on color yield(K/S)was investigated in SFD experiment,and the optimum operating conditions for the above two disperse dyes were obtained as follows:the temperature 120℃,the pressure 25 MPa and the dyeing time 100 min.As compared with SFD,the conventional water dyeing(CWD)was carded out with the same dyes and textile.The results show that the better fastness,IeveIness and apparent color can be achieved in SFD and the SFD process has many significant advantages over the CWD process.

  1. Fibroblasts that reside in mouse and frog injured peripheral nerves produce apolipoproteins. (United States)

    Saada, A; Dunaevsky-Hutt, A; Aamar, A; Reichert, F; Rotshenker, S


    Apolipoprotein synthesis and secretion is upregulated in wallerian degenerating peripheral nerves. A commonly expressed view has been that macrophages are solely responsible for their production. In the present study we provide evidence that (1) nerve-derived fibroblasts contribute to apolipoprotein production, (2) apolipoprotein production is confined to regions where myelin destruction and phagocytosis occur, and (3) some experimental procedures are detrimental for the production of apolipoproteins. Apolipoprotein production was studied in C57BL/6/NHSD (N) and C57/BL/6-WLD/OLA/NHSD (W) mice that display, respectively, rapid and slow progression of wallerian degeneration. In N nerves, apolipoprotein E (apo-E) is produced during in vitro and in vivo degeneration, and in vivo after freeze damage. In W nerves, apo-E is produced at the injury region where degeneration occurs but not farther distally where degeneration fails to develop. Apo-E is also produced in W nerves during in vitro degeneration and in vivo after freeze damage. In culture, N and W mice nerve-derived fibroblasts, but neither macrophages nor Schwann cells produced apo-E. Two apolipoproteins are produced in in vivo wallerian degenerating and freeze-damaged frog nerves, i.e., apo-39 and apo-29. Only apo-39 is produced in in vitro degenerating nerves. Neither apo-39 nor apo-29 is produced during in vivo degeneration in diffusion chambers. In culture, apo-39 is produced by nerve-derived fibroblasts and macrophages but not by Schwann cells.


    This study was conducted to determine the fate of C.I. Disperse Blue 79, one of the largest production volume dyes, and select biodegradation products in a conventionally operated activated sludge process and an anaerobic sludge digestion system. To achieve this objective, a pilo...


    This study was conducted to determine the fate of C.I. Disperse Blue 79, one of the largest production volume dyes, and select biodegradation products in a conventionally operated activated sludge process and an anaerobic sludge digestion system. To achieve this objective, a pilo...

  4. Relationship between depression and apolipoproteins A and B: a case-control study

    Directory of Open Access Journals (Sweden)

    Masoumeh Sadeghi


    Full Text Available OBJECTIVE: To investigate the relation between major depressive disorder and metabolic risk factors of coronary heart disease. INTRODUCTION: Little evidence is available indicating a relationship between major depressive disorder and metabolic risk factors of coronary heart disease such as lipoprotein and apolipoprotein. METHODS: This case-control study included 153 patients with major depressive disorder who fulfilled the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV, and 147 healthy individuals. All participants completed a demographic questionnaire and Hamilton rating scale for depression. Anthropometric characteristics were recorded. Blood samples were taken and total cholesterol, high-and low-density lipoproteins and apolipoproteins A and B were measured. To analyze the data, t-test, χ2 test, Pearson correlation test and linear regression were applied. RESULTS: Depression was a negative predictor of apolipoprotein A (β = -0.328, p<0.01 and positive predictor of apolipoprotein B (β = 0.290, p<0.05. Apolipoprotein A was inversely predicted by total cholesterol (β = -0.269, p<0.05 and positively predicted by high-density lipoprotein (β = 0.401, p<0.01. Also, low-density lipoprotein was a predictor of apolipoprotein B (β = 0.340, p<0.01. The severity of depression was correlated with the increment in serum apolipoprotein B levels and the decrement in serum apolipoprotein A level. CONCLUSION: In view of the relationship between apolipoproteins A and B and depression, it would seem that screening of these metabolic risk factors besides psychological interventions is necessary in depressed patients

  5. Apolipoprotein B100 analysis in microchip with electrochemical detection

    Institute of Scientific and Technical Information of China (English)

    Cheng Cheng Liu; Yun Liu; Hui Xiang Wang; Yan Bo Qi; Peng Yuan Yang; Bao Hong Liu


    Apolipoprotein B100 (apoB-100) is a major protein of the cholesterol-rich low-density lipoprotein (LDL) and reflects a better assessment of total atherogenic burden to the vascular system than LDL. In this work, a simple and sensitive method has been developed to determine picoliter apoB-100s using the PMMA microfluidic chip coupled with electrochemical detection system. This method performs very well with a detectable linear range of 1-800 pg/mL and a detection limit of 1 pg/mL. A real serum sample has further been detected by this microchip-based biosensor. The results show that this kind of method is practicable and has the potential application in clinical analysis and diagnosis.

  6. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello


    Full Text Available Research on apolipoprotein E (APOE has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD. However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

  7. Function and Comorbidities of Apolipoprotein E in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Valérie Leduc


    Full Text Available Alzheimer's disease (AD—the most common type of dementia among the elderly—represents one of the most challenging and urgent medical mysteries affecting our aging population. Although dominant inherited mutation in genes involved in the amyloid metabolism can elicit familial AD, the overwhelming majority of AD cases, dubbed sporadic AD, do not display this Mendelian inheritance pattern. Apolipoprotein E (APOE, the main lipid carrier protein in the central nervous system, is the only gene that has been robustly and consistently associated with AD risk. The purpose of the current paper is thus to highlight the pleiotropic roles and the structure-function relationship of APOE to stimulate both the functional characterization and the identification of novel lipid homeostasis-related molecular targets involved in AD.

  8. Interactions of Apolipoproteins AI, AII, B and HDL, LDL, VLDL with Polyurethane and Polyurethane-PEO Surfaces. (United States)

    Cornelius, R M; Macri, J; Cornelius, K M; Brash, J L


    The lipoproteins (HDL, LDL, VLDL) are important components of blood present in high concentration. Surprisingly, their role in blood-biomaterial interactions has been largely ignored. In previous work apolipoprotein AI (the main protein component of HDL) was identified as a major constituent of protein layers adsorbed from plasma to biomaterials having a wide range of surface properties, and quantitative data on the adsorption of apo AI to a biomedical grade polyurethane were reported. In the present communication quantitative data on the adsorption of apo AI, apo AII and apoB (the latter being a constituent of LDL and VLDL), as well as the lipoprotein particles themselves (HDL, LDL, VLDL), to a biomedical segmented polyurethane (PU) with and without an additive containing poly(ethylene oxide) (material referred to as PEO) are reported. Using radiolabeled apo AI, apo AII, and apoB, adsorption levels on PU from buffer at a protein concentration of 50 μg/mL were found to be 0.34, 0.40, and 0.14 μg/cm(2) (12, 23, and 0.25 nmol/cm(2)) respectively. Adsorption to the PEO surface was PEO as well as to the PU surface. X-ray photoelectron spectra, following exposure of the surfaces to the lipoproteins, showed a strong phosphorus signal, confirming that adsorption had occurred. It therefore appears that a PEO-containing surface that is resistant to apolipoproteins may be less resistant to the corresponding lipoproteins.

  9. Apolipoprotein and lipid abnormalities in chronic liver failure

    Directory of Open Access Journals (Sweden)

    Spósito A.C.


    Full Text Available Total serum lipids, as well as apolipoproteins A-I (apo A-I and B (apo B, were determined in 74 patients with chronic liver failure without cholestasis and in 82 normal subjects. The VLDL, LDL and HDL lipid fractions were reduced in the liver failure group by 36%, 24% and 46%, respectively (P<0.001. Apolipoproteins A-I and B were also reduced by 26% and 25%, respectively (P<0.001. However, the reduction of HDL cholesterol (HDLc was more pronounced than that of apo A-I and the HDLc:apo A-I ratio was significantly lower in the liver failure group. After separating these patients into groups with plasma albumin lower than 3.0, between 3.0 and 3.5, and higher than 3.5 g/dl, the HDLc:apo A-I ratio was proportional to plasma albumin, but the correlation was not statistically significant. When these patients were separated by the Child classification of liver function, there was a correlation between the HDLc:apo A-I ratio and liver function. The differences in the HDLc:apo A-I ratio between the Child groups B and C, and A and C were statistically significant (P<0.05. We conclude that there is a more pronounced reduction in HDL cholesterol than in apo A-I in liver failure patients. Therefore, the HDLc:apo A-I ratio is a marker of liver function, probably because there is a decreased lecithin-cholesterol acyltransferase production by the diseased liver

  10. Apolipoprotein E polymorphism in northern Chinese elderly patients with coronary artery disease

    Institute of Scientific and Technical Information of China (English)

    Yangchun ZOU; Dayi HU; Xiufang HONG; Xingyuan JIA; Xinchun YANG; Liang CUI


    Background and objective Apolipoprotein E is a constituent of lipoproteins with considerable variation due to cysteine-arginine exchanges. We investigated the relationship between apo E gene polymorphism and the occurrence of coronary artery disease(CAD) in the older population of northern China. Methods The distribution of the HhaI polymorphisms of the apolipoprotein E gene was determined among 55 patients with CAD (CAD group), which was compared with that of 36 elderly subjects without CAD(control group). Results Genotype distributions at both sites (apo E gene 112-bp and 158-bp sites ) were different between the CAD and control groups. The CAD group had lower apolipoprotein E"ε2"frequencies than the control group (P<0.05). Conclusion Individuals with apolipoprotein E"ε2"are likely to have a reduced risk of developing coronary artery disease as demonstrated by elderly subjects in Northern China.

  11. Distinct Hepatic Receptors for Low Density Lipoprotein and Apolipoprotein E in Humans (United States)

    Hoeg, Jeffrey M.; Demosky, Stephen J.; Gregg, Richard E.; Schaefer, Ernst J.; Brewer, H. Bryan


    Since the liver is a central organ for lipid and lipoprotein synthesis and catabolism, hepatic receptors for specific apolipoproteins on plasma lipoproteins would be expected to modulate lipid and lipoprotein metabolism. The role of hepatic receptors for low density lipoproteins and apolipoprotein E-containing lipoproteins was evaluated in patients with complementary disorders in lipoprotein metabolism: abetalipoproteinemia and homozygous familial hypercholesterolemia. In addition, hepatic membranes from a patient with familial hypercholesterolemia were studied and compared before and after portacaval shunt surgery. The results establish that the human liver has receptors for apolipoproteins B and E. Furthermore, in the human, hepatic receptors for low density lipoproteins and apolipoprotein E are genetically distinct and can undergo independent control.

  12. Computed profiles of the solar C I multiplets at 1561 and 1657 A (United States)

    Mauas, Pablo J.; Avrett, Eugene H.; Loeser, Rudolf


    A nine-level atomic model is presented for C I lines synthesis in the sun. All the atomic parameters are based on recent experimental and theoretical data. Profiles of the multiplets at 1561 and 1657 A are computed from a model of the solar chromosphere. The sensitivity of the results to changes in the atomic parameters is examined. Partial frequency redistribution must be included in these lines to obtain agreement between calculated and observed profiles.

  13. History of Met Lab Section C-I, May 1943 to April 1944

    Energy Technology Data Exchange (ETDEWEB)

    Seaborg, G.T.


    This is part of a history of the research work of Seaborg and associates in the University of Chicago Metallurgical Laboratory, Chemistry Section C-I. The work was concerned with the development of chemical procedures for the extraction of plutonium, for the purification of plutonium, and for research on the isotopes of other heavy elements including other transuranium elements. The style of the history is that of a diary with footnotes giving additional information. (DLC)

  14. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family

    DEFF Research Database (Denmark)

    Nilsson, Stefan K; Lookene, Aivar; Beckstead, Jennifer A;


    Apolipoprotein A-V is a potent modulator of plasma triacylglycerol levels. To investigate the molecular basis for this phenomenon we explored the ability of apolipoprotein A-V, in most experiments complexed to disks of dimyristoylphosphatidylcholine, to interact with two members of the low densit...... to receptor-covered sensor chips. Our results indicate that apolipoprotein A-V may influence plasma lipid homeostasis by enhancing receptor-mediated endocytosis of triacylglycerol-rich lipoproteins. Udgivelsesdato: 2007-Mar-27......Apolipoprotein A-V is a potent modulator of plasma triacylglycerol levels. To investigate the molecular basis for this phenomenon we explored the ability of apolipoprotein A-V, in most experiments complexed to disks of dimyristoylphosphatidylcholine, to interact with two members of the low density...... lipoprotein receptor family, the low density lipoprotein receptor-related protein and the mosaic type-1 receptor, SorLA. Experiments using surface plasmon resonance showed specific binding of both free and lipid-bound apolipoprotein A-V to both receptors. The binding was calcium dependent and was inhibited...

  15. S.A.C.I.: Incident Combat Support System; S.A.C.I.: Sistema de Apoio ao Combate de Incidentes

    Energy Technology Data Exchange (ETDEWEB)

    Macedo, Antonio R.L. [ARMTEC Tecnologia em Robotica, Fotrtaleza, CE (Brazil); Macedo, Antonio R.M. [Universidade de Fortaleza, CE (Brazil)


    The incidents that occur in the petrochemical industry are extremely dangerous, because of the range of temperature that it reaches and the radius of the explosion. For this reason the S.A.C.I. that is an Incident's Combat Support System was developed. The purpose of this paper is to present the complete operational capability of this machine, and also some of the construction design calculations. It is a controlled-by-distance robot that carries one water cannon that generates fog, stream or foam with a limit pressure of 125 psi. It works within 90 m from the operator, has 3 degrees of freedom and a minimum autonomy of 3 hours. Before this prototype was made, only the United Kingdom by Qinetiq and the Japan by the Tokyo Fire Department had this technology. This prototype is around 70% of the investment of the ones in the market. The tests shown in the paper were made in the training bunker of Ceara's Military Fire Corp. Headquarters and in an arena in the Gloria Marine in Rio de Janeiro. The results of this project is a national product that improves the incident's combat response time, saving the most important resource, that is the human been. (author)

  16. NLTE carbon abundance determination in selected A- and B-type stars and the interpretation of C I emission lines (United States)

    Alexeeva, S. A.; Ryabchikova, T. A.; Mashonkina, L. I.


    We constructed a comprehensive model atom for C I-C II using the most up-to-date atomic data available and evaluated the non-local thermodynamic equilibrium (NLTE) line formation for C I and C II in classical 1D models representing the atmospheres of A- and late B-type stars. Our NLTE calculations predict the emission that appears at effective temperature of 9250 to 10 500 K depending on log g in the C I 8335, 9405 Å singlet lines and at Teff> 15 000 K (log g = 4) in the C I 9061-9111 Å, 9603-9658 Å triplet lines. A pre-requisite of the emission phenomenon is the overionization-recombination mechanism resulting in a depopulation of the lower levels of C I to a greater extent than the upper levels. Extra depopulation of the lower levels of the transitions corresponding to the near-infrared lines, is caused by photon loss in the UV lines C I 2479, 1930, and 1657 Å. We analysed the lines of C I and C II in Vega, HD 73666, Sirius, 21 Peg, π Cet, HD 22136, and ι Her taking advantage of their observed high-resolution spectra. The C I emission lines were detected in the four hottest stars, and they were well reproduced in our NLTE calculations. For each star, the mean NLTE abundances from lines of the two ionization stages, C I and C II, including the C I emission lines, were found to be consistent. We show that the predicted C I emission phenomenon depends strongly on whether accurate or approximate electron-impact excitation rates are applied.

  17. Large-Scale CO and [C I] Emission in the ρ Ophiuchi Molecular Cloud (United States)

    Kulesa, Craig A.; Hungerford, Aimee L.; Walker, Christopher K.; Zhang, Xiaolei; Lane, Adair P.


    We present a comprehensive study of the ρ Ophiuchi molecular cloud that addresses aspects of the physical structure and condition of the molecular cloud and its photodissociation region (PDR) by combining far-infrared and submillimeter-wave observations with a wide range of angular scale and resolution. We present 1600 arcmin2 maps (2.3 pc2) with 0.1 pc resolution in submillimeter CO (4-->3) and [C I] (3P1-->3P0) line emission from the Antarctic Submillimeter Telescope and Remote Observatory (AST/RO) and pointed observations in the CO (7-->6) and [C I] (3P2-->3P1) lines. Within the large-scale maps, smaller spectral line maps of 3000 AU resolution over ~90 arcmin2 (0.2 pc2) of the cloud in CO, CS, HCO+, and their rare isotopomers are made at the Heinrich Hertz Telescope (HHT) in Arizona. Comparison of CO, HCO+, and [C I] maps with far-infrared observations of atomic and ionic species from the Infrared Space Observatory (ISO) far-infrared and submillimeter continuum emission and near-infrared H2 emission allows clearer determination of the physical and chemical structure of the ρ Oph PDR, since each species probes a different physical region of the cloud structure. Although a homogeneous plane-parallel PDR model can reproduce many of the observations described here, the excitation conditions needed to produce the observed HCO+ and [O I] emission imply inhomogeneous structure. Strong chemical gradients are observed in HCO+ and CS; the former is ascribed to a local enhancement in the H2 ionization rate, and the latter is principally due to shocks. Under the assumption of a simple two-component gas model for the cloud, we find that [C II] and [C I] emission predominantly arises from the lower density envelopes (103-104 cm-3) that surround denser cloud condensations, or ``clumps.'' The distribution of [C I] is very similar to that of C18O and is generally consistent with illumination from the ``far'' side of the cloud. A notable exception is found at the western edge

  18. Endothelial cells downregulate apolipoprotein D expression in mural cells through paracrine secretion and Notch signaling. (United States)

    Pajaniappan, Mohanasundari; Glober, Nancy K; Kennard, Simone; Liu, Hua; Zhao, Ning; Lilly, Brenda


    Endothelial and mural cell interactions are vitally important for proper formation and function of blood vessels. These two cell types communicate to regulate multiple aspects of vessel function. In studying genes regulated by this interaction, we identified apolipoprotein D (APOD) as one gene that is downregulated in mural cells by coculture with endothelial cells. APOD is a secreted glycoprotein that has been implicated in governing stress response, lipid metabolism, and aging. Moreover, APOD is known to regulate smooth muscle cells and is found in abundance within atherosclerotic lesions. Our data show that the regulation of APOD in mural cells is bimodal. Paracrine secretion by endothelial cells causes partial downregulation of APOD expression. Additionally, cell contact-dependent Notch signaling plays a role. NOTCH3 on mural cells promotes the downregulation of APOD, possibly through interaction with the JAGGED-1 ligand on endothelial cells. Our results show that NOTCH3 contributes to the downregulation of APOD and by itself is sufficient to attenuate APOD transcript expression. In examining the consequence of decreased APOD expression in mural cells, we show that APOD negatively regulates cell adhesion. APOD attenuates adhesion by reducing focal contacts; however, it has no effect on stress fiber formation. These data reveal a novel mechanism in which endothelial cells control neighboring mural cells through the downregulation of APOD, which, in turn, influences mural cell function by modulating adhesion.

  19. Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan. (United States)

    Walker, David W; Muffat, Julien; Rundel, Colin; Benzer, Seymour


    Increased Apolipoprotein D (ApoD) expression has been reported in various neurological disorders, including Alzheimer's disease, schizophrenia, and stroke, and in the aging brain . However, whether ApoD is toxic or a defense is unknown. In a screen to identify genes that protect Drosophila against acute oxidative stress, we isolated a fly homolog of ApoD, Glial Lazarillo (GLaz). In independent transgenic lines, overexpression of GLaz resulted in increased resistance to hyperoxia (100% O(2)) as well as a 29% extension of lifespan under normoxia. These flies also displayed marked improvements in climbing and walking ability after sublethal exposure to hyperoxia. Overexpression of Glaz also increased resistance to starvation without altering lipid or protein content. To determine whether GLaz might be important in protection against reperfusion injury, we subjected the flies to hypoxia, followed by recovery under normoxia. Overexpression of GLaz was protective against behavioral deficits caused in normal flies by this ischemia/reperfusion paradigm. This and the accompanying paper by Sanchez et al. (in this issue of Current Biology) are the first to manipulate the levels of an ApoD homolog in a model organism. Our data suggest that human ApoD may play a protective role and thus may constitute a therapeutic target to counteract certain neurological diseases.

  20. Meta-analysis of peripheral blood apolipoprotein E levels in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Chong Wang

    Full Text Available BACKGROUND: Peripheral blood Apolipoprotein E (ApoE levels have been proposed as biomarkers of Alzheimer's disease (AD, but previous studies on levels of ApoE in blood remain inconsistent. This meta-analysis was designed to re-examine the potential role of peripheral ApoE in AD diagnosis and its potential value as a candidate biomarker. METHODS: We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews for case-control studies measuring ApoE levels in serum or plasma from AD subjects and healthy controls. The pooled weighted mean difference (WMD and 95% confidence interval (CI were used to estimate the association between ApoE levels and AD risk. RESULTS: Eight studies with a total of 2250 controls and 1498 AD cases were identified and analyzed. The pooled WMD from a random-effect model of AD participants compared with the healthy controls was -5.59 mg/l (95% CI: [-8.12, -3.06]. The overall pattern in WMD was not varied by characteristics of study, including age, country, assay method, publication year, and sample type. CONCLUSIONS: Our meta-analysis supports a lowered level of blood ApoE in AD patients, and indicates its potential value as an important risk factor for AD. Further investigation employing standardized assay for ApoE measurement are still warranted to uncover the precise role of ApoE in the pathophysiology of AD.

  1. Apolipoprotein E4 domain interaction accelerates diet-induced atherosclerosis in hypomorphic Arg-61 Apoe mice (United States)

    Eberlé, Delphine; Kim, Roy Y.; Luk, Fu Sang; de Mochel, Nabora Soledad Reyes; Gaudreault, Nathalie; Olivas, Victor R.; Kumar, Nikit; Posada, Jessica M.; Birkeland, Andrew C.; Rapp, Joseph H.; Raffai, Robert L.


    Objective Apolipoprotein (apo) E4 is an established risk factor for atherosclerosis, but the structural components underlying this association remain unclear. ApoE4 is characterized by two biophysical properties: domain interaction and molten globule state. Substituting Arg-61 for Thr-61 in mouse apoE introduces domain interaction without molten globule state, allowing us to delineate potential pro-atherogenic effects of domain interaction in vivo. Methods and Results We studied atherosclerosis susceptibility of hypomorphic Apoe mice expressing either Thr-61 or Arg-61 apoE (ApoeTh/h or ApoeRh/h mice). On a chow diet, both mouse models were normo-lipidemic with similar levels of plasma apoE and lipoproteins. However, on a high cholesterol diet, ApoeRh/h mice displayed increased levels of total plasma cholesterol and VLDL as well as larger atherosclerotic plaques in the aortic root, arch and descending aorta compared to ApoeTh/h mice. In addition, evidence of cellular dysfunction was identified in peritoneal ApoeRh/h macrophages which released lower amounts of apoE in culture medium and displayed increased expression of MHC class II molecules. Conclusions These data indicate that domain interaction mediates pro-atherogenic effects of apoE4 in part by modulating lipoprotein metabolism and macrophage biology. Pharmaceutical targeting of domain interaction could lead to new treatments for atherosclerosis in apoE4 individuals. PMID:22441102

  2. Extracellular proteolysis of apolipoprotein E (apoE by secreted serine neuronal protease.

    Directory of Open Access Journals (Sweden)

    Irfan Y Tamboli

    Full Text Available Under normal conditions, brain apolipoprotein E (apoE is secreted and lipidated by astrocytes, then taken up by neurons via receptor mediated endocytosis. Free apoE is either degraded in intraneuronal lysosomal compartments or released. Here we identified a novel way by which apoE undergoes proteolysis in the extracellular space via a secreted neuronal protease. We show that apoE is cleaved in neuronal conditioned media by a secreted serine protease. This apoE cleavage was inhibited by PMSF and α1-antichymotrypsin, but not neuroserpin-1 or inhibitors of thrombin and cathepsin G, supporting its identity as a chymotrypsin like protease. In addition, apoE incubation with purified chymotrypsin produced a similar pattern of apoE fragments. Analysis of apoE fragments by mass spectrometry showed cleavages occurring at the C-terminal side of apoE tryptophan residues, further supporting our identification of cleavage by chymotrypsin like protease. Hippocampal neurons were more efficient in mediating this apoE cleavage than cortical neurons. Proteolysis of apoE4 generated higher levels of low molecular weight fragments compared to apoE3. Primary glial cultures released an inhibitor of this proteolytic activity. Together, these studies reveal novel mechanism by which apoE can be regulated and therefore could be useful in designing apoE directed AD therapeutic approaches.

  3. Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription

    Directory of Open Access Journals (Sweden)

    Bin Hong


    Full Text Available Apolipoprotein A-I (Apo A-I is the principal protein component of high density lipoprotein (HDL, which is generally considered as a potential therapeutic target against atherosclerosis. The understanding of the Apo A-I regulation mechanism has fuelled the development of novel HDL targeted therapeutic approaches. To identify novel agents that can upregulate Apo A-I expression, we performed a cell-based reporter assay to screen 25,600 small molecules. Based on the dataset obtained from screening, a series of novel analogs of substituted benzamides containing azaspiro rings were assessed for their ability to induce the transcription of the Apo A-I gene, and the structure-activity relationship (SAR around these analogs was also proposed. The results indicated that the trifluoromethyl substituted benzamide containing an azaspiro ring is a promising backbone for designing Apo A-I transcriptional upregulator and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.

  4. A Study on Apolipoprotein E Polymorphism in Early Onset of Coronary Heart Disease

    Institute of Scientific and Technical Information of China (English)

    朱铁兵; 杨志健; 钱卫冲; 王连生; 马根山; 马文珠


    Objective:To assess the relationship between apolipoprotein E( apoE) polymorphism and early anset of Coronary heart disease(CHD) and the effect of apoE on lipids and lipoproteins in Chinese healthy subjects.Methods:Sixty-eight cases(CHD1) aged less than 55y,136 cases(CHD2) aged more than 65y with CHD and 136 healthy subjects were enrolled and their plamsma levels of triglyceride(TG),total cholesterol(TC) and high density lipoprotein cholesterol(HDL-C) were determined.The apoE genotypes were identified by polymerase chain reaction-restriction fragment lengths polymorphism.Results:apoE3/4 genotype and E4 allele frequency in CHD1 were higher than those in CHD2 and healthy subjects and no difference was found between CHD2 and healthy subjects.Meanwhile the plasma levels of TC and low density lipoprotein cholesterol(LDL-C) were higher in CHD2 than in either CHD1 or healthy subjects.Each apoE isoprotein has variable TC and LDL-C levels characterized by E2(E2/2+E2/3)

  5. Phosphorylation-dependent down-regulation of apolipoprotein A5 by insulin

    Energy Technology Data Exchange (ETDEWEB)

    Nowak, Maxine; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Rommens, Corinne; Martin, Genevieve; Duran-Sandoval, Daniel; Staels, Bart; Rubin, Edward M.; Pennacchio, Len A.; Taskinen, Marja-Riitta; Fruchart-Najib, Jamila; Fruchart, Jean-Charles


    The apolipoprotein A5 (APOA5) gene has been shown to be important in lowering plasma triglyceride levels. Since several studies have shown that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 gene is regulated by insulin. We show here that cell and mouse treatments with insulin down-regulated APOA5 expression in a dose-dependent manner. Furthermore, we determined that insulin decreases APOA5 promoter activity and subsequent deletion analyses revealed an E-box-containing fragment. We showed that Upstream Stimulatory Factors, USF1/USF2, bind to the identified E-box in the APOA5 promoter. Moreover, in cotransfection studies, USF1 stimulates APOA5 promoter activity. The treatment with insulin reduces the binding of USF1/USF2 to APOA5 promoter. The inhibition of PI3K pathway with wortmannin abolished the insulin s effect on APOA5 gene transcription. Using oligoprecipitation method of USF from nuclear extracts, we demonstrated that phosphorylated USF1 failed to bind to APOA5 promoter. This indicates that the APOA5 gene transrepression by insulin involves a phosphorylation of USF through PI3K, that modulate their binding to APOA5 promoter and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in healthy men shows a decrease of the plasma ApoAV level. These data suggest a potential mechanism involving APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.

  6. Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA

    Directory of Open Access Journals (Sweden)

    Paul Halley


    Full Text Available Apolipoprotein A1 (APOA1 is the major protein component of high-density lipoprotein (HDL in plasma. We have identified an endogenously expressed long noncoding natural antisense transcript, APOA1-AS, which acts as a negative transcriptional regulator of APOA1 both in vitro and in vivo. Inhibition of APOA1-AS in cultured cells resulted in the increased expression of APOA1 and two neighboring genes in the APO cluster. Chromatin immunoprecipitation (ChIP analyses of a ∼50 kb chromatin region flanking the APOA1 gene demonstrated that APOA1-AS can modulate distinct histone methylation patterns that mark active and/or inactive gene expression through the recruitment of histone-modifying enzymes. Targeting APOA1-AS with short antisense oligonucleotides also enhanced APOA1 expression in both human and monkey liver cells and induced an increase in hepatic RNA and protein expression in African green monkeys. Furthermore, the results presented here highlight the significant local modulatory effects of long noncoding antisense RNAs and demonstrate the therapeutic potential of manipulating the expression of these transcripts both in vitro and in vivo.

  7. C.I.S.H. Laparoscopic Hysterectomy: The Experience at the "Centro Materno Infantil" (United States)

    Decunto; Traverso; Gibelli; Harpe


    Laparoscopic hysterectomy has been established firmly as a surgical alternative to standard abdominal hysterectomy around the world. In Argentina, we had introduced operative laparoscopy at the Hospital Aleman in May 1993, with a major change from basic diagnostic laparoscopy to advanced operative laparoscopy. A total of 180 major laparoscopic cases have been performed from May 1993 to January 1994, including laparoscopic hysterectomies. Of our first five C.I.S.H. laparoscopic hysterectomies, all had excellent outcomes, with greatly diminished hospital stay and less usage of analgesics postoperatively. The average length of stay was 2.5 days. No major complications occurred.

  8. Skeletal muscle apolipoprotein B expression reduces muscular triglyceride accumulation

    DEFF Research Database (Denmark)

    Bartels, Emil D; Ploug, Thorkil; Størling, Joachim;


    Abstract Background. Lipid accumulation in skeletal muscle is associated with impaired insulin sensitivity in type 2 diabetes. In cardiac myocytes, lipoprotein secretion controlled by apolipoproteinB (apoB) and microsomal triglyceride transfer protein (MTP) affects lipid homeostasis. Design....... In this study, we investigated whether expression of a human apoB transgene affects triglyceride accumulation and insulin sensitivity in skeletal muscle in fat fed obese mice. Results. Expression of apoB and MTP mRNA and the human apoB transgene was seen in skeletal muscle of the transgene mice. Human apo......B transgenic mice accumulated 28% less triglycerides in skeletal myocytes after one year of fat-feeding as compared with WT mice (32 ± 5, n = 10 vs. 44 ± 4 nmol/mg ww, n = 13, p = 0.04). Moreover, expression of human apoB in fat-fed mice was associated with 32% (p = 0.02) and 37% (p = 0.01) lower plasma...

  9. Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

    Directory of Open Access Journals (Sweden)

    Huntington Potter


    Full Text Available The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE. Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

  10. Apolipoprotein M in lipid metabolism and cardiometabolic diseases

    DEFF Research Database (Denmark)

    Borup, Anna; Christensen, Pernille Meyer; Nielsen, Lars B.


    PURPOSE: This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases. RECENT FINDINGS: ApoM's likely role(s) in health and disease has become more diverse after the discovery that apoM functions...... as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P. SUMMARY......: The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also...

  11. Glucose Regulates the Expression of the Apolipoprotein A5 Gene

    Energy Technology Data Exchange (ETDEWEB)

    Fruchart, Jamila; Nowak, Maxime; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Moitrot, Emmanuelle; Rommens, Corinne; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart, Jean-Charles


    The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.

  12. Alzheimer's disease, apolipoprotein E and hormone replacement therapy. (United States)

    Depypere, H; Vierin, A; Weyers, S; Sieben, A


    Alzheimer's disease is the most frequent cause of dementia in older patients. The prevalence is higher in women than in men. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Earlier age at menopause (spontaneous or surgical) is associated with an enhanced risk of developing Alzheimer's disease. Therefore, it is postulated that estrogen could be protective against it. If so, increasing exposure to estrogen through the use of postmenopausal hormone replacement could also be protective against Alzheimer's disease. The results of the clinical studies that have examined this hypothesis are inconclusive, however. One explanation for this is that estrogen treatment is protective only if it is initiated in the years immediately after menopause. Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein E. This protein plays an important role in cholesterol transport to the neurons. Studies that have examined the link between estrogen replacement therapy, Alzheimer's disease and the E4 allele of ApoE are inconclusive. This article reviews the literature on the influence of hormone replacement therapy on the incidence and progression of Alzheimer's disease.

  13. An apolipoprotein B100 mimotope prevents obesity in mice. (United States)

    Kim, Hyo Joon; Lee, Hee Jong; Choi, Jung Soon; Han, Jemin; Kim, Ji Young; Na, Hyun Kyun; Joung, Hae-Jung; Kim, Young Sik; Binas, Bert


    Although apolipoprotein B100 (ApoB100) plays a key role in peripheral fat deposition, it is not considered a suitable therapeutic target in obesity. In the present study we describe a novel ApoB100 mimotope, peptide pB1, and the use of pB1-based vaccine-like formulations (BVFs) against high-fat diet (HFD)-induced obesity. In HFD- compared with chow-fed adolescent mice, BVFs reduced the 3-month body-weight gains attributable to increased dietary fat by 44-65%, and prevented mesenteric fat accumulation and liver steatosis. The body-weight reductions paralleled the titres of pB1-reactive immunoglobulin G (IgG) antibodies, and pB1-reactive antibodies specifically recognized native ApoB100 and a synthetic peptide from the C-terminal half of ApoB100. In cultured 3T3L1 adipocytes, anti-pB1 antibodies increased lipolysis and inhibited low-density lipoprotein (LDL) uptake. In cultured RAW 264.7 macrophages, the same antibodies enhanced LDL uptake (without causing foam cell formation). These findings make ApoB100 a promising target for an immunization strategy against HFD-induced obesity.

  14. The potential applications of Apolipoprotein E in personalized medicine (United States)

    Villeneuve, Sylvia; Brisson, Diane; Marchant, Natalie L.; Gaudet, Daniel


    Personalized medicine uses various individual characteristics to guide medical decisions. Apolipoprotein (ApoE), the most studied polymorphism in humans, has been associated with several diseases. The purpose of this review is to elucidate the potential role of ApoE polymorphisms in personalized medicine, with a specific focus on neurodegenerative diseases, by giving an overview of its influence on disease risk assessment, diagnosis, prognosis, and therapy. This review is not a systematic inventory of the literature, but rather a summary and discussion of novel, influential and promising works in the field of ApoE research that could be valuable for personalized medicine. Empirical evidence suggests that ApoE genotype informs pre-symptomatic risk for a wide variety of diseases, is valuable for the diagnosis of type III dysbetalipoproteinemia, increases risk of dementia in neurodegenerative diseases, and is associated with a poor prognosis following acute brain damage. ApoE status appears to influence the efficacy of certain drugs, outcome of clinical trials, and might also give insight into disease prevention. Assessing ApoE genotype might therefore help to guide medical decisions in clinical practice. PMID:25071563

  15. Apolipoproteins A-I and B in Kuwaiti children. (United States)

    Moussa, M A; Shaltout, A A; Nkansa-Dwamena, D; Mourad, M


    To assess the relation of apolipoproteins (Apos) A-I and B (the carrier proteins for high and low density lipoprotein cholesterol, respectively) with the degree of obesity, body fat distribution, serum lipids, glucose and insulin levels, a case-control study was carried out and included 460 Kuwaiti obese children, 6-13 years old, matched by age and sex to 460 normal-weight controls. Obese children were ascertained in a representative cross-sectional study of 2,400 school children. The Apo A-I levels were not different between obese and non-obese boys, while they were significantly lower in obese girls (p < 0.01). The Apo B mean concentrations were significantly higher in obese boys and girls (p < 0.001), while the Apo A-I:B ratio was significantly lower in obese children (p < 0.001). Apo A-I levels were positively correlated with total cholesterol, high- and low-density lipoprotein cholesterol, but were not correlated with very low-density lipoprotein cholesterol, triglycerides, insulin, glucose or insulin:glucose ratio. Apo B levels were negatively correlated with high-density lipoprotein cholesterol and positively correlated with insulin and insulin:glucose ratio (p < 0.01) in obese children. The study documented an adverse Apo profile in obese Kuwaiti children. Since Apo changes are correctable through management of obesity, their identification in childhood offers prospects for prevention of early onset atherogenesis in adulthood.

  16. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. (United States)

    Haddadi, Mohammad; Nongthomba, Upendra; Jahromi, Samaneh Reiszadeh; Ramesh, S R


    The ε4 isoform of apolipoprotein E (ApoE4) that is involved in neuron-glial lipid metabolism has been demonstrated as the main genetic risk factor in late-onset of Alzheimer's disease. However, the mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We created a transgenic model of neurodegenerative disorder by expressing ε3 and ε4 isoforms of human ApoE in the Drosophila melanogaster. The genetic models exhibited progressive neurodegeneration, shortened lifespan and memory impairment. Genetic interaction studies between amyloid precursor protein and ApoE in axon pathology of the disease revealed that over expression of hApoE in Appl-expressing neurons of Drosophila brain causes neurodegeneration. Moreover, acute oxidative damage in the hApoE transgenic flies triggered a neuroprotective response of hApoE3 while chronic induction of oxidative damage accelerated the rate of neurodegeneration. This Drosophila model may facilitate analysis of the molecular and cellular events implicated in hApoE4 neurotoxicity.

  17. Genetic Variability of Apolipoprotein E in Different Populations from Venezuela

    Directory of Open Access Journals (Sweden)

    M. T. Fernández-Mestre


    Full Text Available The genetic variation at the Apolipoprotein E locus (APOE is an important determinant of plasma lipids and has been implicated in various human pathological conditions. The objective of the present study was to estimate the distribution of APOE alleles in five Venezuelan communities: two Amerindian tribes (Bari and Yucpa, one Negroid population from Curiepe, one Caucasoid population from Colonia Tovar and the mestizo urban population living in Caracas. The APOE*3 allele was the most common allele in all populations studied. However, a significant increase in the APOE*2 allele frequency in the Mestizo (18.96% and Negroid (16.25% populations was found. Similar to results reported in other Native American populations we have found that the APOE*2 allele is completely absent in the Bari and Yucpa Amerindians. Frequencies found in the Colonia Tovar population are in agreement with those reported in the population of Germany, indicating a high degree of relatedness. The results support the notion that the distribution of the APOE alleles shows ethnic variability.

  18. Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population (United States)

    Sierra-Johnson, Justo; Fisher, Rachel M.; Romero-Corral, Abel; Somers, Virend K.; Lopez-Jimenez, Francisco; Öhrvik, John; Walldius, Göran; Hellenius, Mai-Lis; Hamsten, Anders


    Aims Prospective studies indicate that apolipoprotein measurements predict coronary heart disease (CHD) risk; however, evidence is conflicting, especially in the US. Our aim was to assess whether measurements of apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) can improve the ability to predict CHD death beyond what is possible based on traditional cardiovascular (CV) risk factors and clinical routine lipid measurements. Methods and results We analysed prospectively associations of apolipoprotein measurements, traditional CV risk factors, and clinical routine lipid measurements with CHD mortality in a multi-ethnic representative subset of 7594 US adults (mean age 45 years; 3881 men and 3713 women, median follow-up 124 person-months) from the Third National Health and Nutrition Examination Survey mortality study. Multiple Cox-proportional hazards regression was applied. There were 673 CV deaths of which 432 were from CHD. Concentrations of apoB [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.09–3.61], apoA-I (HR 0.48, 95% CI 0.27–0.85) and total cholesterol (TC) (HR 1.17, 95% CI 1.02–1.34) were significantly related to CHD death, whereas high density lipoprotein cholesterol (HDL-C) (HR 0.68, 95% CI 0.45–1.05) was borderline significant. Both the apoB/apoA-I ratio (HR 2.14, 95% CI 1.11–4.10) and the TC/HDL-C ratio (HR 1.10, 95% CI 1.04–1.16) were related to CHD death. Only apoB (HR 2.01, 95% CI 1.05–3.86) and the apoB/apoA-I ratio (HR 2.09, 95% CI 1.04–4.19) remained significantly associated with CHD death after adjusting for CV risk factors. Conclusion In the US population, apolipoprotein measurements significantly predict CHD death, independently of conventional lipids and other CV risk factors (smoking, dyslipidaemia, hypertension, obesity, diabetes and C-reactive protein). Furthermore, the predictive ability of apoB alone to detect CHD death was better than any of the routine clinical lipid measurements. Inclusion of apolipoprotein

  19. Optimisation and evaluation of restriction fragment length polimorfism method for apolipoprotein E

    Directory of Open Access Journals (Sweden)

    Drljević Nevena


    Full Text Available Introduction. Apolipoprotein E gene polymorphism is characterized by the presence of three common alleles, e2, e3 and e4, which encode three isoforms of apolipoprotein E in plasma E2, E3 and E4. Genetic polymorphisms of apolipoprotein E gene are predictive markers for the development of numerous disorders of lipid metabolism, already proven in a large number of clinical trials. This study was aimed at assessing the success rate of restriction fragment length polymorphism method for the detections of genes coding for isoenzymes E2, E3 and E4. Material and Methods. Deoxyribonucleic acid, used in this study, was extracted from blood by standard procedure using chloroform and phenol. The polymerase chain reaction method was used to amplify the coding sequence of fourth exon of the apolipoprotein E gene. Amplification products were digested with HhaI. The fragments obtained were separated by electrophoresis and visualized with ultraviolet light. Results. Our results showed that the restriction fragment length polymorphism method is optimal for detection of apolipoprotein E polymorphisms. The restriction enzyme HhaI achieved the cleavage of the gene on the specific loci, directly depend of presence or absence of mutations at positions 112 and 158, of different alleles. Conclusion. This method enables simple, rapid and efficient analysis of restriction fragment length polymorphisms, directly determining the patient’s genotype.

  20. Secondary radicals derived from chloramines of apolipoprotein B-100 contribute to HOCl-induced lipid peroxidation of low-density lipoproteins

    DEFF Research Database (Denmark)

    Hazell, L J; Davies, Michael Jonathan; Stocker, R


    by an extended period of lipid peroxidation during which further protein oxidation does not occur. The secondary lipid peroxidation process involves EPR-detectable radicals, is attenuated by a radical trap or treatment of HOCl-oxidized LDL with methionine, and occurs less rapidly when the lipoprotein...... was depleted of alpha-tocopherol. The initial reaction of low concentrations of HOCl (400-fold or 800-fold molar excess) with LDL therefore seems to occur primarily by two-electron reactions with side-chain sites on apolipoprotein B-100. Some of the initial reaction products, identified as lysine...

  1. Apolipoprotein A1 in channel catfish: Transcriptional analysis, antimicrobial activity, and efficacy as plasmid DNA immunostimulant against Aeromonas hydrophila infection (United States)

    The objectives of this study were to: 1) determine transcriptional profiles of apolipoprotein A1 (ApoA1) in collected channel catfish tissues after infection with A. hydrophila by bath immersion; 2) investigate whether recombinant channel catfish apolipoprotein A1 produced in E. coli expression syst...

  2. Apolipoprotein A1 as a novel anti-implantation biomarker in polycystic ovary syndrome: A case-control study

    Directory of Open Access Journals (Sweden)

    Fatemehsadat Amjadi


    Full Text Available Background: Women with polycystic ovary syndrome have lower pregnancy rates, possibly due to the decreased uterine receptivity. Successful implantation depends on protein networks that are essential for cross-talk between the embryo and endometrium. Apolipoprotein A1 has been proposed as a putative anti-implantation factor. In this study, we evaluated apolipoprotein A1 expression in human endometrial tissues. Materials and Methods: Endometrial apolipoprotein A1 messenger RNA (mRNA and protein expression were investigated using quantitative real-time polymerase chain reaction (PCR and Western blot. The distribution of apolipoprotein A1 was also detected by immunostaining. Samples were obtained from 10 patients with polycystic ovary syndrome and 15 healthy fertile women in the proliferative (on day 2 or day 3 before ovulation, n = 7 and secretory (on days 3-5 after ovulation, n = 8 phases. Results: Endometrial apolipoprotein A1 expression was upregulated in patients with polycystic ovary syndrome compared to normal subjects. However, apolipoprotein A1 expression in the proliferative phase was significantly higher than in the luteal phase (P value < 0.05. Conclusion: It seems that differentially expressed apolipoprotein A1 negatively affects endometrial receptivity in patients with polycystic ovary syndrome. The results showed that apolipoprotein A1 level significantly changes in the human endometrium during the menstrual cycle with minimum expression in the secretory phase, coincident with the receptive phase (window of implantation. Further studies are required to clarify the clinical application of this protein.

  3. Apolipoprotein B levels, APOB alleles, and risk of ischemic cardiovascular disease in the general population, a review

    DEFF Research Database (Denmark)

    Benn, Marianne


    . The present review examines, with focus on general population studies, apolipoprotein B levels as a predictor of ischemic cardiovascular disease, as well as the association of mutations and polymorphisms in APOB with plasma apolipoprotein B levels, and risk of ischemic cardiovascular disease. The studies can......, or ischemic stroke in the general population....

  4. Atherosclerosis, apolipoprotein E and the prevalence of dementia and Alzheimer's disease in a population-based study: the Rotterdam Study

    NARCIS (Netherlands)

    A. Ott (Alewijn); M.L. Bots (Michiel); A.J.C. Slooter (Arjen); F. van Harskamp (Frans); C.M. van Duijn (Cock); D.E. Grobbee (Diederick); M.M.B. Breteler (Monique); C. van Broeckhoven (Christine); A. Hofman (Albert)


    textabstractBACKGROUND: Vascular disorders have been implicated in dementia, but whether atherosclerosis is related to the most frequent type of dementia, Alzheimer's disease, is not known. The apolipoprotein-E genotype has been associated with Alzheimer's disease, and we postulate that it plays a p

  5. Conformational and aggregation properties of the 1-93 fragment of apolipoprotein A-I

    DEFF Research Database (Denmark)

    Petrlova, Jitka; Bhattacherjee, Arnab; Boomsma, Wouter Krogh;


    Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril-associated ......Several disease-linked mutations of apolipoprotein A-I, the major protein in high-density lipoprotein (HDL), are known to be amyloidogenic, and the fibrils often contain N-terminal fragments of the protein. Here, we present a combined computational and experimental study of the fibril...... that these conformational shifts match well with the effects of these mutations in thioflavin T fluorescence and transmission electron microscopy experiments. Together, our results point to molecular mechanisms that may have a key role in disease-linked aggregation of apolipoprotein A-I....

  6. Lectures given at the C.I.M.E. Summer School

    CERN Document Server

    Gastaldi, Lucia


    Since the early 70's, mixed finite elements have been the object of a wide and deep study by the mathematical and engineering communities. The fundamental role of this method for many application fields has been worldwide recognized and its use has been introduced in several commercial codes. An important feature of mixed finite elements is the interplay between theory and application. Discretization spaces for mixed schemes require suitable compatibilities, so that simple minded approximations generally do not work and the design of appropriate stabilizations gives rise to challenging mathematical problems. This volume collects the lecture notes of a C.I.M.E. course held in Summer 2006, when some of the most world recognized experts in the field reviewed the rigorous setting of mixed finite elements and revisited it after more than 30 years of practice. Applications, in this volume, range from traditional ones, like fluid-dynamics or elasticity, to more recent and active fields, like electromagnetism.

  7. 无名小马也穿墙——C.I.A

    Institute of Scientific and Technical Information of China (English)




  8. Photocatalytic Membrane Reactor for the Removal of C.I. Disperse Red 73

    Directory of Open Access Journals (Sweden)

    Valentina Buscio


    Full Text Available After the dyeing process, part of the dyes used to color textile materials are not fixed into the substrate and are discharged into wastewater as residual dyes. In this study, a heterogeneous photocatalytic process combined with microfiltration has been investigated for the removal of C.I. Disperse Red 73 from synthetic textile effluents. The titanium dioxide (TiO2 Aeroxide P25 was selected as photocatalyst. The photocatalytic treatment achieved between 60% and 90% of dye degradation and up to 98% chemical oxygen demand (COD removal. The influence of different parameters on photocatalytic degradation was studied: pH, initial photocatalyst loading, and dye concentration. The best conditions for dye degradation were pH 4, an initial dye concentration of 50 mg·L−1, and a TiO2 loading of 2 g·L−1. The photocatalytic membrane treatment provided a high quality permeate, which can be reused.

  9. Lectures given at the C.I.M.E. Summer School

    CERN Document Server

    Tian, Gang


    Modern approaches to the study of symplectic 4-manifolds and algebraic surfaces combine a wide range of techniques and sources of inspiration. Gauge theory, symplectic geometry, pseudoholomorphic curves, singularity theory, moduli spaces, braid groups, monodromy, in addition to classical topology and algebraic geometry, combine to make this one of the most vibrant and active areas of research in mathematics. It is our hope that the five lectures of the present volume given at the C.I.M.E. Summer School held in Cetraro, Italy, September 2-10, 2003 will be useful to people working in related areas of mathematics and will become standard references on these topics. The volume is a coherent exposition of an active field of current research focusing on the introduction of new methods for the study of moduli spaces of complex structures on algebraic surfaces, and for the investigation of symplectic topology in dimension 4 and higher.

  10. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. (United States)

    Chen, Hung-Kai; Liu, Zhaoping; Meyer-Franke, Anke; Brodbeck, Jens; Miranda, Rene D; McGuire, James G; Pleiss, Michael A; Ji, Zhong-Sheng; Balestra, Maureen E; Walker, David W; Xu, Qin; Jeong, Dah-eun; Budamagunta, Madhu S; Voss, John C; Freedman, Stephen B; Weisgraber, Karl H; Huang, Yadong; Mahley, Robert W


    Apolipoprotein E4 (apoE4), the major genetic risk factor for late onset Alzheimer disease, assumes a pathological conformation, intramolecular domain interaction. ApoE4 domain interaction mediates the detrimental effects of apoE4, including decreased mitochondrial cytochrome c oxidase subunit 1 levels, reduced mitochondrial motility, and reduced neurite outgrowth in vitro. Mutant apoE4 (apoE4-R61T) lacks domain interaction, behaves like apoE3, and does not cause detrimental effects. To identify small molecules that inhibit domain interaction (i.e. structure correctors) and reverse the apoE4 detrimental effects, we established a high throughput cell-based FRET primary assay that determines apoE4 domain interaction and secondary cell- and function-based assays. Screening a ChemBridge library with the FRET assay identified CB9032258 (a phthalazinone derivative), which inhibits domain interaction in neuronal cells. In secondary functional assays, CB9032258 restored mitochondrial cytochrome c oxidase subunit 1 levels and rescued impairments of mitochondrial motility and neurite outgrowth in apoE4-expressing neuronal cells. These benefits were apoE4-specific and dose-dependent. Modifying CB9032258 yielded well defined structure-activity relationships and more active compounds with enhanced potencies in the FRET assay (IC(50) of 23 and 116 nm, respectively). These compounds efficiently restored functional activities of apoE4-expressing cells in secondary assays. An EPR binding assay showed that the apoE4 structure correction resulted from direct interaction of a phthalazinone. With these data, a six-feature pharmacophore model was constructed for future drug design. Our results serve as a proof of concept that pharmacological intervention with apoE4 structure correctors negates apoE4 detrimental effects in neuronal cells and could be further developed as an Alzheimer disease therapeutic.

  11. Apolipoprotein E promotes lipid accumulation and differentiation in human adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lasrich, Dorothee; Bartelt, Alexander [Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany); Grewal, Thomas, E-mail: [Faculty of Pharmacy A15, The University of Sydney, Sydney, NSW 2006 (Australia); Heeren, Joerg, E-mail: [Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany)


    Several studies in mice indicate a role for apolipoprotein E (APOE) in lipid accumulation and adipogenic differentiation in adipose tissue. However, little is yet known if APOE functions in a similar manner in human adipocytes. This prompted us to compare lipid loading and expression of adipocyte differentiation markers in APOE-deficient and control adipocytes using the differentiated human mesenchymal stem cell line hMSC-Tert as well as primary human and mouse adipocytes as model systems. Differentiated hMSC-Tert were stably transduced with or without siRNA targeting APOE while murine adipocytes were isolated from wild type and Apoe knockout mice. Human APOE knockdown hMSC-Tert adipocytes accumulated markedly less triglycerides compared to control cells. This correlated with strongly decreased gene expression levels of adipocyte markers such as adiponectin (ADIPOQ) and fatty acid binding protein 4 (FABP4) as well as the key transcription factor driving adipocyte differentiation, peroxisome proliferator activator receptor gamma (PPARG), in particular the PPARG2 isoform. Similarly, differentiation of murine Apoe-deficient adipocytes was characterized by reduced gene expression of Adipoq, Fabp4 and Pparg. Interestingly, incubation of APOE-deficient hMSC-Tert adipocytes with conditioned media from APOE3-overexpressing adipocytes or APOE-containing Very Low Density Lipoprotein (VLDL) partially restored triglyceride accumulation, but were unable to induce adipocyte differentiation, as judged by expression of adipocyte markers. Taken together, depletion of endogenous APOE in human adipocytes severely impairs lipid accumulation, which is associated with an inability to initiate differentiation. - Highlights: • Immortalized human mesenchymal stem cells were used to study adipocyte development. • Knockdown of endogenous APOE lead to impaired lipid accumulation and adipogenesis. • APOE supplementation partially restored lipid accumulation but not differentiation.

  12. Heterogeneity of apolipoprotein E polymorphism in different Mexican populations. (United States)

    Aceves, Dolores; Ruiz, Bertha; Nuño, Patricia; Roman, Sonia; Zepeda, Eloy; Panduro, Arturo


    Mexico has approximately 100 million inhabitants. Most of the urban Mexican population has been considered mestizo (Indian and Spanish descent), whereas the Indian population predominates in rural areas and small towns in the countryside. In this study we analyzed the apolipoprotein E (APOE) polymorphism in Guadalajara (the second largest metropolitan area of Mexico) and its surrounding areas, two adjoining states (Nayarit and Durango), and an Indian town (Huichol Indians) from western Mexico. APOE*3 was the most common allele, and APOE*3/*3 was the most common genotype in all populations studied. Guadalajara revealed the highest frequency of the APOE*2 allele (7.8%); the frequency decreased in the rural area (4.4%), followed by Nayarit (1.6%), and was absent in Durango and in the Huichols. On the contrary, the lowest frequency of the APOE*4 allele was in Guadalajara (8.4%); the frequency increased in the rural area (9.3%), in Nayarit and Durango (11.5% and 11.7%), and reached a high frequency in the Huichol Indians (28%). The distribution of the APOE allele in the western population of Mexico is similar to those described in Mexican American migrants living in the United States but is different from those populations living in Mexico City. This study shows the heterogeneity of the Mexican population, where the frequency of the APOE*2 allele is higher in Guadalajara than in other urban areas of Mexico and is similar to frequencies described in the Caucasian population. On the contrary, the Huichols revealed the highest frequency of the APOE*4 allele in Mexico and in the Americas. This information could be useful for the study of dyslipidemias associated with chronic diseases and as markers of ethnic variation in the Americas.


    Directory of Open Access Journals (Sweden)

    A. R. Mesdaghinia


    Full Text Available Because conventional wastewater treatment of effluent containing anthraquinone dye causes notable environmental problems, it is important to find effective alternative methods for dye removal. This study evaluated the efficacy of ozonation for dye removal and Chemical Oxygen Demand reduction and identified optimal operational conditions for parameters such as pH, contact time and concentration of C.I. Reactive Blue 29 dye in a semi-batch reactor. Values of pH between 3 and 11 and contact times between 15 and 120 minutes were investigated. Dye concentrations were based on the American Dye Manufacture Institute standards and ranged from 1000 to 5000. Although results showed that Chemical Oxygen Demand removal by ozone alone was not very efficient (58%, ozonation proved to be an efficient method for decolorizing Reactive Blue 29 (96%. pH was found to significantly influence the effectiveness of Chemical Oxygen Demand removal, and optimal pH conditions (95% confidence interval were between 9 and 11. For decolorization, pH adjustment was not necessary. Degradation and decolorization of dye were found to be strongly influenced by the contact time, optimal conditions (95% confidence interval for degradation and decolorization were 60 and 30 minutes, respectively. The optimal dye concentration was 1000 American Dye Manufacture Institute.

  14. Decolorization and detoxification of sulfonated azo dye C.I. Remazol Red and textile effluent by isolated Lysinibacillus sp. RGS. (United States)

    Saratale, Rijuta G; Gandhi, Soniya S; Purankar, Madhavi V; Kurade, Mayur B; Govindwar, Sanjay P; Oh, Sang Eun; Saratale, Ganesh D


    A novel bacterium was isolated from the soil of Ichalkaranji textile industrial area. Through 16S rRNA sequence matching and morphological observation it was identified as Lysinibacillus sp. RGS. This strain has ability to decolorize various industrial dyes among which, it showed complete decolorization and degradation of toxic sulfonated azo dye C.I. Remazol Red (at 30°C, pH 7.0, under static condition) with higher chemical oxygen demand (COD) reduction (92%) within 6 h of incubation. Various parameters like agitation, pH, temperature and initial dye concentrations were optimized to develop faster decolorization process. The supplementation of cheap co-substrates (e.g., extracts of agricultural wastes) could enhance the decolorization performance of Lysinibacillus sp. RGS. Induction in oxidoreductive enzymes presumably indicates involvement of these enzymes in the decolorization/degradation process. Analytical studies of the extracted metabolites confirmed the significant degradation of Remazol Red into various metabolites. The phytotoxicity assay (with respect to plants Phaseolus mungo and Sorghum vulgare) revealed that the degradation of Remazol Red produced nontoxic metabolites. Finally Lysinibacillus sp. RGS was applied to decolorize mixture of dyes and actual industrial effluent showing 87% and 72% decolorization (in terms of decrease in ADMI value) with 69% and 62% COD reduction within 48 h and 96 h, respectively. The foregoing result increases the applicability of the strain for the treatment of industrial wastewaters containing dye pollutants.

  15. Effect of TNF{alpha} on activities of different promoters of human apolipoprotein A-I gene

    Energy Technology Data Exchange (ETDEWEB)

    Orlov, Sergey V., E-mail: [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Mogilenko, Denis A. [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Shavva, Vladimir S. [Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Dizhe, Ella B.; Ignatovich, Irina A. [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Perevozchikov, Andrej P., E-mail: [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation)


    Research highlights: {yields} TNF{alpha} stimulates the distal alternative promoter of human apoA-I gene. {yields} TNF{alpha} acts by weakening of promoter competition within apoA-I gene (promoter switching). {yields} MEK1/2 and nuclear receptors PPAR{alpha} and LXRs take part in apoA-I promoter switching. -- Abstract: Human apolipoprotein A-I (ApoA-I) is a major structural and functional protein component of high-density lipoproteins. The expression of the apolipoprotein A-I gene (apoA-I) in hepatocytes is repressed by pro-inflammatory cytokines such as IL-1{beta} and TNF{alpha}. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters in TNF{alpha}-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNF{alpha} on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNF{alpha} leads to activation of the distal alternative apoA-I promoter and downregulation of the proximal alternative and the canonical apoA-I promoters. This effect is mediated by weakening of the promoter competition within human apoA-I 5'-regulatory region (apoA-I promoter switching) in the cells treated by TNF{alpha}. The MEK1/2-ERK1/2 cascade and nuclear receptors PPAR{alpha} and LXRs are important for TNF{alpha}-mediated apoA-I promoter switching.

  16. Binding and repressive activities of apolipoprotein E3 and E4 isoforms on the human ApoD promoter. (United States)

    Levros, Louis-Charles; Labrie, Marilyne; Charfi, Cyndia; Rassart, Eric


    Apolipoprotein D (ApoD) gene expression is increased in several neurological disorders such as Alzheimer's disease (AD) and multiple sclerosis. We previously showed that transgenic mice that overexpress human ApoD show a better resistance against paraquat or OC43 coronavirus-induced neurodegeneration. Here, we identified several nuclear factors from the cortex of control and OC43-infected mice which bind a fragment of the proximal ApoD promoter in vitro. Of interest, we detected apolipoprotein E (ApoE). Human ApoE consists of three isoforms (E2, E3, and E4) with the E4 and E2 alleles representing a greater and a lower risk for developping AD, respectively. Our results show that ApoE is located in the nucleus and on the ApoD promoter in human hepatic and glioblastoma cells lines. Furthermore, overexpression of ApoE3 and ApoE4 isoforms but not ApoE2 significantly inhibited the ApoD promoter activity in U87 cells (E3/E3 genotype) cultured under normal or different stress conditions while ApoE knock-down by siRNA had a converse effect. Consistent with these results, we also demonstrated by ChIP assay that E3 and E4 isoforms, but not E2, bind the ApoD promoter. Moreover, using the Allen Brain Atlas in situ hybridization database, we observed an inverse correlation between ApoD and ApoE mRNA expression during development and in several regions of the mouse brain, notably in the cortex, hippocampus, plexus choroid, and cerebellum. This negative correlation was also observed for cortex layers IV-VI based on a new Transcriptomic Atlas of the Mouse Neocortical Layers. These findings reveal a new function for ApoE by regulating ApoD gene expression.

  17. Chromosomal localization of the human apolipoprotein B gene and detection of homologous RNA in monkey intestine

    Energy Technology Data Exchange (ETDEWEB)

    Deeb, S.S.; Disteche, C.; Motulsky, A.G.; Lebo, R.V.; Kan, Y.W.


    A cDNA clone of the human apolipoprotein B-100 was used as a hybridization probe to detect homologous sequences in both flow-sorted and in situ metaphase chromosomes. The results indicate that the gene encoding this protein is on the distal end of the short arm of chromosome 2 (2p23-2p24). RNA isolated from monkey small intestine contained sequences (6.5 and 18 kilobases) homologous to the cDNA of apolipoprotein B-100. These results are consistent with the hypothesis that one gene codes for both the intestinal (B-48) and the hepatic (B-100) forms.

  18. Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins

    DEFF Research Database (Denmark)

    Varkey, Jobin; Isas, Jose Mario; Mizuno, Naoko


    Synucleins and apolipoproteins have been implicated in a number of membrane and lipid trafficking events. Lipid interaction for both types of proteins is mediated by 11 amino acid repeats that form amphipathic helices. This similarity suggests that synucleins and apolipoproteins might have...... of amphipathic helices alone. Moreover, we frequently observed that a-synuclein caused membrane structures that had the appearance of nascent budding vesicles. The ability to function as a minimal machinery for vesicle budding agrees well with recent findings that a-synuclein plays a role in vesicle trafficking...

  19. Influence of domain stability on the properties of human apolipoprotein E3 and E4 and mouse apolipoprotein E. (United States)

    Nguyen, David; Dhanasekaran, Padmaja; Nickel, Margaret; Mizuguchi, Chiharu; Watanabe, Mayu; Saito, Hiroyuki; Phillips, Michael C; Lund-Katz, Sissel


    The human apolipoprotein (apo) E4 isoform, which differs from wild-type apoE3 by the single amino acid substitution C112R, is associated with elevated risk of cardiovascular and Alzheimer’s diseases, but the molecular basis for this variation between isoforms is not understood. Human apoE is a two-domain protein comprising an N-terminal helix bundle and a separately folded C-terminal region. Here, we examine the concept that the ability of the protein to bind to lipid surfaces is influenced by the stability (or readiness to unfold) of these domains. The lipid-free structures and abilities to bind to lipid and lipoprotein particles of a series of human and mouse apoE variants with varying domain stabilities and domain–domain interactions are compared. As assessed by urea denaturation, the two domains are more unstable in apoE4 than in apoE3. To distinguish the contributions of the destabilization of each domain to the greater lipid-binding ability of apoE4, the properties of the apoE4 R61T and E255A variants, which have the same helix bundle stabilities but altered C-terminal domain stabilities, are compared. In these cases, the effects on lipid-binding properties are relatively minor, indicating that the destabilization of the helix bundle domain is primarily responsible for the enhanced lipid-binding ability of apoE4. Unlike human apoE, mouse apoE behaves essentially as a single domain, and its lipid-binding characteristics are more similar to those of apoE4. Together, the results show that the overall stability of the entire apoE molecule exerts a major influence on its lipid- and lipoprotein-binding properties.

  20. Oxidative addition of the C-I bond on aluminum nanoclusters (United States)

    Sengupta, Turbasu; Das, Susanta; Pal, Sourav


    Energetics and the in-depth reaction mechanism of the oxidative addition step of the cross-coupling reaction are studied in the framework of density functional theory (DFT) on aluminum nanoclusters. Aluminum metal in its bulk state is totally inactive towards carbon-halogen bond dissociation but selected Al nanoclusters (size ranging from 3 to 20 atoms) have shown a significantly lower activation barrier towards the oxidative addition reaction. The calculated energy barriers are lower than the gold clusters and within a comparable range with the conventional and most versatile Pd catalyst. Further investigations reveal that the activation energies and other reaction parameters are highly sensitive to the geometrical shapes and electronic structures of the clusters rather than their size, imposing the fact that comprehensive studies on aluminum clusters can be beneficial for nanoscience and nanotechnology. To understand the possible reaction mechanism in detail, the reaction pathway is investigated with the ab initio Born Oppenheimer Molecular Dynamics (BOMD) simulation and the Natural Bond Orbital (NBO) analysis. In short, our theoretical study highlights the thermodynamic and kinetic details of C-I bond dissociation on aluminum clusters for future endeavors in cluster chemistry.Energetics and the in-depth reaction mechanism of the oxidative addition step of the cross-coupling reaction are studied in the framework of density functional theory (DFT) on aluminum nanoclusters. Aluminum metal in its bulk state is totally inactive towards carbon-halogen bond dissociation but selected Al nanoclusters (size ranging from 3 to 20 atoms) have shown a significantly lower activation barrier towards the oxidative addition reaction. The calculated energy barriers are lower than the gold clusters and within a comparable range with the conventional and most versatile Pd catalyst. Further investigations reveal that the activation energies and other reaction parameters are highly

  1. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (United States)

    Liao, Fan; Yoon, Hyejin; Kim, Jungsu


    Purpose of review APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. Recent findings ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis. Summary Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease. PMID:27922847

  2. Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I. (United States)

    Chan, Gary K L; Witkowski, Andrzej; Gantz, Donald L; Zhang, Tianqi O; Zanni, Martin T; Jayaraman, Shobini; Cavigiolio, Giorgio


    High plasma levels of apolipoprotein A-I (apoA-I) correlate with cardiovascular health, whereas dysfunctional apoA-I is a cause of atherosclerosis. In the atherosclerotic plaques, amyloid deposition increases with aging. Notably, apoA-I is the main component of these amyloids. Recent studies identified high levels of oxidized lipid-free apoA-I in atherosclerotic plaques. Likely, myeloperoxidase (MPO) secreted by activated macrophages in atherosclerotic lesions is the promoter of such apoA-I oxidation. We hypothesized that apoA-I oxidation by MPO levels similar to those present in the artery walls in atherosclerosis can promote apoA-I structural changes and amyloid fibril formation. ApoA-I was exposed to exhaustive chemical (H2O2) oxidation or physiological levels of enzymatic (MPO) oxidation and incubated at 37 °C and pH 6.0 to induce fibril formation. Both chemically and enzymatically oxidized apoA-I produced fibrillar amyloids after a few hours of incubation. The amyloid fibrils were composed of full-length apoA-I with differential oxidation of the three methionines. Met to Leu apoA-I variants were used to establish the predominant role of oxidation of Met-86 and Met-148 in the fibril formation process. Importantly, a small amount of preformed apoA-I fibrils was able to seed amyloid formation in oxidized apoA-I at pH 7.0. In contrast to hereditary amyloidosis, wherein specific mutations of apoA-I cause protein destabilization and amyloid deposition, oxidative conditions similar to those promoted by local inflammation in atherosclerosis are sufficient to transform full-length wild-type apoA-I into an amyloidogenic protein. Thus, MPO-mediated oxidation may be implicated in the mechanism that leads to amyloid deposition in the atherosclerotic plaques in vivo.

  3. Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. (United States)

    Cash, James G; Kuhel, David G; Basford, Joshua E; Jaeschke, Anja; Chatterjee, Tapan K; Weintraub, Neal L; Hui, David Y


    Apolipoprotein (apo) E4 is a major genetic risk factor for a wide spectrum of inflammatory metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The initial study confirmed previous reports that APOE4 gene replacement mice were less sensitive than APOE3 mice to diet-induced body weight gain but exhibited hyperinsulinemia, and their adipose tissues were similarly inflamed as those in APOE3 mice. Peritoneal macrophages isolated from APOE4 mice were defective in efferocytosis compared with APOE3 macrophages. Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL. Western blot analysis of cell lysates revealed that APOE4 macrophages displayed elevated JNK phosphorylation indicative of cell stress even under basal culturing conditions. Significantly higher cell stress due mainly to potentiation of endoplasmic reticulum (ER) stress signaling was also observed in APOE4 macrophages after LPS and oxidized LDL activation. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism.

  4. Relationship between apolipoprotein E, D10S1225 polymorphisms and late-onset Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    ZHANG Tai-song; WANG Hua-qiao; WANG Wei-yi; HE Yun-shao; HUANG Shao-kuan


    Background There were some papers published in the Jonrnal of Science, December 2000 suggesting that one or more important susceptibility genes for late onset Alzheimer's disease (LOAD) were located on the long arm of chromosome 10. Linkage analysis showed maximum lod score close to D10S1225 loci, which indicated the loci might contribute to the etiology of Alzheimer's disease (AD). Methods Fifty-nine LOAD patients and 107 controls were recruited. Apolipoprotein E (ApoE) genotypes were determined by reverse dot blotting hybridization assay. The D10S1225 was genotyped by 12% nondenaturing polyacrylamide gels electrophoresis and analyzed by silver staining. Statistical analysis was used to compare genotype and allele distributions between LOAD group and control group for ApoE and D10S1225 polymorphisms.Results ApoE ε4 was significantly higher in LOAD group in comparison with the control group(χ2=6.530, P =0.011). Seven different alleles of D10S1225 have been identified. The length of these gene fragments were 178 bp, 181 bp, 184 bp, 187 bp, 190 bp, 193 bp, and 196 bp, respectively. A total of 21 different genotypes were observed. There was no relationship between D10S1225 polymorphism and LOAD (χ2=4.488, P>0.05). Conclusion This study suggests that ApoEε4 is a risk factor for LOAD, however, the results indicated that there is not any possible linkage for disequilibria with a nearby AD risk gene near D10S1225.

  5. Phospholipids enhance nucleation but not elongation of apolipoprotein C-II amyloid fibrils. (United States)

    Ryan, Timothy M; Teoh, Chai L; Griffin, Michael D W; Bailey, Michael F; Schuck, Peter; Howlett, Geoffrey J


    Amyloid fibrils and their oligomeric intermediates accumulate in several age-related diseases where their presence is considered to play an active role in disease progression. A common characteristic of amyloid fibril formation is an initial lag phase indicative of a nucleation-elongation mechanism for fibril assembly. We have investigated fibril formation by human apolipoprotein (apo) C-II. ApoC-II readily forms amyloid fibrils in a lipid-dependent manner via an initial nucleation step followed by fibril elongation, breaking, and joining. We used fluorescence techniques and stopped-flow analysis to identify the individual kinetic steps involved in the activation of apoC-II fibril formation by the short-chain phospholipid dihexanoyl phosphatidylcholine (DHPC). Submicellar DHPC activates fibril formation by promoting the rapid formation of a tetrameric species followed by a slow isomerisation that precedes monomer addition and fibril growth. Global fitting of the concentration dependence of apoC-II fibril formation showed that DHPC increased the overall tetramerisation constant from 7.5 x 10(-13) to 1.2 x 10(-6) microM(-3) without significantly affecting the rate of fibril elongation, breaking, or joining. Studies on the effect of DHPC on the free pool of apoC-II monomer and on fibril formation by cross-linked apoC-II dimers further demonstrate that DHPC affects nucleation but not elongation. These studies demonstrate the capacity of small lipid compounds to selectively target individual steps in the amyloid fibril forming pathway.

  6. Inhibition of apolipoprotein A-I gene expression by obesity-associated endocannabinoids. (United States)

    Haas, Michael J; Mazza, Angela D; Wong, Norman C W; Mooradian, Arshag D


    Obesity is associated with increased serum endocannabinoid (EC) levels and decreased high-density lipoprotein cholesterol (HDLc). Apolipoprotein A-I (apo A-I), the primary protein component of HDL is expressed primarily in the liver and small intestine. To determine whether ECs regulate apo A-I gene expression directly, the effect of the obesity-associated ECs anandamide and 2-arachidonylglycerol on apo A-I gene expression was examined in the hepatocyte cell line HepG2 and the intestinal cell line Caco-2. Apo A-I protein secretion was suppressed nearly 50% by anandamide and 2-arachidonoylglycerol in a dose-dependent manner in both cell lines. Anandamide treatment suppressed both apo A-I mRNA and apo A-I gene promoter activity in both cell lines. Studies using apo A-I promoter deletion constructs indicated that repression of apo A-I promoter activity by anandamide requires a previously identified nuclear receptor binding site designated as site A. Furthermore, anandamide-treatment inhibited protein-DNA complex formation with the site A probe. Exogenous over expression of cannabinoid receptor 1 (CBR1) in HepG2 cells suppressed apo A-I promoter activity, while in Caco-2 cells, exogenous expression of both CBR1 and CBR2 could repress apo A-I promoter activity. The suppressive effect of anandamide on apo A-I promoter activity in Hep G2 cells could be inhibited by CBR1 antagonist AM251 but not by AM630, a selective and potent CBR2 inhibitor. These results indicate that ECs directly suppress apo A-I gene expression in both hepatocytes and intestinal cells, contributing to the decrease in serum HDLc in obese individuals.

  7. Apolipoprotein A1 gene polymorphisms as risk factors for hypertension and obesity. (United States)

    Chen, Elizabeth Suchi; Mazzotti, Diego Robles; Furuya, Tatiane Katsue; Cendoroglo, Maysa Seabra; Ramos, Luiz Roberto; Araujo, Lara Quirino; Burbano, Rommel Rodriguez; de Arruda Cardoso Smith, Marília


    Several polymorphisms in apolipoprotein A1 (APOA1) gene have been associated with metabolic diseases. Increased transcription efficiency was observed in -75A allele carriers compared to -75G allele homozygotes. +83C allele was associated with higher body mass index and waist-to-hip ratio in type II diabetes subjects. -75G/A and +83C/T polymorphisms were analyzed by RFLP-PCR in 334 individuals from a Brazilian elderly cohort. APOA1 polymorphisms were associated with age-related morbidities, as well as with triglycerides, total cholesterol, HDL, VLDL, LDL, creatinine, urea, albumin, glycated hemoglobin and fasting glucose serum levels. Allele frequencies were 0.102 and 0.21, respectively, for -75A and +83T. -75G allele showed significant association with hypertension (P = 0.001). An association between +83C allele and obesity was observed (P = 0.040) and this allele also showed an association with hypertension in the presence of cardiovascular disease (P = 0.047). Moreover, +83T allele was associated with lower glycated hemoglobin values (P = 0.026). To our knowledge, there is no data associating this polymorphism with glycated hemoglobin. Furthermore, individuals carrying AT haplotype have lower risk for developing hypertension (P = 0.0002), while GT haplotype carriers present decreased risk to develop obesity comparing to GC haplotype (P = 0.025). APOA1 polymorphisms analysis may be a useful tool to identify risk factors for subjects and families and clarify the physiopathological role of these polymorphisms in age-related diseases, such as hypertension and obesity.

  8. Intralipid decreases apolipoprotein M levels and insulin sensitivity in rats.

    Directory of Open Access Journals (Sweden)

    Lu Zheng

    Full Text Available BACKGROUND: Apolipoprotein M (ApoM is a constituent of high-density lipoproteins (HDL. It plays a crucial role in HDL-mediated reverse cholesterol transport. Insulin resistance is associated with decreased ApoM levels. AIMS: To assess the effects of increased free fatty acids (FFAs levels after short-term Intralipid infusion on insulin sensitivity and hepatic ApoM gene expression. METHODS: Adult male Sprague-Dawley (SD rats infused with 20% Intralipid solution for 6 h. Glucose infusion rates (GIR were determined by hyperinsulinemic-euglycemic clamp during Intralipid infusion and plasma FFA levels were measured by colorimetry. Rats were sacrificed after Intralipid treatment and livers were sampled. Human embryonic kidney 293T cells were transfected with a lentivirus mediated human apoM overexpression system. Goto-Kakizaki (GK rats were injected with the lentiviral vector and insulin tolerance was assessed. Gene expression was assessed by real-time RT-PCR and PCR array. RESULTS: Intralipid increased FFAs by 17.6 folds and GIR was decreased by 27.1% compared to the control group. ApoM gene expression was decreased by 40.4% after Intralipid infusion. PPARβ/δ expression was not changed by Intralipid. Whereas the mRNA levels of Acaca, Acox1, Akt1, V-raf murine sarcoma 3611 viral oncogene homolog, G6pc, Irs2, Ldlr, Map2k1, pyruvate kinase and RBC were significantly increased in rat liver after Intralipid infusion. The Mitogen-activated protein kinase 8 (MAPK8 was significantly down-regulated in 293T cells overexpressing ApoM. Overexpression of human ApoM in GK rats could enhance the glucose-lowering effect of exogenous insulin. CONCLUSION: These results suggest that Intralipid could decrease hepatic ApoM levels. ApoM overexpression may have a potential role in improving insulin resistance in vivo and modulating apoM expression might be a future therapeutic strategy against insulin resistance in type 2 diabetes.

  9. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse

    Directory of Open Access Journals (Sweden)

    Balarini Camille M


    Full Text Available Abstract Background Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS and nitric oxide (NO. Sildenafil, a selective phosphodiesterase-5 (PDE5 inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE−/− mice. Methods ApoE−/− mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage were compared to the untreated apoE−/− and the wild-type (WT mice. Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh in all of the groups. In a separate set of experiments, the roles of NO and ROS in the relaxation response to ACh were evaluated by incubating the aortic rings with L-NAME (NO synthase inhibitor or apocynin (NADPH oxidase inhibitor. In addition, the atherosclerotic lesions were quantified and superoxide production was assessed. Results Sildenafil restored the vasodilator response to acetylcholine (ACh in the aortic rings of the apoE−/− mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three groups of mice and revealed an augmented participation of NO in the endothelium-dependent vasodilation in the sildenafil-treated animals. The normalized endothelial function in sildenafil-treated apoE−/− mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Moreover, morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta. Conclusion This is the first study demonstrating the beneficial effects of chronic treatment with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous

  10. Adsorption of C.I. Natural Red 4 onto Spongin Skeleton of Marine Demosponge

    Directory of Open Access Journals (Sweden)

    Małgorzata Norman


    Full Text Available C.I. Natural Red 4 dye, also known as carmine or cochineal, was adsorbed onto the surface of spongin-based fibrous skeleton of Hippospongia communis marine demosponge for the first time. The influence of the initial concentration of dye, the contact time, and the pH of the solution on the adsorption process was investigated. The results presented here confirm the effectiveness of the proposed method for developing a novel dye/biopolymer hybrid material. The kinetics of the adsorption of carmine onto a marine sponge were also determined. The experimental data correspond directly to a pseudo-second-order model for adsorption kinetics (r2 = 0.979–0.999. The hybrid product was subjected to various types of analysis (FT-IR, Raman, 13C CP/MAS NMR, XPS to investigate the nature of the interactions between the spongin (adsorbent and the dye (the adsorbate. The dominant interactions between the dye and spongin were found to be hydrogen bonds and electrostatic effects. Combining the dye with a spongin support resulted with a novel hybrid material that is potentially attractive for bioactive applications and drug delivery systems.

  11. Interaction between toxic azo dye C.I. Acid Red 88 and serum albumins

    Energy Technology Data Exchange (ETDEWEB)

    Naveenraj, Selvaraj [Nanomaterials and Solar Energy Conversion Lab, Department of Chemistry, National Institute of Technology, Tiruchirappalli 620015 (India); Solomon, Rajadurai Vijay; Venuvanalingam, Ponnambalam [School of Chemistry, Bharathidasan University, Tiruchirappalli 620024 (India); Asiri, Abdullah M. [The Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21413, P.O. Box 80203 (Saudi Arabia); Anandan, Sambandam, E-mail: [Nanomaterials and Solar Energy Conversion Lab, Department of Chemistry, National Institute of Technology, Tiruchirappalli 620015 (India)


    Serum albumin-toxic dye interaction studies will be of paramount importance in the field of toxicology due to its relation towards the distribution and transportation of dye in blood. In this regard, the binding between C.I. Acid Red 88 (AR88) and serum albumins (HSA and BSA) was investigated by using combination of spectroscopic and molecular modeling methods. The fluorescence results revealed that AR88 interact with serum albumins through the combination of static and dynamic quenching mechanism. The distance “r” between serum albumin and AR88 was obtained according to the Forster resonance energy transfer (FRET) theory. Synchronous fluorescence and CD spectral results showed alterations in the microenvironment and conformation of serum albumins. The molecular docking method is also employed to understand the interaction of AR88 with serum albumins. All these studies confirm that BSA has more affinity towards AR88 than that of HSA which suggests that AR88 is more easily transported in the body of bovid than human and so it is more hazardous to bovids. -- Highlights: • AR88 interacts with serum albumin through the combination of both static and dynamic quenching mechanism. • The binding site of AR88 in serum albumins is nearer to tryptophan moiety. • Circular Dichroism spectra showed that AR88 alters α-helicity of serum albumin. • This interaction study could be greatly imperative for further investigations in toxicology.

  12. Degradation of C.I. Reactive Red 2 through photocatalysis coupled with water jet cavitation. (United States)

    Wang, Xiaoning; Jia, Jinping; Wang, Yalin


    The decolorization of an azo dye, C.I. Reactive Red 2 was investigated using TiO(2) photocatalysis coupled with water jet cavitation. Experiments were performed in a 4.0 L solution under ultraviolet power of 9 W. The effects of TiO(2) loading, initial dye concentration, solution pH, geometry of cavitation tube, and the addition of anions on the degradation of the dye were evaluated. Degradation of the dye followed a pseudo-first order reaction. The photocatalysis coupled with water jet cavitation elevated degradation of the dye by about 136%, showing a synergistic effect compared to the individual photocatalysis and water jet cavitation. The enhancement of photocatalysis by water jet cavitation could be due to the deagglomeration of catalyst particles as well as the better contact between the catalyst surfaces and the reactants. Venturi tube with smaller diameter and shorter length of throat tube favored the dye decolorization. The degradation efficiency was found to increase with decreasing initial concentration and pH. The presence of NO(3)(-) and SO(4)(2-) enhanced the degradation of RR2, while Cl(-), and especially HCO(3)(-) significantly reduced dye decolorization. The results of this study indicated that the coupled photocatalysis and water jet cavitation is effective in degrading dye in wastewater and provides a promising alternative for treatment of dye wastewater at a large scale.

  13. Biodegradation of C.I. Reactive Red 195 by Enterococcus faecalis strain YZ66. (United States)

    Mate, Madhuri Sahasrabudhe; Pathade, Girish


    Synthetic dyes are extensively used in textile dyeing, paper, printing, colour photography, pharmaceutics, cosmetics and other industries. Among these, azodyes represents the largest and most versatile class of synthetic dyes. As high as 50% of the dyes are released into the environment during manufacture and usage. Traditional methods of treatment are found to be expensive and have operational problems. Biological decolourization has been investigated as a method to transform, degrade or mineralize azo dyes. In the present studies bacteria from soil from dye waste area, dye waste, sewage and dung were subjected to acclimatization with C.I. Reactive Red 195 an azo dye, in the basal nutrient media. The most promising bacterial isolate was used for further dye degradation studies. The 16s rRNA gene sequencing and biochemical characteristics revealed the isolated organism as Enterococcus faecalis strain YZ66. The strain showed 99.5% decolourization of the selected dye (Reactive Red 195-50 mg/l) within one and half hour in static anoxic condition. The optimum pH and temperature for the decolourization was 5.0 and 40°C respectively. The biodegradation was monitored by UV-Vis, FTIR, TLC and HPLC. The final products were characterized by Gas chromatography and Mass Spectrophotometry. Toxicity study demonstrated no toxicity of the biodegradation product. The results suggest that the isolated organism E. faecalis strain YZ 66 can be used as a useful tool to treat waste water containing reactive dyes.

  14. Influence of operating parameters on electrocoagulation of C.I. disperse yellow 3

    Directory of Open Access Journals (Sweden)

    Djamel Ghernaout


    Full Text Available This work deals with the electrocoagulation (EC process for an organic dye removal. The chosen organic dye is C.I. disperse yellow 3 (DY which is used in textile industry. Experiments were performed in batch mode using Al electrodes and for comparison purposes Fe electrodes. The experimental set-up was composed of 1 L beaker, two identical electrodes which are separated 2 cm from each other. The main operating parameters influencing EC process were examined such as pH, supporting electrolyte concentration CNaCl, current density i, and DY concentration. High performance EC process was shown during 45 min for 200 mg/L dye concentration at i = 350 A m-2 (applied voltage 12 V and CNaCl = 1 g L-1 reaching 98 % for pHs 3 and 10 and 99 % for pH 6. After 10 min, DY was also efficiently removed (86 % showing that EC process may be conveniently applied for textile industry wastewater treatment. EC using Fe electrodes exhibited slightly lower performance comparing EC using Al electrodes.

  15. Mutation in apolipoprotein B associated with hypobetalipoproteinemia despite decreased binding to the low density lipoprotein receptor

    DEFF Research Database (Denmark)

    Benn, Marianne; Nordestgaard, Børge G; Jensen, Jan Skov;


    Mutations in apolipoprotein B (APOB) may reduce binding of low density lipoprotein (LDL) to the LDL receptor and cause hypercholesterolemia. We showed that heterozygotes for a new mutation in APOB have hypobetalipoproteinemia, despite a reduced binding of LDL to the LDL receptor. APOB R3480P hete...

  16. Lipid, lipoprotein, and apolipoprotein profiles in active and sedentary men with tetraplegia

    NARCIS (Netherlands)

    Dallmeijer, A J; Hopman, M T; van der Woude, L H


    OBJECTIVE: To investigate whether the risk profile of coronary heart disease (CHD) is more favorable in physically active men with tetraplegia compared with sedentary men with tetraplegia. DESIGN: Using a cross-sectional design, the lipid and (apo)lipoprotein concentrations of 11 active and 13 seden

  17. Improving prediction of ischemic cardiovascular disease in the general population using apolipoprotein B

    DEFF Research Database (Denmark)

    Benn, Marianne; Nordestgaard, Børge G; Jensen, Gorm Boje


    Apolipoprotein B (apoB) levels predict fatal myocardial infarction. Whether apoB also predicts nonfatal ischemic cardiovascular events is unclear. We tested the following hypotheses: apoB predicts ischemic cardiovascular events, and apoB is a better predictor of ischemic cardiovascular events tha...

  18. Plasma apolipoprotein M is reduced in metabolic syndrome but does not predict intima media thickness

    DEFF Research Database (Denmark)

    Dullaart, Robin P F; Plomgaard, Peter; de Vries, Rindert


    BACKGROUND: Apolipoprotein (apo) M may exert anti-atherogenic properties in experimental studies. Its hepatic gene expression may be linked to glucose and lipid metabolism. Plasma apoM is decreased in obese mouse models. We hypothesized that plasma apoM is lower in metabolic syndrome (Met...

  19. Screening for apolipoprotein E gene mutations in 4 patients with lipoprotein glomerulopathy

    Institute of Scientific and Technical Information of China (English)



    Objective To study the mutations of apolipoprotein E (apoE) gene in 4 Chinese lipoprotein glomerulopathy (LPG) patients and their family members, and to investigate the pathogenesis of LPG. Methods Urinalysis was performed on the family members of two patients, and they were screened for the level of serum creatinine, serum lipid and serum lipoprotein. The mutation of apoE

  20. Cinnamon Extract Improves TNF-a Induced Overproduction of Intestinal ApolipoproteinB-48 Lipoproteins (United States)

    TNF-alpha stimulates the overproduction of intestinal apolipoproteins. We evaluated whether a water extract of cinnamon (Cinnulin PF®) improved the dyslipidemia induced by TNF-alpha in Triton WR-1339 treated hamsters, and whether Cinnulin PF® inhibits the TNF-alpha-induced over the secretion of apoB...

  1. Capillary electrophoresis with laser-induced fluorescence detection for fast and reliable apolipoprotein E genotyping

    NARCIS (Netherlands)

    Somsen, GW; Welten, HTME; Mulder, FP; Swart, CW; Kema, IP; de Jong, GJ


    The use of capillary electrophoresis (CE) with laser-induced fluorescence (LIF) detection for the rapid determination of apolipoprotein E (apoE) genotypes was studied. High resolution and sensitive detection of the concerned DNA restriction fragments was achieved using CE buffers with hydroxypropylm

  2. Transcriptional Activation of Apolipoprotein CIII Expression by Glucose May Contribute to Diabetic Dyslipidemia

    NARCIS (Netherlands)

    Caron, Sandrine; Verrijken, An; Mertens, Ilse; Samanez, Carolina Huaman; Mautino, Gisele; Haas, Joel T.; Duran-Sandoval, Daniel; Prawitt, Janne; Francque, Sven; Vallez, Emmanuelle; Muhr-Tailleux, Anne; Berard, Isabelle; Kuipers, Folkert; Kuivenhoven, Jan A.; Biddinger, Sudha B.; Taskinen, Marja-Riitta; Van Gaal, Luc; Staels, Bart


    Objective-Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is


    PURPOSE: Polymorphism of the apolipoprotein E (APOE) gene has been associated with dyslipidemia and cardiovascular disease. This study examines the association of APOE polymorphisms and diabetic retinopathy. DESIGN: Population-based cross-sectional study. METHODS: We studied 1,398 people aged 49 to ...

  4. LNA-enhanced detection of single nucleotide polymorphisms in the apolipoprotein E

    DEFF Research Database (Denmark)

    Jacobsen, Nana; Bentzen, Joan; Meldgaard, Michael;


    Genotyping of single nucleotide polymorphisms (SNPs) in large populations presents a great challenge, especially if the SNPs are embedded in GC-rich regions, such as the codon 112 SNP in the human apolipoprotein E (apoE). In the present study, we have used immobilized locked nucleic acid (LNA) ca...

  5. Apolipoprotein E genotype and association between smoking and early onset Alzheimer's disease.

    NARCIS (Netherlands)

    C.M. van Duijn (Cock); P. de Knijff (Peter); M. Cruts (Marc); A. Wehnert (Anita); L.M. Havekes; C. van Broeckhoven (Christine); A. Hofman (Albert)


    textabstractOBJECTIVE--To investigate the hypothesis that differential survival between smokers and non-smokers leading to a decrease in the frequency of the e4 allele of the apolipoprotein E gene may explain the inverse relation between smoking history and early onset Alzheimer's disease. DESIGN--A

  6. Endotoxin contamination of apolipoprotein A-I: effect on macrophage proliferation--a cautionary tale. (United States)

    Jin, Xueting; Xu, Qing; Champion, Keith; Kruth, Howard S


    This technical report addresses the problem of endotoxin contamination of apolipoprotein reagents. Using a bromodeoxyuridine incorporation cell proliferation assay, we observed that human plasma ApoA-I as low as 1 μg/ml resulted in a >90% inhibition in macrophage proliferation. However, not all ApoA-I from different sources showed this effect. We considered the possibility that endotoxin contamination of the apolipoproteins contributed to the differential inhibition of macrophage cell proliferation. Endotoxin alone very potently inhibited macrophage proliferation (0.1 ng/ml inhibited macrophage proliferation>90%). Measurement of endotoxin levels in the apolipoprotein products, including an analysis of free versus total endotoxin, the latter which included endotoxin that was masked due to binding to protein, suggested that free endotoxin mediated inhibition of macrophage proliferation. Despite the use of an advanced endotoxin removal procedure and agents commonly used to inhibit endotoxin action, the potency of endotoxin precluded successful elimination of endotoxin effect. Our findings show that endotoxin contamination can significantly influence apparent apolipoprotein-mediated cell effects (or effects of any other biological products), especially when these products are tested on highly endotoxin-sensitive cells, such as macrophages.

  7. Plasma apolipoprotein M is reduced in metabolic syndrome but does not predict intima media thickness

    NARCIS (Netherlands)

    Dullaart, Robin P. F.; Plomgaard, Peter; de Vries, Rindert; Dahlback, Bjorn; Nielsen, Lars B.


    Background: Apolipoprotein (apo) M may exert anti-atherogenic properties in experimental studies. Its hepatic gene expression may be linked to glucose and lipid metabolism. Plasma apoM is decreased in obese mouse models. We hypothesized that plasma apoM is lower in metabolic syndrome (MetS) subjects

  8. Expression of apolipoprotein B in the kidney attenuates renal lipid accumulation

    DEFF Research Database (Denmark)

    Krzystanek, Marcin; Pedersen, Tanja Xenia; Bartels, Emil Daniel


    The ability to produce apolipoprotein (apo) B-containing lipoproteins enables hepatocytes, enterocytes, and cardiomyocytes to export triglycerides. In this study, we examined secretion of apoB-containing lipoproteins from mouse kidney and its putative impact on triglyceride accumulation in the tu...... biological effect may be to dampen excess storage of triglycerides in proximal tubule cells....

  9. Genotypes and phenotypes for apolipoprotein E and Alzheimer disease in the Honolulu-Asia aging study

    NARCIS (Netherlands)

    J.W.P.F. Kardaun (Jan); L. White (Lon); H.E. Resnick; H. Petrovitch; S.M. Marcovina; A.M. Saunders (Ann); D.J. Foley (Dan); R.J. Havlik


    textabstractBACKGROUND: The utility of apolipoprotein E (ApoE) type as an indicator of genetic susceptibility to Alzheimer disease (AD) depends on the reliability of typing. Although ApoE protein isoform phenotyping is generally assumed equivalent to genotyping from DNA

  10. Apolipoprotein E genotype predicts 24-month Bayley scales infant development score

    NARCIS (Netherlands)

    Wright, RO; Hu, H; Silverman, EK; Tsaih, SW; Schwartz, J; Bellinger, D; Palazuelos, E; Weiss, ST; Hernandez-Avila, M


    Apolipoprotein E (APOE) regulates cholesterol and fatty acid metabolism, and may mediate synaptogenesis during neurodevelopment. To our knowledge, the effects of APOE4 isoforms on infant development have not been studied. This study was nested within a cohort of mother-infant pairs living in and aro

  11. A case-control study of apolipoprotein E genotypes in Alzheimer's disease associated with Down syndrome.

    NARCIS (Netherlands)

    H.M. Evenhuis (Heleen); C.M. van Duijn (Cock); W.A. van Gool (Willem)


    textabstractThe prevalence of clinical signs and neuropathological findings of Alzheimer's disease (AD) is high in Down's syndrome (DS). In the general population, the apolipoprotein E (ApoE) epsilon 4 isoform is an important risk for AD. We studied the allelic frequencies of ApoE in 26 DS cases ful

  12. The impact of apolipoprotein E on dementia in persons with Down's syndrome.

    NARCIS (Netherlands)

    Coppus, A.M.; Evenhuis, H.M.; Verberne, G.J.; Visser, F.E.; Arias-Vasquez, A.; Sayed-Tabatabaei, F.A.; Vergeer-Drop, J.; Eikelenboom, P.; Gool, W.A. van; Duijn, C.M. van


    Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-base

  13. Fasting and post-prandial apolipoprotein B-48 levels in healthy, obese, and hyperlipidemic subjects (United States)

    Apolipoprotein (apo) B-48 is the only specific marker of intestinal lipoproteins. We evaluated a novel enzyme-linked immunosorbent assay (ELISA) standardized with recombinant apo B-48 to measure apo B-48 in plasma and triglyceride-rich lipoproteins (TRLs, density b1.006 g/mL). Coefficients of variat...

  14. Effects of fenofibrate on hyperlipidemia and postprandial triglyceride metabolism in human apolipoprotein C1 transgenic mice

    NARCIS (Netherlands)

    Jong, M.C.; Dahlmans, V.E.H.; Princen, H.M.G.; Hofker, M.H.; Havekes, L.M.


    To study the in vivo role of apolipoprotein (apo) C1 in lipoprotein metabolism, we have generated transgenic mice expressing the human apo C1 gene. Apo C1 is a small 6.6 kDa protein that is primarily synthesized by the liver and is present on chylomicrons, very low density lipoproteins (VLDL) and hi

  15. Development of atopic dermatitis in mice transgenic for human apolipoprotein C1

    NARCIS (Netherlands)

    Nagelkerken, L.; Verzaal, P.; Lagerweij, T.; Persoon-Deen, C.; Berbee, J.F.P.; Prens, E.P.; Havekes, L.M.; Oranje, A.P.


    Mice with transgenic expression of human apolipoprotein C1 (APOC1) in liver and skin have strongly increased serum levels of cholesterol, triglycerides, and free fatty acids, indicative of a disturbed lipid metabolism. Importantly, these mice display a disturbed skin barrier function, evident from i

  16. Trimerization of apolipoprotein A-I retards plasma clearance and preserves antiatherosclerotic properties

    DEFF Research Database (Denmark)

    Graversen, Jonas Heilskov; Laurberg, Jacob Marsvin; Andersen, Mikkel Holmen


    An increased plasma level of the major high-density lipoprotein (HDL) component, apolipoprotein A-I (apoA-I) is the aim of several therapeutic strategies for combating atherosclerotic disease. HDL therapy by direct intravenous administration of apoA-I is a plausible way; however, a fast renal...

  17. Apolipoprotein A5 and lipoprotein lipase interact to modulate anthropometric measures in Hispanics of Caribbean origin (United States)

    Apolipoprotein A5 (APOA5) and lipoprotein lipase (LPL) proteins interact functionally to regulate lipid metabolism, and single nucleotide polymorphisms (SNPs) for each gene have also been associated independently with obesity risk. Evaluating gene combinations may be more effective than single SNP a...

  18. Higher primates, but not New World monkeys, have a duplicate set of enhancers flanking their apoC-I genes. (United States)

    Puppione, Donald L


    Previous studies have demonstrated that the apoC-I gene and its pseudogene on human chromosome 19 are flanked by a duplicate set of enhancers. Multienhancers, ME.1 and ME.2, are located upstream from the genes and the hepatic control region enhancers, HCR.1 and HCR.2, are located downstream. The duplication of the enhancers has been thought to have occurred when the apoC-I gene was duplicated during primate evolution. Currently, the only primate data are for the human enhancers. Examining the genome of other primates (great and lesser apes, Old and New World monkeys), it was possible to locate the duplicate set of enhancers in apes and Old World monkeys. However, only a single set was found in New World monkeys. These observations provide additional evidence that the apoC-I gene and the flanking enhancers underwent duplication after the divergence of Old and New World monkeys.

  19. Performance of C.I Engine by Using Biodiesel-Mahua Oil.

    Directory of Open Access Journals (Sweden)

    sudheer nandi


    Full Text Available - India is looking at renewable alternative fuel sources to reduce its dependence on foreign imports of oils. As India imports 70% of the oil, the country has been hit hard by increasing cost and uncertainty. Recently the biomass resources are being used as alternative fuels and effective use of those fuels is gaining prominence as a substitute way to solve the problem of global warming and the energy crisis. Among all the alternative fuels existing mahua oil is also one. In this work, conventional laboratory equipment has been used for the transesterification of mahua oil. Various properties of esterified mahua oil have been tested for comparison with diesel fuel; further the investigations are carried out on a laboratory based diesel engine to study its performance.An attempt has been made in the present work to find out the suitability of transesterified mahua oil as a fuel in C.I. engine. Experimental work was carried out on 7B.H.P single cylinder four stroke and vertical, water cooled Kirloskar diesel engine at rated speed of 1500rpm different blends of transesterified mahua oil with diesel were tested at 200bar injection pressure.From the performance characteristics of transesterified mahua oil diesel blends the efficiencies obtained were found to be better with 75% transesterified mahua oil. The thermal efficiencies of transesterified mahua oil are higher at 25% diesel blends. The cost of transesterified mahua oil is low compared to the cost of diesel. Hence mahua oil blended with diesel is more economical and this can provide an immediate, though partial solution to the growing diesel scarcity in developing countries like ours

  20. Effects of Chronic Mild Stress on the Development of Atherosclerosis and Expression of Toll-Like Receptor 4 Signaling Pathway in Adolescent Apolipoprotein E Knockout Mice

    Directory of Open Access Journals (Sweden)

    Hongfeng Gu


    Full Text Available Here, we investigated the effect of chronic mild stress (CMS on the development of atherosclerosis as well as the expression of Toll-like receptors (TLRs signaling pathway in adolescent apolipoprotein E knockout (apoE-/- mice. Mice were subjected to daily CMS for 0, 4, and 12 weeks, respectively. To identify the expression of Toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice subjected to CMS, we compared gene expression in aortas of stressed and unstressed mice using TLRs signaling pathway real-time PCR microarrays consisting of 87 genes. We found that atherosclerosis lesions both in aortic tress and sinuses of CMS mice were significantly increased linearly in response to duration of CMS exposure. Among 87 genes analyzed, 15 genes were upregulated in stressed mice, especially TLR4, myeloid differentiation factor 88 (MyD88, and IL-1β, and 28 genes were downregulated compared with nonstressed mice. CMS mice demonstrated markedly increased aortic atherosclerosis that were associated with significant increases in levels of expression of TLR4, MyD88, nuclear factor κB (NF-κB, MCP-1, IL-1β, TNF-α, and sICAM-1. Taken together, our results suggest an important role for TLR4 signaling pathway in atherosclerosis in a CMS mouse model.

  1. Response surface optimization of electro-oxidation process for the treatment of C.I. Reactive Yellow 186 dye: reaction pathways (United States)

    Rajkumar, K.; Muthukumar, M.


    In this study, central composite design at five levels (-β, -1, 0, +1, +β) combined with response surface methodology has been applied to optimize C.I. Reactive Yellow 186 using electro-oxidation process with graphite electrodes in a batch reactor. The variables considered were the pH (X 1), NaCl concentration (M) (X 2), and electrolysis time (min) (X 3) on C.I. Reactive Yellow 186 were studied. A second-order empirical relationship between the response and independent variables was derived. Analysis of variance showed a high coefficient of determination value (R 2 = 0.9556 and 0.9416 for color and COD, respectively). The optimized condition of the electro-oxidation of Reactive Yellow 186 is as follows: pH 3.9; NaCl concentration 0.11 M; and electrolysis time 18 min. Under this condition, the maximal decolorization efficiency of 99 % and COD removal 73 % was achieved. Detailed physico-chemical analysis of electrode and residues of the electro-oxidation process has also been carried out UV-Visible and Fourier transform infrared spectroscopy. The intermediate compounds formed during the oxidation were identified using a gas chromatography coupled with mass spectrometry. According to these results, response surface methodology could be useful for reducing the time to treat effluent wastewater.

  2. A genome-wide association meta-analysis on apolipoprotein A-IV concentrations. (United States)

    Lamina, Claudia; Friedel, Salome; Coassin, Stefan; Rueedi, Rico; Yousri, Noha A; Seppälä, Ilkka; Gieger, Christian; Schönherr, Sebastian; Forer, Lukas; Erhart, Gertraud; Kollerits, Barbara; Marques-Vidal, Pedro; Ried, Janina; Waeber, Gerard; Bergmann, Sven; Dähnhardt, Doreen; Stöckl, Andrea; Kiechl, Stefan; Raitakari, Olli T; Kähönen, Mika; Willeit, Johann; Kedenko, Ludmilla; Paulweber, Bernhard; Peters, Annette; Meitinger, Thomas; Strauch, Konstantin; Study Group, Kora; Lehtimäki, Terho; Hunt, Steven C; Vollenweider, Peter; Kronenberg, Florian


    Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 (-)  (44)), rs5104 in APOA4 (P = 1.79 × 10(-)(24)) and rs4241819 in KLKB1 (P = 5.6 × 10(-)(14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 (-)  (07)). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10(-)(05)). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

  3. Levels of Circulating MMCN-151, a Degradation Product of Mimecan, Reflect Pathological Extracellular Matrix Remodeling in Apolipoprotein E Knockout Mice

    DEFF Research Database (Denmark)

    Barascuk, N; Vassiliadis, E; Zheng, Qiuju;


    Arterial extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs) is one of the major hallmarks of atherosclerosis. Mimecan, also known as osteoglycin has been implicated in the integrity of the ECM. This study assessed the validity of an enzyme-linked immunosorbent assay (ELISA)......) developed to measure a specific MMP12-derived fragment of mimecan, MMCN-151, in apolipoprotein-E knockout (ApoE-KO) mice....

  4. Amphipathic α-Helices in Apolipoproteins Are Crucial to the Formation of Infectious Hepatitis C Virus Particles (United States)

    Nakamura, Shota; Ono, Chikako; Shiokawa, Mai; Yamamoto, Satomi; Motomura, Takashi; Okamoto, Toru; Okuzaki, Daisuke; Yamamoto, Masahiro; Saito, Izumu; Wakita, Takaji; Koike, Kazuhiko; Matsuura, Yoshiharu


    Apolipoprotein B (ApoB) and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV), but their precise roles remain uncertain. Here we show that amphipathic α-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB) and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO) cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic α-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic α-helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly. PMID:25502789

  5. Amphipathic α-helices in apolipoproteins are crucial to the formation of infectious hepatitis C virus particles.

    Directory of Open Access Journals (Sweden)

    Takasuke Fukuhara


    Full Text Available Apolipoprotein B (ApoB and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV, but their precise roles remain uncertain. Here we show that amphipathic α-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic α-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic α-helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly.

  6. Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease

    DEFF Research Database (Denmark)

    Lundegaard, Christiane; Tybjærg-Hansen, Anne; Grande, Peer


    Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD).......Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD)....

  7. A Highly Expressed Human Protein, Apolipoprotein B-100, Serves as an Autoantigen in a Subgroup of Patients With Lyme Disease. (United States)

    Crowley, Jameson T; Drouin, Elise E; Pianta, Annalisa; Strle, Klemen; Wang, Qi; Costello, Catherine E; Steere, Allen C


    To discover novel autoantigens associated with Lyme arthritis (LA), we identified T-cell epitopes presented in vivo by human leukocyte antigen (HLA)-DR molecules in patients' inflamed synovial tissue or joint fluid and tested each epitope for autoreactivity. Using this approach, we identified the highly expressed human protein, apolipoprotein B-100 (apoB-100), as a target of T- and B-cell responses in a subgroup of LA patients. Additionally, the joint fluid of these patients had markedly elevated levels of apoB-100 protein, which may contribute to its autoantigenicity. In patients with antibiotic-refractory LA, the magnitude of apoB-100 antibody responses correlated with increased numbers of plasma cells in synovial tissue, greater numbers and activation of endothelial cells, and more synovial fibroblast proliferation. Thus, a subset of LA patients have high levels of apoB-100 in their joints and autoreactive T- and B-cell responses to the protein, which likely contributes to pathogenic autoimmunity in patients with antibiotic-refractory LA.

  8. 2C-I-NBOMe, an "N-bomb" that kills with "Smiles". Toxicological and legislative aspects. (United States)

    Nikolaou, Panagiota; Papoutsis, Ioannis; Stefanidou, Maria; Spiliopoulou, Chara; Athanaselis, Sotiris


    Substituted phenethylamines are a class of designer drugs that have recently emerged in the drug abuse market. Such substances remain legal to use, possess, and supply until these compounds become classified as scheduled. 2C-I-NBOMe or 25I-NBOMe is the N-benzyl-derivative of the iodo-substituted dimethoxy-phenethylamine (2C-I) that appeared recently in the drug market under the street name "N-Bomb". Due to its high potency, intoxications and fatal cases related to 2C-I-NBOMe use are increased worldwide. The use and trafficking of this substituted phenethylamine is banned only in some countries. A comprehensive review was performed using PubMed and Medline databases, together with additional non-peer reviewed information sources, including books and publications of state authorities in different countries, regarding chemistry, availability, pharmacology, and toxicology of 2C-I-NBOMe. Intoxications or lethal cases, published or reported, as well as the current legislation on this newly introduced drug are also reviewed.

  9. Sexual differences in lipoprotein composition in a family with dyslipidemic hypertension with premature atheroschlerosis: deficiency of high-density lipoprotein-L and high-density lipoprotein-M "apolipoprotein-I alone" particle. (United States)

    Hughes, T A; Moore, M A; Joyce, M; Go, R C; Segrest, J P; Blackwell, T


    This article describes a family with a high incidence of premature atherosclerosis and primary hypertriglyceridemia in the women. The lipoprotein composition of this family was investigated with a new methodology that combines gradient ultracentrifugation to isolate lipoprotein subfractions with high-performance liquid chromatography to quantitate apolipoproteins. The major lipoprotein abnormalities that were identified in the hyperlipidemic women in this family were (1) an increased mass of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) with triglyceriderich VLDL but normal IDL composition; (2) triglyceride-rich low-density lipoprotein (LDL) with normal cholesterol and apolipoprotein B concentrations; (3) a relatively normal total mass of high-density lipoprotein (HDL)-L and HDL-M but with a reduction in the apolipoprotein A-I/A-II ratio and a decrease in the cholesterol to triglyceride ratio; (4) an elevation of HDL-D apolipoprotein A-I. The reduction in the apolipoprotein A-I/A-II ratio was also seen in the hyperlipidemic men and in most of nonhyperlipidemic family members and was the most common lipoprotein abnormality that was identified in this family (9 of 11 family members who were not on lipid-lowering medications were affected). The hypertriglyceridemic women appeared to have an increase in the "A-I + A-II" HDL particles in all subfractions and an increase in the "A-I alone" particles in HDL-D. These increases provided the apparently normal total mass of HDL that was observed in these women. These increases in HDL were not seen in the hypertriglyceridemic men. We conclude that a deficiency of the "A-I alone" particle in HDL-L and HDL-M may contribute to the premature atherosclerosis that was seen in this family and that it appears to precede the appearance of hypertriglyceridemia. The increase in the "A-I + A-II" HDL particles did not appear to provide the same protection as would be expected from "A-I alone" HDL.

  10. The structure of dimeric apolipoprotein A-IV and its mechanism of self-association. (United States)

    Deng, Xiaodi; Morris, Jamie; Dressmen, James; Tubb, Matthew R; Tso, Patrick; Jerome, W Gray; Davidson, W Sean; Thompson, Thomas B


    Apolipoproteins are key structural elements of lipoproteins and critical mediators of lipid metabolism. Their detergent-like properties allow them to emulsify lipid or exist in a soluble lipid-free form in various states of self-association. Unfortunately, these traits have hampered high-resolution structural studies needed to understand the biogenesis of cardioprotective high-density lipoproteins (HDLs). We derived a crystal structure of the core domain of human apolipoprotein (apo)A-IV, an HDL component and important mediator of lipid absorption. The structure at 2.4 Å depicts two linearly connected 4-helix bundles participating in a helix swapping arrangement that offers a clear explanation for how the protein self-associates as well as clues to the structure of its monomeric form. This also provides a logical basis for antiparallel arrangements recently described for lipid-containing particles. Furthermore, we propose a "swinging door" model for apoA-IV lipid association.

  11. The Structure of Dimeric Apolipoprotein A-IV and Its Mechanism of Self-Association

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Xiaodi; Morris, Jamie; Dressmen, James; Tubb, Matthew R.; Tso, Patrick; Jerome, W. Gray; Davidson, W. Sean; Thompson, Thomas B. (UCIN); (Vanderbilt)


    Apolipoproteins are key structural elements of lipoproteins and critical mediators of lipid metabolism. Their detergent-like properties allow them to emulsify lipid or exist in a soluble lipid-free form in various states of self-association. Unfortunately, these traits have hampered high-resolution structural studies needed to understand the biogenesis of cardioprotective high-density lipoproteins (HDLs). We derived a crystal structure of the core domain of human apolipoprotein (apo)A-IV, an HDL component and important mediator of lipid absorption. The structure at 2.4 {angstrom} depicts two linearly connected 4-helix bundles participating in a helix swapping arrangement that offers a clear explanation for how the protein self-associates as well as clues to the structure of its monomeric form. This also provides a logical basis for antiparallel arrangements recently described for lipid-containing particles. Furthermore, we propose a 'swinging door' model for apoA-IV lipid association.

  12. Further studies of the influence of apolipoprotein B alleles on glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Bentzen, Joan; Poulsen, Pernille; Vaag, Allan;


    The effect of five genetic polymorphisms in the apolipoprotein B gene on parameters of lipid and glucose metabolism was assessed in 564 Danish mono- and dizygotic twins. Genotypes in apolipoprotein B T71I (ApaLI RFLP), A591V (AluI RFLP), L2712P (MvaI RFLP), R3611Q (MspI RFLP), and E4154K (Eco...... was seen in the dizygotic twins. The effect of the polymorphisms on lipid and glucose parameters could be mediated through linkage to genes with known effect on glucose metabolism or through free fatty acids exerting their effect on glucose metabolism.......RI RFLP) were established using polymerase chain reaction and restriction enzyme digests. The effect of genotypes on lipid levels and on glucose, insulin, and HOMA (i.e., calculated parameters of beta-cell function and insulin resistance) was assessed by multivariate analyses of variance correcting...

  13. Suppressive effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient mice. (United States)

    Natsume, Midori; Baba, Seigo


    Previous studies in humans have shown that the cacao polyphenols, (-)-epicatechin and its oligomers, prevent in vitro and ex vivo low-density lipoprotein oxidation mediated by free radical generators and metal ions and also reduce plasma LDL-cholesterol levels. The aim of this study was to examine the effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient (-/-) mice. Mice aged 8 weeks (n = 90) were randomized into three groups, and fed either normal mouse chow (controls) or chow supplemented with 0.25 or 0.40 % cacao polyphenols for 16 weeks. The mean plaque area in cross-sections of the brachiocephalic trunk was measured and found to be lower in the 0.25 % cacao polyphenol group than in the control group (p cacao polyphenol group (p cacao polyphenols inhibit the development of atherosclerosis in apolipoprotein E-deficient (-/-) mice by reducing oxidative stress and inflammatory responses.

  14. Apolipoprotein M affecting lipid metabolism or just catching a ride with lipoproteins in the circulation?

    DEFF Research Database (Denmark)

    Dahlbäck, B; Nielsen, Lars Bo


    M retains its signal peptide, which serves as a hydrophobic anchor to the lipoproteins. This prevents apoM from being lost in the urine. Approximately 5% of HDL carries an apoM molecule. ApoM in plasma (1 microM) correlates strongly with both low-density lipoprotein (LDL) and HDL cholesterol, suggesting......Apolipoprotein M (apoM) is a novel apolipoprotein found mainly in high-density lipoproteins (HDL). Its function is yet to be defined. ApoM (25 kDa) has a typical lipocalin ss-barrel fold and a hydrophobic pocket. Retinoids bind apoM but with low affinity and may not be the natural ligands. Apo......; possible mechanisms include increased formation of pre-ss HDL, enhanced cholesterol mobilization from foam cells, and increased antioxidant properties....

  15. Further studies of the influence of apolipoprotein B alleles on glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Bentzen, Joan; Poulsen, Pernille; Vaag, Allan


    The effect of five genetic polymorphisms in the apolipoprotein B gene on parameters of lipid and glucose metabolism was assessed in 564 Danish mono- and dizygotic twins. Genotypes in apolipoprotein B T71I (ApaLI RFLP), A591V (AluI RFLP), L2712P (MvaI RFLP), R3611Q (MspI RFLP), and E4154K (Eco...... on the insulin-to-glucose ratio (p = 0.04), and E4154K (EcoRI RFLP) influenced HOMAbeta (p = 0.04). Significant interactions were observed between genotype in T71I (ApaLI RFLP), A591V (AluI RFLP), R3611Q (MspI RFLP), and E4154K (EcoRI RFLP) and glucose tolerance on lipid-related parameters (0.03

  16. Apolipoprotein A-I mutant proteins having cysteine substitutions and polynucleotides encoding same (United States)

    Oda, Michael N.; Forte, Trudy M.


    Functional Apolipoprotein A-I mutant proteins, having one or more cysteine substitutions and polynucleotides encoding same, can be used to modulate paraoxonase's arylesterase activity. These ApoA-I mutant proteins can be used as therapeutic agents to combat cardiovascular disease, atherosclerosis, acute phase response and other inflammatory related diseases. The invention also includes modifications and optimizations of the ApoA-I nucleotide sequence for purposes of increasing protein expression and optimization.

  17. Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E


    Nathoo, N; Chetty, R; van Dellen, J R; Barnett, G H


    Apolipoprotein E (APOE) is thought to be responsible for the transportation of lipids within the brain, maintaining structural integrity of the microtubule within the neurone, and assisting with neural transmission. Possession of the APOE ɛ4 allele has also been shown to influence neuropathological findings in patients who die from traumatic brain injury, including the accumulation of amyloid β protein. Previous clinical studies reporting varying outcome severities of traumatic brain injury, ...

  18. Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

    DEFF Research Database (Denmark)

    Elsøe, Sara; Ahnström, Josefin; Christoffersen, Christina;


    Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being...... a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL....

  19. Cacao polyphenols influence the regulation of apolipoprotein in HepG2 and Caco2 cells. (United States)

    Yasuda, Akiko; Natsume, Midori; Osakabe, Naomi; Kawahata, Keiko; Koga, Jinichiro


    Cocoa powder is rich in polyphenols, such as catechins and procyanidins, and has been shown to inhibit low-density lipoprotein (LDL) oxidation and atherogenesis in a variety of models. Human studies have also shown daily intake of cocoa increases plasma high-density lipoprotein (HDL) and decreases LDL levels. However, the mechanisms responsible for these effects of cocoa on cholesterol metabolism have yet to be fully elucidated. The present study investigated the effects of cacao polyphenols on the production of apolipoproteins A1 and B in human hepatoma HepG2 and intestinal Caco2 cell lines. The cultured HepG2 cells or Caco2 cells were incubated for 24 h in the presence of cacao polyphenols such as (-)-epicatechin, (+)-catechin, procyanidin B2, procyanidin C1, and cinnamtannin A2. The concentration of apolipoproteins in the cell culture media was quantified using an enzyme-linked immunoassay, and the mRNA expression was quantified by RT-PCR. Cacao polyphenols increased apolipoprotein A1 protein levels and mRNA expression, even though apolipoprotein B protein and the mRNA expression were slightly decreased in both HepG2 cells and Caco2 cells. In addition, cacao polyphenols increased sterol regulatory element binding proteins (SREBPs) and activated LDL receptors in HepG2 cells. These results suggest that cacao polyphenols may increase the production of mature form SREBPs and LDL receptor activity, thereby increasing ApoA1 and decreasing ApoB levels. These results elucidate a novel mechanism by which HDL cholesterol levels become elevated with daily cocoa intake.

  20. CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking



    α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-β. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, apolipoprotein E (APOE) ε4 status and smoking on dementia risk. This cas...

  1. Biodegradation of C.I. Acid Blue 92 by Nasturtium officinale: Study of Some Physiological Responses and Metabolic Fate of Dye. (United States)

    Torbati, S; Movafeghi, A; Khataee, A R


    The present study was conducted to evaluate the potential of aquatic vascular plant, Nasturtium officinale, for degradation of C.I. Acid Blue 92 (AB92). The effect of operational parameters such as initial dye concentration, plant biomass, pH, and temperature on the efficiency of biological decolorization process was determined. The reusability of the plant in long term repetitive operations confirmed the biological degradation process. The by-products formed during biodegradation process were identified by GC-MS technique. The effects of the dye on several plant physiological responses such as photosynthetic pigments content and antioxidant enzymes activity were investigated. The content of chlorophyll and carotenoids was significantly reduced at 20 mg/L of the dye. The activities of superoxide dismutase and peroxidase were remarkably increased in the plant root verifying their importance in plant tolerance to the dye contamination.

  2. Altered plasma apolipoprotein modifications in patients with pancreatic cancer: protein characterization and multi-institutional validation.

    Directory of Open Access Journals (Sweden)

    Kazufumi Honda

    Full Text Available BACKGROUND: Among the more common human malignancies, invasive ductal carcinoma of the pancreas has the worst prognosis. The poor outcome seems to be attributable to difficulty in early detection. METHODS: We compared the plasma protein profiles of 112 pancreatic cancer patients with those of 103 sex- and age-matched healthy controls (Cohort 1 using a newly developed matrix-assisted laser desorption/ionization (oMALDI QqTOF (quadrupole time-of-flight mass spectrometry (MS system. RESULTS: We found that hemi-truncated apolipoprotein AII dimer (ApoAII-2; 17252 m/z, unglycosylated apolipoprotein CIII (ApoCIII-0; 8766 m/z, and their summed value were significantly decreased in the pancreatic cancer patients [P = 1.36×10(-21, P = 4.35×10(-14, and P = 1.83×10(-24 (Mann-Whitney U-test; area-under-curve values of 0.877, 0.798, and 0.903, respectively]. The significance was further validated in a total of 1099 plasma/serum samples, consisting of 2 retrospective cohorts [Cohort 2 (n = 103 and Cohort 3 (n = 163] and a prospective cohort [Cohort 4 (n = 833] collected from 8 medical institutions in Japan and Germany. CONCLUSIONS: We have constructed a robust quantitative MS profiling system and used it to validate alterations of modified apolipoproteins in multiple cohorts of patients with pancreatic cancer.

  3. The effects of apolipoprotein F deficiency on high density lipoprotein cholesterol metabolism in mice.

    Directory of Open Access Journals (Sweden)

    William R Lagor

    Full Text Available Apolipoprotein F (apoF is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP based on its ability to inhibit cholesteryl ester transfer protein (CETP-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20-25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/-0.9 mg/dl vs. WT: 1.2+/-0.3 mg/dl, p<0.05. No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls.

  4. Interferon-γ Protects from Staphylococcal Alpha Toxin-Induced Keratinocyte Death through Apolipoprotein L1. (United States)

    Brauweiler, Anne M; Goleva, Elena; Leung, Donald Y M


    Staphylococcus aureus is a bacterial pathogen that frequently infects the skin, causing lesions and cell destruction through its primary virulence factor, alpha toxin. Here we show that interferon gamma (IFN-?) protects human keratinocytes from cell death induced by staphylococcal alpha toxin. We find that IFN-? prevents alpha toxin binding and reduces expression of the alpha toxin receptor, a disintegrin and metalloproteinase 10 (ADAM10). We determine that the mechanism for IFN-?-mediated resistance to alpha toxin involves the induction of autophagy, a process of cellular adaptation to sublethal damage. We find that IFN-? potently stimulates activation of the primary autophagy effector, light chain 3 (LC3). This process is dependent on upregulation of apolipoprotein L1. Depletion of apolipoprotein L1 by small interfering RNA significantly increases alpha toxin-induced lethality and inhibits activation of light chain 3. We conclude that IFN-? plays a significant role in protecting human keratinocytes from the lethal effects of staphylococcal alpha toxin through apolipoprotein L1-induced autophagy.

  5. Apolipoproteins: Good Markers for Cardiovacular Risk in Patients with Chronic Kidney Disease and Dyslipidemia

    Directory of Open Access Journals (Sweden)

    Tudor Mirela - Nicoleta


    Full Text Available Background and aims. Dyslipidemia (DLP is a common complication of chronic kidney disease (CKD and may accelerate its progression. Circulating lipoproteins and their constituent proteins, apolipoproteins, are risk factors for CKD and cardiovascular diseases (CVD. The aim of the study was to determine whether there is a correlation between apolipoproteins and estimated glomerular filtration rate (eGFR or between apolipoproteins and anthropometrical and laboratory parameters or between evaluated cardiovascular risk (CV and dyslipidemia/CKD. Material and methods. We performed a study on 51 subjects from the Nephrology Department of Emergency Clinical County Hospital of Craiova, from November 2011 to July 2013. Results. We found statistically significant correlations between eGFR and Apo A1. Also we found a linear correlation between C-reactive protein (CRP and Apo B. When we evaluated the CV risk using CRP, we found statistically significant differences between the groups (CKD and DLP, only CKD, only DLP and control group, patients with CKD and DLP showing the highest levels of CRP. Conclusions. Elevated levels of Apo A1 are associated with a low rate of CKD. DLP and chronic inflammation play an important role in the progression of CKD. Patients with CKD and DLP had a high cardiovascular risk.

  6. Crystallization and preliminary X-ray diffraction analysis of apolipoprotein E-containing lipoprotein particles

    Energy Technology Data Exchange (ETDEWEB)

    Newhouse, Yvonne [Gladstone Institutes of Cardiovascular and Neurological Disease, University of California, San Francisco, CA 94158 (United States); Peters-Libeu, Clare [Gladstone Institutes of Cardiovascular and Neurological Disease, University of California, San Francisco, CA 94158 (United States); Cardiovascular Research Institute, University of California, San Francisco, CA 94158 (United States); Weisgraber, Karl H., E-mail: [Gladstone Institutes of Cardiovascular and Neurological Disease, University of California, San Francisco, CA 94158 (United States); Cardiovascular Research Institute, University of California, San Francisco, CA 94158 (United States); Department of Pathology, University of California, San Francisco, CA 94158 (United States)


    Further understanding of the structure and function of plasma apolipoproteins requires the determination of their high-resolution structures when complexed with lipids. In these studies, the production of homogeneous, biologically active lipoprotein particles of apolipoprotein E complexed with dipalmitoylphosphatidylcholine and their crystallization and X-ray diffraction are demonstrated. High-resolution structural information is available for several soluble plasma apolipoproteins (apos) in a lipid-free state. However, this information provides limited insight into structure–function relationships, as this class of proteins primarily performs its functions of lipid transport and modulation of lipid metabolism in a lipid-bound state on lipoprotein particles. Here, the possibility of generating homogeneous lipoprotein particles that could be crystallized was explored, opening the possibility of obtaining high-resolution structural information by X-ray crystallography. To test this possibility, apoE4 complexed with the phospholipid dipalmitoylphosphatidylcholine was chosen. Uniform particles containing 50% lipid and 50% apoE4 were obtained and crystallized using the hanging-drop method. Two crystal forms diffract to beyond 8 Å resolution.

  7. Differential expression of apolipoprotein D in male reproductive system of rats by high-fat diet. (United States)

    Lim, W; Bae, H; Song, G


    Apolipoprotein D, a 29-kDa secreted glycoprotein that belongs to the lipocalin superfamily, is widely expressed in various tissues and associated with lipid metabolism as a component of high-density lipoproteins. Although Apolipoprotein D binds to small hydrophobic ligands including cholesterol, little is known about effects of high-fat diet with cholesterol on expression of Apolipoprotein D in the male reproductive tract. Therefore, we investigated Apod expression in penises, prostate glands, and testes from rats fed a high-fat diet including a high amount of cholesterol. Our previous research indicated that a high-fat diet induces dyslipidemia leading to histological changes and dysfunction of male reproduction in rats. Consistent with these results, Apod mRNA expression was significantly (p high-fat diet as compared with normal diet. In addition, Apod mRNA and protein were detected predominantly in urethral epithelium and penile follicle from rats. Moreover, changes in expression of specific microRNAs (miR-229b-3p, miR-423-3p, and miR-490-3p) regulating Apod in the penises and prostate glands were negatively associated with Apod expression. Collectively, results of this study suggest that Apod is a novel regulatory gene in the male reproductive system, especially in penises of rats fed a high-cholesterol diet, and that expression of Apod is regulated at the posttranscriptional level by target microRNAs.

  8. Acrolein modification impairs key functional features of rat apolipoprotein E: identification of modified sites by mass spectrometry. (United States)

    Tran, Tuyen N; Kosaraju, Malathi G; Tamamizu-Kato, Shiori; Akintunde, Olayemi; Zheng, Ying; Bielicki, John K; Pinkerton, Kent; Uchida, Koji; Lee, Yuan Yu; Narayanaswami, Vasanthy


    Apolipoprotein E (apoE), an antiatherogenic apolipoprotein, plays a significant role in the metabolism of lipoproteins. It lowers plasma lipid levels by acting as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins, in addition to playing a role in promoting macrophage cholesterol efflux in atherosclerotic lesions. The objective of this study is to examine the effect of acrolein modification on the structure and function of rat apoE and to determine the sites and nature of modification by mass spectrometry. Acrolein is a highly reactive aldehyde, which is generated endogenously as one of the products of lipid peroxidation and is present in the environment in pollutants such as tobacco smoke and heated oils. In initial studies, acrolein-modified apoE was identified by immunoprecipitation using an acrolein-lysine specific antibody in the plasma of 10-week old male rats that were exposed to filtered air (FA) or low doses of environmental tobacco smoke (ETS). While both groups displayed acrolein-modified apoE in the lipoprotein fraction, the ETS group had higher levels in the lipid-free fraction compared with the FA group. This observation provided the rationale to further investigate the effect of acrolein modification on rat apoE at a molecular level. Treatment of recombinant rat apoE with a 10-fold molar excess of acrolein resulted in (i) a significant decrease in lipid-binding and cholesterol efflux abilities, (ii) impairment in the LDLr- and heparin-binding capabilities, and (iii) significant alterations in the overall stability of the protein. The disruption in the functional abilities is attributed directly or indirectly to acrolein modification yielding an aldimine adduct at K149 and K155 (+38); a propanal adduct at K135 and K138 (+56); an N(ε)-(3-methylpyridinium)lysine (MP-lysine) at K64, K67, and K254 (+76), and an N(ε)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) derivative at position K68 (+94), as determined by matrix

  9. Lipoprotein lipase activity and mass, apolipoprotein C-II mass and polymorphisms of apolipoproteins E and A5 in subjects with prior acute hypertriglyceridaemic pancreatitis

    Directory of Open Access Journals (Sweden)

    García-Arias Carlota


    Full Text Available Abstract Background Severe hypertriglyceridaemia due to chylomicronemia may trigger an acute pancreatitis. However, the basic underlying mechanism is usually not well understood. We decided to analyze some proteins involved in the catabolism of triglyceride-rich lipoproteins in patients with severe hypertriglyceridaemia. Methods Twenty-four survivors of acute hypertriglyceridaemic pancreatitis (cases and 31 patients with severe hypertriglyceridaemia (controls were included. Clinical and anthropometrical data, chylomicronaemia, lipoprotein profile, postheparin lipoprotein lipase mass and activity, hepatic lipase activity, apolipoprotein C II and CIII mass, apo E and A5 polymorphisms were assessed. Results Only five cases were found to have LPL mass and activity deficiency, all of them thin and having the first episode in childhood. No cases had apolipoprotein CII deficiency. No significant differences were found between the non-deficient LPL cases and the controls in terms of obesity, diabetes, alcohol consumption, drug therapy, gender distribution, evidence of fasting chylomicronaemia, lipid levels, LPL activity and mass, hepatic lipase activity, CII and CIII mass or apo E polymorphisms. However, the SNP S19W of apo A5 tended to be more prevalent in cases than controls (40% vs. 23%, NS. Conclusion Primary defects in LPL and C-II are rare in survivors of acute hypertriglyceridaemic pancreatitis; lipase activity measurements should be restricted to those having their first episode during chilhood.

  10. Noninvasive in vivo magnetic resonance imaging of injury-induced neointima formation in the carotid artery of the apolipoprotein-E null mouse. (United States)

    Manka, D R; Gilson, W; Sarembock, I; Ley, K; Berr, S S


    Mice deficient in apolipoprotein-E (apoE) experience severe hypercholesterolemia, are prone to atherosclerosis, and recently have emerged as a powerful tool in the study of plaque formation. In this study, we developed magnetic resonance (MR) imaging methods to detect the progression of atherosclerosis noninvasively in a mouse model of arterial injury. Four 14-week-old apoE-deficient mice were imaged 5 weeks after beginning an atherogenic Western diet and 4 weeks after wire denudation injury of the left common carotid artery (LCCA). Information from several images was combined into high-information content images using methods previously developed. The image resolution was 47 x 47 x 750 microm(3). We acquired T1-, T2-, and proton density (PD)-weighted images (TR/TE 650/14, 2000/60, and 2000/14 msec, respectively). Each 8-bit image was placed in a separate color channel to produce a 24-bit color image (red = T1, green = PD, and blue = T2). The composite image created contrast between different tissue types that was superior to that of any single image and revealed significant luminal narrowing of the LCCA, but not the uninjured RCCA. MR images were compared with corresponding histopathology cross sections and luminal area measurements from each method correlated(r2= 0.61). Atherosclerotic luminal narrowing was successfully detected through MR imaging in a mouse model of arterial injury that is small, reproduces quickly, and lends itself to genetic analysis and manipulation.

  11. Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels (United States)

    Bandarian, Fatemeh; Daneshpour, Maryam Sadat; Hedayati, Mehdi; Naseri, Mohsen; Azizi, Fereidoun


    Background: Apolipoprotein A2 (APOA2) is the second major apolipoprotein of the high-density lipoprotein cholesterol (HDL-C). The study aim was to identify APOA2 gene variation in individuals within two extreme tails of HDL-C levels and its relationship with HDL-C level. Methods: This cross-sectional survey was conducted on participants from Tehran Glucose and Lipid Study (TLGS) at Research Institute for Endocrine Sciences, Tehran, Iran from April 2012 to February 2013. In total, 79 individuals with extreme low HDL-C levels (≤5th percentile for age and gender) and 63 individuals with extreme high HDL-C levels (≥95th percentile for age and gender) were selected. Variants were identified using DNA amplification and direct sequencing. Results: Screen of all exons and the core promoter region of APOA2 gene identified nine single nucleotide substitutions and one microsatellite; five of which were known and four were new variants. Of these nine variants, two were common tag single nucleotide polymorphisms (SNPs) and seven were rare SNPs. Both exonic substitutions were missense mutations and caused an amino acid change. There was a significant association between the new missense mutation (variant Chr.1:16119226, Ala98Pro) and HDL-C level. Conclusion: None of two common tag SNPs of rs6413453 and rs5082 contributes to the HDL-C trait in Iranian population, but a new missense mutation in APOA2 in our population has a significant association with HDL-C. PMID:26590203

  12. Cryptogenic cirrhosis in a patient with familial hypocholesterolemia due to a new truncated form of apolipoprotein B. (United States)

    Bonnefont-Rousselot, Dominique; Condat, Bertrand; Sassolas, Agnès; Chebel, Sabrina; Bittar, Randa; Federspiel, Marie-Christine; Cazals-Hatem, Dominique; Bruckert, Eric


    Familial hypobetalipoproteinemia (FHBL) is an autosomal codominantly inherited disorder of lipoprotein metabolism characterized by decreased concentrations of low-density lipoprotein-cholesterol and of apolipoprotein B (apoB). Mutations of APOB gene lead to the formation of truncated forms of apoB. The study aimed at determining the truncated form of apoB responsible for FHBL associated with liver cirrhosis in a 27-year-old man. Analysis of the patient's lipoproteins has been performed by SDS-PAGE electrophoresis followed by immunoblotting with monoclonal antibodies. DNA of the family (proband, daughter, wife, father, and mother) was extracted, and PCR amplification was realized; amplicons were screened and sequenced. Electrophoresis allowed us to identify a truncated form of apoB (close to apoB 59%), associated with a new heterozygous apoB variant, 8402 C>G. This mutation creates a stop codon (TAC>TAG, Y2807X) and predicts to generate a truncated protein (apoB-61.9%). No other causes of cirrhosis were established by comprehensive clinical and biological investigations. We described here an unusual clinical observation of a patient with FHBL and early development of liver cirrhosis due to a new truncated form of apoB.

  13. Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer's disease. (United States)

    Rohn, Troy T


    Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%-80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to undergo proteolytic cleavage generating N- and C-terminal fragments. The purpose of this review will be to examine the mechanisms by which apoE4 contributes to AD pathogenesis focusing on the potential loss or gain of function that may occur following cleavage of the full-length protein. In this context, a discussion of whether targeting apoE4 therapeutically is a rationale approach to treating this disease will be assessed.

  14. Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology. (United States)

    Mahley, Robert W; Huang, Yadong


    An attractive strategy to treat proteinopathies (diseases caused by malformed or misfolded proteins) is to restore protein function by inducing proper three-dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimer's disease and other neurodegenerative disorders. ApoE4's detrimental effects result from its altered protein conformation ("domain interaction"), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function and how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based "structure correctors" that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4's neurotoxic effects in cultured neurons and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases.

  15. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: No cosegregation with severe hyperlipidemia

    Energy Technology Data Exchange (ETDEWEB)

    Maagdenberg, A.M.J.M. van den; Bruijn, I.H. de; Hofker, M.H.; Frants, R.R. (Leiden Univ. (Netherlands)); Knijff, P. de; Smelt, A.H.M.; Leuven, J.A.G.; van' t Hooft, F.; Assmann, G.; Havekes, L.M. (Univ. Hospital, Leiden (Netherlands)); Weng, Wei; Funke, H. (Westfalische Wilhelms-Universitaet, Muester (Germany))


    Assessment of the apolipoprotein E (apoE) phenotype by isoelectric focusing of both hyperlipidemic and normolipidemic individuals identified five new variants. All mutations were confined to the downstream part of the APOE gene by using denaturing gradient gel electrophoresis (DGGE). Sequence analysis revealed five new mutations causing unique amino acid substitutions in the carboxyl-terminal part of the protein containing the putative lipid-binding domain. Three hyperlipoproteinemic probands were carriers of the APOE*2(Va1236[r arrow]Glu) allele, the APOE*3(Cys112-Arg; Arg251[r arrow]Gly) allele, or the APOE*1(Arg158[r arrow]Cys; Leu252[r arrow]Glu) allele. DGGE of the region encoding the receptor-binding domain was useful for haplotyping the mutations at codons 112 and 158. Family studies failed to demonstrate cosegregation between the new mutations and severe hyperlipoproteinemia, although a number of carriers for the APOE*3(Cys112[r arrow]Arg; Arg251[r arrow]Gly) allele and the APOE*1(Arg158-Cys; Leu252[r arrow]Glu) allele expressed hypertriglyceridemia and/ or hypercholesterolemia. Two other mutant alleles, APOE*4[sup [minus

  16. Molecular Characterization and Growth Association of Two Apolipoprotein A-Ib Genes in Common Carp (Cyprinus carpio). (United States)

    Wang, Xinhua; Yu, Xiaomu; Tong, Jingou


    Apolipoprotein A-I (ApoA-I) is functionally involved in the transportation and metabolism of lipids in vertebrates. In this study, two isoforms of apoA-Ib in common carp (Cyprinus carpio L.) were characterized. Sequence comparison and phylogenetic analysis showed that C. carpio ApoA-Ib is relatively conserved within cyprinid fishes. During embryonic development, C. carpio apoA-Ib was first expressed at the stage of multi-cells, and the highest mRNA level was observed at the stage of optic vesicle. A ubiquitous expression pattern was detected in various tissues with extreme predominance in the liver. Significantly different expression levels were observed between light and heavy body weight groups and also in the compensatory growth test. Seventeen and eight single-nucleotide polymorphisms (SNPs) were identified in matured mRNA of the C. carpio apoA-Ib.1 and apoA-Ib.2, respectively. Two of these SNPs (apoA-Ib.2-g.183A>T and apoA-Ib.2-g.1753C>T) were significantly associated with body weight and body length in two populations of common carp. These results indicate that apoA-Ib may play an important role in the modulation of growth and development in common carp.

  17. The Keck Carbon Cycle AMS Laboratory, U.C.I.: Initial operation and a background surprise


    Southon, John R.; Santos, Guaciara M.; Druffel-Rodriguez, K C; Druffel, Ellen R. M.; Trumbore, Susan E.; Xu, Xiaomei; Griffin, Sheila; Ali, S.; Mazon, M.


    A new 14C accelerator mass spectrometry (AMS) laboratory for carbon cycle studies has been established at the University of California, Irvine. The 0.5 MV AMS system was installed in mid-2002 and has operated routinely since October of that year. This paper briefly describes the spectrometer and summarizes lessons learned during the first year of operation. In the process of setting up the system, we identified and largely suppressed a previously unreported radiocarbon AMS b...

  18. Molecular docking study investigating the possible mode of binding of C.I. Acid Red 73 with DNA. (United States)

    Guo, Yumei; Yue, Qinyan; Gao, Baoyu


    C.I. Acid Red 73 is a reactive azo dye with a variable potential carcinogenicity. The mechanism mediating interactions that occur between the dye and DNA have not been completely understood thus far. In this study, molecular docking techniques were applied to describe the most probable mode of DNA binding as well as the sequence selectivity of the C.I. Acid Red 73 dye. These docking experiments revealed that the dye is capable of interacting with the minor groove of the DNA on the basis of its curved shape, which fits well with the topology of double-stranded DNA. In addition, the dye can bind selectively to the minor groove of the DNA by applying CGT sequence selectivity. Further, the minor groove can be recognized although DNA targets present intercalation gaps. However, intercalative binding can also occur when the DNA target possesses an appropriate intercalation gap. Compared with the other eight DNA sequences that were studied, the DNA dodecamer d(CGCGATATCGCG)(2) (PDB ID: 1DNE) presents a very favorable target for the binding of C.I. Acid Red 73 to the minor groove, with the lowest binding free energy -9.19 kcal/mol. Results reported from this study are expected to provide useful information for research involving further simulations of molecular dynamics and toxicology investigations of the dye.

  19. Discovery and consequences of apolipoprotein-epsilon(3Groningen) : a G-insertion in codon 95/96 that is predicted to cause a premature stop codon

    NARCIS (Netherlands)

    Dijck-Brouwer, DAJ; van Doormaal, JJ; Kema, IP; Brugman, AM; Kingma, AW; Muskiet, FAJ


    Background We found an unexplained, persistent discrepancy between the outcomes of two apolipoprotein-E (apo-E) genotyping methods for a patient with features of familial dysbetalipoproteinaemia (FD). Polymerase chain reaction restriction fragment length polymorphism resulted in the apo-epsilon(2)/e

  20. Polymorphism of apolipoprotein E gene and post-stroke vascular dementia

    Institute of Scientific and Technical Information of China (English)

    Xinjing Lin; Changlin Hu; Yunlan Xie; Xin Zhang; Xiangping Liu; Ge Yan


    BACKGROUND: Studies have indicated that the more certain etiological factors of vascular dementia are the sites, size and number of cerebrovascular lesions, but there are arguments all the time in the relationship of genetic factors, especially apolipoprotein E gene, with the occurrence and development of vascular dementia. OBJECTIVE: To analyze the relationship between the polymorphism of apolipoprotein E gene and vascular dementia in stroke patients. DESIGN: A non-randomized grouped comparative observation at the same time. SETTING: The Laboratory of Neurology, the Second Affiliated Hospital of Chongqing University of Medical Sciences.PARTICIPANTS: Totally 121 inpatients with stroke were selected from the Department of Neurology, the Second Affiliated Hospital of Chongqing University of Medical Sciences from January 2000 to December 2001. All the patients were accorded with the diagnostic standards for cerebrovascular diseases set by the Second National Academic Meeting for Cerebrovascular Disease, and confirmed by cranial CT or MRI. According to with vascular dementia or not, they were divided into vascular dementia group (n =58) and non-vascular dementia group (n =63). In the vascular dementia group, there were 37 males and 21 females, the average age was (59±8) years. They were all in accordance with the standard of the third edition of Diagnostic and Statistical Manual of Mental Disorders (DMS-Ⅲ), without conscious disturbance and language disorder; hospitalized within 3 days after the attack of cerebrovascular disease. In the non-vascular dementia group, there were 37 males and 26 females, the average age was (59±9.5) years. They all had no intellectual disturbance within 3 months after the attack of cerebrovascular disease. All the subjects agreed to supply blood samples for the experiment. METHODS: ①Fasting venous blood (2 mL) was drawn from each patient in the morning to extract DNA. The frequencies of apolipoprotein E genotypes and alleles were

  1. Identifying Activity

    CERN Document Server

    Lewis, Adrian S


    Identification of active constraints in constrained optimization is of interest from both practical and theoretical viewpoints, as it holds the promise of reducing an inequality-constrained problem to an equality-constrained problem, in a neighborhood of a solution. We study this issue in the more general setting of composite nonsmooth minimization, in which the objective is a composition of a smooth vector function c with a lower semicontinuous function h, typically nonsmooth but structured. In this setting, the graph of the generalized gradient of h can often be decomposed into a union (nondisjoint) of simpler subsets. "Identification" amounts to deciding which subsets of the graph are "active" in the criticality conditions at a given solution. We give conditions under which any convergent sequence of approximate critical points finitely identifies the activity. Prominent among these properties is a condition akin to the Mangasarian-Fromovitz constraint qualification, which ensures boundedness of the set of...

  2. Identification of apolipoprotein N-acyltransferase (Lnt) in mycobacteria. (United States)

    Tschumi, Andreas; Nai, Corrado; Auchli, Yolanda; Hunziker, Peter; Gehrig, Peter; Keller, Peter; Grau, Thomas; Sander, Peter


    Lipoproteins of Gram-negative and Gram-positive bacteria carry a thioether-bound diacylglycerol but differ by a fatty acid amide bound to the alpha-amino group of the universally conserved cysteine. In Escherichia coli the N-terminal acylation is catalyzed by the N-acyltransferase Lnt. Using E. coli Lnt as a query in a BLASTp search, we identified putative lnt genes also in Gram-positive mycobacteria. The Mycobacterium tuberculosis lipoprotein LppX, heterologously expressed in Mycobacterium smegmatis, was N-acylated at the N-terminal cysteine, whereas LppX expressed in a M. smegmatis lnt::aph knock-out mutant was accessible for N-terminal sequencing. Western blot analyses of a truncated and tagged form of LppX indicated a smaller size of about 0.3 kDa in the lnt::aph mutant compared with the parental strain. Matrix-assisted laser desorption ionization time-of-flight/time-of-flight analyses of a trypsin digest of LppX proved the presence of the diacylglycerol modification in both strains, the parental strain and lnt::aph mutant. N-Acylation was found exclusively in the M. smegmatis parental strain. Complementation of the lnt::aph mutant with M. tuberculosis ppm1 restored N-acylation. The substrate for N-acylation is a C16 fatty acid, whereas the two fatty acids of the diacylglycerol residue were identified as C16 and C19:0 fatty acid, the latter most likely tuberculostearic acid. We demonstrate that mycobacterial lipoproteins are triacylated. For the first time to our knowledge, we identify Lnt activity in Gram-positive bacteria and assigned the responsible genes. In M. smegmatis and M. tuberculosis the open reading frames are annotated as MSMEG_3860 and M. tuberculosis ppm1, respectively.

  3. [Interaction of human apolipoprotein AI and HIV-1 envelope proteins with the native and recombinant CD4 receptors]. (United States)

    Panin, L E; Kostina, N E


    The method of enzyme-linked immunosorbent assay (ELISA) was used to show an interaction of soluble recombinant CD4-receptor (rsCD4) with human apolipoprotein A-1. Competitive interactions between envelope proteins VIH-1 (gp120 and gp41), on the one hand, and human apolipoprotein A-1 with CD4 receptor, present in the cellular membranes of line MT4 human lymphocytes, were demonstrated by the method of flow cytofluorimetry. It was suggested that the competitive interactions between the above proteins could manifest in respect to the apolipoprotein A-1 receptor, which affects the involvement of the latter in the regulation of protein biosynthesis and which leads to a decrease in the body weight of HIV-infected patients.

  4. Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction

    DEFF Research Database (Denmark)

    Langsted, A.; Freiberg, J.J.; Nordestgaard, Børge


    BACKGROUND: Lipid profiles are usually measured after fasting. We tested the hypotheses that these levels change only minimally in response to normal food intake and that nonfasting levels predict cardiovascular events. METHODS AND RESULTS: We cross-sectionally studied 33 391 individuals 20 to 95...... to HDL cholesterol, and ratio of apolipoprotein B to apolipoprotein A1 did not change in response to normal food intake. The maximum changes after normal food and fluid intake from fasting levels were -0.2 mmol/L for total cholesterol, -0.2 mmol/L for low-density lipoprotein cholesterol, -0.1 mmol...... and lowest versus highest tertile of nonfasting HDL cholesterol and apolipoprotein A1 predicted 1.7- to 2.4-fold increased risk of cardiovascular events. CONCLUSIONS: Lipid profiles at most change minimally in response to normal food intake in individuals in the general population. Furthermore, nonfasting...

  5. Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population

    DEFF Research Database (Denmark)

    Benn, M; Stene, MC; Nordestgaard, BG;


    CONTEXT: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result in not only severe hypercholesterolemia and ischemic heart disease but also hypocholesterolemia. Despite this, common single-nucleotide polymorphisms (SNPs) in APOB have not convincingly been...... on cholesterol and apolipoprotein B levels. However, as predicted from the magnitude of the observed LDL cholesterol effects, none of these SNPs predicted risk of ischemic heart disease prospectively in the general population, in a case-control study, or as haplotypes. CONCLUSIONS: Multiple common and rare...... demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. OBJECTIVE: We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. DESIGN...

  6. Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis. (United States)

    Olson, Gary E; Winfrey, Virginia P; Nagdas, Subir K; Hill, Kristina E; Burk, Raymond F


    Selenium is a micronutrient that is essential for the production of normal spermatozoa. The selenium-rich plasma protein selenoprotein P (Sepp1) is required for maintenance of testis selenium and for fertility of the male mouse. Sepp1 trafficking in the seminiferous epithelium was studied using conventional methods and mice with gene deletions. Immunocytochemistry demonstrated that Sepp1 is present in vesicle-like structures in the basal region of Sertoli cells, suggesting that the protein is taken up intact. Sepp1 affinity chromatography of a testicular extract followed by mass spectrometry-based identification of bound proteins identified apolipoprotein E receptor 2 (ApoER2) as a candidate testis Sepp1 receptor. In situ hybridization analysis identified Sertoli cells as the only cell type in the seminiferous epithelium with detectable ApoER2 expression. Testis selenium levels in apoER2(-/-) males were sharply reduced from those in apoER2(+/+) males and were comparable with the depressed levels found in Sepp1(-/-) males. However, liver selenium levels were unchanged by deletion of apoER2. Immunocytochemistry did not detect Sepp1 in the Sertoli cells of apoER2(-/-) males, consistent with a defect in the receptor-mediated Sepp1 uptake pathway. Phase contrast microscopy revealed identical sperm defects in apoER2(-/-) and Sepp1(-/-) mice. Co-immunoprecipitation analysis demonstrated an interaction of testis ApoER2 with Sepp1. These data demonstrate that Sertoli cell ApoER2 is a Sepp1 receptor and a component of the selenium delivery pathway to spermatogenic cells.

  7. The age dependency of gene expression for plasma lipids, lipoproteins, and apolipoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Snieder, H.; Doornen, L.J.P. van; Boomsma, D.I. [Vrije Universiteit, Amsterdam (Netherlands)


    The aim of this study was to investigate and disentangle the genetic and nongenetic causes of stability and change in lipids and (apo)lipoproteins that occur during the lifespan. Total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) were measured in a group of 160 middle-aged parents and their twin offspring (first project) and in a group of 203 middle-aged twin pairs (second project). Combining the data of both projects enabled the estimation of the extent to which measured lipid parameters are influenced by different genes in adolescence and adulthood. To that end, an extended quantitative genetic model was specified, which allowed the estimation of heritabilities for each sex and generation separately. Heritabilities were similar for both sexes and both generations. Larger variances in the parental generation could be ascribed to proportional increases in both unique environmental and additive genetic variance from childhood to adulthood, which led to similar heritability estimates in adolescent and middle-aged twins. Although the magnitudes of heritabilities were similar across generations, results showed that, for total cholesterol, triglycerides, HDL, and LDL, partly different genes are expressed in adolescence compared to adulthood. For triglycerides, only 46% of the genetic variance was common to both age groups; for total cholesterol this was 80%. Intermediate values were found for HDL (66%) and LDL (76%). For ApoA1, ApoB, and Lp(a), the same genes seem to act in both generations. 56 refs., 2 figs., 5 tabs.

  8. Lectures given at the 3rd Session of the Centro Internazionale Matematico Estivo (C.I.M.E.)

    CERN Document Server


    The C.I.M.E. Summer School at Como in 1986 was the first in that series on the subject of combinatorial optimization. Situated between combinatorics, computer science and operations research, the subject draws on a variety of mathematical methods to deal with problems motivated by real-life applications. Recent research has focussed on the connections to theoretical computer science, in particular to computational complexity and algorithmic issues. The Summer School's activity centered on the 4 main lecture courses, the notes of which are included in this volume:

  9. Lectures given at the 1st Session of the Centro Internazionale Matematico Estivo (C.I.M.E.)

    CERN Document Server


    The courses given at the 1st C.I.M.E. Summer School of 1988 dealt with the main areas on the borderline between applied logic and theoretical computer science. These courses are recorded here in five expository papers: S. Homer: The Isomorphism Conjecture and its Generalization.- A. Nerode: Some Lectures on Intuitionistic Logic.- R.A. Platek: Making Computers Safe for the World. An Introduction to Proofs of Programs. Part I. - G.E. Sacks: Prolog Programming.- A. Scedrov: A Guide to Polymorphic Types.

  10. Lectures given at the 2nd Session of the Centro Internazionale Matematico Estivo (C.I.M.E.)

    CERN Document Server


    This volume contains the texts of the four series of lectures presented by B.Cockburn, C.Johnson, C.W. Shu and E.Tadmor at a C.I.M.E. Summer School. It is aimed at providing a comprehensive and up-to-date presentation of numerical methods which are nowadays used to solve nonlinear partial differential equations of hyperbolic type, developing shock discontinuities. The most effective methodologies in the framework of finite elements, finite differences, finite volumes spectral methods and kinetic methods, are addressed, in particular high-order shock capturing techniques, discontinuous Galerkin methods, adaptive techniques based upon a-posteriori error analysis.

  11. Erythrocyte-bound apolipoprotein B in relation to atherosclerosis, serum lipids and ABO blood group.

    Directory of Open Access Journals (Sweden)

    Boudewijn Klop

    Full Text Available INTRODUCTION: Erythrocytes carry apolipoprotein B on their membrane, but the determining factors of erythrocyte-bound apolipoprotein B (ery-apoB are unknown. We aimed to explore the determinants of ery-apoB to gain more insight into potential mechanisms. METHODS: Subjects with and without CVD were included (N = 398. Ery-apoB was measured on fresh whole blood samples using flow cytometry. Subjects with ery-apoB levels ≤ 0.20 a.u. were considered deficient. Carotid intima media thickness (CIMT was determined as a measure of (subclinical atherosclerosis. RESULTS: Mean ery-apoB value was 23.2% lower in subjects with increased CIMT (0.80 ± 0.09 mm, N = 140 compared to subjects with a normal CIMT (0.57 ± 0.08 mm, N = 258 (P = 0.007, adjusted P<0.001. CIMT and ery-apoB were inversely correlated (Spearman's r: -0.116, P = 0.021. A total of 55 subjects (13.6% were considered ery-apoB deficient, which was associated with a medical history of CVD (OR: 1.86, 95% CI 1.04-3.33; adjusted OR: 1.55; 95% CI 0.85-2.82. Discontinuation of statins in 54 subjects did not influence ery-apoB values despite a 58.4% increase in serum apolipoprotein B. Subjects with blood group O had significantly higher ery-apoB values (1.56 ± 0.94 a.u. when compared to subjects with blood group A (0.89 ± 1.15 a.u, blood group B (0.73 ± 0.1.12 a.u. or blood group AB (0.69 ± 0.69 a.u. (P-ANOVA = 0.002. CONCLUSION: Absence or very low values of ery-apoB are associated with clinical and subclinical atherosclerosis. While serum apolipoprotein B is not associated with ery-apoB, the ABO blood group seems to be a significant determinant.

  12. Analysis of cell surface alterations in Legionella pneumophila cells treated with human apolipoprotein E. (United States)

    Palusinska-Szysz, Marta; Zdybicka-Barabas, Agnieszka; Cytryńska, Małgorzata; Wdowiak-Wróbel, Sylwia; Chmiel, Elżbieta; Gruszecki, Wiesław I


    Binding of human apolipoprotein E (apoE) to Legionella pneumophila lipopolysaccharide was analysed at the molecular level by Fourier-transform infrared spectroscopy, thereby providing biophysical evidence for apoE-L. pneumophila lipopolysaccharide interaction. Atomic force microscopy imaging of apoE-exposed L. pneumophila cells revealed alterations in the bacterial cell surface topography and nanomechanical properties in comparison with control bacteria. The changes induced by apoE binding to lipopolysaccharide on the surface of L. pneumophila cells may participate in: (1) impeding the penetration of host cells by the bacteria; (2) suppression of pathogen intracellular growth and eventually; and (3) inhibition of the development of infection.

  13. Apolipoprotein D is associated with long-term outcome in patients with schizophrenia

    DEFF Research Database (Denmark)

    Hansen, T; Hemmingsen, R P; Wang, A G;


    , genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find Apo......Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second...

  14. Apolipoprotein D is associated with long-term outcome in patients with schizophrenia

    DEFF Research Database (Denmark)

    Hansen, Thomas Folkmann; Hemmingsen, R P; Wang, A G;


    Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second......, genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find Apo...

  15. Analytical isoelectric focusing of apolipoprotein B of human plasma low-density lipoproteins in the presence of a nonionic and a zwitterionic detergent. (United States)

    Melnik, B C; Melnik, S F


    A method for the analytical isoelectric focusing of Nonidet-P40-delipidated apolipoprotein B of human plasma low-density lipoproteins has been developed. Isoelectric focusing was performed in the presence of the zwitterionic nondenaturing detergent Chaps, 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate, and the nonionic surfactant Nonidet-P40, polyoxyethyleneglycol p-t-octylphenol with a mean of 9.0 ethylene oxide units per molecule. Low-density lipoprotein (LDL) apolipoprotein B (apo-B) entered 3.75% polyacrylamide gels without precipitation at the sites of sample application, permitting apoprotein recoveries of greater than 90% in the migrating bands. LDL apo-B exhibited 10 distinguishable bands with apparent isoelectric points of 7.34 (band 1), 7.27 (band 2), 7.16 (band 3), 7.02 (band 4), 6.88 (band 5), 6.70 (band 6), 6.61 (band 7), 6.48 (band 8), 6.40 (band 9), and 6.24 (band 10), respectively. Bands 3 and 4, 6 and 7, as well as 8 and 9 could be identified as major double bands. When the focused apo-B was run in a second dimension by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the same relative molecular weight of B-100 was obtained for all focused bands. After electrotransfer to nitrocellulose paper, all bands reacted with polyclonal anti-human LDL antibody. Furthermore, the detergent-solubilized apo-B retained the immunological properties of native low-density lipoproteins when tested by double immunodiffusion against polyvalent anti-human LDL sera.

  16. The apolipoprotein m-sphingosine-1-phosphate axis

    DEFF Research Database (Denmark)

    Arkensteijn, Bas W C; Berbée, Jimmy F P; Rensen, Patrick C N;


    M was identified as a carrier of the bioactive lipid sphingosine-1-phosphate (S1P). S1P activates five different G-protein-coupled receptors, known as the S1P-receptors 1-5 and, hence, affects a wide range of biological processes, such as lymphocyte trafficking, angiogenesis, wound repair and even virus...... suppression and cancer. The ability of apoM to bind S1P is due to a lipophilic binding pocket within the lipocalin structure of the apoM molecule. Mice overexpressing apoM have increased plasma S1P concentrations, whereas apoM-deficient mice have decreased S1P levels. ApoM-S1P is able to activate the S1P...

  17. Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil

    Directory of Open Access Journals (Sweden)

    Sumeet S Mitter


    Full Text Available OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ received 200,000 IU of retinol (every four months, zinc (40 mg twice weekly, or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-forheight z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6 later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+, with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+ children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+ children and improved delta lactulose/mannitol. Apolipoprotein E4(- children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may

  18. The effect of six polymorphisms in the Apolipoprotein B gene on parameters of lipid metabolism in a Danish population

    DEFF Research Database (Denmark)

    Bentzen, J; Jørgensen, T; Fenger, M


    Lipoproteins are vehicles for the distribution of plasma lipids and polymorphisms in the genes for apolipoproteins could influence the amount of lipid in plasma. We examined the effect of six single nucleotide polymorphisms in codons 71, 591, 2488, 2712, 3611, and 4154 of the apolipoprotein B gene...... on fasting levels of triglyceride, VLDL-, LDL-, HDL- and total cholesterol and on body mass index (BMI) in a cohort of 2656 Danes aged 40-70 years using a linear model correcting for the effects of gender, age, BMI, smoking, alcohol consumption and physical activity. The codon 2488 polymorphism was the most...

  19. Study of the electrochemical oxidation and reduction of C.I. Reactive Orange 4 in sodium sulphate alkaline solutions. (United States)

    del Río, A I; Molina, J; Bonastre, J; Cases, F


    Synthetic solutions of hydrolysed C.I. Reactive Orange 4, a monoazo textile dye commercially named Procion Orange MX-2R (PMX2R) and colour index number C.I. 18260, was exposed to electrochemical treatment under galvanostatic conditions and Na2SO4 as electrolyte. The influence of the electrochemical process as well as the applied current density was evaluated. Ti/SnO2-Sb-Pt and stainless steel electrodes were used as anode and cathode, respectively, and the intermediates generated on the cathode during electrochemical reduction were investigated. Aliquots of the solutions treated were analysed by UV-visible and FTIR-ATR spectroscopy confirming the presence of aromatic structures in solution when an electro-reduction was carried out. Electro-oxidation degraded both the azo group and aromatic structures. HPLC measures revealed that all processes followed pseudo-first order kinetics and decolourisation rates showed a considerable dependency on the applied current density. CV experiments and XPS analyses were carried out to study the behaviour of both PMX2R and intermediates and to analyse the state of the cathode after the electrochemical reduction, respectively. It was observed the presence of a main intermediate in solution after an electrochemical reduction whose chemical structure is similar to 2-amino-1,5-naphthalenedisulphonic acid. Moreover, the analysis of the cathode surface after electrochemical reduction reveals the presence of a coating layer with organic nature.

  20. Association of apolipoprotein E polymorphism in late-onset Alzheimer's disease and vascular dementia in Brazilians

    Directory of Open Access Journals (Sweden)

    D.R.S. Souza


    Full Text Available The genetic basis for dementias is complex. A common polymorphism in the apolipoprotein E (APOE gene is considered to be the major risk factor in families with sporadic and late-onset Alzheimer's disease as well as in the general population. The distribution of alleles and genotypes of the APOE gene in late-onset Alzheimer's disease (N = 68, other late-life dementias (N = 39, and in cognitively normal controls (N = 58 was determined, as also was the risk for Alzheimer's disease associated with the epsilon4 allele. Peripheral blood samples were obtained from a total of 165 individuals living in Brazil aged 65-82 years. Genomic DNA was amplified by the polymerase chain reaction and the products were digested with HhaI restriction enzyme. APOE epsilon2 frequency was considerably lower in the Alzheimer's disease group (1%, and the epsilon3 allele and epsilon3/epsilon3 genotype frequencies were higher in the controls (84 and 72%, respectively as were the epsilon4 allele and epsilon3/epsilon4 genotype frequencies in Alzheimer's disease (25 and 41%, respectively. The higher frequency of the epsilon4 allele in Alzheimer's disease confirmed its role as a risk factor, while epsilon2 provided a weak protection against development of the disease. However, in view of the unexpectedly low frequency of the epsilon4 allele, additional analyses in a more varied Brazilian sample are needed to clarify the real contribution of apolipoprotein E to the development of Alzheimer's disease in this population.

  1. Does Apolipoprotein E genotype affect cardiovascular risk in subjects with acromegaly? (United States)

    Bozok Cetintas, Vildan; Zengi, Ayhan; Tetik, Asli; Karadeniz, Muammer; Ergonen, Faruk; Kucukaslan, Ali Sahin; Tamsel, Sadik; Kosova, Buket; Sahin, Serap Baydur; Saygılı, Fusun; Eroglu, Zuhal


    Acromegaly is a syndrome that results when the pituitary gland produces excess growth hormone after epiphyseal closure at puberty. Usually, subjects with acromegaly exhibit a 2- to 3-fold higher mortality rate from diseases that are associated with cardiovascular complications when compared to the normal population. In this study, we therefore aimed to evaluate whether a well-established cardiovascular risk factor, the Apolipoprotein E (Apo E) genotype, contributes to increased risk of cardiovascular complications in subjects with acromegaly. A total of 102 unrelated acromegaly subjects were prospectively included into this case-control association study and constituted our study group. The study group was comparable by age and gender with 200 unrelated healthy subjects constituting our control group. Genomic DNA was isolated from the peripheral blood leukocytes of all subjects and Apo E genotype (codon 112/158) was assessed by melting temperature analyses after using a real-time PCR protocol. The Apolipoprotein E4 allele was found at a significantly higher frequency in the study group when compared with the control group (P = 0.032). Subjects with the E2 allele, on the other hand, had significantly increased values in body mass index (P = 0.004), waist circumference (P = 0.001), C-reactive protein (CRP) (P acromegaly since it is concurrently present with other cardiovascular risk factors such as the left-side carotid intima media thickness and CRP.

  2. The N-terminal domain of apolipoprotein B-100: structural characterization by homology modeling

    Directory of Open Access Journals (Sweden)

    Khachfe Hassan M


    Full Text Available Abstract Background Apolipoprotein B-100 (apo B-100 stands as one of the largest proteins in humans. Its large size of 4536 amino acids hampers the production of X-ray diffraction quality crystals and hinders in-solution NMR analysis, and thus necessitates a domain-based approach for the structural characterization of the multi-domain full-length apo B. Results The structure of apo B-17 (the N-terminal 17% of apolipoprotein B-100 was predicted by homology modeling based on the structure of the N-terminal domain of lipovitellin (LV, a protein that shares not only sequence similarity with B17, but also a functional aspect of lipid binding and transport. The model structure was first induced to accommodate the six disulfide bonds found in that region, and then optimized using simulated annealing. Conclusion The content of secondary structural elements in this model structure correlates well with the reported data from other biophysical probes. The overall topology of the model conforms with the structural outline corresponding to the apo B-17 domain as seen in the EM representation of the complete LDL structure.

  3. Molecular structure of an apolipoprotein determined at 2. 5- angstrom resolution

    Energy Technology Data Exchange (ETDEWEB)

    Breiter, D.R.; Benning, M.M.; Wesenberg, G.; Holden, H.M.; Rayment, I. (Univ. of Wisconsin, Madison (USA)); Kanost, M.R.; Law, J.H.; Wells, M.A. (Univ. of Arizona, Tucson (USA))


    The three-dimensional structure of an apolipoprotein isolated from the African migratory locust Locusta migratoria has been determined by X-ray analysis to a resolution of 2.5 {angstrom}. The overall molecular architecture of this protein consists of five long {alpha}-helices connected by short loops. As predicted from amino acid sequence analyses, these helices are distinctly amphiphilic with the hydrophobic residues pointing in toward the interior of the protein and the hydrophilic side chains facing outward. The molecule falls into the general category of up-and-down {alpha}-helical bundles as previously observed, for example, in cytochrome c{prime}. Although the structure shows the presence of five long amphiphilic {alpha}-helices, the {alpha}-helical moment and hydrophobicity of the entire molecule fall into the range found for normal globular proteins. Thus, in order for the amphiphilic helices to play a role in the binding of the protein to a lipid surface, there must be a structural reorganization of the protein which exposes the hydrophobic interior to the lipid surface. The three dimensional motif of this apolipoprotein is compatible with a model in which the molecule binds to the lipid surface via a relatively nonpolar end and then spreads on the surface in such a way as to cause the hydrophobic side chains of the helices to come in contact with the lipid surface, the charged and polar residues to remain in contact with water, and the overall helical motif of the protein to be maintained.

  4. Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes (United States)

    Åvall, Karin; Ali, Yusuf; Leibiger, Ingo B.; Leibiger, Barbara; Moede, Tilo; Paschen, Meike; Dicker, Andrea; Daré, Elisabetta; Köhler, Martin; Ilegems, Erwin; Abdulreda, Midhat H.; Graham, Mark; Crooke, Rosanne M.; Tay, Vanessa S. Y.; Refai, Essam; Nilsson, Stefan K.; Jacob, Stefan; Selander, Lars; Berggren, Per-Olof; Juntti-Berggren, Lisa


    Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca2+ concentration ([Ca2+]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus. PMID:25941406

  5. Lifelong expression of apolipoprotein D in the human brainstem: correlation with reduced age-related neurodegeneration.

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    Ana Navarro

    Full Text Available The lipocalin apolipoprotein D (Apo D is upregulated in peripheral nerves following injury and in regions of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, during aging and progression of certain neurological diseases. In contrast, few studies have examined Apo D expression in the brainstem, a region necessary for survival and generally less prone to age-related degeneration. We measured Apo D expression in whole human brainstem lysates by slot-blot and at higher spatial resolution by quantitative immunohistochemistry in eleven brainstem nuclei (the 4 nuclei of the vestibular nuclear complex, inferior olive, hypoglossal nucleus, oculomotor nucleus, facial motor nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve, and Roller`s nucleus. In contrast to cortex, hippocampus, and cerebellum, apolipoprotein D was highly expressed in brainstem tissue from subjects (N = 26, 32-96 years of age with no history of neurological disease, and expression showed little variation with age. Expression was significantly stronger in somatomotor nuclei (hypoglossal, oculomotor, facial than visceromotor or sensory nuclei. Both neurons and glia expressed Apo D, particularly neurons with larger somata and glia in the periphery of these brainstem centers. Immunostaining was strongest in the neuronal perinuclear region and absent in the nucleus. We propose that strong brainstem expression of Apo D throughout adult life contributes to resistance against neurodegenerative disease and age-related degeneration, possibly by preventing oxidative stress and ensuing lipid peroxidation.

  6. Resonance assignments and secondary structure of apolipoprotein E C-terminal domain in DHPC micelles. (United States)

    Lo, Chi-Jen; Chyan, Chia-Lin; Chen, Yi-Chen; Chang, Chi-Fon; Huang, Hsien-Bin; Lin, Ta-Hsien


    Human apolipoprotein E (apoE) has been known to play a key role in the transport of plasma cholesterol and lipoprotein metabolism. It is an apolipoprotein of 299 amino acids with a molecular mass, ~34 kDa. ApoE has three major isoforms, apoE2, apoE3, and apoE4 which differ only at residue 112 or 158. ApoE consists of two independently folded domains (N-terminal and C-terminal domain) separated by a hinge region. The N-terminal domain and C-terminal domain of apoE are responsible for the binding to receptor and to lipid, respectively. Since the high resolution structures of apoE in lipids are still unavailable to date, we therefore aim to resolve the structures in lipids by NMR. Here, we reported the resonance assignments and secondary structure distribution of the C-terminal domain of wild-type human apoE (residue 195-299) in the micelles formed by dihexanoylphosphatidylcholine. Our results may provide a novel structural model of apoE in micelles and may shed new light on the molecular mechanisms underlying the apoE related biological processes.

  7. Plasma Apolipoprotein-M (ApoM Response to a Circuit Resistance Training Program

    Directory of Open Access Journals (Sweden)

    Abbass Ghanbari-Niaki


    Full Text Available Apolipoprotein M (Apo-M is a human novel protein of apolipoprotein classes and highly expressed in liver and kidney tissues. ApoM is mainly associated with high-density lipoprotein (HDL, and act as a chaperone for sphingosine-1-phosphate (S1P, promotes mobilization of cellular cholesterol, formation of larger-size of pre β-HDL, and a new biomarker in sepsis. The level of apoM in plasma/serum is affected by several factors such as pregnancy, hyperglycemia, plasma leptin concentration, obesity, diabetes, insulin concentration and physical exercise. It has been shown that the level of plasma ApoM was significantly lower in strenuous exercise group when compared with the non-exercise group. In the present study a reduction was observed after the 4 weeks of circuit resistance training program. This reduction might be due to a decrease in ApoM expression in liver and kidney or an increase in ApoM clearance, degradation and excretion in urine.

  8. Expression of human apolipoprotein B and assembly of lipoprotein(a) in transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Callow, M.J.; Stoltzfus, L.J.; Rubin, E.M. [Lawrence Berkeley Lab., CA (United States); Lawn, R.M. [Stanford Univ., CA (United States)


    The atherogenic macromolecule lipoprotein(a) [Lp(a)] has resisted in vivo analyses partly because it is found in a limited number of experimental animals. Although transgenic mice expressing human apolipoprotein (a) [apo(a)] have previously been described, they failed to assemble Lp(a) particles because of the inability of human apo(a) to associate with mouse apolipoprotein B (apoB). The authors isolated a 90-kilobase P1 phagemid containing the human apoB gene and with this DNA generated 13 lines of transgenic mice of which 11 expressed human apoB. The human apoB transcript was expressed and edited in the liver of the transgenic mice. Plasma concentrations of human apoB, as well as low density lipoprotein (LDL), were related to transgene copy number; the transgenic line with the most copies of human apoB had a >4-fold increase in LDL cholesterol compared with nontransgenics and a lipoprotein profile similar to that of humans. When human apoB and apo(a) transgenic mice were bred together, plasma apo(a) in mice expressing both human proteins was tightly associated with lipoproteins in the LDL density region. These studies demonstrate the successful expression of human apoB and the efficient assembly of Lp(a) in mice.

  9. [Relationship between apolipoprotein E polymorphism and cognitive function in patients with primary hypertension]. (United States)

    Su, Yanling; Chen, Xiaoping; Huang, Yan; Jiang, Lingyun; Huang, He


    To explore the relationship between apolipoprotein E polymorphism and cognitive function in primary hypertension patients, we collected 200 Chinese primary hypertensive patients. Blood pressure (BP), heart rate (HR), height, body weight, waistline, hip circumference were measured. The Mini Mental State Examination (MMSE) was applied to test the cognitive function and compute score. Full-automatic bio-chemistry analyzer was used to determine total cholesterol (TC) and triglyeride (TG) and fasting glucose. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP) was used for the analysis of the apolipoprotein E polymorphism. We found that in primary hypertension patients, the genotype frequency of epsilon3/4 and epsilon4/4 were significantly higher in the cognitive impairment group than that in the cognitive normal group. The allele frequency of e4 is obviously higher in the cognitive impairment group than that in the cognitive normal group. Age and epsilon4/4 genetype were positively correlated with hypertensive-cognitive impairment, while cultural level was negtively correlated with it. ApoEepsilon4 allele and age might be risk factors for the cognitive impairment in hypertensive patients. The epsilon4 homozygote (epsilon4/4) might be an important influencing factor for the progression of cognitive impairment.

  10. 微胶囊C.I.分散蓝56对PLA织物的无助剂染色%Dyeing of PLA fibers using microencapsulated C.I. Disperse Blue 56 without auxiliaries

    Institute of Scientific and Technical Information of China (English)

    董晓雯; 钟毅; 杜鹃; 罗艳


    C.I.分散蓝56的微胶囊染料与商品染料分别对PLA织物实施无助剂染色及常规助剂染色,比较相应的上染曲线、提升力曲线、匀染性、摩擦牢度及皂洗牢度.结果表明:微胶囊分散染料可在不经还原清洗、更少工艺步骤且无需助剂的条件下对PLA织物染得和商品分散染料常规助剂染色相当的色深,各项色牢度亦相当.故微胶囊分散染料可对生态聚酯类PLA织物实施无助剂清洁染色.%The Polylactide (PLA) fabrics were dyed by microencapsulated C.I. Disperse Blue 56 without auxiliary and commercial dye with auxiliary, respectively. The corresponding dyeing properties, such as exhausting curve, building up property, leveling property, rubbing fastness and soaping fastness were compared in details. The results showed that the color depth and color fastness of microencapsulated disperse dyed PLA fabric in the absence of auxiliaries and without reduction clearing were similar with those of commercial dyed fabric with auxiliary. Accordingly, microencapsulated disperse dye could be applied in dyeing of ecological polyester type PLA fabric without auxiliary.

  11. Analysis of the Association Between Apolipoprotein E Polymorphism and Cardiovascular Risk Factors in an Elderly Population with Longevity

    Directory of Open Access Journals (Sweden)

    Schwanke Carla Helena Augustin


    Full Text Available OBJECTIVE: To establish the allelic and genotypic frequencies related to apolipoprotein E (ApoE polymorphism and association of the genotypes with risk factors and cardiovascular morbidity in an elderly population with longevity. METHODS: We analyzed 70 elderly patients aged 80 years or more who were part of the Projeto Veranópolis. We used the gene amplification technique through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and cleavage with the restriction enzyme Hha I to identify the ApoE genotypes. The most frequent genotypes were compared considering biological variables and cardiovascular risks and morbidity. RESULTS: The frequencies of the E2, E3, and E4 alleles were 0.05, 0.84, and 0.11, respectively, and of the genotypes were as follows: E3E3 (0.70, E3E4 (0.22, E2E3 (0.06, and E2E2 (0.02. Individuals with the E3E4 had a mean age greater than those with the E3E3. No association was observed between the genotypes and the variables analyzed, except for obesity, which was associated with the E3E3 genotype. Individuals with the E3E4 genotype had high levels of LDL-cholesterol and fibrinogen as compared with those with the E3E3 genotype. CONCLUSION: The results suggest that the E4E4 genotype may be associated with early mortality. A balance between the protective or neutral factors and the cardiovascular risk factors may occur among the individuals with different genotypes, attenuating the negative effects of the E4 allele.

  12. Role of apolipoprotein E polymorphism as a prognostic marker in traumatic brain injury and neurodegenerative disease: a critical review. (United States)

    Maiti, Tanmoy Kumar; Konar, Subhas; Bir, Shyamal; Kalakoti, Piyush; Bollam, Papireddy; Nanda, Anil


    OBJECT The difference in course and outcome of several neurodegenerative conditions and traumatic injuries of the nervous system points toward a possible role of genetic and environmental factors as prognostic markers. Apolipoprotein E (Apo-E), a key player in lipid metabolism, is recognized as one of the most powerful genetic risk factors for dementia and other neurodegenerative diseases. In this article, the current understanding of APOE polymorphism in various neurological disorders is discussed. METHODS The English literature was searched for various studies describing the role of APOE polymorphism as a prognostic marker in neurodegenerative diseases and traumatic brain injury. The wide ethnic distribution of APOE polymorphism was discussed, and the recent meta-analyses of role of APOE polymorphism in multiple diseases were analyzed and summarized in tabular form. RESULTS Results from the review of literature revealed that the distribution of APOE is varied in different ethnic populations. APOE polymorphism plays a significant role in pathogenesis of neurodegeneration, particularly in Alzheimer's disease. APOE ε4 is considered a marker for poor prognosis in various diseases, but APOE ε2 rather than APOE ε4 has been associated with cerebral amyloid angiopathy-related bleeding and sporadic Parkinson's disease. The role of APOE polymorphism in various neurological diseases has not been conclusively elucidated. CONCLUSIONS Apo-E is a biomarker for various neurological and systemic diseases. Therefore, while analyzing the role of APOE polymorphism in neurological diseases, the interpretation should be done after adjusting all the confounding factors. A continuous quest to look for associations with various neurological diseases and wide knowledge of available literature are required to improve the understanding of the role of APOE polymorphism in these conditions and identify potential therapeutic targets.

  13. A systematic review and meta-analysis of the association between the apolipoprotein E genotype and delirium. (United States)

    Adamis, Dimitrios; Meagher, David; Williams, John; Mulligan, Owen; McCarthy, Geraldine


    The role of apolipoprotein E (APOE) in Alzheimer's disease and other dementias has been investigated intensively. However, the relationship between APOE and delirium has only recently been explored in studies that have included relatively small samples. A meta-analysis of the published pooled data is timely to explore the relationship between APOE and delirium and to inform further research in this topic. PubMed, EBSCOhost, Google Scholar, Scopus, all EBM Reviews (OVID) and the Cochrane Database of Systematic Reviews were searched with relevant keywords and from the references of relevant papers. Ten papers were found that examined the relationship between APOE and delirium. Data were extracted from eight of them and pooled for meta-analysis using random effects with R software. Data from 1762 participants, of whom 479 (27.2%) were diagnosed with delirium, showed low heterogeneity (Q=13.11, d.f.=7, P=0.07; I=44.86%). The possession of the APOE ε4 allele has a small (log odds ratio: 0.18, 95% confidence interval: 0.23-0.59), nonsignificant (P=0.38) effect on the presence of delirium. No publication bias was identified. The metapower of the pooled data was low (α=0.05, power=0.65). On analysing the studies to date, it seems that there is no association between APOE and the occurrence of delirium. We suggest that further studies are needed with greater number of patients to clarify any association as well as to examine for other patterns of association including relevance for subgroups of patients who develop delirium and for effects on the phenotype of delirium and the outcomes.

  14. Apolipoprotein J/Clusterin is a novel structural component of human erythrocytes and a biomarker of cellular stress and senescence.

    Directory of Open Access Journals (Sweden)

    Marianna H Antonelou

    Full Text Available BACKGROUND: Secretory Apolipoprotein J/Clusterin (sCLU is a ubiquitously expressed chaperone that has been functionally implicated in several pathological conditions of increased oxidative injury, including aging. Nevertheless, the biological role of sCLU in red blood cells (RBCs remained largely unknown. In the current study we identified sCLU as a component of human RBCs and we undertook a detailed analysis of its cellular topology. Moreover, we studied the erythrocytic membrane sCLU content during organismal aging, in conditions of increased organismal stress and accelerated RBCs senescence, as well as during physiological in vivo cellular senescence. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of molecular, biochemical and high resolution microscopical methods we found that sCLU is a novel structural component of RBCs extra- and intracellular plasma membrane and cytosol. We observed that the RBCs membrane-associated sCLU decreases during organismal aging or exposure to acute stress (e.g. smoking, in patients with congenital hemolytic anemia, as well as during RBCs in vivo senescence. In all cases, sCLU reduction paralleled the expression of typical cellular senescence, redox imbalance and erythrophagocytosis markers which are also indicative of the senescence- and oxidative stress-mediated RBCs membrane vesiculation. CONCLUSIONS/SIGNIFICANCE: We propose that sCLU at the mature RBCs is not a silent remnant of the erythroid precursors, but an active component being functionally implicated in the signalling mechanisms of cellular senescence and oxidative stress-responses in both healthy and diseased organism. The reduced sCLU protein levels in the RBCs membrane following cell exposure to various endogenous or exogenous stressors closely correlates to the levels of cellular senescence and redox imbalance markers, suggesting the usefulness of sCLU as a sensitive biomarker of senescence and cellular stress.

  15. Ledipasvir/sofosbuvir treatment of hepatitis C virus is associated with reduction in serum apolipoprotein levels. (United States)

    Younossi, Z M; Elsheikh, E; Stepanova, M; Gerber, L; Nader, F; Stamm, L M; Brainard, D M; McHutchinson, J G


    The interaction of lipoproteins with hepatitis C virus (HCV) has pathogenic and therapeutic implications. Our aim was to evaluate changes in the apolipoprotein profile of patients with chronic hepatitis C during and after successful cure with ledipasvir and sofosbuvir (LDV/SOF) with and without ribavirin (RBV). One hundred HCV genotype 1 patients who had achieved SVR-12 after treatment with 12 weeks of LDV/SOF ± RBV were selected from the ION-1 clinical trial. Frozen serum samples from baseline, end of treatment and week 4 of follow-up were used to assay apolipoproteins (apoAI, apoAII, apoB, apoCII, apoCIII, apoE) using the Multiplex platform to assess for changes in the apolipoprotein levels. At the end of treatment compared to baseline, a significant reduction in apoAII levels (-14.97 ± 63.44 μg/mL, P = 0.0067) and apoE levels (-4.38 ± 12.19 μg/mL, P < 0.001) was noted. These declines from baseline in apoAII (-16.59 ±66.15 μg/mL, P = 0.0075) and apoE (-2.66 ± 12.64 μg/mL, P = 0.015) persisted at 4 weeks of post-treatment follow-up. In multivariate analysis, treatment with LDV/SOF + RBV was independently associated with reduction in apoE (beta = 5.31 μg/mL, P = 0.002) (compared to RBV-free LDV/SOF) (P < 0.05). In contrast, apoCII levels overall increased from baseline to end of treatment (+2.74 ±11.76 μg/mL, P = 0.03) and persisted at 4 weeks of follow-up (+4.46 ± 12.81 μg/mL from baseline, P = 0.0005). Subgroup analysis revealed an increase in apoCII during treatment only in patients receiving LDV/SOF without RBV (+5.52 ± 11.92 μg/mL, P = 0.0007) but not in patients receiving LDV/SOF + RBV (P = 0.638). Treatment with LDV/SOF ± RBV is associated with a persistent reduction in the apolipoprotein AII and E after achieving cure. These data suggest that treatment with LDV/SOF ± RBV may be associated with alterations in serum apolipoproteins which could potentially impact viral eradication.

  16. The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

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    Steinmetz, Martin, E-mail: [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Internal Medicine II, University Hospital Bonn, 53105 Bonn (Germany); Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Mallat, Ziad [INSERM, Unit 970, Paris Cardiovascular Research Center, 75015 Paris (France); Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke' s Hospital, Cambridge, CB2 2QQ (United Kingdom)


    Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10{sup 7} OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen

  17. The effect of an energy restricted low glycemic index diet on blood lipids, apolipoproteins and lipoprotein (a) among adolescent girls with excess weight: a randomized clinical trial. (United States)

    Rouhani, Mohammad Hossein; Kelishadi, Roya; Hashemipour, Mahin; Esmaillzadeh, Ahmad; Azadbakht, Leila


    Some studies focused on the effect of the dietary glycemic index on lipoproteins and apolipoproteins in adults; however, little evidence exists among adolescents regarding the effect of a low glycemic index (LGI) diet on apolipoproteins and lipoprotein (a) (Lpa). This study was conducted to evaluate the effect of an LGI diet on the lipid profile, apolipoproteins and Lpa among overweight and obese adolescent girls. For this parallel designed randomized clinical trial, 50 healthy overweight/obese girls at pubertal ages were randomly allocated to an LGI or a healthy nutritional recommendations (HNR) based diet. Equal macronutrient distributed diets were prescribed to both groups. Biochemical measurements included lipid profile, apolipoprotein A, apolipoprotein B and Lpa were conducted before and after 10 weeks of intervention. Forty one adolescent girls completed the study. The dietary glycemic index in the LGI group was 42.67 ± 0.067. There were no differences in the mean of blood lipid indices baseline and after intervention between two groups. There were no significant differences between the two groups regarding lipid profiles, apolipoproteins and Lpa. There were no significant differences in lipid profiles, apolipoproteins and Lpa between the LGI diet and the HNR-based diet and the impact of these two diets on lipid profile was equal in this trial.

  18. Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention

    NARCIS (Netherlands)

    Matualatupauw, J.C.; Radonjic, M.; Rest, van de O.; Groot, de C.P.G.M.; Geleijnse, J.M.; Müller, M.R.; Afman, L.A.


    People who carry the apolipoprotein E4 (APOE4) single nucleotide polymorphism have an increased risk of cardiovascular disease (CVD). Fish-oil supplementation may help in the prevention of CVD, though interindividual differences in the response to n-3 PUFAs have been observed. We aimed to

  19. Effects of dietary fish oil on serum lipids and VLDL kinetics in hyperlipidemic apolipoprotein E*3-Leiden transgenic mice

    NARCIS (Netherlands)

    Vlijmen, B.J.M. van; Mensink, R.P.; Hof, H.B. van 't; Offermans, R.F.G.; Hofker, M.H.; Havekes, L.M.


    Studying the effects of dietary fish oil on VLDL metabolism in humans is subject to both large intra- and interindividual variability. In the present study we therefore used hyperlipidentic apolipoprotein (APO) E*3-Leiden mice, which have impaired chylomicron and very low density lipoprotein (VDL) r

  20. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study

    NARCIS (Netherlands)

    A.J.C. Slooter (Arjen); M. Cruts (Marc); S. Kalmijn (Sandra); M.M.B. Breteler (Monique); C.M. van Duijn (Cock); C. van Broeckhoven (Christine); A. Hofman (Albert)


    textabstractOBJECTIVES: To provide risk estimates of dementia and Alzheimer disease as a function of the apolipoprotein E (APOE) genotypes and to assess the proportion of dementia that is attributable to the APOE genotypes. DESIGN: Case-control study nested in a population-based cohort study with a

  1. Apolipoprotein A2 polymorphism interacts with intakes of dairy foods to influence body weight in 2 U.S. populations (United States)

    The interaction between a functional apolipoprotein A2 gene (APOA2) variant and saturated fatty acids (SFAs) for the outcome of body mass index (BMI) is among the most widely replicated gene-nutrient interactions. Whether this interaction can be extrapolated to food-based sources of SFAs, specifical...

  2. Apolipoprotein A4-1/2 polymorphism and response of serum lipids to dietary cholesterol in humans

    NARCIS (Netherlands)

    Weggemans, R.M.; Zock, P.L.; Meyboom, S.; Funke, H.; Katan, M.B.


    The response of serum lipids to dietary changes is to some extent an innate characteristic. One candidate genetic factor that may affect the response of serum lipids to a change in cholesterol intake is variation in the apolipoprotein A4 gene, known as the APOA4-1/2 or apoA-IVGln360His polymorphism.

  3. Lipid profiles reflecting high and low risk for coronary heart disease : Contribution of apolipoprotein E polymorphism and lifestyle

    NARCIS (Netherlands)

    Boer, J.M.A.; Feskens, E.J.M.; Schouten, E.G.; Havekes, L.M.; Seidell, J.C.; Kromhout, D.


    To elucidate the role of modifiable factors and the apolipoprotein E polymorphism in explaining lipid profiles reflecting low, average and high risk for coronary heart disease, we selected subjects from a large population-based study. Subjects with low total cholesterol (TC) (< 15th percentile) and

  4. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J


    to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...

  5. Variations in apolipoprotein e frequency with age in a pooled analysis of a large group of older people

    NARCIS (Netherlands)

    G.J. McKay (Gareth); G. Silvestri (Giuliana); U. Chakravarthy (Usha); S. Dasari (Shilpa); L.G. Fritsche (Lars); B.H.F. Weber (Bernhard); P.J. Francis (Peter); C.N. Keilhauer (Claudia); M.L. Klein (Michael); C.C.W. Klaver (Caroline); J.R. Vingerling (Hans); L. Ho (Lintje); P.T.V.M. de Jong (Paulus); M. Dean (Michael Emmans); J. Sawitzke (Julie); P.N. Baird (Paul); R.H. Guymer (Robyn); D.E. Stambolian (Dwight); A. Orlin (Anton); J.M. Seddon (Johanna); I. Peter (Inga); A.F. Wright (Alan); C. Hayward (Caroline); A.J. Lotery (Andrew); S. Ennis (Sarah); M.B. Gorin (Michael); C.-L. Kuo; A. Hingorani (Aroon); R. Sofat (Reecha); F. Cipriani (Francesco); A. Swaroop (Anand); M.I. Othman (Mohammad); A. Kanda (Atsuhiro); W. Chen (Wei); G.R. Abecasis (Gonçalo); J.R. Yates (John); A.R. Webster (Andrew); A.T. Moore (Anthony); J.H. Seland (Johan ); M. Rahu (Mati); G. Soubrane (Gisele); L. Tomazzoli (Laura); F. Topouzis (Fotis); J. Vioque (Jesus); I.S. Young (Ian); A.E. Fletcher (Astrid E.); C.C. Patterson (Chris); D.E. Weeks (Daniel)


    textabstractVariation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (

  6. Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention

    NARCIS (Netherlands)

    Matualatupauw, J.C.; Radonjic, M.; Rest, O. van de; Groot, L.C.P.G.M. de; Geleijnse, J.M.; Müller, M.; Afman, L.A.


    Scope: People who carry the apolipoprotein E4 (APOE4) single nucleotide polymorphism have an increased risk of cardiovascular disease (CVD). Fish-oil supplementation may help in the prevention of CVD, though interindividual differences in the response to n-3 PUFAs have been observed. We aimed to ass

  7. The concentration of apolipoprotein A-I decreases during experimentally induced acute-phase processes in pigs

    DEFF Research Database (Denmark)

    Carpintero, R.; Pineiro, M.; Andres, M.


    In this work, apolipoprotein A-I (ApoA-I) was purified from pig sera. The responses of this protein after sterile inflammation and in animals infected with Actinobacillus pleuropneumoniae or Streptococcus suis were investigated. Decreases in the concentrations of ApoA-I, two to five times lower...

  8. Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake

    NARCIS (Netherlands)

    Berg, S.A.A. van den; Heemskerk, M.M.; Geerling, J.J.; Klinken, J.B. van; Schaap, F.G.; Bijland, S.; Berbée, J.F.P.; Harmelen, V.J.A. van; Pronk, A.C.M.; Schreurs, M.; Havekes, L.M.; Rensen, P.C.N.; Dijk, K.W. van


    Mutations in apolipoprotein A5 (APOA5) have been associated with hypertriglyceridemia in humans and mice. This has been attributed to a stimulating role for APOA5 in lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles. However, because of the lo

  9. Effect of an isoenergetic traditional Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome (United States)

    The impact of the Mediterranean diet (MedDiet) on high-density lipoprotein (HDL) kinetics has not been studied to date. The objective of this study was therefore to investigate the effect of the MedDiet in the absence of changes in body weight on apolipoprotein (apo) A-I kinetic in men with metaboli...

  10. Effect of Mediterranean diet with and without weight loss on apolipoprotein B100 metabolism in men with metabolic syndrome (United States)

    The objective of this study was to assess the effect of a Mediterranean diet (MedDiet) with and without weight loss (WL) on apolipoprotein B100 (apoB100) metabolism in men with metabolic syndrome. The diet of 19 men with metabolic syndrome (age, 24–62 years) was first standardized to a North America...


    NARCIS (Netherlands)



    The chicken very low density apolipoprotein II (apoVLDLII) gene is estrogen-inducible and specifically expressed in liver. We examined the possible involvement of the retinoid X receptor (RXR) and its ligand 9-cis-retinoic acid (9-cis-RA) in the activation of the apoVLDLII promoter. We first concent

  12. A comparative estimation of C.I. engine fuelled with methyl esters of punnai, neem and waste cooking oil

    Directory of Open Access Journals (Sweden)

    D. Subramaniam, A. Murugesan, A. Avinashy


    Full Text Available In this experimental study, performance, emission, and combustion characteristics of methyl esters of Punnai, Neem, Waste Cooking Oil and their diesel blends in a C.I. engine was experimentally examined. For the study, Punnai oil methyl esters (POME, neem oil methyl esters (NOME, and Waste Cooking Oil Methyl Esters (WCOME were prepared by tranesterification process. The Bio diesel-diesel blends were prepared by mixing 10%, 30%, 50%, and 70% of bio diesel with diesel. The effects of three methyl esters and their diesel blends on engine performance, combustion, and exhaust emissions were examined at different engine loads. Experimental results concluded that up to 30% of methyl esters did not affect the performance, combustion, and emissions characteristics. On the other hand, above B30 (30% Bio diesel with 70% diesel a reduction in performance, combustion, and emission characteristics were clear from the study.

  13. A comparative estimation of C.I. engine fuelled with methyl esters of punnai, neem and waste cooking oil

    Energy Technology Data Exchange (ETDEWEB)

    Subramaniam, D.; Avinash, A. [Department of Mechanical Engineering - K.S.Rangasamy College of Technology –Tiruchengode, 637215 Tamil Nadu (India); Murugesan, A. [Department of Mechatronics Engineering - K.S.Rangasamy College of Technology – Tiruchengode, 637215 Tamil Nadu (India)


    In this experimental study, performance, emission, and combustion characteristics of methyl esters of Punnai, Neem, Waste Cooking Oil and their diesel blends in a C.I. engine was experimentally examined. For the study, Punnai oil methyl esters (POME), neem oil methyl esters (NOME), and Waste Cooking Oil Methyl Esters (WCOME) were prepared by tranesterification process. The Bio diesel-diesel blends were prepared by mixing 10%, 30%, 50%, and 70% of bio diesel with diesel. The effects of three methyl esters and their diesel blends on engine performance, combustion, and exhaust emissions were examined at different engine loads. Experimental results concluded that up to 30% of methyl esters did not affect the performance, combustion, and emissions characteristics. On the other hand, above B30 (30% Bio diesel with 70% diesel) a reduction in performance, combustion, and emission characteristics were clear from the study.

  14. Biological Decolorization of C.I. Basic Green 4 Solution by Chlorella sp.:Effect of Operational Parameters

    Institute of Scientific and Technical Information of China (English)

    Khataee A. R.; Pourhassan M.; Ayazloo M.


    In recent years, the ability of microorganisms to decolorize textile wastewater has received great attention due to the environmental persistence and toxicity of these pollutants. In this paper biological decolorization of triphenylmethane dye, C.I. Basic Green 4 (BG 4), by Chlorella species was investigated. The effect of operational parameters (temperature, pH, initial dye concentration and algal concentration) on decolorization efficiency was examined. Results indicated that the desired initial pH was 9. The stability and efficiency of the algae in long-term repetitive operations were also examined. Michaelis-Menten kinetics was employed to describe the apparent correlation between the decolorization rate and dye concentration. The optimal kinetic parameters, Vmax (specific decolorization rate) and Km (maximum specific decolorization rate) were 4.6 mg dye g cell-1 h-1and 151.0 mg L-1, respectively. Fig 10, Tab 2, Ref24

  15. Biodegradation of C.I. Acid Red 1 by indigenous bacteria Stenotrophomonas sp. BHUSSp X2 isolated from dye contaminated soil. (United States)

    Kumari, Lata; Tiwary, Dhanesh; Mishra, Pradeep Kumar


    A significant proportion of xenobiotic recalcitrant azo dyes are being released in environment during carpet dyeing. The bacterial strain Stenotrophomonas sp. BHUSSp X2 was isolated from dye contaminated soil of carpet industry, Bhadohi, India. The isolated bacterial strain was identified morphologically, biochemically, and on the basis of 16S rRNA gene sequence. The isolate decolorized 97 % of C.I. Acid Red 1 (Acid RED G) at the concentration of 200 mg/l within 6 h under optimum static conditions (temperature -35 °C, pH 8, and initial cell concentration 7 × 10(7) cell/ml). Drastic reduction in dye degradation rate was observed beyond initial dye concentration from 500 mg/l (90 %), and it reaches to 25 % at 1000 mg/l under same set of conditions. The analysis related to decolorization and degradation was done using UV-Vis spectrophotometer, HPLC, and FTIR, whereas the GC-MS technique was utilized for the identification of degradation products. Phytotoxicity analysis revealed that degradation products are less toxic as compared to the original dye.

  16. Decolorization of azo dye C.I. Reactive Black 5 by ozonation in aqueous solution: influencing factors, degradation products, reaction pathway and toxicity assessment. (United States)

    Zheng, Qing; Dai, Yong; Han, Xiangyun


    In this study, ozonation treatment of C.I. Reactive Black 5 (RB5) was investigated at various operating parameters. The results showed that the aqueous solution initially containing 200 mg/L RB5 was quickly decolorized at pH 8.0 with an ozone dose of 3.2 g/h. Reaction intermediates with m/z 281, 546, 201, 350, 286 and 222 were elucidated using liquid chromatography-mass spectrometry, while sulfate ion, nitrate ion and three carboxylic acids (i.e., oxalic acid, formic acid, and acetic acid) were identified by ion exchange chromatography. Thus, the cleavage of the azo bond and the introduction of OH groups in the corresponding positions were proposed as the predominant reaction pathway. The detachment of sulfonic groups was also commonly observed during the ozonation treatment. The proposed degradation mechanism was confirmed by frontier electron density calculations, suggesting the feasibility of predicting the major events in the whole ozonation process with the computational method. Compared with RB5 degradation, the reduction of total organic carbon (TOC) proceeded much more slowly, and approximately 54% TOC was removed after 4 h of ozonation. Acute toxicity tests with Photobacterium phosphoreum showed that the toxicity of reaction solution was firstly increased and then decreased to a negligible level after 160 min.

  17. Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice. (United States)

    Chan, Elizabeth S; Chen, Christopher; Cole, Gregory M; Wong, Boon-Seng


    It is unclear how human apolipoprotein E4 (ApoE4) increases the risk for Alzheimer's disease (AD). Although Aβ levels can lead to insulin signaling impairment, these experiments were done in the absence of human ApoE. To examine ApoE role, we crossed the human ApoE-targeted replacement mice with mutant human amyloid precursor protein (APP) mice. In 26 week old mice with lower Aβ levels, the expression and phosphorylation of insulin signaling proteins remained comparable among APP, ApoE3xAPP and ApoE4xAPP mouse brains. When the mice aged to 78 weeks, these proteins were markedly reduced in APP and ApoE4xAPP mouse brains. While Aβ can bind to insulin receptor, how ApoE isoforms modulate this interaction remains unknown. Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration. In contrast, ApoE4 bound more Aβ42 with increasing peptide levels. Using primary hippocampal neurons, we showed that ApoE3 and ApoE4 neurons are equally sensitive to physiological levels of insulin. However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons. Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

  18. Carbon Abundances of Three Carbon-Enhanced Metal-Poor Stars from High-Resolution Gemini-S/bHROS Spectra of the 8727A [C I] Line

    CERN Document Server

    Schuler, S C; Sivarani, T; Asplund, M; Smith, V V; Cunha, K; Beers, T C


    We present the results from an analysis of the 8727ang forbidden [C I] line in high-resolution Gemini-S/bHROS spectra of three CEMP stars. We find the [C/Fe] ratios based on the [C I] abundances of the two most Fe-rich stars in our sample (HIP 0507-1653: [Fe/H] = -1.42 and HIP 0054-2542: [Fe/H] = -2.66) to be in good agreement with previously determined CH and C_2 line-based values. For the most Fe-deficient star in our sample (HIP 1005-1439: [Fe/H] = -3.08), however, the [C/Fe] ratio is found to be 0.34 dex lower than the published molecular-based value. We have carried out 3D local thermodynamic equilibrium (LTE) calculations for [C I], and the resulting corrections are found to be modest for all three stars, suggesting that the discrepancy between the [C I] and molecular-based C abundances of HIP 1005-1439 is due to more severe 3D effects on the molecular lines. Carbon abundances are also derived from C I high-excitation lines and are found to be 0.45-0.64 dex higher than the [C I]-based abundances. Previo...

  19. Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E. (United States)

    Nathoo, N; Chetty, R; van Dellen, J R; Barnett, G H


    Apolipoprotein E (APOE) is thought to be responsible for the transportation of lipids within the brain, maintaining structural integrity of the microtubule within the neurone, and assisting with neural transmission. Possession of the APOE epsilon4 allele has also been shown to influence neuropathological findings in patients who die from traumatic brain injury, including the accumulation of amyloid beta protein. Previous clinical studies reporting varying outcome severities of traumatic brain injury, including cognitive and functional recovery, all support the notion that APOE epsilon4 allele possession is associated with an unfavourable outcome. Evidence from experimental and clinical brain injury studies confirms that APOE plays an important role in the response of the brain to injury.

  20. Study on relationship of apolipoprotein E gene polymorphism and genetic susceptibility of stress urinary incontinence

    Institute of Scientific and Technical Information of China (English)

    Tong Jia-li; Lang Jing-he; Zhu lan


    Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility of stress urinary incontinence (SUI).Methods: ApoE genotypes were examined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) technique in 99 patients with SUI and 101 asymptomatic controls. Results: The frequency of allele e3 of ApoE was slightly lower in patients with anatomic SUI than that in controls (79.44% vs. 81.68%), while the frequency of allele e4 of ApoE was slightly higher in patients with anatomic SUI than that in controls (10.00% vs. 9.90%). No significant difference was found in frequency of allele e3 or e4 between SUI patients and controls (χ2=0.523, P=0.770).Conclusion: The gene polymorphism of ApoE is not independently involved in the development of SUI.

  1. Apolipoprotein E gene polymorphism in cerebrovascular diseases of the Chinese Naxi populations from Yunnan province

    Institute of Scientific and Technical Information of China (English)

    Hong Xu; Qihong Yuan; Xijun Fan; Guoqiang He


    Currently it is not well known whether apolipoprotein E (ApoE) is a genetic susceptibility factor for cerebrovascular diseases in the Chinese Naxi population. The present study detected and sequenced ApoE polymorphisms of 90 patients with cerebrovascular diseases (58 cases of cerebral infarction and 32 cases of intracerebral hemorrhage), and 50 normal people of Naxi nationality from Yunnan province, China. The populations were used to analyze the relationship of ApoE polymorphisms with cerebral infarction and intracerebral hemorrhage. Results showed an association between ApoE gene polymorphism and the onset of cerebral infarction, and a possibility that the ε4 allele is a susceptibility locus for the risk of cerebral infarction. However, there was no evidence of a relationship between the ApoE gene polymorphism and cerebral hemorrhage.

  2. Plasma levels of apolipoprotein E and risk of dementia in the general population

    DEFF Research Database (Denmark)

    Rasmussen, Katrine L.; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G;


    whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype. RESULTS: Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia......OBJECTIVE: The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis. METHODS: Using 75,708 participants from the general population, we tested...... increased from the highest to the lowest apoE tertile (p for trends dementia, respectively. After further...

  3. Parental vitamin deficiency affects the embryonic gene expression of immune-, lipid transport- and apolipoprotein genes (United States)

    Skjærven, Kaja H.; Jakt, Lars Martin; Dahl, John Arne; Espe, Marit; Aanes, Håvard; Hamre, Kristin; Fernandes, Jorge M. O.


    World Health Organization is concerned for parental vitamin deficiency and its effect on offspring health. This study examines the effect of a marginally dietary-induced parental one carbon (1-C) micronutrient deficiency on embryonic gene expression using zebrafish. Metabolic profiling revealed a reduced 1-C cycle efficiency in F0 generation. Parental deficiency reduced the fecundity and a total of 364 genes were differentially expressed in the F1 embryos. The upregulated genes (53%) in the deficient group were enriched in biological processes such as immune response and blood coagulation. Several genes encoding enzymes essential for the 1-C cycle and for lipid transport (especially apolipoproteins) were aberrantly expressed. We show that a parental diet deficient in micronutrients disturbs the expression in descendant embryos of genes associated with overall health, and result in inherited aberrations in the 1-C cycle and lipid metabolism. This emphasises the importance of parental micronutrient status for the health of the offspring.

  4. Serum apolipoproteins in relation to intakes of fish in population of Arkhangelsk County

    Directory of Open Access Journals (Sweden)

    Petrenya Natalia


    Full Text Available Abstract Background Diets rich in omega-3 fatty acids and low in saturated fat were found beneficially associated with blood lipids and cardio-vascular health. Lean reindeer meet and local cold water white-fish species high in omega-3 are among the main sources of nutrients in the rural area of the Nenets Autonomous Okrug (NAO in Russia and are not normally consumed by the urban population from the same region. The aims of the study were firstly, to compare serum lipid profiles of residents of urban (Arkhangelsk city and rural (NAO regions of Arkhangelsk County, and secondly, to investigate the effects of fish consumption on the predictor of cardiovascular events apolipoprotein (Apo B/ApoA-I ratio in these populations. Methods A cross-sectional study conducted in Arkhangelsk County, Russia. Sample size of 249 adults: 132 subjects from Arkhangelsk city, aged 21–70 and 117 subject (87% Ethnic Nenets from NAO, aged 18–69. Results We observed more favorable lipid levels in NAO compared to Arkhangelsk participants. Age-adjusted geometric means of ApoB/ApoA-I ratio were 1.02 and 0.98 in men and women from Arkhangelsk; 0.84 and 0.91 in men and women from NAO respectively. Age and consumption of animal fat were positively associated with ApoB/ApoA-I ratio in women (pooled samples from Arkhangelsk and NAO. Body mass index and low levels of physical activity were positively associated with ApoB/ApoA-I ratio in men (pooled samples from Arkhangelsk and NAO. Reported oily fish consumption was not significantly correlated with ApoB/ApoA-I ratio. Conclusion The population sample from rural NAO, consisting largely of the indigenous Arctic population Nenets with healthier dietary sources, had a relatively less atherogenic lipid profile compared to the urban Arkhangelsk group. Fish consumption had no effect on apolipoproteins profile.

  5. Comparison of Serum Apolipoprotein Levels of Diabetic Children and Healthy Children with or without Diabetic Parents

    Directory of Open Access Journals (Sweden)

    Mohammad Hashemi


    Full Text Available Introduction. The association of diabetes and atherosclerosis with disorders of lipids and lipoproteins, notably high apolipoprotein B (apoB and low apolipoprotein A1(apoA1 is well established. Because of the beginning of the atherosclerosis' process from early life, in this study, the plasma levels of apoA1 and apoB were compared in diabetic children with type I diabetes mellitus(DM, healthy children with diabetic parents (HDPs,and healthy children with nondiabetic parents (HNDPs. Methods. This case-control study was conducted among 90 children aged 9–18 years. Serum levels of apoA and apoB were compared among 30 diabetic children (DM, 30 healthy children with diabetic parents (HDPs, and 30 healthy children with nondiabetic parents (HNDP. Results. The mean serum apoA1 was higher in DM (153±69 mg/dL followed by HNDPs (138±58 mg/dL and HDPs (128±56 mg/dl, but the difference was not statistically significant. The mean apoB value in HNDPs was significantly lower than DM and HDPs (90±21 mg/dL versus 127±47 and 128±38 mg/dL, P0.05. Conclusions. Diabetic children and healthy children with diabetic parent(s are at higher risk of dyslipidemia and atherosclerosis. Thus for primordial and primary prevention of atherosclerosis, we suggest screening these children for low plasma apoA1 and high plasma apoB levels.

  6. Secretion of hepatitis C virus envelope glycoproteins depends on assembly of apolipoprotein B positive lipoproteins.

    Directory of Open Access Journals (Sweden)

    Vinca Icard

    Full Text Available The density of circulating hepatitis C virus (HCV particles in the blood of chronically infected patients is very heterogeneous. The very low density of some particles has been attributed to an association of the virus with apolipoprotein B (apoB positive and triglyceride rich lipoproteins (TRL likely resulting in hybrid lipoproteins known as lipo-viro-particles (LVP containing the viral envelope glycoproteins E1 and E2, capsid and viral RNA. The specific infectivity of these particles has been shown to be higher than the infectivity of particles of higher density. The nature of the association of HCV particles with lipoproteins remains elusive and the role of apolipoproteins in the synthesis and assembly of the viral particles is unknown. The human intestinal Caco-2 cell line differentiates in vitro into polarized and apoB secreting cells during asymmetric culture on porous filters. By using this cell culture system, cells stably expressing E1 and E2 secreted the glycoproteins into the basal culture medium after one week of differentiation concomitantly with TRL secretion. Secreted glycoproteins were only detected in apoB containing density fractions. The E1-E2 and apoB containing particles were unique complexes bearing the envelope glycoproteins at their surface since apoB could be co-immunoprecipitated with E2-specific antibodies. Envelope protein secretion was reduced by inhibiting the lipidation of apoB with an inhibitor of the microsomal triglyceride transfer protein. HCV glycoproteins were similarly secreted in association with TRL from the human liver cell line HepG2 but not by Huh-7 and Huh-7.5 hepatoma cells that proved deficient for lipoprotein assembly. These data indicate that HCV envelope glycoproteins have the intrinsic capacity to utilize apoB synthesis and lipoprotein assembly machinery even in the absence of the other HCV proteins. A model for LVP assembly is proposed.

  7. Apolipoprotein E alleles in Alzheimer`s and Parkinson`s patients

    Energy Technology Data Exchange (ETDEWEB)

    Poduslo, S.E. [Texas Tech Univ., Lubbock, TX (United States); Schwankhaus, J.D. [Department of Veterans Affairs, Lubbock, TX (United States)


    A number of investigators have found an association between the apolipoprotein E4 allele and Alzheimer`s disease. The E4 allele appears at a higher frequency in late onset familial Alzheimer`s patients. In our studies we obtained blood samples from early and late onset familial and sporadic Alzheimer`s patients and spouses, as well as from Parkinson`s patients. The patients were diagnosed as probable Alzheimer`s patients after a neurological examination, extensive blood work, and a CAT scan. The diagnosis was made according to the NINCDS-ADRDA criteria. The apolipoprotein E4 polymorphism was detected after PCR amplification of genomic DNA, restriction enzyme digestion with Hhal, and polyacrylamide gel electrophoresis. Ethidium bromide-stained bands at 91 bp were designated as allele 3, at 83 bp as allele 2, and at 72 bp as allele 4. Of the 84 probable Alzheimer`s patients (all of whom were Caucasian), 47 were heterozygous and 13 were homozygous for the E4 allele. There were 26 early onset patients; 13 were heterozygous and 7 homozygous for the E4 allele. The frequencies for the E4 allele for late onset familial patients was 0.45 and for sporadic patients was 0.37. We analyzed 77 spouses with an average age of 71.9 {plus_minus} 7.4 years as controls, and 15 were heterozygous for the E4 allele for an E4 frequency of 0.097. Of the 53 Parkinson`s patients, 11 had the E4 allele for a frequency of 0.113. Thus our findings support the association of the ApoE4 allele with Alzheimer`s disease.

  8. Tryptophan probes reveal residue-specific phospholipid interactions of apolipoprotein C-III. (United States)

    Pfefferkorn, Candace M; Walker, Robert L; He, Yi; Gruschus, James M; Lee, Jennifer C


    Apolipoproteins are essential human proteins for lipid metabolism. Together with phospholipids, they constitute lipoproteins, nm to μm sized particles responsible for transporting cholesterol and triglycerides throughout the body. To investigate specific protein-lipid interactions, we produced and characterized three single-Trp containing apolipoprotein C-III (ApoCIII) variants (W42 (W54F/W65F), W54 (W42F/W65F), W65 (W42F/W54F)). Upon binding to phospholipid vesicles, wild-type ApoCIII adopts an α-helical conformation (50% helicity) as determined by circular dichroism spectroscopy with an approximate apparent partition constant of 3×10(4) M(-1). Steady-state and time-resolved fluorescence measurements reveal distinct residue-specific behaviors with W54 experiencing the most hydrophobic environment followed by W42 and W65. Interestingly, time-resolved anisotropy measurements show a converse trend for relative Trp mobility with position 54 being the least immobile. To determine the relative insertion depths of W42, W54, and W65 in the bilayer, fluorescence quenching experiments were performed using three different brominated lipids. W65 had a clear preference for residing near the headgroup while W54 and W42 sample the range of depths ~8-11 Å from the bilayer center. On average, W54 is slightly more embedded than W42. Based on Trp spectral differences between ApoCIII binding to phospholipid vesicles and sodium dodecyl sulfate micelles, we suggest that ApoCIII adopts an alternate helical conformation on the bilayer which could have functional implications.

  9. Tissue sites of degradation of high density lipoprotein apolipoprotein A-IV in rats

    Energy Technology Data Exchange (ETDEWEB)

    Dallinga-Thie, G.M.; Van ' t Hooft, F.M.; Van Tol, A.


    The in vivo metabolism of high density lipoprotein (HDL), labeled by incorporation of /sup 125/I-apolipoprotein (apo) A-IV, was studied in the rat and compared with the metabolism of HDL labeled with 131I-apo A-I. The /sup 125/I-apo A-IV labeled HDL was obtained by adding small amounts of radioiodinated apo A-IV to rat serum, followed by separation of the different lipoprotein fractions by chromatography on 6% agarose columns in order to avoid stripping of apolipoproteins by ultracentrifugation. Under both in vitro and in vivo conditions, the /sup 125/I-apo A-IV remained an integral component of HDL and was not exchanged to other lipoproteins, including the free apo A-IV fraction. The serum half-life, measured at between 8 and 28 hours after intravenous injection of labeled HDL, was 8.5 +/- 0.5 hours for HDL apo A-IV and 10.2 +/- 0.7 hours for HDL apo A-I. The tissue sites of catabolism of HDL apo A-IV and HDL apo A-I were analyzed in the leupeptin-model. Only the kidneys and liver showed a significant leupeptin-dependent accumulation of radioactivity. At 4 hours after injection of 125I-apo A-IV/131I-apo A-I labeled HDL, 3.5% +/- 1.0% and 8.4% +/- 2.0% of HDL apo A-IV and 4.6% +/- 1.3% and 2.6% +/- 0.6% of the HDL apo A-I were accumulated in a leupeptin-dependent process in the kidneys and liver, respectively. Immunocytochemical studies revealed that the renal localization of apo A-IV was intracellular and confined to the epithelial cells of the proximal tubuli.

  10. Distribution of apolipoprotein E gene polymorphism in students and in high-educated elderly from Serbia

    Directory of Open Access Journals (Sweden)

    Maksimović Nela


    Full Text Available Apolipoprotein E (ApoE play important role in lipid metabolism and in processes of remodeling and reparation in central nervous system. Three common ApoE isoforms, ApoE2, ApoE3 and ApoE4, show strong genetic determination by ε2, ε3, and ε4 allele. In human genome gene encoding Apolipoprotein E (APOE is located on cromosome 19, and ε2/ε3/ε4 haplotype system is defined by 2 non-synonymous single nucleotide polymorphisms (SNPs in the APOE exon 4. The frequency of the three APOE alleles and corresponding genotypes varies across human populations, with possible clinical implications. At least, variable distribution of ε4 allele may contribute to the regional risk of cardiovascular and Alzheimer’s diseases. Allele-frequency comparisons between younger and older populations suggest an effect of APOE on mortality, but these data are not consistently confirmed. In the present study we have analyzed the distribution of APOE gene polymorphism in a group of University students and retained University professors living in Serbia. After DNA extraction from peripheral blood samples, the APOE genotype was determined by polymerase chain reaction (PCR followed with HhaI restriction digestion. We found no statistically significant difference in alleles and genotypes distribution between younger and elder group of participants. Also, there was no significant difference compared to APOE data previously obtained in YUSAD cohort of healthy school children (15 y of age from different regions of Serbia. In both of our groups, as well as in YUSAD cohort, frequency of APOE ε4 allele was <10%. The observed frequencies are lower than in neighboring countries, but similar with Spanish data and some Asian populations. Our results do not support important role of APOE ε4 in the morbidity and mortality in Serbian population, but gene-environmental-social interactions should be considered. [Projekat Ministarstva nauke Republike Srbije, br. ON175091

  11. A non-invasive, rapid method to genotype late-onset Alzheimer’s disease-related apolipoprotein E gene polymorphisms

    Institute of Scientific and Technical Information of China (English)

    Li Yi; Ting Wu; Wenyuan Luo; Wen Zhou; Jun Wu


    The apolipoprotein E geneε4 allele is considered a negative factor for neural regeneration in late-onset Alzheimer’s disease cases. The aim of this study was to establish a non-invasive, rapid method to genotype apolipoprotein E gene polymorphisms. Genomic DNA from mouth swab specimens was extracted using magnetic nanoparticles, and genotyping was performed by real-time PCR using TaqMan-BHQ probes. Genotyping accuracy was validated by DNA se-quencing. Our results demonstrate 100%correlation to DNA sequencing, indicating reliability of our protocol. Thus, the method we have developed for apolipoprotein E genotyping is accurate and reliable, and also suitable for genotyping large samples, which may help determine the role of the apolipoprotein Eε4 allele in neural regeneration in late-onset Alzheimer’s disease cases.

  12. Proteomic profiling of pretreatment serum from HIV-infected patients identifies candidate markers predictive of lymphoma development

    DEFF Research Database (Denmark)

    Vase, Maja Ølholm; Ludvigsen, Maja; Bendix, Knud;


    Objective: HIV-infected individuals have an increased risk of developing lymphoma. We sought to identify markers predictive of lymphoma development by comparing protein expression patterns in serum obtained at the time of HIV diagnosis from patients who later developed malignant lymphoma or benign...... protein spots were detected. Using principal components analysis, spots containing immunoglobulin J chain, apolipoprotein A-I, procollagen C-endopeptidase enhancer-1 and complement C4-A were associated with lymphoma development (P...

  13. Photocatalytic removal of C.I. Basic Red 46 on immobilized TiO2 nanoparticles: artificial neural network modelling. (United States)

    Khataee, A R


    C.I. Basic Red 46, commonly used as a textile dye, was photocatalytically removed using supported TiO2 nanoparticles irradiated by a 30 W UV-C lamp in a batch reactor. The investigated photocatalyst was industrial Degussa P25 (crystallite mean size 21 nm) immobilized on glass beads by a heat attachment method. The catalyst was characterized by XRD, SEM, TEM and BET techniques. The process of the dye decolorization in the presence of TiO2 nanoparticles was experimentally studied through changing the initial dye concentration, UV light intensity and initial pH. The influence of inorganic anions such as chloride, sulphate, bicarbonate, carbonate and phosphate on the photocatalytic decolorization of BR46 was investigated. The decolorization of BR46 follows the pseudo-first-order kinetic according to the Langmuir-Hinshelwood model (k1 = 0.273 mg L(-1) min(-1), 2 = 0.313 (mg L(-1))(-1)). The efficiency parameters such as apparent quantum yield and electrical energy per order (EEO) were estimated. An artificial neural network model (ANN) was developed to predict the photocatalytic decolorization of BR46 solution. The findings indicated that the ANN provided reasonable predictive performance (R2 = 0.96). The influence of each parameter on the variable studied was assessed: initial concentration of the dye being the most significant factor, followed by the initial pH and reaction time.

  14. Influence of electrochemical reduction and oxidation processes on the decolourisation and degradation of C.I. Reactive Orange 4 solutions. (United States)

    del Río, A I; Molina, J; Bonastre, J; Cases, F


    The electrochemical treatment of wastewaters from textile industry is a promising treatment technique for substances which are resistant to biodegradation. This paper presents the results of the electrochemical decolourisation and degradation of C.I. Reactive Orange 4 synthetic solutions (commercially known as Procion Orange MX2R). Electrolyses were carried out under galvanostatic conditions in a divided or undivided electrolytic cell. Therefore, oxidation, reduction or oxido-reduction experiences were tested. Ti/SnO(2)-Sb-Pt and stainless steel electrodes were used as anode and cathode, respectively. Degradation of the dye was followed by TOC, total nitrogen, COD and BOD(5) analyses. TOC removal after an oxidation process was higher than after oxido-reduction while COD removal after this last process was about 90%. Besides, the biodegradability of final samples after oxido-reduction process was studied and an improvement was observed. UV-Visible spectra revealed the presence of aromatic structures in solution when an electro-reduction was carried out while oxido-reduction process degraded both azo group and aromatic structures. HPLC analyses indicated the presence of a main intermediate after the reduction process with a chemical structure closely similar to 2-amine-1, 5-naphthalenedisulfonic acid. The lowest decolourisation rate corresponded to electrochemical oxidation. In these experiences a higher number of intermediates were generated as HPLC analysis demonstrated. The decolourisation process for the three electrochemical processes studied presented a pseudo-first order kinetics.

  15. Tamarindus indica extract alters release of alpha enolase, apolipoprotein A-I, transthyretin and Rab GDP dissociation inhibitor beta from HepG2 cells.

    Directory of Open Access Journals (Sweden)

    Ursula Rho Wan Chong

    Full Text Available BACKGROUND: The plasma cholesterol and triacylglycerol lowering effects of Tamarindus indica extract have been previously described. We have also shown that the methanol extract of T. indica fruit pulp altered the expression of lipid-associated genes including ABCG5 and APOAI in HepG2 cells. In the present study, effects of the same extract on the release of proteins from the cells were investigated using the proteomics approach. METHODOLOGY/PRINCIPAL FINDINGS: When culture media of HepG2 cells grown in the absence and presence of the methanol extract of T. indica fruit pulp were subjected to 2-dimensional gel electrophoresis, the expression of seven proteins was found to be significantly different (p<0.03125. Five of the spots were subsequently identified as alpha enolase (ENO1, transthyretin (TTR, apolipoprotein A-I (ApoA-I; two isoforms, and rab GDP dissociation inhibitor beta (GDI-2. A functional network of lipid metabolism, molecular transport and small molecule biochemistry that interconnects the three latter proteins with the interactomes was identified using the Ingenuity Pathways Analysis software. CONCLUSION/SIGNIFICANCE: The methanol extract of T. indica fruit pulp altered the release of ENO1, ApoA-I, TTR and GDI-2 from HepG2 cells. Our results provide support on the effect of T. indica extract on cellular lipid metabolism, particularly that of cholesterol.

  16. Apolipoprotein E isoforms 3/3 and 3/4 differentially interact with circulating stearic, palmitic, and oleic fatty acids and lipid levels in Alaskan Natives. (United States)

    Castellanos-Tapia, Lyssia; López-Alvarenga, Juan Carlos; Ebbesson, Sven O E; Ebbesson, Lars O E; Tejero, M Elizabeth


    Lifestyle changes in Alaskan Natives have been related to the increase of cardiovascular disease and metabolic syndrome in the last decades. Variation of the apolipoprotein E (Apo E) genotype may contribute to the diverse response to diet in lipid metabolism and influence the association between fatty acids in plasma and risk factors for cardiovascular disease. The aim of this investigation was to analyze the interaction between Apo E isoforms and plasma fatty acids, influencing phenotypes related to metabolic diseases in Alaskan Natives. A sample of 427 adult Siberian Yupik Alaskan Natives was included. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, Apo A1, and Apo B plasma concentrations were measured using reference methods. Concentrations of 13 fatty acids in fasting plasma were analyzed by gas chromatography, and Apo E variants were identified. Analyses of covariance were conducted to identify Apo E isoform and fatty acid main effects and multiplicative interactions. The means for body mass index and age were 26 ± 5.2 and 47 ± 1.5, respectively. Significant main effects were observed for variation in Apo E and different fatty acids influencing Apo B levels, triglycerides, and total cholesterol. Significant interactions were found between Apo E isoform and selected fatty acids influencing total cholesterol, triglycerides, and Apo B concentrations. In summary, Apo E3/3 and 3/4 isoforms had significant interactions with circulating levels of stearic, palmitic, oleic fatty acids, and phenotypes of lipid metabolism in Alaskan Natives.

  17. Identification of an amino-terminal fragment of apolipoprotein E4 that localizes to neurofibrillary tangles of the Alzheimer's disease brain. (United States)

    Rohn, Troy T; Catlin, Lindsey W; Coonse, Kendra G; Habig, Jeffrey W


    Although the risk factor for harboring the apolipoprotein E4 (apoE4) allele in late-onset Alzheimer's disease (AD) is well known, the mechanism by which apoE4 contributes to AD pathogenesis has yet to be clarified. Preferential cleavage of the ApoE4 isoform relative to other polymorphic forms appears to be significant, as the resulting fragments are associated with hallmarks of AD. To examine the possible role of apoE4 proteolysis in AD, we designed a site-directed antibody directed at position D172, which would yield a predicted amino-terminal fragment previously identified in AD brain extracts. Western blot analysis utilizing this novel antibody, termed the amino-terminal apoE4 cleavage fragment (nApoE4CF) Ab, consistently identified the predicted amino-terminal fragment (∼18kDa) in several commercially available forms of human recombinant apoE4 purified from E. coli. Mass spectrometry confirmed the identity of this 18kDa fragment as being an amino-terminal fragment of apoE4. Immunohistochemical experiments indicated the nApoE4CF Ab specifically labeled neurofibrillary tangles (NFTs) in AD frontal cortex sections that colocalized with the mature tangle marker PHF-1. Taken together, these results suggest a novel cleavage event of apoE4, generating an amino-terminal fragment that localizes within NFTs of the AD brain.

  18. Lifestyle and Dietary Determinants of Serum Apolipoprotein A1 and Apolipoprotein B Concentrations: Cross-Sectional Analyses within a Swedish Cohort of 24,984 Individuals

    Directory of Open Access Journals (Sweden)

    Kasper Frondelius


    Full Text Available Low serum apolipoprotein (Apo A1 concentrations and high serum ApoB concentrations may be better markers of the risk of cardiovascular disease than high-density lipoprotein (HDL and low-density lipoprotein (LDL. However, the associations between modifiable lifestyle factors and Apo concentrations have not been investigated in detail. Therefore, this study investigated the associations between Apo concentrations and education, lifestyle factors and dietary intake (macronutrients and 34 food groups. These cross-sectional associations were examined among 24,984 individuals in a Swedish population-based cohort. Baseline examinations of the cohort were conducted between 1991 and 1996. Dietary intake was assessed using a modified diet history method. The main determinants of high ApoA1 concentrations (r between 0.05 and 0.25 were high alcohol consumption, high physical activity, non-smoking, and a low body mass index (BMI, and the main determinants of high ApoB concentrations were smoking and a high BMI. The intake of sucrose and food products containing added sugar (such as pastries, sweets, chocolate, jam/sugar and sugar-sweetened beverages was negatively correlated with ApoA1 concentrations and positively correlated with ApoB concentrations and the ApoB/ApoA1 ratio, whereas the intake of fermented dairy products, such as fermented milk and cheese, was positively correlated with ApoA1 concentrations and negatively correlated with the ApoB/ApoA1 ratio. These results indicate that smoking, obesity, low physical activity, low alcohol consumption and a diet high in sugar and low in fermented dairy products are correlated with an unfavorable Apo profile.

  19. Apolipoprotein AIF gene variant S347 is associated with increased risk of coronary heart disease and lower apolipoprotein AIV plasma concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Wai-man R.; Hawe, Emma; Li, Lai K.; Miller, George J.; Nicaud, Viviane; Pennacchio, Len A.; Humphries, Steve E.; Talmud, Philippa J.


    The impact of common variants in the apolipoprotein gene cluster (APOC3-A4-A5) on prospective CHD risk was examined in healthy UK men. Of the 2808 men followed over nine years, 187 had a clinically defined CHD event. Examination of 9 single nucleotide polymorphisms (SNPs) in this group revealed that homozygotes for APOA4 S347 had significantly increased risk of CHD [Hazard ratio (HR) of 2.07 (95%CI 1.04-4.12)] while men homozygous for APOC3 1100T were protected (HR 0.28 (95%CI 0.09-0.87)). In stepwise multiple regression analysis, after entering all the variants and adjusting for established risk factors APOA4 T347S alone remained in the model. Using nine-SNP haplotype analysis, highest risk-estimate haplotypes carried APOA4 S347 and rare alleles of the two flanking intergenic markers. The protective effect of APOC31100T could be explained by negative linkage disequilibrium with these alleles. To determine the association of APOA4 T347S with apoAIVlevels, the relationship was examined in over 1600 healthy young European men and women. S347 homozygotes had significantly lower apoAIV plasma levels (13.48 + 0.6mg/dl) compared to carriers of the T347 allele (14.85 + 0.12 mg/dl) (p=0.025). These results demonstrate that genetic variation in and around APOA4, independent of effects of TG, is associated with risk of CHD and apoAIV levels, supporting an anti-atherogenic role for apoAIV.

  20. Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Christie, R.H.; Chung, Haeyong; Rebeck, G.W.; Hyman, B.T. [Massachusetts General Hospital, Boston, MA (United States)] [and others


    The very low density lipoprotein receptor (VLDL-r) is a cell-surface molecule specialized for the internalization of multiple diverse ligands, including apolipoprotein E (apoE)-containing lipoprotein particles, via clathrin-coated pits. Its structure is similar to the low-density lipoprotein receptor (LDL-r), although the two have substantially different systemic distributions and regulatory pathways. The present work examines the distribution of VLDL-r in the central nervous system (CNS) and in relation to senile plaques in Alzheimer disease (AD). VLDL-r is present on resting and activated microglia, particularly those associated with senile plaques (SPs). VLDL-r immunoreactivity is also found in cortical neurons. Two exons of VLDL-r mRNA are differentially spliced in the mature receptor mRNA. One set of splice forms gives rise to receptors containing (or lacking) an extracellular O-linked glycosylation domain near the transmembrane portion of the molecule. The other set of splice forms appears to be brain-specific, and is responsible for the presence or absence of one of the cysteine-rich repeat regions in the binding region of the molecule. Ratios of the receptor variants generated from these splice forms do not differ substantially across different cortical areas or in AD. We hypothesize that VLDL-r might contribute to metabolism of apoE and apoE/A{beta} complexes in the brain. Further characterization of apoE receptors in Alzheimer brain may help lay the groundwork for understanding the role of apoE in the CNS and in the pathophysiology of AD. 43 refs., 5 figs.

  1. Evaluation of antioxidant enzymes activities and identification of intermediate products during phytoremediation of an anionic dye (C.I. Acid Blue 92) by pennywort (Hydrocotyle vulgaris). (United States)

    Vafaei, Fatemeh; Movafeghi, Ali; Khataee, Alireza


    The potential of pennywort (Hydrocotyle vulgaris) for phytoremediation of C.I. Acid Blue 92 (AB92) was evaluated. The effects of various experimental parameters including pH, temperature, dye concentration and plant weight on dye removal efficiency were investigated. The results showed that the optimal condition for dye removal were pH 3.5 and temperature 25 degree C. Moreover, the absolute dye removal enhanced with increase in the initial dye concentration and plant weight. Pennywort showed the same removal efficiency in repeated experiments (four runs) as that obtained from the first run (a 6-day period). Therefore, the ability of the plant in consecutive removal of AB92 confirmed the biodegradation process. Accordingly, a number of produced intermediate compounds were identified. The effect of treatment on photosynthesis and antioxidant defense system including superoxide dismutase, peroxidase and catalase in plant roots and leaves were evaluated. The results revealed a reduction in photosynthetic pigments content under dye treatments. Antioxidant enzyme responses showed marked variations with respect to the plant organ and dye concentration in the liquid medium. Overall, the increase in antioxidant enzyme activity under AB92 stress in the roots was much higher than that in the leaves. Nevertheless, no significant increase in malondialdehyde content was detected in roots or leaves, implying that the high efficiency of antioxidant system in the elimination of reactive oxygen species. Based on these results, pennywort was founded to be a capable species for phytoremediation of AB92-contaminated water, may be effective for phytoremediation dye-contaminated polluted aquatic ecosystems.

  2. Effect of air plasma treatment on the dyeing of Tencel fabric with C.I. Reactive Black 5 (United States)

    Zhang, L. S.; Liu, H. L.; Yu, W. D.


    The Tencel fabrics were treated by the atmospheric pressure plasma with air for different length of time and dyed with the C.I. Reactive Black 5 at 1%, 5% and 10% o.m.f. The effect of the prolonged plasma treatment time was characterized by both the weight loss and the whiteness index analyses, which implied that with the increase of the plasma treatment time, the treated fabrics were lighter and yellower than the untreated ones. The contact angle decreased dramatically from 139° to instantly spread. The results of SEM showed that, with the prolonged treatment time, more significant crater-like surface morphology on the fiber of Tencel samples was formed. Compared with untreated samples, the values of dye bath exhaustion and total fixation effect were higher. But they did not increase with the prolonged plasma treatment time. With the prolonged storage time after the plasma treatment, the result to ageing effect indicated that the values of dye bath exhaustion and total fixation effect reduced. The Integ values for characterizing the coloring effect were evaluated by the CIE system of color measurement. In most cases, the Integ values reached the highest ones when the plasma treatment time was 10 or 20 min. When the concentration of the dye bath was low (at 1% o.m.f.), the longer plasma treatment time was, the higher the Integ value was. However, if the fabrics after plasma treatment were stored for 21 days, the longer plasma treatment time did not cause the larger Integ value. When the concentration was 1%, the Integ value increased with the weight loss increasing, which was different from the values of fabrics with 5% and 10% concentration. If the dyeing concentration was low, the fixation had a more significant effect on the color fastness to wet rubbing; in contrast, if the dyeing concentration was high, the surface roughness had a more important effect on it.

  3. Solid lipid nanoparticles as a vehicle for brain-targeted drug delivery: two new strategies of functionalization with apolipoprotein E (United States)

    Rute Neves, Ana; Fontes Queiroz, Joana; Weksler, Babette; Romero, Ignacio A.; Couraud, Pierre-Olivier; Reis, Salette


    Nanotechnology can be an important tool to improve the permeability of some drugs for the blood-brain barrier. In this work we created a new system to enter the brain by functionalizing solid lipid nanoparticles with apolipoprotein E, aiming to enhance their binding to low-density lipoprotein receptors on the blood-brain barrier endothelial cells. Solid lipid nanoparticles were successfully functionalized with apolipoprotein E using two distinct strategies that took advantage of the strong interaction between biotin and avidin. Transmission electron microscopy images revealed spherical nanoparticles, and dynamic light scattering gave a Z-average under 200 nm, a polydispersity index below 0.2, and a zeta potential between -10 mV and -15 mV. The functionalization of solid lipid nanoparticles with apolipoprotein E was demonstrated by infrared spectroscopy and fluorimetric assays. In vitro cytotoxic effects were evaluated by MTT and LDH assays in the human cerebral microvascular endothelial cells (hCMEC/D3) cell line, a human blood-brain barrier model, and revealed no toxicity up to 1.5 mg ml-1 over 4 h of incubation. The brain permeability was evaluated in transwell devices with hCMEC/D3 monolayers, and a 1.5-fold increment in barrier transit was verified for functionalized nanoparticles when compared with non-functionalized ones. The results suggested that these novel apolipoprotein E-functionalized nanoparticles resulted in dynamic stable systems capable of being used for an improved and specialized brain delivery of drugs through the blood-brain barrier.

  4. The apolipoprotein E epsilon4-allele and antihypertensive treatment are associated with increased risk of cerebral MRI white matter hyperintensities

    DEFF Research Database (Denmark)

    Høgh, P; Garde, Ellen; Mortensen, Erik Lykke;


    OBJECTIVE: Apolipoprotein E-epsilon4 (APOE-epsilon4) is a potential risk factor for cerebral vascular disease. The aim of the present study was to examine the relative importance of APOE-epsilon4 and other relevant risk factors for the extent of cerebral white matter hyperintensity (WMH...... the relative importance of the potential risk factors. RESULTS: APOE genotype and antihypertensive treatment were significantly associated with severity of total WMH load (P epsilon4 and WMH. Pharmaceutical treatment for arterial...

  5. Apolipoprotein E4 (1–272 fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells

    Directory of Open Access Journals (Sweden)

    Michikawa Makoto


    Full Text Available Abstract Background Apolipoprotein E allele ε4 (apoE4 is a strong risk factor for developing Alzheimer's disease (AD. Secreted apoE has a critical function in redistributing lipids among central nervous system cells to maintain normal lipid homeostasis. In addition, previous reports have shown that apoE4 is cleaved by a protease in neurons to generate apoE4(1–272 fragment, which is associated with neurofibrillary tanglelike structures and mitochondria, causing mitochondrial dysfunction. However, it still remains unclear how the apoE fragment associates with mitochondria and induces mitochondrial dysfunction. Results To clarify the molecular mechanism, we carried out experiments to identify intracellular apoE-binding molecules and their functions in modulating mitochondria function. Here, we found that apoE4 binds to ubiquinol cytochrome c reductase core protein 2 (UQCRC2 and cytochrome C1, both of which are components of mitochondrial respiratory complex III, and cytochrome c oxidase subunit 4 isoform 1 (COX IV 1, which is a component of complex IV, in Neuro-2a cells. Interestingly, these proteins associated with apoE4(1–272 more strongly than intact apoE4(1–299. Further analysis showed that in Neuro-2a cells expressing apoE4(1–272, the enzymatic activities of mitochondrial respiratory complexes III and IV were significantly lower than those in Neuro-2a cells expressing apoE4(1–299. Conclusion ApoE4(1–272 fragment expressed in Neuro2a cells is associated with mitochondrial proteins, UQCRC2 and cytochrome C1, which are component of respiratory complex III, and with COX IV 1, which is a member of complex IV. Overexpression of apoE4(1–272 fragment impairs activities of complex III and IV. These results suggest that the C-terminal-truncated fragment of apoE4 binds to mitochondrial complexes and affects their activities, and thereby leading to neurodegeneration.

  6. Association of apolipoprotein E gene polymorphism with small-vessel lesions and stroke type in moyamoya disease: a preliminary study. (United States)

    Jang, Dong-Kyu; Huh, Pil Woo; Lee, Kwan-Sung


    OBJECT The present study was conducted to investigate whether microbleeds or microinfarcts are associated with apolipoprotein E (APOE) gene polymorphisms in patients with moyamoya disease (MMD), and if so, whetherAPOE gene polymorphisms are also associated with stroke type in patients with MMD. METHODS This cross-sectional, multicenter study included 86 consecutive patients with MMD who underwent T2*-weighted gradient echo or susceptibility-weighted MR imaging and 83 healthy control volunteers. Baseline clinical and radiological characteristics were recorded at diagnosis, and inter- and intragroup differences in the APOE genotypes were assessed. Multivariate binary logistic regression models were used to determine the association factors for small-vessel lesions (SVLs) and hemorrhagic presentation in patients with MMD. RESULTS There was no difference in APOE gene polymorphism and the incidence of SVLs between patients with MMD and healthy controls (p > 0.05). In the MMD group, 7 (8.1%) patients had microbleeds and 32 (37.2%) patients had microinfarcts. Microbleeds were more frequently identified in patients with hemorrhagic-type than in nonhemorrhagictype MMD (p = 0.003). APOE genotypes differed according to the presence of microbleeds (p = 0.024). APOE ε2 or ε4 carriers also experienced microbleeds more frequently than APOE ε3/ε3 carriers (p = 0.013). In the multivariate regression analysis in patients with MMD, microbleeds were significantly related to APOE ε2 or ε4 carrier status (OR 7.86; 95% CI1.20-51.62; p = 0.032) and cerebral aneurysm (OR 17.31; 95% CI 2.09-143.57; p = 0.008). Microinfarcts were independently associated with hypertension (OR 3.01; 95% CI 1.05-7.86; p = 0.007). Hemorrhagic presentation was markedly associated with microbleeds (OR 10.63; 95% CI 1.11-102.0; p = 0.041). CONCLUSIONS These preliminary results did not show a difference in APOE gene polymorphisms between patients with MMD and healthy persons. However, they imply that APOE

  7. Dihydrotestosterone regulating apolipoprotein M expression mediates via protein kinase C in HepG2 cells

    Directory of Open Access Journals (Sweden)

    Yi-zhou Ye


    Full Text Available Abstract Background Administration of androgens decreases plasma concentrations of high-density lipid cholesterol (HDL-C. However, the mechanisms by which androgens mediate lipid metabolism remain unknown. This present study used HepG2 cell cultures and ovariectomized C57BL/6 J mice to determine whether apolipoprotein M (ApoM, a constituent of HDL, was affected by dihydrotestosterone (DHT. Methods HepG2 cells were cultured in the presence of either DHT, agonist of protein kinase C (PKC, phorbol-12-myristate-13-acetate (PMA, blocker of androgen receptor flutamide together with different concentrations of DHT, or DHT together with staurosporine at different concentrations for 24 hrs. Ovariectomized C57BL/6 J mice were treated with DHT or vehicle for 7d or 14d and the levels of plasma ApoM and livers ApoM mRNA were measured. The mRNA levels of ApoM, ApoAI were determined by real-time RT-PCR. ApoM and ApoAI were determined by western blotting analysis. Results Addition of DHT to cell culture medium selectively down-regulated ApoM mRNA expression and ApoM secretion in a dose-dependent manner. At 10 nM DHT, the ApoM mRNA levels were about 20% lower than in untreated cells and about 40% lower at 1000 nM DHT than in the control cells. The secretion of ApoM into the medium was reduced to a similar extent. The inhibitory effect of DHT on ApoM secretion was not blocked by the classical androgen receptor blocker flutamide but by an antagonist of PKC, Staurosporine. Agonist of PKC, PMA, also reduced ApoM. At 0.5 μM PMA, the ApoM mRNA levels and the secretion of ApoM into the medium were about 30% lower than in the control cells. The mRNA expression levels and secretion of another HDL-associated apolipoprotein AI (ApoAI were not affected by DHT. The levels of plasma ApoM and liver ApoM mRNA of DHT-treated C57BL/6 J mice were lower than those of vehicle-treated mice. Conclusions DHT directly and selectively down-regulated the level of ApoM mRNA and the

  8. Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice. (United States)

    Dolejší, Eva; Liraz, Ori; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; Michaelson, Daniel M


    Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Evoked ACh release from hippocampal and cortical slices is similar in 4-month-old apoE4 and apoE3 mice but is specifically and significantly reduced in hippocampus, but not cortex, of 12-month-old apoE4 mice. This effect is accompanied by decreased VAChT levels. These findings show that

  9. Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development (United States)

    Mei, Xiaohu; Atkinson, David


    Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1–184] forms a helix bundle while the C-terminal domain [185–243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three intermediate states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain. PMID:26048453

  10. ApolipoproteinE ε4 allelic variant, cognitive decline and psychosis in Alzheimer disease: a review of the literature and suggestions for upcoming studies

    Directory of Open Access Journals (Sweden)

    Ilaria Spoletini


    Full Text Available Apolipoprotein E (ApoE ε4 allele represents a well known vascular risk factor for developing Alzheimer disease (AD and differences in ApoE genotypes may explain a part of the variability in AD phenotypes. In fact, ApoE ε4 allele possession seems to be associated with a more precocious age of onset, greater episodic memory impairment, and psychotic symptoms. The first question we discuss regards the role of ApoE ε4 on cognitive progression of AD. In fact, while a general agreement exists about the role played by ApoE ε4 on the precocious onset of AD, cognitive decline has been differently associated with ApoE ε4 allele possession in AD patients in a continuum of faster decline, no effect, and slower decline. An attemptable interpretation is that the biological processes leading to the onset of AD are different from those involved in determining its clinical course. The second question regards the possible relationship between the presence of the degenerative pathological hallmarks of the disease in specific cerebral areas and different cognitive or behavioural symptoms. In fact, there is evidence that degenerative pathology in hippocampal formation and frontal cortex reflects the progression of cognitive deficits in brain aging and AD and that hypometabolism in right frontal lobe and greater frontal neuropsychological deficits occur in AD patients with psychosis in comparison to those without. The third question regards, specifically, the relationship between ApoE ε4 variant and behavioural symptoms. In fact, there is evidence supporting the link between being carriers of ApoE ε4 allele and severity of delusions, mostly at the early stage of the illness. In an interpretative challenge, we suggest that the link between being carriers of ApoE ε4 allele and suffering from delusions in AD may be explained by frontal lobe dysfunctions. Finally, we hypothesize that the most precocious onset of AD illness, described in carriers of ApoE ε4

  11. The modulation of endoplasmic reticulum stress by chemical chaperone upregulates immune negative cytokine IL-35 in apolipoprotein E-deficient mice. (United States)

    Wang, Bo; Dai, Shen; Dong, Zhaojing; Sun, Yue; Song, Xingguo; Guo, Chun; Zhu, Faliang; Wang, Qun; Zhang, Lining


    Interleukin (IL)-35 is a newly identified immune negative molecule which is secreted by CD4(+)Foxp3(+) T regulatory cells (Tregs) and contributes to their suppressive capacity. Early data have shown that IL-35 inhibits development of several autoimmune diseases. However, the role of IL-35 in atherosclerosis, a lipid-driven chronic inflammatory disease in arterial wall, remains to be investigated. Here, we found that IL-35 was involved in atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. ApoE(-/-) mice with established atherosclerotic lesion displayed a lower level of IL-35 compared to age-matched wild type C57BL/6 mice without plaque. However, IL-35 expression increased significantly in ApoE(-/-) mice with attenuated plaque. More importantly, we found that modulation of ER stress treated by chemical chaperone, 4-Phenyl butyric acid (PBA) in vivo, mainly upregulated immune negative regulating molecule IL-35, as well as IL-10 and Foxp3, accompanied by increased Tregs. However, no obvious impact on pro-inflammatory molecules such as TNF-α, IFN-γ, IL-17 and IL-23 was observed, which provides new insight into the benefit of ER stress recovery from attenuated plaque. Our results suggest that IL-35 might have a potential value for atherosclerotic therapy.

  12. Increased sensitivity of apolipoprotein E knockout mice to copper-induced oxidative injury to the liver. (United States)

    Chen, Yuan; Li, Bin; Zhao, Ran-ran; Zhang, Hui-feng; Zhen, Chao; Guo, Li


    Apolipoprotein E (ApoE) genotypes are related to clinical presentations in patients with Wilson's disease, indicating that ApoE may play an important role in the disease. However, our understanding of the role of ApoE in Wilson's disease is limited. High copper concentration in Wilson's disease induces excessive generation of free oxygen radicals. Meanwhile, ApoE proteins possess antioxidant effects. We therefore determined whether copper-induced oxidative damage differ in the liver of wild-type and ApoE knockout (ApoE(-/-)) mice. Both wild-type and ApoE(-/-) mice were intragastrically administered with 0.2 mL of copper sulfate pentahydrate (200 mg/kg; a total dose of 4 mg/d) or the same volume of saline daily for 12 weeks, respectively. Copper and oxidative stress markers in the liver tissue and in the serum were assessed. Our results showed that, compared with the wild-type mice administered with copper, TBARS as a marker of lipid peroxidation, the expression of oxygenase-1 (HO-1), NAD(P)H dehydrogenase, and quinone 1 (NQO1) significantly increased in the ApoE(-/-) mice administered with copper, meanwhile superoxide dismutase (SOD) activity significantly decreased. Thus, it is concluded that ApoE may protect the liver from copper-induced oxidative damage in Wilson's disease.

  13. Effects of Simvastatin on adiponectin and endothelial function in apolipoprotein E-deficient mice

    Institute of Scientific and Technical Information of China (English)

    Meng Liu; Donghua Yin; Ming Gui; Kejiang Cao


    0bjective:To investigate the effects of simvastatin,a 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor,on adiponectin and markers of endothelial function in apolipoprotein E-deficient mice at an early stage of atherosclerosis.Methods:Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups:control group(normal saline) and treatment group[simvastatin(5 mg/(kg·d)].Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 4 weeks.Total cholesterol(TC),superoxide dismutase(SOD),malondialdehyde (MDA),and nitric oxide(NO) were measured by biochemical analysis,and adiponectin was measured by an ABC-ELISA method.Results:There was no significant difference in serum TC between control and treatment groups.Compared with the control animals,simvastafin-treated animals exhibited a significant increase in serurn levels of adponectin,SOD and NO,and decrease in serum MDA(P <0.01).Conclusion:Simvastatin protects endothelial function by increasing serum adiponectin,which may increase serum SOD and NO,and decrease serum MDA.This study suggests that sirnvastatin has therapeutic advantages,unrelated to its cholesterol-lowering effect,that are mediated by adiponectin.

  14. Nanoparticle charge-transfer interactions induce surface dependent conformational changes in apolipoprotein biocorona

    CERN Document Server

    Raghavendra, Achyut J; Brown, Jared M; Podilaa, Ramakrishna


    Upon introduction into a biological system, engineered nanomaterials (ENMs) rapidly associate with a variety of biomolecules such as proteins and lipids to form a biocorona. The presence of biocorona influences nano-bio interactions considerably, and could ultimately result in altered biological responses. Apolipoprotein A-I (ApoA-I), the major constituent of high-density lipoprotein (HDL), is one of the most prevalent proteins found in ENM-biocorona irrespective of ENM nature, size, and shape. Given the importance of ApoA-I in HDL and cholesterol transport, it is necessary to understand the mechanisms of ApoA-I adsorption and the associated structural changes for assessing consequences of ENM exposure. Here, we used a comprehensive array of microscopic and spectroscopic tools to elucidate the interactions between ApoA-I and 100 nm Ag nanoparticles (AgNPs) with four different surface functional groups. We found that the protein adsorption and secondary structural changes are highly dependent on the surface fu...

  15. Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice

    Directory of Open Access Journals (Sweden)

    Montine Thomas J


    Full Text Available Abstract Background Inheritance of the three different alleles of the human apolipoprotein (apo E gene (APOE are associated with varying risk or clinical outcome from a variety of neurologic diseases. ApoE isoform-specific modulation of several pathogenic processes, in addition to amyloid β metabolism in Alzheimer's disease, have been proposed: one of these is innate immune response by glia. Previously we have shown that primary microglia cultures from targeted replacement (TR APOE mice have apoE isoform-dependent innate immune activation and paracrine damage to neurons that is greatest with TR by the ε4 allele (TR APOE4 and that derives from p38 mitogen-activated protein kinase (p38MAPK activity. Methods Primary cultures of TR APOE2, TR APOE3 and TR APOE4 astrocytes were stimulated with lipopolysaccharide (LPS. ApoE secretion, cytokine production, and nuclear factor-kappa B (NF-κB subunit activity were measured and compared. Results Here we showed that activation of primary astrocytes from TR APOE mice with LPS led to TR APOE-dependent differences in cytokine secretion that were greatest in TR APOE2 and that were associated with differences in NF-κB subunit activity. Conclusion Our results suggest that LPS activation of innate immune response in TR APOE glia results in opposing outcomes from microglia and astrocytes as a result of TR APOE-dependent activation of p38MAPK or NF-κB signaling in these two cell types.

  16. Anti-atherogenic peptide Ep1.B derived from apolipoprotein E induces tolerogenic plasmacytoid dendritic cells. (United States)

    Bellemore, S M; Nikoopour, E; Au, B C Y; Krougly, O; Lee-Chan, E; Haeryfar, S M; Singh, B


    Tolerogenic dendritic cells (DCs) play a critical role in the induction of regulatory T cells (Tregs ), which in turn suppress effector T cell responses. We have previously shown the induction of DCs from human and mouse monocytic cell lines, mouse splenocytes and human peripheral blood monocytes by a novel apolipoprotein E (ApoE)-derived self-peptide termed Ep1.B. We also showed that this C-terminal region 239-252 peptide of ApoE has strong anti-atherogenic activity and reduces neointimal hyperplasia after vascular surgery in rats and wild-type as well as ApoE-deficient mice. In this study, we explored the phenotype of DC subset induced by Ep1.B from monocytic cell lines and from the bone marrow-derived cells. We found Ep1.B treatment induced cells that showed characteristics of plasmacytoid dendritic cells (pDC). We explored in-vitro and in-vivo effects of Ep1.B-induced DCs on antigen-specific T cell responses. Upon in-vivo injection of these cells with antigen, the subsequent ex-vivo antigen-specific proliferation of lymph node cells and splenocytes from recipient mice was greatly reduced. Our results suggest that Ep1.B-induced pDCs promote the generation of Treg cells, and these cells contribute to the induction of peripheral tolerance in adaptive immunity and potentially contribute its anti-atherogenic activity.

  17. Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain. (United States)

    Teter, Bruce; LaDu, Mary Jo; Sullivan, Patrick M; Frautschy, Sally A; Cole, Greg M


    The Apolipoprotein E (ApoE) isotype ApoE4 is a prevalent genetic risk factor for Alzheimer's disease (AD) that can modulate systemic and central inflammation, independent of amyloid accumulation. Although disruption of innate immune toll receptor signaling is modulated by ApoE and observed in AD, ApoE isotype-specific effects remain poorly understood. Therefore, we examined the effect of the ApoE isotype on the brain levels of major regulators of TLR signaling including miR146a, a microRNA enriched in the brain. We used 6-month-old ApoE3 or ApoE4 targeted replacement mice with and without mutant familial AD transgenes. ApoE4 reduced the levels of miR146a compared with ApoE3, both in the brain (29%; PmiR146) that correlated inversely with miR146a levels (r=0.637; P<0.0001). Reduced negative feedback of toll-like receptor signaling (by miRNA146a) can explain early-life hypersensitivity to innate immune stimuli (including Aβ) in ApoE4 carriers. Thus, ApoE4 causes early dysregulation of a central controller of the innate immune system both centrally and systemically. This defect persists with familial AD pathology and may be relevant to ApoE4 AD risk.

  18. Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer's disease in a Southern Brazilian population

    Directory of Open Access Journals (Sweden)

    de-Andrade F.M.


    Full Text Available Apolipoprotein E (protein: apo E; gene: APOE plays an important role in the multifactorial etiology of both Alzheimer's disease (AD and lipid level concentrations. The polymerase chain reaction (PCR was used to investigate the APOE gene polymorphism in 446 unrelated Caucasians, among them 23 AD patients, and 100 Afro-Brazilians living in Porto Alegre, Brazil. The frequencies of the APOE*2, APOE*3 and APOE*4 alleles were 0.075, 0.810 and 0.115 in Caucasians and 0.075, 0.700 and 0.225 in Afro-Brazilians, respectively (c2 = 8.72, P = 0.013. A highly significant association was observed between the APOE*4 allele and AD in this population-based sample. The APOE*4 frequency in AD patients (39% was about four times higher than in the general Caucasian population (11.5%. The influence of each of the three common APOE alleles on lipid traits was evaluated by the use of the average excess statistic. The E*2 allele is associated with lower levels of triglycerides and of total and non-HDL cholesterol in both men and women. Conversely, the E*4 allele is associated with higher levels of these traits in women only. The effect of APOE alleles was of greater magnitude in women.

  19. Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study.

    LENUS (Irish Health Repository)

    Trompet, Stella


    Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

  20. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. (United States)

    Huang, Yadong; Mahley, Robert W


    Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalize apoE-containing lipoprotein particles; thus, apoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function. Elucidation of the functional domains within this protein and of the three-dimensional structure of the major isoforms of apoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. It is likely that apoE, with its multiple cellular origins and multiple structural and biophysical properties, is involved widely in processes of lipid metabolism and neurobiology, possibly encompassing a variety of disorders of neuronal repair, remodeling, and degeneration by interacting with different factors through various pathways.

  1. Characterization and measurement of human apolipoprotein A-II by radioimmunoassay. (United States)

    Goldberg, R B; Karlin, J B; Juhn, D J; Scanu, A M; Edelstein, C; Rubenstein, A H


    The development of a radioimmunoassay for apolipoprotein A-II (apo A-II) is described. Initial studies revealed a lack of immunological identity between purified apo A-II used as the standard and serum or HDL. Extensive testing of different buffers, standards, antisera, tracers, utilization of a detergent, and heating of sera failed to resolve the problem. Gel filtration of iodinated and non-iodinated apo A-II on Sephadex G-100 columns showed that apo A-II, in dilute solution, elutes in a higher molecular zone than expected with a broad, assymetrical profile. The use of a subfraction of the tracer in the assay resulted in parallelism in the serum and standard dilution curves. The apo A-II assay was sensitive, specific, and reproducible. Apo A-II added to sera was fully recovered and delipidation did not affect the immunoreactivity of either serum or HDL. Apo A-II contributed approximately 20% to the protein mass of HDL. Comparison of these results with those obtained by radial immunodiffusion, and with previously reported data, indicates that the reactivity of apo A-II in its native and delipidated forms may be markedly influenced by different immunologic methodologies and their specific reagents. Caution should thus be shown at present in assigning absolute concentrations to apo A-II in serum or HDL.

  2. The insertion of human apolipoprotein H into phospholipid membranes: a monolayer study. (United States)

    Wang, S X; Cai, G P; Sui, S F


    Apolipoprotein H (ApoH) is a plasma glycoprotein isolated from human serum. The interactions of ApoH with lipid membrane were reported to be essential for its physiological and pathogenic roles. In this paper we studied the ability of ApoH to insert into phospholipid membranes using the monolayer approach. The results show that ApoH is surface active and can insert into the lipid monolayers. The insertion ability of ApoH is stronger when a higher content of negatively charged lipids is present in the membrane. The acidic-pH and low-ionic-strength conditions will also enhance ApoH insertion, but these factors may not have much influence on the final insertion ability of ApoH, suggesting that, in the mechanism of ApoH insertion, not only electrostatic forces, but also hydrophobic interactions, are evidently involved. Modification by heat inactivation and reduction/alkylation does not change the critical insertion pressure (pic) of ApoH, suggesting a stable domain, maybe a linear sequence motif, but not the native three-dimensional structure of ApoH, is responsible for its insertion. The extent to which insertion of ApoH into phospholipid membranes may facilitate the 'immune cleaning' of plasma liposomes is discussed.

  3. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Obinata, Hideru; Kumaraswamy, Sunil B


    Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did...... not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM......(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung...

  4. Expression of the human apolipoprotein E gene suppresses steroidogenesis in mouse Y1 adrenal cells

    Energy Technology Data Exchange (ETDEWEB)

    Reyland, M.E.; Forgez, P.; Prack, M.M.; Williams, D.L. (State Univ. of New York, Stony Brook (United States)); Gwynne, J.T. (Univ. of North Carolina, Chapel Hill (United States))


    The lipid transport protein, apolipoprotein E (apoE), is expressed in many peripheral tissues in vivo including the adrenal gland and testes. To investigate the role of apoE in adrenal cholesterol homeostasis, the authors have expressed a human apoE genomic clone in the Y1 mouse adrenocortical cell line. Y1 cells do not express endogenous apoE mRNA or protein. Expression of apoE in Y1 cells resulted in a dramatic decrease in basal steroidogenesis; secretion of fluorogenic steroid was reduced 7- to {gt}100-fold relative to Y1 parent cells. Addition of 5-cholesten-3{beta},25-idol failed to overcome the suppression of steroidogenesis in these cells. Cholesterol esterification under basal conditions, as measured by the production of cholesteryl ({sup 14}C)oleate, was similar in the Y1 parent and the apoE-transfected cell lines. Upon incubation with adrenocorticotropin or dibutyryl cAMP, production of cholesteryl ({sup 14}C)oleate decreased 5-fold in the Y1 parent cells but was unchanged in the apoE-transfected cell lines. These results suggest that apoE may be an important modulator of cholesterol utilization and steroidogenesis in adrenal cells.

  5. Mechanism of lipid lowering in mice expressing human apolipoprotein A5

    Energy Technology Data Exchange (ETDEWEB)

    Fruchart-Najib, Jamila; Bauge, Eric; Niculescu, Loredan-Stefan; Pham, Tatiana; Thomas, Benoit; Rommens, Corinne; Majd, Zouher; Brewer, Bryan; Rubin, Edward M.; Pennacchio, Len A.; Fruchart, Jean-Charles


    Recently, we reported that apoAV plays key role in triglycerides lowering. Here, we attempted to determine the mechanism underlying this hypotriglyceridemic effect. We showed that triglyceride turnover is faster in hAPOA5 transgenic compared to wild type mice. Moreover, both apoB and apoCIII are decreased and LPL activity is increased in postheparin plasma of hAPOA5 transgenic mice. These data suggest a decrease in size and number of VLDL. To further investigate the mechanism of hAPOA5 in hyperlipidemic background, we intercrossed hAPOA5 and hAPOC3 transgenic mice. The effect resulted in a marked decreased of VLDL triglyceride, cholesterol, apolipoproteins B and CIII. In postprandial state, the triglyceride response is abolished in hAPOA5 transgenic mice. We demonstrated that in response to the fat load in hAPOA5XhAPOC3 mice, apoAV shifted from HDL to VLDL, probably to limit the elevation of triglycerides. In vitro, apoAV activates lipoprotein lipase. However, apoAV does not interact with LPL but interacts physically with apoCIII. This interaction does not seem to displace apoCIII from VLDL but may induce conformational change in apoCIII and consequently change in its function leading the activation of lipoprotein lipase.

  6. Mononuclear cell therapy reverts cuff-induced thrombosis in apolipoprotein E-deficient mice

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    Lima Leandro C F


    Full Text Available Abstract Background Stem/progenitor cell-based therapy has successfully been used as a novel therapeutic strategy for vascular diseases triggered by endothelial dysfunction. The aim of this study was to investigate the effects of mononuclear cell (MNC therapy in situ on carotid cuff-induced occlusive thrombus in the apolipoprotein E knockout (apoE-/- mouse. Methods Spleen-derived MNCs were isolated from green fluorescent protein (GFP-transgenic mice for cell treatment. A cuff-induced thrombus model was produced by placing a nonconstrictive silastic collar around the left common carotid artery in 20-week-old female apoE-/- mice. After 10 days, the cuff was removed, and the animals received in situ MNCs (Cuff-MNC or vehicle (Cuff-Vehicle and were compared with sham-operated animals (Sham. Results The histological analysis showed that the MNC treatment reverted occlusive thrombus formation compared to the vehicle and the vessel lumen area to that observed in the Sham group (MNC, 50 ± 4; Vehicle, 20 ± 4; Sham, 55 ± 2 x103 μm2; p -/- mice. Conclusion In situ short-term MNC therapy was able to revert cuff-induced occlusive thrombi in the carotid arteries of apoE-/- mice, possibly through the homing of EPCs, reduction of oxidative stress and decreased apoptosis.

  7. Homologue of mammalian apolipoprotein A-Ⅱ in non-mammalian vertebrates

    Institute of Scientific and Technical Information of China (English)

    Malay Choudhury; Shoji Yamada; Masaharu Komatsu; Hideki Kishimura; Seiichi Ando


    Although apolipoprotein with molecular weight 14 kDa (apo-14 kDa) is associated with fish plasma highdensity lipoproteins(HDLs),it remains to be determined whether apo-14 kDa is the homologue of mammalian apoA-Ⅱ.We have obtained the full cDNA sequences that encode Japanese eel and rainbow trout apo-14 kDa.Homologues of Japanese eel apo-14 kDa sequence could be found in 14 fish species deposited in the DDBJ/EMBL/GenBank or TGI database.Fish apo14 kDa lacks propeptide and contains more internal repeats than mammalian apoA-Ⅱ.Nevertheless,phylogenetic analysis allowed fish apo-14 kDa to be the homologue of mammalian apoA-Ⅱ.In addition,in silico cloning of the TGI,Ensembl,or NCBI database revealed apoA-Ⅱs in dog,chicken,green anole lizard,and African clawed frog whose sequences had not so far been available,suggesting both apoA-Ⅰ and apoA-Ⅱas fundamental constituents of vertebrate HDLs.

  8. Taurine reduces the secretion of apolipoprotein B100 and lipids in HepG2 cells

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    Nagao Koji


    Full Text Available Abstract Background Higher concentrations of serum lipids and apolipoprotein B100 (apoB are major individual risk factors of atherosclerosis and coronary heart disease. Therefore ameliorative effects of food components against the diseases are being paid attention in the affluent countries. The present study was undertaken to investigate the effect of taurine on apoB secretion and lipid metabolism in human liver model HepG2 cells. Results The results demonstrated that an addition of taurine to the culture media reduces triacylglycerol (TG-mass in the cells and the medium. Similarly, cellular cholesterol-mass was decreased. Taurine inhibited the incorporation of [14C] oleate into cellular and medium TG, suggesting the inhibition of TG synthesis. In addition, taurine reduced the synthesis of cellular cholesterol ester and its secretion, suggesting the inhibition of acyl-coenzyme A:cholesterol acyltransferase activity. Furthermore, taurine reduced the secretion of apoB, which is a major protein component of very low-density lipoprotein. Conclusion This is a first report to demonstrate that taurine inhibits the secretion of apoB from HepG2 cells.

  9. Dementia and Diabetes Mellitus: Association with Apolipoprotein E4 Polymorphism from a Hospital in Southern India

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    Lakshmi Narayanan Kota


    Full Text Available Objective. To evaluate the association of Apolipoprotein E4 (ApoE4 in Alzheimer's dementia (AD with comorbid diabetes mellitus (DM. Methods. The study included subjects with Alzheimer's dementia (AD (n=209, individuals with non-Alzheimer's dementia (nAD (n=122, individuals with parental history of AD (f/hAD (n=70, and control individuals who had normal cognitive functions and no parental history of dementia (NC (n=193. Dementia was diagnosed using International Classification of Diseases-10 revision (ICD-10 criteria. DM was assessed on the basis of self-report and/or use of antidiabetic medications. ApoE genotyping was done using sequence-specific primer polymerase chain reaction. Results. ApoE4 allele frequencies were highest among AD with comorbid DM (0.35 followed by AD without DM (0.25, nAD with DM (0.13, nAD without comorbid DM (0.12, and NC (0.08. Frequency of ApoE4 in persons with f/hAD was 0.13. The association of AD with co-morbid DM in ApoE4 carriers was more in comparison to NC with DM (OR=5.68, P=0.04. Conclusion. There is a significant association between AD with co-morbid DM and ApoE4 genotype.

  10. VLDL lipolysis products increase VLDL fluidity and convert apolipoprotein E4 into a more expanded conformation. (United States)

    Tetali, Sarada D; Budamagunta, Madhu S; Simion, Catalina; den Hartigh, Laura J; Kálai, Tamás; Hideg, Kálmán; Hatters, Danny M; Weisgraber, Karl H; Voss, John C; Rutledge, John C


    Our previous work indicated that apolipoprotein (apo) E4 assumes a more expanded conformation in the postprandial period. The postprandial state is characterized by increased VLDL lipolysis. In this article, we tested the hypothesis that VLDL lipolysis products increase VLDL particle fluidity, which mediates expansion of apoE4 on the VLDL particle. Plasma from healthy subjects was collected before and after a moderately high-fat meal and incubated with nitroxyl-spin labeled apoE. ApoE conformation was examined by electron paramagnetic resonance spectroscopy using targeted spin probes on cysteines introduced in the N-terminal (S76C) and C-terminal (A241C) domains. Further, we synthesized a novel nitroxyl spin-labeled cholesterol analog, which gave insight into lipoprotein particle fluidity. Our data revealed that the order of lipoprotein fluidity was HDL approximately LDL

  11. C-terminal interactions of apolipoprotein E4 respond to the postprandial state. (United States)

    Tetali, Sarada D; Budamagunta, Madhu S; Voss, John C; Rutledge, John C


    Increased triglyceride-rich lipoproteins (TGRLs) in the postprandial state are associated with atherosclerosis. We investigated whether the postprandial state induced structural changes at the apolipoprotein E4 (apoE4) C terminus, its principal lipid binding domain, using electron paramagnetic resonance (EPR) spectroscopy of a site-directed spin label attached to the cysteine of apoE4-W264C. Spin coupling between labels located in the C termini was followed after mixing with preprandial and postprandial human plasma samples. Our results indicate that postprandial plasma triggers a reorganization of the protein such that the dipolar broadening is diminished, indicating a reduction in C-terminal interaction. The loss of spectral broadening was directly correlated with an increase in postprandial plasma triglycerides and was reduced with delipidated plasma. The spin-labeled apoE4 displayed a lipid preference of VLDL > LDL > HDL in the preprandial and postprandial states. The apoE4 shift to VLDL during the postprandial state was accompanied by a loss in spectral broadening of the protein. These findings suggest that apoE4 associated with LDL maintains self-association via its C terminus and that this association is diminished in VLDL-associated protein. Lipolyzed TGRL reflected a depletion of the C-terminal interaction of apoE4. Addition of palmitate to VLDL gave a similar response as lipolyzed TGRL, suggesting that lipolysis products play a major role in reorganizing apoE4 during the postprandial state.

  12. Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo (United States)

    Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis; McNeill, Eileen; Manmadhan, Arun; Recio, Carlota; Carmineri, Alfredo; Brodermann, Maximillian H; White, Gemma E; Cooper, Dianne; DiDonato, Joseph A; Zamanian-Daryoush, Maryam; Hazen, Stanley L; Channon, Keith M


    Apolipoprotein A1 (apoA1) is the major protein component of high-density lipoprotein (HDL) and has well documented anti-inflammatory properties. To better understand the cellular and molecular basis of the anti-inflammatory actions of apoA1, we explored the effect of acute human apoA1 exposure on the migratory capacity of monocyte-derived cells in vitro and in vivo. Acute (20–60 min) apoA1 treatment induced a substantial (50–90%) reduction in macrophage chemotaxis to a range of chemoattractants. This acute treatment was anti-inflammatory in vivo as shown by pre-treatment of monocytes prior to adoptive transfer into an on-going murine peritonitis model. We find that apoA1 rapidly disrupts membrane lipid rafts, and as a consequence, dampens the PI3K/Akt signalling pathway that coordinates reorganization of the actin cytoskeleton and cell migration. Our data strengthen the evidence base for therapeutic apoA1 infusions in situations where reduced monocyte recruitment to sites of inflammation could have beneficial outcomes. DOI: PMID:27572261

  13. Is apolipoprotein E4 an important risk factor for vascular dementia? (United States)

    Rohn, Troy T


    Despite the fact that vascular dementia (VaD) represents the seconding leading cause of dementia in the USA, behind only Alzheimer's disease (AD), there remains a lack of consensus on the pathological criteria required for diagnosis of this disease. A number of clinical diagnostic criteria exist but are poorly validated and inconsistently applied. It is clear that vascular risk factors play an important role in the etiology of VaD, including hypertension, stroke, diabetes, and atherosclerosis. Vascular risk factors may increase the risk for VaD by promoting inflammation, cerebral vascular disease, white matter lesions, and hippocampal sclerosis. Because vascular risk factors seem to impart a high degree of risk for conferring VaD, it seems logical that the apolipoprotein E (APOE) status of individuals may be important. APOE plays a critical role in transporting cholesterol in and out of the CNS and in AD it is known that harboring the APOE allele increases the risk of AD perhaps due to the improper functioning of this protein. The purpose of this review is to examine the important pathological features and risk factors for VaD and to provide a critical assessment of the current literature regarding whether or not apoE4 also confers disease risk in VaD. The preponderance of data suggests that harboring one or both APOE4 alleles elevates the risk for VaD, but not to the same extent as found in AD.

  14. An ultrasensitive electrochemical immunosensor for apolipoprotein E4 based on fractal nanostructures and enzyme amplification. (United States)

    Liu, Yibiao; Xu, Li-Ping; Wang, Shuqi; Yang, Weizhao; Wen, Yongqiang; Zhang, Xueji


    Human apolipoprotein E4 (APOE4) is a major risk factor for Alzheimer's disease (AD) and can greatly increase the morbidity. In this work, an ultrasensitive sandwich-type electrochemical immunosensor for the quantitative detection of APOE4 was designed based on fractal gold (FracAu) nanostructures and enzyme amplification. The FracAu nanostructures were directly electrodeposited by hydrogen tetrachloroaurate (HAuCl4) on polyelectrolytes modified indium tin oxide (ITO) electrode. The sensing performances of the modified interface were investigated by cyclic voltammetry (CV). After functionalization with HRP-labeled APOE4 antibody, the human APOE4 could be detected quantitatively by current response. The current response has a linear relationship with the logarithm of human APOE4 concentrations in a range from 1.0 to 10,000.0 ng/mL, with a detection limit of 0.3 ng/mL. The fabricated APOE4 electrochemical immunosensor exhibits strong specificity, high sensitivity, low detection limit and wide linear range. The detection of human APOE4 provides a strong support for the prevention of AD and early-stage warning for those susceptible populations.

  15. Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice. (United States)

    Knoferle, Johanna; Yoon, Seo Yeon; Walker, David; Leung, Laura; Gillespie, Anna K; Tong, Leslie M; Bien-Ly, Nga; Huang, Yadong


    Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.

  16. Computational design of apolipoprotein E4 inhibitors for Alzheimer's disease therapy from traditional Chinese medicine. (United States)

    Huang, Hung-Jin; Chen, Hsin-Yi; Lee, Cheng-Chun; Chen, Calvin Yu-Chian


    Apolipoprotein E4 (Apo E4) is the major genetic risk factor in the causation of Alzheimer's disease (AD). In this study we utilize virtual screening of the world's largest traditional Chinese medicine (TCM) database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD) simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB) penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.

  17. Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders. (United States)

    Morgan, E E; Woods, S P; Letendre, S L; Franklin, D R; Bloss, C; Goate, A; Heaton, R K; Collier, A C; Marra, C M; Gelman, B B; McArthur, J C; Morgello, S; Simpson, D M; McCutchan, J A; Ellis, R J; Abramson, I; Gamst, A; Fennema-Notestine, C; Smith, D M; Grant, I; Vaida, F; Clifford, D B


    This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.

  18. Cognitive functions, lipid profile, and Apolipoprotein E gene polymorphism in postmenopausal women

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    Iwona Bojar


    Full Text Available The objective of the study was investigation of the relationship between cognitive functions and lipid profile, BMI and change of body weight in postmenopausal women carriers of Apolipoprotein E gene polymorphisms (APOE. A group of 170 women was recruited to the study. The inclusion criteria were: minimum of two years after the last menstruation, FSH concentration 30 U/ml and no signs of dementia on the Montreal Cognitive Assessment (MoCA. A computerized battery of Central Nervous System Vital Signs (CNS VS was used for diagnostic cognitive functions. APOE genotype was performed by multiplex PCR. In blood plasma were determined: triglycerides, total cholesterol and its fractions: HDL cholesterol and LDL cholesterol. Statistical analysis was performed using two-way analysis of variance in STATISTICA software. In the postmenopausal women examined, the carrier state of APOE gene polymorphism was associated with the level of triglycerides, and results concerning three cognitive functions: executive functions, psychomotor speed, and cognitive flexibility. Loss of body weight in postmenopausal women was related with lower results in neurocognitive index and the majority of cognitive functions. The results concerning cognitive functions in postmenopausal women in the study were not significantly related with lipid profile. Significant differences were observed according to APOE gene polymorphism in correlations between LDL/HDL and CHOL/HDL ratios, and results in the processing speed and reaction time, as well as between the BMI and results in processing speed in the postmenopausal women examined.

  19. Structural and Functional Analysis of the ApolipoproteinA-I A164S Variant.

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    Jonathan Dalla-Riva

    Full Text Available Apolipoprotein A-I (apoA-I is the main protein involved in the formation of high-density lipoprotein (HDL, it is the principal mediator of the reverse cholesterol transfer (RCT pathway and provides cardio-protection. In addition to functional wild-type apoA-I, several variants have been shown to associate with hereditary amyloidosis. In this study we have performed biophysical and biochemical analyses of the structure and functional properties of the A164S variant of apoA-I (1:500 in the Danish general population, which is the first known mutation of apoA-I that leads to an increased risk of ischaemic heart disease (IHD, myocardial infarction and mortality without associated low HDL cholesterol levels. Despite the fact that epidemiologically IHD is associated with low plasma levels of HDL, the A164S mutation is linked to normal plasma levels of lipids, HDL and apoA-I, suggesting impaired functionality of this variant. Using biophysical techniques (e.g., circular dichroism spectroscopy and electron microscopy to determine secondary structure, stability and pro-amyloidogenic property of the lipid free A164S apoA-I variant, our observations suggest similarity in structural properties between apoA-I WT and apoA-I A164S. However, the A164S apoA-I variant exhibits lower binding affinity to lipids but forms similar sized HDL particles to those produced by WT.

  20. Longitudinal Trajectories of Cholesterol from Midlife through Late Life according to Apolipoprotein E Allele Status

    Directory of Open Access Journals (Sweden)

    Brian Downer


    Full Text Available Background: Previous research indicates that total cholesterol levels increase with age during young adulthood and middle age and decline with age later in life. This is attributed to changes in diet, body composition, medication use, physical activity, and hormone levels. In the current study we utilized data from the Framingham Heart Study Original Cohort to determine if variations in apolipoprotein E (APOE, a gene involved in regulating cholesterol homeostasis, influence trajectories of total cholesterol, HDL cholesterol, and total: HDL cholesterol ratio from midlife through late life. Methods: Cholesterol trajectories from midlife through late life were modeled using generalized additive mixed models and mixed-effects regression models. Results: APOE e2+ subjects had lower total cholesterol levels, higher HDL cholesterol levels, and lower total: HDL cholesterol ratios from midlife to late life compared to APOE e3 and APOE e4+ subjects. Statistically significant differences in life span cholesterol trajectories according to gender and use of cholesterol-lowering medications were also detected. Conclusion: The findings from this research provide evidence that variations in APOE modify trajectories of serum cholesterol from midlife to late life. In order to efficiently modify cholesterol through the life span, it is important to take into account APOE allele status.

  1. Screening for the familial defective apolipoprotein B-100 R3500W by mutagenic primers PCR

    Institute of Scientific and Technical Information of China (English)

    冯纪安; 冯铮


    Objective A method combining the mutagenic primers PCR and restriction enzyme digestion was designed to facilitate the detection of gene mutation in familial defective apolipoprotein B-1O0 R3500W. Methods A pair of primer was designed and a mismatch nucleotide was introduced in its upstream primer. A segment of target DNA including the possibly mutated nucleotide was amplified by PCR and the products were digested by restriction enzyme Nco 1. To overcome the potential false negative results due to improper digestion conditions, a segment of DNA with Ncol cut size was added as reference.Results The target sequence was successfully amplified by PCR, producing a 144 bp DNA fragment as expected. When incubated with Ncol, the enzyme could digest the DNA, producing a 114 bp segment,only if it was amplified from the mutated gene, but not from the normal allele. This difference in length of DNA could be separated by electrophoresis on a 2 %agarose gel. Thus we successfully detected two carriers of heterozygous FDB R3500W in 162 hypercholesterolemic patients. Conclusions Mutagenic primers PCR can be used to detect the gene mutation of apo B-100 R3500W, two cases were detected among 162patients with hypercholesterolemia. It suggests that this mutation is not rare in mainland China.

  2. Multiple members of the plasminogen-apolipoprotein(a) gene family associated with thrombosis

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    Ichinose, Akitada (Univ. of Washington, Seattle (United States))


    Plasminogen and apolipoprotein(a) (apo(a)) are closely related plasma proteins that are associated with hereditary thrombophilia. Low plasminogen levels are found in some patients who developed venous thrombosis, while a population with high plasma concentrations of apo(a) have a higher incidence of arterial thrombosis. Two different gene coding for human apo(a) have been isolated and characterized in order to study and compare these genes with four other closely related genes in the plasminogen-apo(a) gene family. These include the gene coding for plasminogen, two unique plasminogen-related genes, and a gene coding for hepatocyte growth factor. Nucleotide sequence analysis of these genes revealed that the exons and their boundaries of these genes for plasminogen and apo(a), and the plasminogen-related genes, differ only 1-5% in sequence. The types of exon/intron junctions and positions of introns in the molecules are also exactly identical, suggesting that these genes have evolved from an ancestral plasminogen gene via duplication and exon shuffling. By utilizing these results, gene-specific probes have been designed for the analysis of each of the genes in this gene family. The plasminogen and two apo(a) genes were all localized to chromosome 6 by employing the gene-specific primers and genomic DNAs from human-hamster cell hybrids. These data also make it possible to characterize the apo(a) and plasminogen genes in individuals by in vitro amplification.

  3. Relationship Between Plasma Insulin Level and Apolipoprotein E Gene Polymorphysm in Alzheimer′s Disease

    Institute of Scientific and Technical Information of China (English)

    Luo Zhuming; Yuan Qiang


    Objective: To study relationship between plasma insulin level and apolipoprotein E Gene polymorphysm in Alzheimcr′s Disease. Background: Recent researches have shown that there was a close relationship between ApoE- ε 4 allele and AD. Because of the discovery of hyperinsulineamia in AD patients, the study of insulin on the pathogenesis of AD become a hot point of AD reseearch. Methods: We apply PCR-RFLP to the ApoE genotype study of 45 AD paticnts and 32 normal controls. At the same time, plasma insulin and glucose level was measured in the abovc objects. Results and Discussion: The frequency of ApoE- ε 4 in AD (32.2%) is much higher than in controls (10.9%). On the contrary, the frequency of ApeE- ε 4 is relatively lower in AD than in thc controls. The resistence of hyperinsulineamia in AD. Insulin sensitivity decreased in AD. Conclusion: When gene dose of ApoE- ε 4 increases, the prcvalance of AD increase, while the on-set ages of AD decrease (P<0.05). These findings indicatc that AD patients may have insulin resistance anbd insulin probably play a role in AD pathogenesis. In addition, the s 4 homozygote AD patients seem to have loweer plasma insulin level that the non- ε 4 homozygote AD patients (P<0.05). But this situation need to be replicated in studies of larger sample.

  4. Production of human apolipoprotein(a) transgenic NIBS miniature pigs by somatic cell nuclear transfer. (United States)

    Shimatsu, Yoshiki; Horii, Wataru; Nunoya, Tetsuo; Iwata, Akira; Fan, Jianglin; Ozawa, Masayuki


    Most cases of ischemic heart disease and stroke occur as a result of atherosclerosis. The purpose of this study was to produce a new Nippon Institute for Biological Science (NIBS) miniature pig model by somatic cell nuclear transfer (SCNT) for studying atherosclerosis. The human apolipoprotein(a) (apo(a)) genes were transfected into kidney epithelial cells derived from a male and a female piglet. Male cells were used as donors initially, and 275 embryos were transferred to surrogates. Three offspring were delivered, and the production efficiency was 1.1% (3/275). Serial female cells were injected into 937 enucleated oocytes. Eight offspring were delivered (production efficiency: 0.9%) from surrogates. One male and 2 female transgenic miniature pigs matured well. Lipoprotein(a) was found in the male and one of the female transgenic animals. These results demonstrate successful production of human apo(a) transgenic NIBS miniature pigs by SCNT. Our goal is to establish a human apo(a) transgenic NIBS miniature pig colony for studying atherosclerosis.

  5. Evolutionary analysis of apolipoprotein E by Maximum Likelihood and complex network methods

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    Leandro de Jesus Benevides

    Full Text Available Abstract Apolipoprotein E (apo E is a human glycoprotein with 299 amino acids, and it is a major component of very low density lipoproteins (VLDL and a group of high-density lipoproteins (HDL. Phylogenetic studies are important to clarify how various apo E proteins are related in groups of organisms and whether they evolved from a common ancestor. Here, we aimed at performing a phylogenetic study on apo E carrying organisms. We employed a classical and robust method, such as Maximum Likelihood (ML, and compared the results using a more recent approach based on complex networks. Thirty-two apo E amino acid sequences were downloaded from NCBI. A clear separation could be observed among three major groups: mammals, fish and amphibians. The results obtained from ML method, as well as from the constructed networks showed two different groups: one with mammals only (C1 and another with fish (C2, and a single node with the single sequence available for an amphibian. The accordance in results from the different methods shows that the complex networks approach is effective in phylogenetic studies. Furthermore, our results revealed the conservation of apo E among animal groups.

  6. Hypercholesterolemia promotes early renal dysfunction in apolipoprotein E-deficient mice

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    Balarini Camille M


    Full Text Available Abstract Background Aging and dyslipidemia are processes which can lead to deleterious consequences to renal function. Therefore, the aim of this study was to determine the effects of both hypercholesterolemia and aging on renal function in mice. Methods Male hypercholesterolemic apolipoprotein E-deficient mice (ApoE, n = 13 and age-matched C57BL/6 control mice (C57, n = 15 were studied at 2 (young and 8 (adult month-old. At each time point, animals were placed in metabolic cages for 24 hours to urine volume and urinary creatinine quantification. Blood samples were collected for serum cholesterol, urea and creatinine measurements. Glomerular filtration rate (GFR was estimated through creatinine clearance determination. Mesangial expansion was evaluated by Periodic Acid Schiff staining, renal fibrosis was determined through Masson's trichrome staining and neuronal nitric oxide synthase (nNOS expression in the kidney was performed by Western Blotting. To statistical analysis two-way ANOVA followed by Fisher's post hoc test was used. Results Total plasma cholesterol was increased about 5-fold in ApoE mice at both time points compared to C57 animals. At 2-month-old, GFR was already markedly reduced in ApoE compared to C57 mice (187 ± 28 vs 358 ± 92 μL/min, p Conclusions These data show that both hypercholesterolemia and aging contribute to the loss of renal function in mice.

  7. Apolipoprotein E polymorphisms increase the risk of post-stroke depression

    Institute of Scientific and Technical Information of China (English)

    Xue-bin Li; Jie Wang; An-ding Xu; Jian-min Huang; Lan-qing Meng; Rui-ya Huang; Jun-li Wang


    Recent reports have shown that apolipoprotein E (APOE) polymorphisms are involved in neurodegenerative disease. However, it is unclear whetherAPOE affects post-stroke depression. Accordingly, we hypothesized thatAPOE polymorphisms modify the risk of post-stroke depression. Here, we performed a hospital-based case-control study (including 76 cerebral infarction cases with post-stroke depression, 88 cerebral infarction cases without post-stroke depression, and 109 controls without any evidence of post-stroke depression or cerebral infarction) to determine possible association betweenAPOE rs429358 and rs7412 polymorphisms and risk of post-stroke depression. Our ifndings show no difference among the groups with regards genotype distribution of the rs7412 polymorphism. In contrast,APOE genotypes with rs429358-C alleles increased the risk of post-stroke depression. Further, the rs429358 polymorphism was associated with significantly decreased regional cerebral blood flow values in the left temporal lobe of post-stroke depression cases. Additionally, the rs429358 polymorphism was not only associated with depression severity, but with increasing serum levels of total cholesterol. These re-sults suggest that theAPOE rs429358 polymorphism is associated with increased risk of developing post-stroke depression, and thatAPOE rs429358-C allele genotypes may be detrimental to recovery of nerve function atfer stoke. Indeed, these ifndings provide clinical data for future post-stroke depression gene interventions.

  8. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur Nationality

    Institute of Scientific and Technical Information of China (English)


    This paper investigated the correlation between polymorphisms and haplotypes in the apolipoprotein B (apoB) gene (SP-I/D, XbaI-RFLP, VNTR) and natural longevity persons among the Uygur people in Xin-jiang. For this purpose, 191 healthy Uygur individuals aged above 90 from Hetian area of Xinjiang were recruited, and another 53 persons aged 65—70 from the same nationality, the same region and with the same gender ratio, served as the control group. Genotyping was performed by PCR-SSP, PCR-RFLP and PCR-sequencing methods. Logistic regression analyses revealed that the frequencies of X+X+ genotype, M and L alleles and the genetypes composed of M and L were significantly higher in the longevity group than in the control group. In haplotype analyses, we found that, in the long-lived people, the frequency of haplotypes composed of the X+ and M alleles was significantly higher whereas the frequency of haplotypes composed of the X- and S alleles was significantly lower (both P<0.05) I than those of their controls. These results indicated that the S allele, SS genotype and X+-S, D-S, D-X+-S haplotypes were the possible adverse factors, whereas the M, L alleles, X+X+, MM, ML, LL genotypes and I-X+-M, X+-M haplotypes were the possibe protective factors for the naturally long-lived Uygur people in China.

  9. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur Nationality

    Institute of Scientific and Technical Information of China (English)

    JIANG WenXi; QIU ChangChun; CHENG ZuHeng; ZHOU WenYu; GU MingLiang; XU Qun; FANG MingWu; NIU WenQuan


    This paper investigated the correlation between polymorphisms and haplotypes in the apolipoprotein B (apoB) gene (SP-I/D, XbaI-RFLP, VNTR) and natural longevity persons among the Uygur people in Xinjiang. For this purpose, 191 healthy Uygur individuals aged above 90 from Hetian area of Xinjiang were recruited, and another 53 persons aged 65-70 from the same nationality, the same region and with the same gender ratio, served as the control group. Genotyping was performed by PCR-SSP, PCR-RFLP and PCR-sequencing methods. Logistic regression analyses revealed that the frequencies of X+X+ genotype, M and L alleles and the genetypes composed of M and L were significantly higher in the longevity group than in the control group. In haplotype analyses, we found that, in the long-lived people, the frequency of haplotypes composed of the X+ and M alleles was significantly higher whereas the frequency of haplotypes composed of the X- and S alleles was significantly lower (both P<0.05) I than those of their controls. These results indicated that the S allele, SS genotype and X+-S, D-S, D-X+-S haplotypes were the possible adverse factors, whereas the M, L alleles, X+X+, MM, ML, LL genotypes and I-X+-M, X+-M haplotypes were the possibe protective factors for the naturally long-lived Uygur people in China.

  10. Polymorphism of Apolipoprotein A5 is a Risk Factor for Cerebral Infarction in Type 2 Diabetes

    Institute of Scientific and Technical Information of China (English)

    Xuefeng LI; Yancheng XU; Yan DING; Chengming QIN; Zhe DAI; Li NIU


    This study investigated the association of apolipoprotein A5 (apoAS) gene polymorphism at position -113 ITC with cerebral infarction in patients with type 2 diabetes. A total of 256 type 2 diabetic patients without cerebral infarction (T2DM), 220 type 2 diabetic patients with cerebral infarction (T2DMCI) and 340 healthy subjects were recruited from the same region (Hubei province,China). The genotype of apoA5 -1131TC was analyzed by polymerase chain reaction, followed by restriction fragment length polymorphism (PCR-RFLP). Total cholesterol, HDL cholesterol,LDL-cholesterol and trigiycerides were quantitatively detected by using standard enzymatic techniques. The results showed that the prevalence of the apoA5 -1131C allele was significantly higher in T2DMCI group than that in control group (42.7% versus 31.2%, P<0.01). The carriers of rare C allele had higher TG levels as compared with carders of common allele in the three groups (P<0.01). Logistic regression models, which were adjusted for age, gender, blood pressure, BMI, FBS, smoking,LDL-C and HDL-C, revealed that patients carrying the apoA5 -1131C allele and CC homozygotes were at high risk for T2DMCI. It was concluded that the apoA5 -ll31C allele variant is an independent genetic risk factor for T2DMCI.

  11. Apolipoprotein C-II and C-III metabolism in a kindred of familial hypobetalipoproteinemia

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    Malmendier, C.L.; Delcroix, C.; Lontie, J.F.; Dubois, D.Y. (Research Foundation on Atherosclerosis, Brussels (Belgium))


    Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) showed low levels of triglycerides, low-density lipoprotein (LDL)-cholesterol, and apolipoproteins (apo) B, C-II, and C-III. Turnover of iodine-labeled apo C-II and apo C-III associated in vitro to plasma lipoproteins was studied after intravenous injection. Radioactivity in plasma and lipoproteins (95% recovered in high-density lipoprotein (HDL) density range) and in 24-hour urine samples was observed for 16 days. A parallelism of the slowest slopes of plasma decay curves was observed between apo C-II and apo C-III, indicating a partial common catabolic route. Urine/plasma radioactivity ratio (U/P) varied with time, suggesting heterogeneity of metabolic pathways. A new compartmental model using the SAAM program was built, not only fitting simultaneously plasma and urine data, but also taking into account the partial common metabolism of lipoprotein particles (LP) containing apo C-II and apo C-III. The low apo C-II and C-III plasma concentrations observed in HBL compared with normal resulted from both an increased catabolism and a reduced synthesis, these changes being more marked for apo C-III. The modifications in the rate constants of the different pathways calculated from the new model are in favor of an increased direct removal of particles following the fast pathway, likely in the very-low-density lipoprotein (VLDL) density range.

  12. Multiple reaction monitoring and multiple reaction monitoring cubed based assays for the quantitation of apolipoprotein F. (United States)

    Kumar, Abhinav; Gangadharan, Bevin; Zitzmann, Nicole


    Apolipoprotein F (APO-F) is a novel low abundance liver fibrosis biomarker and its concentration decreases in human serum and plasma across liver fibrosis stages. Current antibody based assays for APO-F suffer from limitations such as unspecific binding, antibody availability and undetectable target if the protein is degraded; and so an antibody-free assay has the potential to be a valuable diagnostic tool. We report an antibody-free, rapid, sensitive, selective and robust LC-MS/MS (MRM and MRM(3)) method for the detection and quantitation of APO-F in healthy human plasma. With further analysis of clinical samples, this LC-MS based method could be established as the first ever antibody-free biomarker assay for liver fibrosis. We explain the use of Skyline software for peptide selection and the creation of a reference library to aid in true peak identification of endogenous APO-F peptides in digests of human plasma without protein or peptide enrichment. Detection of a glycopeptide using MRM-EPI mode and reduction of interferences using MRM3 are explained. The amount of APO-F in human plasma from a healthy volunteer was determined to be 445.2ng/mL, the coefficient of variation (CV) of precision for 20 injections was <12% and the percentage error of each point along the calibration curve was calculated to be <8%, which is in line with the assay requirements for clinical samples.

  13. Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response. (United States)

    Halberstadt, Adam L; Geyer, Mark A


    N-benzyl substitution markedly enhances the affinity of phenethylamine hallucinogens at the 5-HT(2A) receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT(2A) receptor activation in rats and mice, and is widely used as a behavioral proxy for hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1-10 mg/kg SC), 25I-NBOMe (0.1-1 mg/kg SC), and 25I-NBMD (1-10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT(2A) antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine hallucinogens induce the HTR by activating 5-HT(2A) receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT(2A) affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these hallucinogens will become more widespread in the future.

  14. Serum Proteome Signature of Radiation Response: Upregulation of Inflammation-Related Factors and Downregulation of Apolipoproteins and Coagulation Factors in Cancer Patients Treated With Radiation Therapy—A Pilot Study

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    Widlak, Piotr, E-mail: [Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice (Poland); Jelonek, Karol; Wojakowska, Anna; Pietrowska, Monika [Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice (Poland); Polanska, Joanna [Institute of Automatics Control, Silesian University of Technology, Gliwice (Poland); Marczak, Łukasz [Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan (Poland); Miszczyk, Leszek; Składowski, Krzysztof [Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice (Poland)


    Purpose: Ionizing radiation affects the proteome of irradiated cells and tissue, yet data concerning changes induced during radiation therapy (RT) in human blood are fragmentary and inconclusive. We aimed to identify features of serum proteome and associated processes involved in response to partial body irradiation during cancer treatment. Methods and Materials: Twenty patients with head and neck squamous cell cancer (HNSCC) and 20 patients with prostate cancer received definitive intensity modulated RT. Blood samples were collected before RT, just after RT, and 1 month after the end of RT. Complete serum proteome was analyzed in individual samples, using a shotgun liquid chromatography-tandem mass spectrometry approach which allowed identification of approximately 450 proteins. Approximately 100 unique proteins were quantified in all samples after exclusion of immunoglobulins, and statistical significance of differences among consecutive samples was assessed. Processes associated with quantified proteins and their functional interactions were predicted using gene ontology tools. Results: RT-induced changes were marked in the HNSCC patient group: 22 upregulated and 33 downregulated proteins were detected in post-RT sera. Most of the changes reversed during follow-up, yet levels of some proteins remained affected 1 month after the end of RT. RT-upregulated proteins were associated with acute phase, inflammatory response, and complement activation. RT-downregulated proteins were associated with transport and metabolism of lipids (plasma apolipoproteins) and blood coagulation. RT-induced changes were much weaker in prostate cancer patients, which corresponded to differences in acute radiation toxicity observed in both groups. Nevertheless, general patterns of RT-induced sera proteome changes were similar in both of the groups of cancer patients. Conclusions: In this pilot study, we proposed to identify a molecular signature of radiation response, based on specific

  15. Proteomic Analysis of Plasma from California Sea Lions (Zalophus californianus Reveals Apolipoprotein E as a Candidate Biomarker of Chronic Domoic Acid Toxicosis.

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    Benjamin A Neely

    Full Text Available Domoic acid toxicosis (DAT in California sea lions (Zalophus californianus is caused by exposure to the marine biotoxin domoic acid and has been linked to massive stranding events and mortality. Diagnosis is based on clinical signs in addition to the presence of domoic acid in body fluids. Chronic DAT further is characterized by reoccurring seizures progressing to status epilepticus. Diagnosis of chronic DAT is often slow and problematic, and minimally invasive tests for DAT have been the focus of numerous recent biomarker studies. The goal of this study was to retrospectively profile plasma proteins in a population of sea lions with chronic DAT and those without DAT using two dimensional gel electrophoresis to discover whether individual, multiple, or combinations of protein and clinical data could be utilized to identify sea lions with DAT. Using a training set of 32 sea lion sera, 20 proteins and their isoforms were identified that were significantly different between the two groups (p<0.05. Interestingly, 11 apolipoprotein E (ApoE charge forms were decreased in DAT samples, indicating that ApoE charge form distributions may be important in the progression of DAT. In order to develop a classifier of chronic DAT, an independent blinded test set of 20 sea lions, seven with chronic DAT, was used to validate models utilizing ApoE charge forms and eosinophil counts. The resulting support vector machine had high sensitivity (85.7% with 92.3% negative predictive value and high specificity (92.3% with 85.7% positive predictive value. These results suggest that ApoE and eosinophil counts along with machine learning can perform as a robust and accurate tool to diagnose chronic DAT. Although this analysis is specifically focused on blood biomarkers and routine clinical data, the results demonstrate promise for future studies combining additional variables in multidimensional space to create robust classifiers.

  16. Body Mass Index, Blood Lipid and Apolipoprotein levels and Coronary Heart Disease among middle aged Punjabi Khatris of Northwest India

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    Full Text Available Background: Studies have suggested that an elevated plasma concentration of apolipoprotein (apo B coupled with obesity may be considered as an important risk factor for coronary heart disease (CHD than the traditional lipid factors. Coronary artery disease (CAD is a multifactorial disease resulting from interaction among various hereditary, cultural and environment factors. Population specific studies are rare. Aim: The aim of this study was to evaluate the association of body mass index (BMI, blood lipids and apolipoproteins with the CAD among the Khatri caste, which is an indigenous population of Northwest India. Materials and Methods: The study was carried on 150 CAD patients and 150 normal controls belonging to the Punjabi Khatri caste ranging in age from 35-45 years. Height and body weight was measured using standard techniques. Blood was drawn from each subject to analyze serum concentrations of lipids and apolipoproteins. Results: The study demonstrated that CAD patients had elevated BMI in both males and females than normal controls. Apo B levels were an important predictor of CAD. ApoA/ApoB ratio among CAD patients was 0.74 compared with 1.53 in normal subjects; controls had 105.79% higher ApoA/ApoB ratio than CAD subjects. Total cholesterol, LDL-C, triglycerides, LDL-C/HDL-C ratio of the two groups also showed significant differences. Prevalence of obesity in CAD patients was 70.7% compared with 10% in normal controls. Conclusions: Apo B levels were found to the best predictor of CAD, even though significant differences were also found between CAD and normal subjects for other lipoprotein traits. Obesity was high CAD patients than normal controls.

  17. Influence of infant and juvenile diets on serum cholesterol, lipoprotein cholesterol, and apolipoprotein concentrations in juvenile baboons (Papio sp.). (United States)

    Mott, G E; McMahan, C A; Kelley, J L; Farley, C M; McGill, H C


    The long-term effects of infant diet (breast milk or formula containing 2, 30, or 60 mg/dl cholesterol) and subsequent dietary cholesterol (1 mg/kcal) and fat (saturated or unsaturated) on serum lipid and apolipoprotein concentrations were estimated using 82 juvenile baboons 4-6 years of age. A significant interaction of infant diet (breast vs formula) with type of fat (saturated vs unsaturated) at 4-6 years of age was observed on HDL cholesterol and apolipoprotein A-I (apoA-I) concentrations. That is, animals breast-fed as infants had higher HDL cholesterol and apoA-I concentrations when fed unsaturated fat from weaning to 4-6 years of age than those fed saturated fat (77 vs 68 mg/dl). In contrast, animals fed formulas in infancy followed by a diet containing unsaturated fat had lower HDL cholesterol and apoA-I concentrations at 4-6 years of age than did those fed saturated fat (67 vs 78 mg/dl). However, breast feeding or feeding formulas containing various levels of cholesterol for 3 months during infancy did not result in statistically significant differences in total serum cholesterol, VLDL + LDL cholesterol and apolipoprotein B (apoB) concentrations. Dietary cholesterol after infancy significantly increased serum total cholesterol, VLDL + LDL and HDL cholesterol, apoA-I and apoB concentrations. All of these response variables also were higher in animals fed saturated fat compared to those fed unsaturated fat on the same level of cholesterol. At 4-6 years of age, regardless of diet, females had significantly higher serum VLDL + LDL cholesterol (57 vs 43 mg/dl) and apoB concentrations (39 vs 30 mg/dl) than did males.

  18. Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila. (United States)

    Sanchez, Diego; López-Arias, Begoña; Torroja, Laura; Canal, Inmaculada; Wang, Xiaohui; Bastiani, Michael J; Ganfornina, Maria D


    The vertebrate Apolipoprotein D (ApoD) is a lipocalin secreted from subsets of neurons and glia during neural development and aging . A strong correlation exists between ApoD overexpression and numerous nervous system pathologies as well as obesity, diabetes, and many forms of cancer . However, the exact relationship between the function of ApoD and the pathophysiology of these diseases is still unknown. We have generated loss-of-function Drosophila mutants for the Glial Lazarillo (GLaz) gene , a homolog of ApoD in the fruit fly, mainly expressed in subsets of adult glial cells. The absence of GLaz reduces the organism's resistance to oxidative stress and starvation and shortens male lifespan. The mutant flies exhibit a smaller body mass due to a lower amount of neutral lipids stored in the fat body. Apoptotic neural cell death increases in aged flies or upon paraquat treatment, which also impairs neural function as assessed by behavioral tests. The higher sensitivity to oxidative stress and starvation and the reduced fat storage revert to control levels when a GFP-GLaz fusion protein is expressed under the control of the GLaz natural promoter. Finally, GLaz mutants have a higher concentration of lipid peroxidation products, pointing to a lipid peroxidation protection or scavenging as the mechanism of action for this lipocalin. In agreement with Walker et al. (, in this issue of Current Biology), who analyze the effects of overexpressing GLaz, we conclude that GLaz has a protective role in stress situations and that its absence reduces lifespan and accelerates neurodegeneration.

  19. Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of apolipoprotein E deficient mice

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    Xiao, Hong-Bo, E-mail: [College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128 (China); Lu, Xiang-Yang; Sun, Zhi-Liang [Hunan Agricultural University, Changsha 410128 (China); Zhang, Heng-Bo [Furong District Red Cross Hospital, Changsha 410126 (China)


    Recent studies show that osteopontin (OPN) and its receptor cluster of differentiation 44 (CD44) are two pro-inflammatory cytokines contributing to the development of atherosclerosis. The objective of this study was to explore the inhibitory effect of kaempferol, a naturally occurring flavonoid compound, on atherogenesis and the mechanisms involved. The experiments were performed in aorta and plasma from C57BL/6J control and apolipoprotein E-deficient (ApoE{sup -/-}) mice treated or not with kaempferol (50 or 100 mg/kg, intragastrically) for 4 weeks. Kaempferol treatment decreased atherosclerotic lesion area, improved endothelium-dependent vasorelaxation, and increased the maximal relaxation value concomitantly with decrease in the half-maximum effective concentration, plasma OPN level, aortic OPN expression, and aortic CD44 expression in ApoE{sup -/-} mice. In addition, treatment with kaempferol also significantly decreased reactive oxygen species production in mice aorta. The present results suggest that kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of ApoE{sup -/-} mice. -- Graphical abstract: Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis of ApoE{sup -/-} mice. Highlights: Black-Right-Pointing-Pointer OPN-CD44 pathway plays a critical role in the development of atherosclerosis. Black-Right-Pointing-Pointer We examine lesion area, OPN and CD44 changes after kaempferol treatment. Black-Right-Pointing-Pointer Kaempferol treatment decreased atherosclerotic lesion area in ApoE{sup -/-} mice. Black-Right-Pointing-Pointer Kaempferol treatment decreased aortic OPN and CD44 expressions in ApoE{sup -/-} mice. Black-Right-Pointing-Pointer Kaempferol regulates OPN-CD44 pathway to inhibit the atherogenesis.

  20. Intracellular maturation of apolipoprotein[a] and assembly of lipoprotein[a] in primary baboon hepatocytes. (United States)

    White, A L; Rainwater, D L; Lanford, R E


    The glycoprotein apolipoprotein[a] (apo[a]) is present in plasma at highly variable concentrations and appears as a number of genetically determined size isoforms (400-800 kDa), disulfide linked to apoB-100 in low density lipoprotein to produce lipoprotein [a](Lp[a]). Apo[a] is synthesized by the liver, but the site of association of apo[a] and apoB and factors that regulate its production are unknown. To examine the morphogenesis of the Lp[a] particle, baboon hepatocytes expressing a single, low molecular weight isoform of apo[a] were labeled with [35S]cysteine and methionine, and apo[a] was analyzed by immunoprecipitation and SDS-PAGE. Steady-state labeling revealed two molecular weight forms of apo[a] inside the cell. Only the large form was recovered from the culture medium. Pulse-chase studies and endoglycosidase treatment revealed that the lower molecular weight form of apo[a] represented a precursor with a prolonged residence time in the endoplasmic reticulum or an early Golgi compartment, after which it was processed to the mature form. A proportion of the mature form of apo[a] was rapidly secreted after synthesis, whereas the remainder had a prolonged residence time in a late Golgi compartment. In all experiments, apoB co-precipitated with apo[a] from the culture medium, but not from cell lysates. Density gradient ultracentrifugation and immunoblot analysis revealed that the majority of apo[a] was secreted into the medium in a free form, suggesting that the association between apo[a] and apoB occurred after secretion. Regulation of the movement of apo[a] between intracellular compartments may be one mechanism by which the plasma levels of Lp[a] are influenced.

  1. Effects of Apolipoprotein E Isoforms in Diabetic Nephropathy of Chinese Type 2 Diabetic Patients

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    YongWei Jiang


    Full Text Available Diabetic nephropathy (DN is one of the major chronic complications of diabetes. Genetic polymorphism of Apolipoprotein E (ApoE has been proposed to participating in DN. The purpose of the study was to evaluate the relationship between ApoE genetic polymorphism and the presence of DN in Chinese type 2 diabetic patients. We studied 845 diabetic patients who were divided into DN group (n=429 and control group (n=416. ApoE genotype was determined by ApoE genotyping chip and the plasmatic biochemical characterization was performed on all subjects. There were differences (P<0.001 in HbA1c, creatinine, and urinary albumin between the two groups. The ApoE ε2 allelic frequency was 7.69% in DN group versus 3.49% in control group (OR = 2.22, 95% CI = 1.41–3.47, and P<0.05, as expected, ApoE E2/E2 and E2/E3 genotype frequency were higher in DN group (13.75% versus 6.49%, P<0.05. The ApoE ε4 allelic frequency was 7.93% in DN group versus 11.54% in control group (OR = 0.70, 95% CI = 0.50–0.97, and P<0.05, and DN group presented a lower frequency of ApoE E3/E4 and E4/E4 genotype frequency (14.91% versus 19.96%, P<0.05. These results suggest ApoE ε2 allele may be a risk factor; however ApoE ε4 allele may play a protective role of DN in Chinese type 2 diabetic patients.

  2. Effects of Apolipoprotein E Isoforms in Diabetic Nephropathy of Chinese Type 2 Diabetic Patients (United States)

    Ma, Liang; Han, ChengWu; Liu, Qian; Cong, Xiao; Xu, YaPing; Zhao, TingTing


    Diabetic nephropathy (DN) is one of the major chronic complications of diabetes. Genetic polymorphism of Apolipoprotein E (ApoE) has been proposed to participating in DN. The purpose of the study was to evaluate the relationship between ApoE genetic polymorphism and the presence of DN in Chinese type 2 diabetic patients. We studied 845 diabetic patients who were divided into DN group (n = 429) and control group (n = 416). ApoE genotype was determined by ApoE genotyping chip and the plasmatic biochemical characterization was performed on all subjects. There were differences (P < 0.001) in HbA1c, creatinine, and urinary albumin between the two groups. The ApoE ε2 allelic frequency was 7.69% in DN group versus 3.49% in control group (OR = 2.22, 95% CI = 1.41–3.47, and P < 0.05), as expected, ApoE E2/E2 and E2/E3 genotype frequency were higher in DN group (13.75% versus 6.49%, P < 0.05). The ApoE ε4 allelic frequency was 7.93% in DN group versus 11.54% in control group (OR = 0.70, 95% CI = 0.50–0.97, and P < 0.05), and DN group presented a lower frequency of ApoE E3/E4 and E4/E4 genotype frequency (14.91% versus 19.96%, P < 0.05). These results suggest ApoE ε2 allele may be a risk factor; however ApoE ε4 allele may play a protective role of DN in Chinese type 2 diabetic patients. PMID:28326331

  3. Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation

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    Higuchi, Yoshinori; Nelson, G.A.; Slater, J.M.; Pearlstein, R.D. [Loma Linda Univ., CA (United States). Medical Center; Vazquez, M. [Brookhaven National Lab., Upton, NY (United States); Laskowitz, D.T. [Duke Univ., Durham, NC (United States). Medical Center


    Apolipoprotein E (apoE) is a lipid binding protein that plays an important role in tissue repair following brain injury. In the present studies, we have investigated whether apoE affects the behavioral toxicity of high charge, high energy (HZE) particle radiation. Sixteen male apoE knockout (KO) mice and sixteen genetically matched wild-type (WT) C57BL mice were used in this experiment. Half of the KO and half of the WT animals were irradiated with 600 MeV/amu iron particles (2 Gy whole body). The effect of irradiation on motor coordination and stamina (Rotarod test), exploratory behavior (open field test), and spatial working and reference memory (Morris water maze) was assessed. Rotarod test: Performance was adversely affected by radiation exposure in both KO and WT groups at 30 d after irradiation. By 60 d after radiation, the radiation effect was lost in WT, but still apparent in irradiated KO mice. Open field test: Radiation reduced open field exploratory activity 14, 28, 56, 84, and 168 d after irradiation of KO mice, but had no effect on WT mice. Morris water maze: Radiation adversely affected spatial working memory in the KO mice, but had no discernible effect in the WT mice as assessed 180 d after irradiation. In contrast, irradiated WT mice showed marked impairment of spatial reference memory in comparison to non-irradiated mice, while no effect of radiation was observed in KO mice. These studies show that apoE expression influences the behavioral toxicity of HZE particle radiation and suggest that apoE plays a role in the repair/recovery from radiation injury of the central nervous system (CNS). ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process. (author)

  4. Apolipoprotein D Transgenic Mice Develop Hepatic Steatosis through Activation of PPARγ and Fatty Acid Uptake.

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    Marilyne Labrie

    Full Text Available Transgenic mice (Tg overexpressing human apolipoprotein D (H-apoD in the brain are resistant to neurodegeneration. Despite the use of a neuron-specific promoter to generate the Tg mice, they expressed significant levels of H-apoD in both plasma and liver and they slowly develop hepatic steatosis and insulin resistance. We show here that hepatic PPARγ expression in Tg mice is increased by 2-fold compared to wild type (WT mice. Consequently, PPARγ target genes Plin2 and Cide A/C are overexpressed, leading to increased lipid droplets formation. Expression of the fatty acid transporter CD36, another PPARgamma target, is also increased in Tg mice associated with elevated fatty acid uptake as measured in primary hepatocytes. Elevated expression of AMPK in the liver of Tg leads to phosphorylation of acetyl CoA carboxylase, indicating a decreased activity of the enzyme. Fatty acid synthase expression is also induced but the hepatic lipogenesis measured in vivo is not significantly different between WT and Tg mice. In addition, expression of carnitine palmitoyl transferase 1, the rate-limiting enzyme of beta-oxidation, is slightly upregulated. Finally, we show that overexpressing H-apoD in HepG2 cells in presence of arachidonic acid (AA, the main apoD ligand, increases the transcriptional activity of PPARγ. Supporting the role of apoD in AA transport, we observed enrichment in hepatic AA and a decrease in plasmatic AA concentration. Taken together, our results demonstrate that the hepatic steatosis observed in apoD Tg mice is a consequence of increased PPARγ transcriptional activity by AA leading to increased fatty acid uptake by the liver.

  5. The effect of apolipoprotein E4 on synchronous neural interactions in brain cultures. (United States)

    Christopoulos, Vassilios; Georgopoulos, Angeliki; Georgopoulos, Apostolos P


    In a previous study, we assessed the synchronous neural interactions (SNI) in a developing neural network in brain cultures on multielectrode arrays (Christopoulos et al. in J Neural Eng 9:046008, 2012). Here, we report on the effects of apolipoprotein E4 (apoE4) on these neural interactions. We carried out six experiments (five using rodent brain cultures and one using neuroblastoma cultures) in which we recorded local field potentials (LFP) from 59 sites for several days in vitro under the following conditions. In one experiment, we added to the culture media triglyceride (TG)-rich lipoproteins from a human subject with the apoE4/4 genotype, whereas in the other experiments, we added recombinant human apoE4. We found that SNI in the apoE4-treated cultures had higher coefficient of SNI variation, as compared to control cultures. These findings further document the role of SNI as a fundamental aspect of the dynamic organization of neural networks (Langheim et al. in Proc Natl Acad Sci USA 103:455-459, 2006. doi: 10.1073/pnas.0509623102 ; Georgopoulos et al. in J Neural Eng 4:349-355, 2007) and extend the effect of apoE4 on SNI (Leuthold et al. in Exp Brain Res 226:525-536, 2013) across different brain species (human, rodents), apoE source (TG-rich lipoproteins, recombinant), neural signals (MEG, LFP), and brain network (intact brain, developing brain in vitro). To our knowledge, this is the first study of the effects of apoE4 on neural network function in vitro.

  6. Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review

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    Nebel Almut


    Full Text Available Abstract Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show isoform-specific functional properties including different susceptibilities to diseases. ApoE4 is an accepted risk factor for Alzheimer's disease and cardiovascular disorders. Recently, associations between apoE4 and infectious diseases have been demonstrated. This review summarises how apoE4 may be involved in the infection incidence and associated pathologies of specific infectious diseases, namely hepatitis C, human immunodeficiency virus disease and herpes simplex. ApoE4 seems to be protective against chronic hepatitis C virus infection and retards fibrosis progression. In contrast apoE4 enhances the fusion rate of human immunodeficiency virus with target cell membranes, resulting in accelerated cell entry and faster disease progression. Its association with human immunodeficiency virus-associated dementia remains controversial. Regarding herpes simplex virus infection, apoE4 intensifies virus latency and is associated with increased oxidative damage of the central nervous system, and there is some evidence that herpes simplex virus infection in combination with the apoE4 genotype may be associated with an increased risk of Alzheimer's disease. In addition to reviewing available data from human trials, evidence derived from a variety of cell culture and animal models are considered in this review in order to provide mechanistic insights into observed association between apoE4 genotype and viral disease infection and pathology.

  7. Apolipoprotein E4 allele and the risk of left ventricular dysfunction in thalassemia major

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    M Bazrgar


    Full Text Available Background: Left ventricular (LV failure is the main cause of death in thalassemia. Iron overload in thesepatients leads to formation of oxygen free radicals. Apolipoprotein (ApoE E4 allele is the least efficient inoxidative stress condition compared with apoE2 and apoE3 alleles. This study was performed to determinethe association of three different ApoE alleles with LV dysfunction in thalassemia major patients in southernIran.Methods: The present study comprised 202 patients with thalassemia major divided into three groups accordingto echocardiographic findings: Group 1 (n=135 had no cardiac impairment; Group 2 (n=38 exhibitedLV dilatation but normal LV systolic function and Group 3 (n=29 showed LV systolic dysfunction.DNA was obtained from all patients and 198 healthy control subjects for ApoE genotyping.Results: Frequency of both apoE3/E4 genotype and apoE4 allele in Group 3 were higher than the controlgroup with corresponding values of P<0.05, Odds Ratio=2.97, 1.06<8.32 and P<0.01, OR=3.01,1.15<7.69, respectively and confidence Interval of 95%. There were no differences observed betweencontrols and patient groups in relation to other genotype and allele frequencies. Interventricular septumthickness and LV end diastolic diameter in apoE4/- patients were more than those of apoE3/E3 patients.Conclusion: ApoE4 allele increases the risk of LV impairment in thalassemia major.

  8. Apolipoprotein E4 frequencies in a Japanese population with Alzheimer's disease and dementia with Lewy bodies.

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    Seiju Kobayashi

    Full Text Available BACKGROUND: The apolipoprotein E (APOE ε4 allele has been reported to be a risk factor for Alzheimer's disease (AD and dementia with Lewy bodies (DLB. Previous neuropathological studies have demonstrated similar frequencies of the APOE ε4 allele in AD and DLB. However, the few ante-mortem studies on APOE allele frequencies in DLB have shown lower frequencies than post-mortem studies. One reason for this may be inaccuracy of diagnosis. We examined APOE genotypes in subjects with AD, DLB, and a control group using the latest diagnostic criteria and MRI, SPECT, and MIBG myocardial scintigraphy. METHODS: The subjects of this study consisted of 145 patients with probable AD, 50 subjects with probable DLB, and a control group. AD subjects were divided into two groups based on age of onset: early onset AD (EOAD and late onset AD (LOAD. All subjects had characteristic features on MRI, SPECT, and/or myocardial scintigraphy. RESULTS: The rate of APOE4 carrier status was 18.3% and the frequency of the ε4 allele was 9.7% in controls. The rate of APOE4 carrier status and the frequency of the ε4 allele were 47% and 27% for LOAD, 50% and 31% for EOAD, and 42% and 31% for DLB, respectively. CONCLUSION: The APOE4 genotypes in this study are consistent with previous neuropathological studies suggesting accurate diagnosis of AD and DLB. APOE4 genotypes were similar in AD and DLB, giving further evidence that the ε4 allele is a risk factor for both disorders.

  9. In vivo human apolipoprotein E isoform fractional turnover rates in the CNS.

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    Kristin R Wildsmith

    Full Text Available Apolipoprotein E (ApoE is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4 each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD. Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS, we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

  10. Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma

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    FJ Vizoso; L Rodrigo; M Rodriguez; A Altadill; ML González-Diéguez; A Linares; LO González; S Junquera; F Fresno-Forcelledo; MD Corte


    AIM: To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis.METHODS We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls)to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitive score based on their intensity, and the percentage of immunostained cells was measured.RESULTS: A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However,the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis.CONCLUSION: Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.

  11. Relevance of apolipoprotein E4 for the lipid profile of Brazilian patients with coronary artery disease

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    D.R.S. Souza


    Full Text Available Apolipoprotein E (apoE - e2, e3, e4 alleles plays a role in the regulation of lipid metabolism, with the e4 considered to be a risk factor for coronary artery disease (CAD. We aimed to evaluate the apoE polymorphisms in Brazilians with CAD and their influence on the lipid profile and other risk factors (hypertension, diabetes mellitus, smoking. Two hundred individuals were examined: 100 patients with atherosclerosis confirmed by coronary angiography and 100 controls. Blood samples were drawn to determine apoE polymorphisms and lipid profile. As expected, the e3 allele was prevalent in the CAD (0.87 and non-CAD groups (0.81; P = 0.099, followed by the e4 allele (0.09 and 0.14, respectively; P = 0.158. The e3/3 (76 and 78% and e3/4 (16 and 23% were the most common genotypes for patients and controls, respectively. The lipid profile was altered in patients compared to controls (P < 0.05, independently of the e4 allele. However, in the controls this allele was prevalent in individuals with elevated LDL-cholesterol levels only (odds ratio = 2.531; 95% CI = 1.028-6.232. The frequency of risk factors was higher in the CAD group (P < 0.05, but their association with the lipid profile was not demonstrable in e4 carriers. In conclusion, the e4 allele is not associated with CAD or lipid profile in patients with atherosclerosis. However, its frequency in the non-CAD group is associated with increased levels of LDL-cholesterol, suggesting an independent effect of the e4 allele on lipid profile when the low frequency of other risk factors in this group is taken into account.

  12. Effects of simvastatin on apolipoprotein M in vivo and in vitro

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    Nilsson-Ehle Peter


    Full Text Available Abstract Objective To investigate effects of lipid lowering drug, simvastatin, on apolipoprotein M expression in the hyperlipidemic mice and in hepatic cell line, HepG2 cells. Methods Swiss male mice were randomly divided into the high fat group and control group, and were intragastrically fed with 0.9% saline (control group or lipid emulsion (high fat group at the daily dosage of 15 ml/kg body weight, respectively. After 8 weeks feeding, the hyperlipidemic model was successfully induced and these hyperlipidemic mice were then randomly divided into three experimental groups: vehicle control group, high-dose simvastatin-treated group (100 mg/kg body weight, and low-dose simvastatin-treated group (10 mg/kg body weight. Mice were dosed daily for 6 weeks of simvastatin before mice were sacrificed for determining serum lipid profile and apoM protein levels that was determined by using dot blotting analysis. Effects of simvastatin on apoM mRNA expression in the HepG2 cells were determined by real-time RT-PCR. Results Comparing to high fat model mice without simvastatin treatment, 100 mg/kg simvastatin could significantly increase serum total cholesterol (P P Conclusion The present study suggested that simvastatin, in vivo, had no effect on apoM levels in the hyperlipidemic mouse model. ApoM serum levels in mice were significantly correlated to the animal's age, whereas in cell cultures simvastatin does inhibit apoM expression in the HepG2 cells. The mechanism behind it is not known yet.

  13. Cardiomyocyte Regulation of Systemic Lipid Metabolism by the Apolipoprotein B-Containing Lipoproteins in Drosophila (United States)

    Ishikawa, Zachary


    The heart has emerged as an important organ in the regulation of systemic lipid homeostasis; however, the underlying mechanism remains poorly understood. Here, we show that Drosophila cardiomyocytes regulate systemic lipid metabolism by producing apolipoprotein B-containing lipoproteins (apoB-lipoproteins), essential lipid carriers that are so far known to be generated only in the fat body. In a Drosophila genetic screen, we discovered that when haplo-insufficient, microsomal triglyceride transfer protein (mtp), required for the biosynthesis of apoB-lipoproteins, suppressed the development of diet-induced obesity. Tissue-specific inhibition of Mtp revealed that whereas knockdown of mtp only in the fat body decreases systemic triglyceride (TG) content on normal food diet (NFD) as expected, knockdown of mtp only in the cardiomyocytes also equally decreases systemic TG content on NFD, suggesting that the cardiomyocyte- and fat body-derived apoB-lipoproteins serve similarly important roles in regulating whole-body lipid metabolism. Unexpectedly, on high fat diet (HFD), knockdown of mtp in the cardiomyocytes, but not in fat body, protects against the gain in systemic TG levels. We further showed that inhibition of the Drosophila apoB homologue, apolipophorin or apoLpp, another gene essential for apoB-lipoprotein biosynthesis, affects systemic TG levels similarly to that of Mtp inhibition in the cardiomyocytes on NFD or HFD. Finally, we determined that HFD differentially alters Mtp and apoLpp expression in the cardiomyocytes versus the fat body, culminating in higher Mtp and apoLpp levels in the cardiomyocytes than in fat body and possibly underlying the predominant role of cardiomyocyte-derived apoB-lipoproteins in lipid metabolic regulation. Our findings reveal a novel and significant function of heart-mediated apoB-lipoproteins in controlling lipid homeostasis. PMID:28095410

  14. Effect of peripheral administration of cholecystokinin on food intake in apolipoprotein AIV knockout mice. (United States)

    Yoshimichi, Go; Lo, Chunmin C; Tamashiro, Kellie L K; Ma, Liyun; Lee, Dana M; Begg, Denovan P; Liu, Min; Sakai, Randall R; Woods, Stephen C; Yoshimatsu, Hironobu; Tso, Patrick


    Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 μg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 μg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.

  15. Synergistic effects of high fat feeding and apolipoprotein E deletion on enterocytic amyloid-beta abundance

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    Dhaliwal Satvinder S


    Full Text Available Abstract Background Amyloid-β (Aβ, a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Ingestion of saturated fat significantly enhances enterocytic Aβ abundance whereas fasting abolishes expression. Apolipoprotein (apo E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. In addition, apo E modulates villi length, which may indirectly modulate Aβ as a consequence of differences in lipid absorption. This study compared Aβ abundance and villi length in wild-type (WT and apo E knockout (KO mice maintained on either a low-fat or high-fat diet. Wild-type C57BL/6J and apo E KO mice were randomised for six-months to a diet containing either 4% (w/w unsaturated fats, or chow comprising 16% saturated fats and 1% cholesterol. Quantitative immunohistochemistry was used to assess Aβ abundance in small intestinal enterocytes. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls. Results The saturated fat diet substantially increased enterocytic Aβ in WT and in apo E KO mice, however the effect was greater in the latter. Villi height was significantly greater in apo E KO mice than for WT controls when given the low-fat diet. However, WT mice had comparable villi length to apo E KO when fed the saturated fat and cholesterol enriched diet. There was no effect of the high-fat diet on villi length in apo E KO mice. Conclusion The findings of this study are consistent with the notion that lipid substrate availability modulates enterocytic Aβ. Apo E may influence enterocytic lipid availability by modulating absorptive capacity.

  16. Tau hyperphosphorylation in apolipoprotein E-deficient and control mice after closed head injury. (United States)

    Genis, L; Chen, Y; Shohami, E; Michaelson, D M


    Apolipoprotein E (apoE)-deficient mice have learning and memory impairments that are associated with specific neurochemical changes and hyperphosphorylation of distinct epitopes of the cytoskeletal protein tau. Furthermore, such mice are highly susceptible to the sequelae of brain trauma and their ability to recover from head injury is impaired. In the present study we investigated the extent that the neuronal maintenance and repair impairments of apoE-deficient mice are related to aberrations at the tau phosphorylation level. This was pursued by subjecting control and apoE-deficient mice to closed head injury (CHI) and examination, utilizing immunoblot assays, of the resulting effects on tau phosphorylation. The results thus obtained revealed that tau of apoE-deficient mice is hyperphosphorylated before CHI and that this insult results in transient tau hyperphosphorylation, whose extent and time course in the two mouse groups varied markedly. Tau hyperphosphorylation in the injured controls was maximal by about 4 hr after injury and reverted to basal levels by 24 hr. In contrast, almost no head injury-induced tau hyperphosphorylation was observed in the apoE-deficient mice at 4 hr after injury. Some tau hyper-phosphorylation was detected in the head-injured apoE-deficient mice after longer time intervals, but its extent was markedly lower than the maximal values obtained in the head injured controls. These findings show that the chronic neuronal impairments brought about by apoE deficiency and the acute response to head injury are both associated with hyperphosphorylation of the same tau domain and that the ability of apoE-deficient mice to mount the acute tau hyperphosphorylation response to head injury is impaired.

  17. Alimentary lipemia: plasma high-density lipoproteins and apolipoproteins CII and CIII in healthy subjects. (United States)

    Kashyap, M L; Barnhart, R L; Srivastava, L S; Perisutti, G; Allen, C; Hogg, E; Glueck, C J; Jackson, R L


    Three healthy male and three female inpatient volunteers consumed isocaloric diets for 4 wk. At weekly intervals, a fatty meal (100 g fat) was consumed by each fasting subject and blood drawn at 2 h intervals for 12 h. Of the four oral fat loads, two contained saturated fat (polyunsaturated/saturated fat ratio = 0.34) and two contained unsaturated fat (polyunsaturated/saturated fat = 2.21). The magnitude of alimentary lipemia, expressed as area under the plasma triglyceride curve, was 3- to 4-fold higher in males than females. Alimentary lipemia was inversely related to the subjects' fasting plasma high-density lipoprotein (HDL)-cholesterol, HDL apolipoprotein (apo) CIII and directly related to plasma triglycerides. The P/S ratios of the daily diet or the fat meal did not significantly influence the plasma triglyceride curve. After fat intake, mean (+/- SEM) plasma total apoCII and CIII fell to 54 +/- 20% and 73 +/- 5% of base-line, respectively, at 12 h in five of six subjects. After oral fat, an initial fall and a subsequent rise in apoCII and CIII in HDL was associated with reciprocal changes in apoC concentrations in very low-density lipoproteins. We speculate from the data that 1) plasma HDL and their apoC concentrations are important determinants of chylomicron clearance and 2) transfer of apoCs from HDL to triglyceride-rich lipoproteins in the early phase of fat absorption does not result in the total recycling of apoCs from these lipoproteins to HDL during the late phase of alimentary lipemia.

  18. Fluorescence analysis of the lipid binding-induced conformational change of apolipoprotein E4. (United States)

    Mizuguchi, Chiharu; Hata, Mami; Dhanasekaran, Padmaja; Nickel, Margaret; Phillips, Michael C; Lund-Katz, Sissel; Saito, Hiroyuki


    Apolipoprotein (apo) E is thought to undergo conformational changes in the N-terminal helix bundle domain upon lipid binding, modulating its receptor binding activity. In this study, site-specific fluorescence labeling of the N-terminal (S94) and C-terminal (W264 or S290) helices in apoE4 by pyrene maleimide or acrylodan was employed to probe the conformational organization and lipid binding behavior of the N- and C-terminal domains. Guanidine denaturation experiments monitored by acrylodan fluorescence demonstrated the less organized, more solvent-exposed structure of the C-terminal helices compared to the N-terminal helix bundle. Pyrene excimer fluorescence together with gel filtration chromatography indicated that there are extensive intermolecular helix-helix contacts through the C-terminal helices of apoE4. Comparison of increases in pyrene fluorescence upon binding of pyrene-labeled apoE4 to egg phosphatidylcholine small unilamellar vesicles suggests a two-step lipid-binding process; apoE4 initially binds to a lipid surface through the C-terminal helices followed by the slower conformational reorganization of the N-terminal helix bundle domain. Consistent with this, fluorescence resonance energy transfer measurements from Trp residues to acrylodan attached at position 94 demonstrated that upon binding to the lipid surface, opening of the N-terminal helix bundle occurs at the same rate as the increase in pyrene fluorescence of the N-terminal domain. Such a two-step mechanism of lipid binding of apoE4 is likely to apply to mostly phospholipid-covered lipoproteins such as VLDL. However, monitoring pyrene fluorescence upon binding to HDL(3) suggests that not only apoE-lipid interactions but also protein-protein interactions are important for apoE4 binding to HDL(3).

  19. Fluorescence study of domain structure and lipid interaction of human apolipoproteins E3 and E4. (United States)

    Mizuguchi, Chiharu; Hata, Mami; Dhanasekaran, Padmaja; Nickel, Margaret; Okuhira, Keiichiro; Phillips, Michael C; Lund-Katz, Sissel; Saito, Hiroyuki


    Human apolipoprotein E (apoE) isoforms exhibit different conformational stabilities and lipid-binding properties that give rise to altered cholesterol metabolism among the isoforms. Using Trp-substituted mutations and site- directed fluorescence labeling, we made a comprehensive comparison of the conformational organization of the N- and C-terminal domains and lipid interactions between the apoE3 and apoE4 isoforms. Trp fluorescence measurements for selectively Trp-substituted variants of apoE isoforms demonstrated that apoE4 adopts less stable conformations in both the N- and C-terminal domains compared to apoE3. Consistent with this, the conformational reorganization of the N-terminal helix bundle occurs at lower guanidine hydrochloride concentration in apoE4 than in apoE3 as monitored by fluorescence resonance energy transfer (FRET) from Trp residues to acrylodan attached at the N-terminal helix. Upon binding of apoE3 and apoE4 variants to egg phosphatidylcholine small unilamellar vesicles, similar changes in Trp fluorescence or FRET efficiency were observed for the isoforms, indi- cating that the opening of the N-terminal helix bundle occurs similarly in apoE3 and apoE4. Introduction of mutations into the C-terminal domain of the apoE isoforms to prevent self-association and maintain the monomeric state resulted in great increase in the rate of binding of the C-terminal helices to a lipid surface. Overall, our results demonstrate that the different conformational organizations of the N- and C-terminal domains have a minor effect on the steady-state lipid-binding behavior of apoE3 and apoE4: rather, self-association property is a critical determinant in the kinetics of lipid binding through the C-terminal helices of apoE isoforms.

  20. Cognitive deficits and disruption of neurogenesis in a mouse model of apolipoprotein E4 domain interaction. (United States)

    Adeosun, Samuel O; Hou, Xu; Zheng, Baoying; Stockmeier, Craig; Ou, Xiaoming; Paul, Ian; Mosley, Thomas; Weisgraber, Karl; Wang, Jun Ming


    Apolipoprotein E4 (apoE4) allele is the major genetic risk factor for sporadic Alzheimer disease (AD) due to the higher prevalence and earlier onset of AD in apoE4 carriers. Accumulating data suggest that the interaction between the N- and the C-terminal domains in the protein may be the main pathologic feature of apoE4. To test this hypothesis, we used Arg-61 mice, a model of apoE4 domain interaction, by introducing the domain interaction feature of human apoE4 into native mouse apoE. We carried out hippocampus-dependent learning and memory tests and related cellular and molecular assays on 12- and 3-month-old Arg-61 and age-matched background C57BL/6J mice. Learning and memory task performance were impaired in Arg-61 mice at both old and young ages compared with C57BL/6J mice. Surprisingly, young Arg-61 mice had more mitotic doublecortin-positive cells in the subgranular zone; mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB were also higher in 3-month-old Arg-61 hippocampus compared with C57BL/6J mice. These early-age neurotrophic and neurogenic (proliferative) effects in the Arg-61 mouse may be an inadequate compensatory but eventually detrimental attempt by the system to "repair" itself. This is supported by the higher cleaved caspase-3 levels in the young animals that not only persisted, but increased in old age, and the lower levels of doublecortin at old age in the hippocampus of Arg-61 mice. These results are consistent with human apoE4-dependent cognitive and neuro-pathologic changes, supporting the principal role of domain interaction in the pathologic effect of apoE4. Domain interaction is, therefore, a viable therapeutic/prophylactic target for cognitive impairment and AD in apoE4 subjects.

  1. Association of amyloid burden, brain atrophy and memory deficits in aged apolipoprotein ε4 mice. (United States)

    Yin, Junxiang; Turner, Gregory H; Coons, Stephen W; Maalouf, Marwan; Reiman, Eric M; Shi, Jiong


    Apolipoprotein E ε4 allele (ApoE4) has been associated with increased risk of sporadic Alzheimer's disease (AD) and of conversion from mild cognitive impairment to AD. But the underlying mechanism of ApoE4 affecting brain atrophy and cognition is not fully understood. We investigated the effect of ApoE4 on amyloid beta (Aβ) protein burden and its correlation with the structure change of hippocampus and cortex, cognitive and behavioral changes in ApoE4 transgenic mice. Male ApoE4 transgenic mice and age-matched control mice at age 12 months and 24 months were tested in the Morris Water Maze (MWM). Brain volume changes (including whole brain, hippocampus, cortex, total ventricles and caudate putamen) were assessed by using small animal 7T-MRI. Aβ level was assessed by immunohistochemistry (IHC) and immunoprecipitation/western blot. In MWM, escape latency was longer and time spent in the target quadrant was shorter in aged ApoE4 mice (12- and 24-month-old), suggesting age- and ApoE4-dependent visuospatial deficits. Atrophy on MRI was prominent in the hippocampus (p=0.039) and cortex (p=0.013) of ApoE4 mice (24-month-old) as compared to age-matched control mice. IHC revealed elevated Aβ deposition in the hippocampus. Consistently, both soluble and insoluble Aβ aggregates were increased in aged ApoE4 mice. This increase was correlated inversely with hippocampal atrophy and cognitive deficits. These data give further evidence that ApoE4 plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition.

  2. Epistatic Interactions between apolipoprotein E and hemoglobin S Genes in regulation of malaria parasitemia.

    Directory of Open Access Journals (Sweden)

    Virginie Rougeron

    Full Text Available Apolipoprotein E is a monomeric protein secreted by the liver and responsible for the transport of plasma cholesterol and triglycerides. The APOE gene encodes 3 isoforms Ɛ4, Ɛ3 and Ɛ2 with APOE Ɛ4 associated with higher plasma cholesterol levels and increased pathogenesis in several infectious diseases (HIV, HSV. Given that cholesterol is an important nutrient for malaria parasites, we examined whether APOE Ɛ4 was a risk factor for Plasmodium infection, in terms of prevalence or parasite density. A cross sectional survey was performed in 508 children aged 1 to 12 years in Gabon during the wet season. Children were screened for Plasmodium spp. infection, APOE and hemoglobin S (HbS polymorphisms. Median parasite densities were significantly higher in APOE Ɛ4 children for Plasmodium spp. densities compared to non-APOE Ɛ4 children. When stratified for HbS polymorphisms, median Plasmodium spp. densities were significantly higher in HbAA children if they had an APOE Ɛ4 allele compared to those without an APOE Ɛ4 allele. When considering non-APOE Ɛ4 children, there was no quantitative reduction of Plasmodium spp. parasite densities for HbAS compared to HbAA phenotypes. No influence of APOE Ɛ4 on successful Plasmodium liver cell invasion was detected by multiplicity of infection. These results show that the APOE Ɛ4 allele is associated with higher median malaria parasite densities in children likely due to the importance of cholesterol availability to parasite growth and replication. Results suggest an epistatic interaction between APOE and HbS genes such that sickle cell trait only had an effect on parasite density in APOE Ɛ4 children. This suggests a linked pathway of regulation of parasite density involving expression of these genes. These findings have significance for understanding host determinants of regulation of malaria parasite density, the design of clinical trials as well as studies of co-infection with Plasmodium and other

  3. The apolipoprotein epsilon4 allele confers additional risk in children with familial hypercholesterolemia. (United States)

    Wiegman, Albert; Sijbrands, Eric J G; Rodenburg, Jessica; Defesche, Joep C; de Jongh, Saskia; Bakker, Henk D; Kastelein, John J P


    Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 +/- 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 +/- 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 allele explained 72.4% of the variance of HDL cholesterol levels (-0.15 mmol/L, 95% confidence interval -0.24 to -0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the epsilon4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.

  4. Apolipoprotein B100 is required for hepatitis C infectivity and Mipomersen inhibits hepatitis C (United States)

    Schaefer, Esperance A K; Meixiong, James; Mark, Christina; Deik, Amy; Motola, Daniel L; Fusco, Dahlene; Yang, Andrew; Brisac, Cynthia; Salloum, Shadi; Lin, Wenyu; Clish, Clary B; Peng, Lee F; Chung, Raymond T


    AIM To characterize the role of apolipoprotein B100 (apoB100) in hepatitis C viral (HCV) infection. METHODS In this study, we utilize a gene editing tool, transcription activator-like effector nucleases (TALENs), to generate human hepatoma cells with a stable genetic deletion of APOB to assess of apoB in HCV. Using infectious cell culture-competent HCV, viral pseudoparticles, replicon models, and lipidomic analysis we determined the contribution of apoB to each step of the viral lifecycle. We further studied the effect of mipomersen, an FDA-approved antisense inhibitor of apoB100, on HCV using in vitro cell-culture competent HCV and determined its impact on viral infectivity with the TCID50 method. RESULTS We found that apoB100 is indispensable for HCV infection. Using the JFH-1 fully infectious cell-culture competent virus in Huh 7 hepatoma cells with TALEN-mediated gene deletion of apoB (APOB KO), we found a significant reduction in HCV RNA and protein levels following infection. Pseudoparticle and replicon models demonstrated that apoB did not play a role in HCV entry or replication. However, the virus produced by APOB KO cells had significantly diminished infectivity as measured by the TCID-50 method compared to wild-type virus. Lipidomic analysis demonstrated that these virions have a fundamentally altered lipidome, with complete depletion of cholesterol esters. We further demonstrate that inhibition of apoB using mipomersen, an FDA-approved anti-sense oligonucleotide, results in a potent anti-HCV effect and significantly reduces the infectivity of the virus. CONCLUSION ApoB is required for the generation of fully infectious HCV virions, and inhibition of apoB with mipomersen blocks HCV. Targeting lipid metabolic pathways to impair viral infectivity represents a novel host targeted strategy to inhibit HCV. PMID:28018102

  5. High serum apolipoprotein E determines hypertriglyceridemic dyslipidemias, coronary disease and apoA-I dysfunctionality. (United States)

    Onat, Altan; Can, Günay; Ornek, Ender; Ayhan, Erkan; Erginel-Ünaltuna, Nihan; Murat, Sani N


    The relevance of serum apolipoprotein E (apoE) levels to two hypertriglyceridemic dyslipidemias has not been clarified. We explored, in a cross-sectional (and short-term prospective) evaluation, the independent relationship of serum apoE to the atherogenic dyslipidemia, hypertriglyceridemia with elevated apoB (HtgB) and to apoA-I dysfunctionality, previously shown in Turkish adults to be independent of apoE genotype. Serum apoE concentrations were measured by immunonephelometry in 1,127 middle-aged adults. In multivariable regression analysis, apoE concentrations showed log-linear associations with apoB and apoA-I levels, waist circumference, independent of C-reactive protein (CRP), homeostatic model assessment (HOMA) index and other confounders. The likelihood of atherogenic dyslipidemia and of HtgB roughly tripled per 1-SD increment in apoE concentrations, additively to apoE genotype, HOMA, apoA-I, CRP concentrations and waist circumference; yet apoA-I, protective against atherogenic dyslipidemia, appeared to promote HtgB, a finding consistent with apoA-I dysfunctionality in this setting. Each 1-SD increment in the apoE level was moreover, associated in both genders with MetS (at OR 1.5), after adjustment for sex, age, apoB, apoA-I and CRP, or for apoE genotypes. Circulating apoE predicted in both genders age-adjusted prevalent and incident coronary heart disease (CHD), independent of apoE genotype and CRP (OR 1.32 [95 % CI 1.11; 1.58]). To conclude, in a general population prone to MetS, elevated apoE concentrations are strongly linked to HtgB and atherogenic dyslipidemia, irrespective of apoE genotype, are associated with MetS and CHD. Excess apoE reflects pro-inflammatory state and likely autoimmune activation.

  6. Apolipoprotein E and Alzheimer disease: Genotype-specific risks by age and sex

    Energy Technology Data Exchange (ETDEWEB)

    Bickeboeller, H. [INSERM, Paris (France)]|[IMSE, Munich (Germany); Babron, M.C.; Clerget-Darpoux, F. [INSERM, Paris (France)] [and others


    The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE {epsilon}3 allele, an increased risk associated with the APOE {epsilon}4 allele (odds ratio [OR] [{epsilon}4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE {epsilon}2 allele (OR[{epsilon}2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the {epsilon}4 allele dosage on susceptibility was confirmed (OR[{epsilon}4/{epsilon}4] vs. the {epsilon}3/{epsilon}3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[{epsilon}3/{epsilon}4] vs. the {epsilon}3/{epsilon}3 genotype = 2.2 [95% Cl = 1.5-3.5]). The frequency of the {epsilon}4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the {epsilon}4 allele versus the {epsilon}3 allele, OR({epsilon}4), were not equal in all age classes: OR({epsilon}4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In {epsilon}3/{epsilon}4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women. 53 refs., 1 fig., 3 tabs.

  7. Safrole-2',3'-oxide induces atherosclerotic plaque vulnerability in apolipoprotein E-knockout mice. (United States)

    Su, Le; Zhang, Haiyan; Zhao, Jing; Zhang, Shangli; Zhang, Yun; Zhao, Baoxiang; Miao, Junying


    Safrole-2',3'-oxide (SFO) is the major electrophilic metabolite of safrole (4-allyl-1, 2-methylenedioxybenzene), a natural plant constituent found in essential oils of numerous edible herbs and spices and in food containing these herbs, such as pesto sauce, cola beverages and bologna sausages. The effects of SFO in mammalian systems, especially the cardiovascular system, are little known. Disruption of vulnerable atherosclerotic plaques in atherosclerosis, a chronic inflammatory disease, is the main cause of cardiovascular events. In this study, we investigated SFO-induced atherosclerotic plaque vulnerability (possibility of rupture) in apolipoprotein E-knockout (apoE(-/-)) mice. Lipid area in vessel wall reached 59.8% in high dose SFO (SFO-HD) treated group, which is only 31.2% in control group. SFO treatment changed the lesion composition to an unstable phenotype, increased the number of apoptotic cells in plaque and the endothelium in plaques was damaged after SFO treatment. Furthermore, compared with control groups, the plaque endothelium level of p75(NTR) was 3-fold increased and the liver level of p75(NTR) was 17.4-fold increased by SFO-HD. Meanwhile, the serum level of KC (a functional homolog of IL-8 and the main proinflammatory alpha chemokine in mice) in apoE(-/-) mice was up to 357pg/ml in SFO-HD treated group. Thus, SFO contributes to the instability of atherosclerotic plaque in apoE(-/-) mice through activating p75(NTR) and IL-8 and cell apoptosis in plaque.

  8. Apolipoprotein E-epsilon 4 allele and familial risk in Alzheimer's disease. (United States)

    Li, G; Silverman, J M; Altstiel, L D; Haroutunian, V; Perl, D P; Purohit, D; Birstein, S; Lantz, M; Mohs, R C; Davis, K L


    Recent studies have found an association between presence of apolipoprotein E (APOE) epsilon 4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the epsilon 4 allele with the relatives of AD probands not carrying epsilon 4 and with relatives of non-demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying epsilon 4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 non-demented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age > or = 45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the epsilon 4 allele was significantly higher than that in the relatives of non-demented controls. However, the increased risk in the relatives of AD probands with the epsilon 4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without epsilon 4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with epsilon 4 (3.1-fold increase) was found compared to relatives of probands without epsilon 4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-epsilon 4 allele relative to controls suggests that familial factors in addition to APOE-epsilon 4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with

  9. Apolipoprotein C-III Nanodiscs Studied by Site-Specific Tryptophan Fluorescence. (United States)

    Brisbois, Chase A; Lee, Jennifer C


    Apolipoprotein C-III (ApoC-III) is found on high-density lipoproteins (HDLs) and remodels 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicles into HDL-like particles known as nanodiscs. Using single-Trp-containing ApoC-III mutants, we have studied local side chain environments and interactions in nanodiscs at positions W42, W54, and W65. Using transmission electron microscopy and circular dichroism spectroscopy, nanodiscs were characterized at the ultrastructural and secondary conformational levels, respectively. Nearly identical particles (15 ± 2 nm) were produced from all proteins containing approximately 25 ± 4 proteins per particle with an average helicity of 45-51% per protein. Distinct residue-specific fluorescence properties were observed with W54 residing in the most hydrophobic environment followed by W42 and W65. Interestingly, time-resolved anisotropy measurements revealed that Trp side chain mobility is uncorrelated to the polarity of its surroundings. W54 is the most mobile compared to W65 and W42, which are more immobile in a nanodisc-bound state. On the basis of Trp spectral comparisons of ApoC-III in micellar and vesicle environments, ApoC-III binding within nanodiscs more closely resembles a bilayer-bound state. Despite the nanodiscs being structurally similar, we found marked differences during nanodisc formation by the Trp variants as a function of temperature, with W42 behaving the most like the wild-type protein. Our data suggest that despite the modest mutations of Trp to Phe at two of the three native sites, the interfacial location of W42 is important for lipid binding and nanodisc assembly, which may be biologically meaningful as of the three Trp residues, only W42 is invariant among mammals.

  10. Production of Cloned Miniature Pigs Expressing High Levels of Human Apolipoprotein(a in Plasma.

    Directory of Open Access Journals (Sweden)

    Masayuki Ozawa

    Full Text Available High lipoprotein(a [Lp(a] levels are a major risk factor for the development of atherosclerosis. However, because apolipoprotein(a [apo(a], the unique component of Lp(a, is found only in primates and humans, the study of human Lp(a has been hampered due to the lack of appropriate animal models. Using somatic cell nuclear transfer (SCNT techniques, we produced transgenic miniature pigs expressing human apo(a in the plasma. First, we placed the hemagglutinin (HA-tagged cDNA of human apo(a under the control of the β-actin promoter and cytomegalovirus enhancer, and then introduced this construct into kidney epithelial cells. Immunostaining of cells with anti-HA antibody allowed identification of cells stably expressing apo(a; one of the positive clones was used to provide donor cells for SCNT, yielding blastocysts that expressed apo(a. Immunohistochemical analysis of tissue sections and RT-PCR analysis of total RNA from organs of cloned piglet revealed that apo(a is expressed in various tissues/organs including heart, liver, kidney, and intestine. More importantly, a transgenic line exhibited a high level (>400 mg/dL of Lp(a in plasma, and the transgenic apo(a gene was transmitted to the offspring. Thus, we generated a human apo(a-transgenic miniature pig that can be used as a model system to study advanced atherosclerosis related to human disease. The anatomical and physiological similarities between the swine and human cardiovascular systems will make this pig model a valuable source of information on the role of apo(a in the formation of atherosclerosis, as well as the mechanisms underlying vascular health and disease.

  11. Off-target effects of thrombolytic drugs: apolipoprotein A-I proteolysis by alteplase and tenecteplase. (United States)

    Gomaraschi, Monica; Ossoli, Alice; Vitali, Cecilia; Pozzi, Silvia; Vitali Serdoz, Laura; Pitzorno, Cristina; Sinagra, Gianfranco; Franceschini, Guido; Calabresi, Laura


    The administration of thrombolytic drugs is of proven benefit in a variety of clinical conditions requiring acute revascularization, including acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism, and venous thrombosis. Generated plasmin can degrade non-target proteins, including apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoproteins (HDL). Aim of the present study was to compare the extent of apoA-I proteolytic degradation in AMI patients treated with two thrombolytic drugs, alteplase and the genetically engineered t-PA variant tenecteplase. ApoA-I degradation was evaluated in sera from 38 AMI patients treated with alteplase or tenecteplase. In vitro, apoA-I degradation was tested by incubating control sera or purified HDL with alteplase or tenecteplase at different concentrations (5-100 μg/ml). Treatment with alteplase and tenecteplase results in apoA-I proteolysis; the extent of apoA-I degradation was more pronounced in alteplase-treated patients than in tenecteplase-treated patients. In vitro, the extent of apoA-I proteolysis was higher in alteplase-treated sera than in tenecteplase-treated sera, in the whole drug concentration range. No direct effect of the two thrombolytic agents on apoA-I degradation was observed. In addition to apoA-I, apoA-IV was also degraded by the two thrombolytic agents and again proteolytic degradation was higher with alteplase than tenecteplase. In conclusion, this study indicates that both alteplase and tenecteplase cause plasmin-mediated proteolysis of apoA-I, with alteplase resulting in a greater apoA-I degradation than tenecteplase, potentially causing a transient impairment of HDL atheroprotective functions.

  12. CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking. (United States)

    Weng, Pei-Hsuan; Chen, Jen-Hau; Chen, Ta-Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen-Ching


    α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-β. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, apolipoprotein E (APOE) ε4 status and smoking on dementia risk. This case-control study recruited 254 late-onset Alzheimer's disease (LOAD) and 115 vascular dementia (VaD) cases (age ≥65) from the neurology clinics of three teaching hospitals in Taiwan during 2007-2010. Controls (N = 435) were recruited from health checkup programs and volunteers during the same period. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among APOE ε4 non-carriers, CHRNA7 rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio = 0.29, 95% confidence interval = 0.13-0.64, P = 0.002). Similar findings were observed for carriers of GT haplotype in CHRNA7 block4. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. These findings help to understand dementia pathogenesis.

  13. Functional network endophenotypes unravel the effects of apolipoprotein E epsilon 4 in middle-aged adults.

    Directory of Open Access Journals (Sweden)

    Joseph S Goveas

    Full Text Available Apolipoprotein E-ε4 (APOE-ε4 accentuates memory decline, structural volume loss and cerebral amyloid deposition in cognitively healthy adults. We investigated whether APOE-ε4 carriers will show disruptions in the intrinsic cognitive networks, including the default mode (DMN, executive control (ECN and salience (SN networks, relative to noncarriers in middle-aged healthy adults; and the extent to which episodic-memory performance is related to the altered functional connectivity (Fc in these networks. Resting-state functional connectivity MRI (R-fMRI was used to measure the differences in the DMN, ECN and SN Fc between 20 APOE-ε4 carriers and 26 noncarriers. Multiple linear regression analyses were performed to determine the relationship between episodic-memory performance and Fc differences in the three resting-state networks across all subjects. There were no significant differences in the demographic and neuropsychological characteristics and the gray-matter volumes in the carriers and noncarriers. While mostly diminished DMN and ECN functional connectivities were seen, enhanced connections to the DMN structures were found in the SN in ε4 carriers. Altered DMN and ECN were associated with episodic memory performance. Significant Fc differences in the brain networks implicated in cognition were seen in middle-aged individuals with a genetic risk for AD, in the absence of cognitive decline and gray-matter atrophy. Prospective studies are essential to elucidate the potential of R-fMRI technique as a biomarker for predicting conversion from normal to early AD in healthy APOE-ε4 carriers.

  14. Apolipoprotein E polymorphism influences postprandial retinyl palmitate but not triglyceride concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Boerwinkle, E. (Univ. of Texas Health Science Center, Houston, TX (United States)); Brown, S.; Patsch, W. (Methodist Hospital and Baylor College of Medicine, Houston, TX (United States)); Sharrett, A.R. (National Heart, Lung, and Blood Institute, Bethesda, MD (United States)); Heiss, G. (Univ. of North Carolina, Chapel Hill, NC (United States))


    To quantify the effect of the apolipoprotein (apo) E polymorphism on the magnitude of postprandial lipemia, the authors have defined its role in determining the response to a single high-fat meal in a large sample of (N = 474) individuals taking part in the biethnic Atherosclerosis Risk in Communities Study. The profile of postprandial response in plasma was monitored over 8 h by triglyceride, triglyceride-rich lipoprotein (TGRL)-triglyceride, apo B-48/apo B-100 ratio, and retinyl palmitate concentrations, and the apo E polymorphism was determined by DNA amplification and digestion. The frequency of the apo E alleles and their effects on fasting lipid levels in this sample with vitamin A was significantly different among apo E genotypes, with delayed clearance in individuals with an [var epsilon]2 allele, compared with [var epsilon]3/3 and [var epsilon]3/4 individuals. In the sample of 397 Caucasians, average retinyl palmitate response was 1,489 [mu]g/dl in [var epsilon]2/3 individuals, compared with 1,037 [mu]g/dl in [var epsilon]3/3 individuals and 1,108 [mu]g/dl in [var epsilon]3/4 individuals. The apo E polymorphism accounted for 7.1% of the interindividual variation in postprandial retinyl palmitate response, a contribution proportionally greater than its well-known effect on fasting LDL-cholesterol. However, despite this effect on postprandial retinyl palmitate, the profile of postprandial triglyceride response was not significantly different among apo E genotypes. The profile of postprandial response was consistent between the sample of Caucasians and a smaller sample of black subjects. While these data indicate that the removal of remnant particles from circulation is delayed in subjects with the [var epsilon]2/3 genotype, there is no reported evidence that the [var epsilon]2 allele predisposes to coronary artery disease (CAD). 82 refs., 6 figs., 4 tabs.

  15. [Investigation of neuroprotective activity of apolipoprotein E peptide mimetic Cog1410 in transgenic lines of Drosophila melanogaster]. (United States)

    Latypova, E M; Timoshenko, S I; Kislik, G A; Vitek, M; Shvartsman, A L; Sarantseva, S V


    The neuroprotective activity of apolipoprotein E (apoE) peptide mimetic Cog1410, containing amino acid sequence of the receptor-binding domain apoE, has been investigated in transgenic lines of Drosophila melanogaster expressing human APP and beta-secretase. Expression of two transgenes caused neuropathological processes attributed to Alzheimer's disease: neurodegeneration, cognitive abnormality and amyloid deposits formation in brain. It was shown that Cog 1410 reduces neurodegeneration in brain of transgenic flies and improves cognitive functions (odor recognition). These data suggest that Cog1410 is a potential neuroprotector that can be used in AD treatment.

  16. Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease. (United States)

    Patterson, C E; Todd, S A; Passmore, A P


    Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ε4 (APOE ε4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) ≥21) (P<0.01). In moderate-to-severe AD (MMSE ≤15), presence of the BCHE-K variant was associated with late response to cholinesterase inhibitor treatment (P=0.02). Testing for APOE and BCHE genotypes may be useful in therapeutic decision making.

  17. Relationship of plasma apolipoprotein M with proprotein convertase subtilisin-kexin type 9 levels in non-diabetic subjects

    DEFF Research Database (Denmark)

    Kappelle, Paul J W H; Lambert, Gilles; Dahlbäck, Björn;


    PURPOSE: Apolipoprotein M (apoM) retards atherosclerosis development in murine models, and may be regulated by pathways involved in LDL metabolism. Proprotein convertase subtilisin-kexin type 9 (PCSK9) plays a key role in LDL receptor processing. We determined the extent to which plasma apo......M is related to PCSK9 levels in subjects with varying degrees of obesity. METHODS: We sought correlations between plasma apoM and PCSK9, measured using recently developed ELISAs, in 79 non-diabetic subjects. RESULTS: ApoM and PCSK9 levels were both correlated positively with total cholesterol, non-HDL...... cholesterol, LDL cholesterol and apoB (P

  18. High 99mTc-DPD myocardial uptake in a patient with apolipoprotein AI-related amyloidotic cardiomyopathy. (United States)

    Quarta, Candida Cristina; Obici, Laura; Guidalotti, Pier Luigi; Pieroni, Maurizio; Longhi, Simone; Perlini, Stefano; Verga, Laura; Merlini, Giampaolo; Rapezzi, Claudio


    Amyloidotic cardiomyopathy is still a widely underdiagnosed condition that usually requires endomyocardial biopsy (EMB) for a definite diagnosis. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has proven highly sensitive for detecting amyloidotic cardiomyopathy due to transthyretin-related amyloid deposition. Herein we report the first description of the (99mTc-DPD scintigraphy profile in a patient with suspected amyloidotic cardiomyopathy and a final EMB- and genetically-proven diagnosis of familial apolipoprotein AI amyloidosis due to Leu174Ser variant.

  19. XbaⅠpolymorphisms of apolipoprotein B gene:Another risk factor of gallstone formation after radical gastrectomy

    Institute of Scientific and Technical Information of China (English)


    AIM:To prospectively investigate the association between the XbaⅠpolymorphisms of apolipoprotein B (APOB)gene and gallstone formation following gastrectomy.METHODS:The study was conducted between January 2005 and December 2006.A total of 186 gastric cancer patients who had undergone radical gastrectomy were grouped according to XbaⅠpolymorphisms of APOB gene(X+X-group,n=24 and X-X-group,n =162)and compared.The XbaⅠpolymorphisms of APOB gene were detected by polymerase chain reaction-restriction fragment len...

  20. Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake

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    Jessica P. Otis


    Full Text Available Improved understanding of lipoproteins, particles that transport lipids throughout the circulation, is vital to developing new treatments for the dyslipidemias associated with metabolic syndrome. Apolipoproteins are a key component of lipoproteins. Apolipoproteins are proteins that structure lipoproteins and regulate lipid metabolism through control of cellular lipid exchange. Constraints of cell culture and mouse models mean that there is a need for a complementary model that can replicate the complex in vivo milieu that regulates apolipoprotein and lipoprotein biology. Here, we further establish the utility of the genetically tractable and optically clear larval zebrafish as a model of apolipoprotein biology. Gene ancestry analyses were implemented to determine the closest human orthologs of the zebrafish apolipoprotein A-I (apoA-I, apoB, apoE and apoA-IV genes and therefore ensure that they have been correctly named. Their expression patterns throughout development were also analyzed, by whole-mount mRNA in situ hybridization (ISH. The ISH results emphasized the importance of apolipoproteins in transporting yolk and dietary lipids: mRNA expression of all apolipoproteins was observed in the yolk syncytial layer, and intestinal and liver expression was observed from 4–6 days post-fertilization (dpf. Furthermore, real-time PCR confirmed that transcription of three of the four zebrafish apoA-IV genes was increased 4 hours after the onset of a 1-hour high-fat feed. Therefore, we tested the hypothesis that zebrafish ApoA-IV performs a conserved role to that in rat in the regulation of food intake by transiently overexpressing ApoA-IVb.1 in transgenic larvae and quantifying ingestion of co-fed fluorescently labeled fatty acid during a high-fat meal as an indicator of food intake. Indeed, ApoA-IVb.1 overexpression decreased food intake by approximately one-third. This study comprehensively describes the expression and function of eleven zebrafish

  1. The P-A-C-I-E-N-T-E Protocol: An instrument for breaking bad news adapted to the Brazilian medical reality

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    Carolina Rebello Pereira

    Full Text Available Summary Objective: There are plenty of published tools for breaking bad medical news; however, none of them is culturally appropriate to our reality or published in the Brazilian literature. This study proposes a genuinely Brazilian communication tool and evaluates its acceptance among doctors and nurses. Method: This was a prospective study. The data were collected after specific training of doctors and nurses on the bad news communication techniques based on the P-A-C-I-E-N-T-E ("patient," in Portuguese Protocol. This instrument is in accordance with the Brazilian reality and was based on the SPIKES communication tool. Results: The worst task to be performed during communication is "talking about death" followed by "discussing the end of curative treatment attempts" and "diagnosis" itself. Among the respondents, 48% reported they did not receive formal training for communicating. Also, 52% of respondents do not use any systematic approach in their daily practice when communicating with patients, but 97% considered the proposed P-A-C-I-E-N-T-E Protocol as a useful and appropriate communication tool. Conclusion: The P-A-C-I-E-N-T-E Protocol proved to be suitable to the Brazilian context.

  2. An investigation of human apolipoproteins B and E polymorphisms in two African populations from Ethiopia and Benin. (United States)

    Corbo, R.M.; Scacchi, R.; Rickards, O.; Martinez-Labarga, C.; De Stefano, G.F.


    Three polymorphisms (XbaI, EcoRI, and Ins/Del) of the apolipoprotein B (APOB) gene and the polymorphism of apolipoprotein E (APOE) were investigated in two population samples of Amhara and Oromo origin from Ethiopia, and in two population samples of Bariba and Berba origin from Benin. No heterogeneity was observed within each major group. The cumulated frequencies of the APOB X+, R+, and D alleles for the Ethiopia and the Benin groups were 0.268 and 0.133, 0.958 and 0.818, 0.206 and 0.223, respectively. Regarding APOE, the cumulated allele frequencies of Ethiopia and Benin were 0.031 and 0.103 for epsilon*2 allele, 0.811 and 0.742 for epsilon*3, and 0.143 and 0.155 for epsilon*4, respectively. APOE typing performed at the protein level only in the Ethiopians revealed a variant allele, epsilon*5, found at the polymorphic level both in the Amhara and in the Oromo (cumulated frequency: 0.015). A tentative explanation for the higher frequencies of epsilon*4 and epsilon*5 alleles was sought in relation to the lifestyle and ethnicity of the two populations. Am. J. Hum. Biol. 11:297-304, 1999. Copyright 1999 Wiley-Liss, Inc.

  3. Human ApoD, an apolipoprotein up-regulated in neurodegenerative diseases, extends lifespan and increases stress resistance in Drosophila. (United States)

    Muffat, Julien; Walker, David W; Benzer, Seymour


    Apolipoprotein D (ApoD) expression increases in several neurological disorders and in spinal cord injury. We provide a report of a physiological role for human ApoD (hApoD): Flies overexpressing hApoD are long-lived and protected against stress conditions associated with aging and neurodegeneration, including hyperoxia, dietary paraquat, and heat stress. We show that the fly ortholog, Glial Lazarillo, is strongly up-regulated in response to these extrinsic stresses and also can protect in vitro-cultured cells in situations modeling Alzheimer's disease (AD) and Parkinson's disease (PD). In adult flies, hApoD overexpression reduces age-associated lipid peroxide accumulation, suggesting a proximal mechanism of action. Similar data obtained in the mouse [Ganfornina, M.D., et al., (2008) Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress. Aging Cell 10.1111/j.1474-9726.2008.00395.] as well as in plants (Charron et al., personal communication) suggest that ApoD and its orthologs play an evolutionarily conserved role in response to stress, possibly managing or preventing lipid peroxidation.

  4. Reduction of Risk Factor Coagulation Oxidative Apolipoprotein and Development of Atherosclerosis by Apple Cider Vinegar in Hypercholesterolemic Rabbits

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    Mahbubeh Setorki


    Full Text Available Introduction: Apple cider vinegar is an antioxidant compound and it has many medical uses. In this research we have investigated effects of apple cider vinegar on some risk factors of atherosclerosis and on the development of atherosclerosis in hypercholesterolemic rabbit. Methods: Thirty two male New Zealand rabbits were randomly divided into four groups: normal diet group high cholesterol diet group (%1cholesterol %1 cholesterol with 5ml apple cider vinegar group and %1 cholesterol with 10ml apple cider vinegar group .The malondialdehyde (MDA oxidized-LDL (oxLDL fibrinogen factor VII apolipoprotein A (ApoA and apolipoprotein B (ApoB were measured before the experiment and at the end period (2month. At the end of study using Chekanov method fatty streak formation in aorta artery was determined in all groups. Results: Using both doses of apple cider vinegar significantly decreased fibrinogen oxLDL MDA ApoB ApoB/ApoA VIIlevels in comparison with hypercholesterolemic diet (P0.05. Also consumption of apple cider vinegar induced significant decrease in atherosclerotic lesions in aorta artery compared to the hypercholesterolemic diet. Conclusion: This study suggests that apple cider vinegar (as an antioxidant might have some protective effects on biochemical risk factors of atherosclerosis.

  5. Common and Rare Alleles in Apolipoprotein B Contribute to Plasma Levels of LDL Cholesterol in the General Population

    DEFF Research Database (Denmark)

    Benn, M; Stene, MC; Nordestgaard, BG;


    demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. OBJECTIVE: We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. DESIGN......: This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study. SETTING: The study was conducted in the Danish general population. PARTICIPANTS: Participants included 9185 women and men aged 20-80+ yr. MAIN OUTCOME MEASURES: Levels of LDL cholesterol and apolipoprotein B and risk of ischemic......Q (0.09), E4154K (0.17), and N4311S (0.21). SNPs were associated with increases (T71I, Ivs181708g>t, T2488Tc>t, R3611) or decreases (Ivs4+171c>a, A591V, Ivs18+379a>c, P2712L, E4154, N4311S) in LDL cholesterol from -4.7 to +8.2% (-0.28 to 0.30 mmol/liter; P

  6. In silico analysis of the apolipoprotein E and the amyloid beta peptide interaction: misfolding induced by frustration of the salt bridge network.

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    Jinghui Luo


    Full Text Available The relationship between Apolipoprotein E (ApoE and the aggregation processes of the amyloid beta (A beta peptide has been shown to be crucial for Alzheimer's disease (AD. The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the A beta peptide are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. Here, computer simulations have been used to investigate the process of A beta interaction with the N-terminal domain of the human ApoE isoforms (ApoE2, ApoE3 and ApoE4. Molecular docking combined with molecular dynamics simulations have been undertaken to determine the A beta peptide binding sites and the relative stability of binding to each of the ApoE isoforms. Our results show that from the several ApoE isoforms investigated, only ApoE4 presents a misfolded intermediate when bound to A beta. Moreover, the initial alpha-helix used as the A beta peptide model structure also becomes unstructured due to the interaction with ApoE4. These structural changes appear to be related to a rearrangement of the salt bridge network in ApoE4, for which we propose a model. It seems plausible that ApoE4 in its partially unfolded state is incapable of performing the clearance of A beta, thereby promoting amyloid forming processes. Hence, the proposed model can be used to identify potential drug binding sites in the ApoE4-A beta complex, where the interaction between the two molecules can be inhibited.

  7. Apolipoprotein E gene ε4ε4 is associated with elevated risk of primary open angle glaucoma in Asians: a meta-analysis (United States)


    Background Epidemiological studies have evaluated the association between Apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism and glaucoma susceptibility. However, the published data are still inconclusive. The aim of the present study is to evaluate the impact of APOE gene ε2/ε3/ε4 polymorphism on glaucoma risk by using meta-analysis. Methods A comprehensive literature search of PubMed, EMBASE, Cochrane, Elsevier Science Direct and CNKI databases was conducted to identify relevant articles, with the last report up to January 5, 2014. Pooled odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association by using the fixed or random effect model. Results Fifteen separate studies including 2,700 cases and 2,365 controls were included in the meta-analysis. We did not detect a significant association between APOE gene ε2/ε3/ε4 polymorphism and glaucoma in overall population (P > 0.0083). In Asians, we detected an association of the ε4ε4 genotype with elevated risk for glaucoma (OR = 5.22, 95% CI = 1.85-14.68, P = 0.002), mainly for primary open angle glaucoma (OR = 4.98, 95% CI = 1.75-14.20, P = 0.003). Conclusions The meta-analysis suggests that APOE gene ε4ε4 may be associated with elevated risk for primary open angle glaucoma in Asians. However, more epidemiologic studies based on larger sample size, case–control design and stratified by ethnicity as well as types of glaucoma are suggested to further clarify the relationship between APOE gene ε2/ε3/ε4 polymorphism and genetic predisposition to glaucoma. PMID:24885013

  8. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

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    C.V. Araújo


    Full Text Available Apolipoprotein E (APOE=gene, apoE=protein is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/- and wild-type (APOE+/+ C57BL6J male and female mice (N=86 were given either Ala-Gln (100 mM or phosphate buffered saline (PBS by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU challenge (450 mg/kg, via intraperitoneal injection. Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1 and B-cell lymphoma 2 (Bcl-2 intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001 in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05 were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/--challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

  9. Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity

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    Maezawa Izumi


    Full Text Available Abstract Background Innate immune activation, including a role for cluster of differentiation 14/toll-like receptor 4 co-receptors (CD14/TLR-4 co-receptors, has been implicated in paracrine damage to neurons in several neurodegenerative diseases that also display stratification of risk or clinical outcome with the common alleles of the apolipoprotein E gene (APOE: APOE2, APOE3, and APOE4. Previously, we have shown that specific stimulation of CD14/TLR-4 with lipopolysaccharide (LPS leads to greatest innate immune response by primary microglial cultures from targeted replacement (TR APOE4 mice and greatest p38MAPK-dependent paracrine damage to neurons in mixed primary cultures and hippocampal slice cultures derived from TR APOE4 mice. In contrast, TR APOE2 astrocytes had the highest NF-kappaB activity and no neurotoxicity. Here we tested the hypothesis that direct activation of CD14/TLR-4 in vivo would yield different amounts of paracrine damage to hippocampal sector CA1 pyramidal neurons in TR APOE mice. Methods We measured in vivo changes in dendrite length in hippocampal CA1 neurons using Golgi staining and determined hippocampal apoE levels by Western blot. Neurite outgrowth of cultured primary neurons in response to astrocyte conditioned medium was assessed by measuring neuron length and branch number. Results Our results showed that TR APOE4 mice had slightly but significantly shorter dendrites at 6 weeks of age. Following exposure to intracerebroventricular LPS, there was comparable loss of dendrite length at 24 hr among the three TR APOE mice. Recovery of dendrite length over the next 48 hr was greater in TR APOE2 than TR APOE3 mice, while TR APOE4 mice had failure of dendrite regeneration. Cell culture experiments indicated that the enhanced neurotrophic effect of TR APOE2 was LDL related protein-dependent. Conclusion The data indicate that the environment within TR APOE2 mouse hippocampus was most supportive of dendrite regeneration

  10. Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Araújo, C.V. [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Lazzarotto, C.R. [Laboratório de Biologia Molecular e do Desenvolvimento, Universidade de Fortaleza, Fortaleza, CE (Brazil); Aquino, C.C.; Figueiredo, I.L.; Costa, T.B.; Oliveira Alves, L.A. de [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Ribeiro, R.A. [Laboratório da Inflamação e Câncer, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Bertolini, L.R. [Laboratório de Biologia Molecular e do Desenvolvimento, Universidade de Fortaleza, Fortaleza, CE (Brazil); Lima, A.A.M. [Laboratório de Doenças Infecciosas, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Brito, G.A.C. [Laboratório da Inflamação e Câncer, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil); Oriá, R.B. [Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, INCT - Instituto de Biomedicina do Semiárido Brasileiro, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE (Brazil)


    Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE{sup -/-}) and wild-type (APOE{sup +/+}) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE{sup -/-} mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE{sup +/+} mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE{sup -/-}-challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU

  11. 18F-fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons. (United States)

    Knopman, David S; Jack, Clifford R; Wiste, Heather J; Lundt, Emily S; Weigand, Stephen D; Vemuri, Prashanthi; Lowe, Val J; Kantarci, Kejal; Gunter, Jeffrey L; Senjem, Matthew L; Mielke, Michelle M; Roberts, Rosebud O; Boeve, Bradley F; Petersen, Ronald C


    Our objective was to examine associations between glucose metabolism, as measured by (18)F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer's disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer's Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and (11)C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype

  12. Sex differences in apolipoprotein A1 and nevirapine-induced toxicity

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    Aline Marinho


    Full Text Available Nevirapine (NVP is associated with severe liver and skin toxicity through sulfotransferase (SULT bioactivation of the phase I metabolite 12-hydroxy-NVP [1–3]. The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression (4 and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1 increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabolism and liver function. The study protocol was firstly approved by the hospitals’ Ethics Committees. All included individuals were HIV-infected patients treated with NVP for at least one month. The plasma concentrations of NVP and its phase I metabolites were quantified by HPLC [7]. ApoA1 levels were assessed by an immunoturbidimetric assay. Forty-nine HIV-infected patients on NVP were included (53% men, 59% Caucasian. NVP plasma levels were correlated with HDL-cholesterol (Spearman r=0.2631; p=0.0441 and ApoA1 (Spearman r=0.3907; p=0.0115. Women had higher ApoA1 levels than men (Student's t Test; p=0.0051. In both sexes, 12-hydroxy-NVP levels were negatively correlated with ApoA1 (male: Spearman r=−0.3810; p=0.0499 female: Spearman r=−0.5944; p=0.0415. In men, ApoA1 was positively correlated with aspartate aminotransferase (AST, Spearman r=0.5507; p=0.0413, while in women ApoA1 was associated (Spearman r=0.6408; p=0.0056 with alanine aminotransferase (ALT. These results show sex differences in NVP-induced ApoA1 synthesis. The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12-hydroxy-NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP-induced toxicity.

  13. Synthesis of apolipoprotein B lipoparticles to deliver hydrophobic/amphiphilic materials. (United States)

    Chu, Hsueh-Liang; Cheng, Tsai-Mu; Chen, Hung-Wei; Chou, Fu-Hsuan; Chang, Yu-Chuan; Lin, Hsin-Yu; Liu, Shih-Yi; Liang, Yu-Chuan; Hsu, Ming-Hua; Wu, Dian-Shyeu; Li, Hsing-Yuan; Ho, Li-Ping; Wu, Ping-Ching; Chen, Fu-Rong; Chen, Gong-Shen; Shieh, Dar-Bin; Chang, Chia-Seng; Su, Chia-Hao; Yao, Zemin; Chang, Chia-Ching


    To develop a drug delivery system (DDS), it is critical to address challenging tasks such as the delivery of hydrophobic and amphiphilic compounds, cell uptake, and the metabolic fate of the drug delivery carrier. Low-density lipoprotein (LDL) has been acknowledged as the human serum transporter of natively abundant lipoparticles such as cholesterol, triacylglycerides, and lipids. Apolipoprotein B (apo B) is the only protein contained in LDL, and possesses a binding moiety for the LDL receptor that can be internalized and degraded naturally by the cell. Therefore, synthetic/reconstituting apoB lipoparticle (rABL) could be an excellent delivery carrier for hydrophobic or amphiphilic materials. Here, we synthesized rABL in vitro, using full-length apoB through a five-step solvent exchange method, and addressed its potential as a DDS. Our rABL exhibited good biocompatibility when evaluated with cytotoxicity and cell metabolic response assays, and was stable during storage in phosphate-buffered saline at 4 °C for several months. Furthermore, hydrophobic superparamagnetic iron oxide nanoparticles (SPIONPs) and the anticancer drug M4N (tetra-O-methyl nordihydroguaiaretic acid), used as an imaging enhancer and lipophilic drug model, respectively, were incorporated into the rABL, leading to the formation of SPIONPs- and M4N- containing rABL (SPIO@rABL and M4N@rABL, respectively). Fourier transform infrared spectroscopy suggested that rABL has a similar composition to that of LDL, and successfully incorporated SPIONPs or M4N. SPIO@rABL presented significant hepatic contrast enhancement in T2-weighted magnetic resonance imaging in BALB/c mice, suggesting its potential application as a medical imaging contrast agent. M4N@rABL could reduce the viability of the cancer cell line A549. Interestingly, we developed solution-phase high-resolution transmission electron microscopy to observe both LDL and SPIO@rABL in the liquid state. In summary, our LDL-based DDS, rABL, has

  14. High- and low-temperature unfolding of human high-density apolipoprotein A-2. (United States)

    Gursky, O; Atkinson, D


    Human plasma apolipoprotein A-2 (apoA-2) is the second major protein of the high-density lipoproteins that mediate the transport and metabolism of cholesterol. Using CD spectroscopy and differential scanning calorimetry, we demonstrate that the structure of lipid-free apoA-2 in neutral low-salt solutions is most stable at approximately 25 degrees C and unfolds reversibly both upon heating and cooling from 25 degrees C. High-temperature unfolding of apoA-2, monitored by far-UV CD, extends from 25-85 degrees C with midpoint Th = 56 +/- 2 degrees C and vant Hoff's enthalpy delta H(Th) = 17 +/- 2 kcal/mol that is substantially lower than the expected enthalpy of melting of the alpha-helical structure. This suggests low-cooperativity apoA-2 unfolding. The apparent free energy of apoA-2 stabilization inferred from the CD analysis of the thermal unfolding, delta G(app)(25 degrees) = 0.82 +/- 0.15 kcal/mol, agrees with the value determined from chemical denaturation. Enhanced low-temperature stability of apoA-2 observed upon increase in Na2HPO4 concentration from 0.3 mM to 50 mM or addition of 10% glycerol may be linked to reduced water activity. The close proximity of the heat and cold unfolding transitions, that is consistent with low delta G(app)(25 degrees), indicates that lipid-free apoA-2 has a substantial hydrophobic core but is only marginally stable under near-physiological solvent conditions. This suggests that in vivo apoA-2 transfer is unlikely to proceed via the lipid-free state. Low delta H(Th) and low apparent delta Cp approximately 0.52 kcal/mol.K inferred from the far-UV CD analysis of apoA-2 unfolding, and absence of tertiary packing interactions involving Tyr groups suggested by near-UV CD, are consistent with a molten globular-like state of lipid-free apoA-2.

  15. Blocking TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in apolipoprotein E-deficient mice

    Institute of Scientific and Technical Information of China (English)

    Xiao-xing WANG; Xiao-xi LV; Jia-ping WANG; Hui-min YAN; Zi-yan WANG; Han-zhi LIU; Xiao-ming FU


    Aim:Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis.The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis.Methods:Forty-week old apolipoprotein E-deficient (ApoE-/-) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks.Double-knockout ApoE-/-Tlr2-/-mice were taken as a positive control.At the end of the treatments,the plasma lipid levels were measured,and the plaque morphology,pro-inflammatory cytokines expression and apoptosis in arteries were analyzed.In the second part of this study,6-week old ApoE-/-and ApoE-/-Tlr2-/-mice fed on a high-cholesterol diet for 12 to 24 weeks,the expression levels of TLR2 and apoptotic markers in arteries were examined.Results:Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE-/-mice.However,the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis,and increased plaque stability in the brachiocephalic arteries.The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-KB and Stat3.In addition,blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries,which could promote the resolution of necrotic cores in advanced atherosclerosis.Moreover,high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE-/-mice than in ApoE-/-Tlr2-/-mice.Conclusion:The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE-/-mice.Thus,targeting TLR2 signaling may be a promising therapeutic strategy against

  16. Apolipoprotein E gene polymorphisms are associated with primary hyperuricemia in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jie Wu

    Full Text Available OBJECTIVE: Primary hyperuricemia, an excess of uric acid in the blood, is a major public health problem. In addition to the morbidity that is attributable to gout, hyperuricemia is also associated with metabolic syndrome, hypertension, and cardiovascular disease. This study aims to assess the genetic associations between Apolipoprotein E (APOE polymorphisms and hyperuricemia in a Chinese population. METHODS: A total of 770 subjects (356 hyperuricemic cases and 414 normouricemic controls were recruited from the Ningxia Hui Autonomous Region, China. A physical examination was performed and fasting blood was collected for biochemical tests, including determination of the levels of serum lipid, creatinine, and uric acid. Multi-ARMS PCR was applied to determine the APOE genotypes, followed by an investigation of the distribution of APOE genotypes and alleles frequencies in the controls and cases. RESULTS: The frequencies of the APOE-ε2ε3 genotype (17.70% vs. 10.39%, P = 0.003 and the APOE-ε2 allele (10.53% vs. 5.80%, P = 0.001 were significantly higher in the hyperuricemic group than in the normouricemic group. Furthermore, male cases were more likely to have the APOE-ε2ε3 genotype and APOE-ε2 allele, compared with male controls. In both Han and Hui subjects, cases were more likely to have the APOE-ε2ε3 genotype and the APOE-ε2 allele compared with controls. Furthermore, multivariate logistic regression showed that carriers of the APOE-ε2ε3 genotype (P = 0.001, OR = 2.194 and the ε2 allele (P = 0.001, OR = 2.099 were significantly more likely to experience hyperuricemia than carriers of the ε3/ε3 genotype and the ε3 allele after adjustment for sex, body mass index (BMI, diastolic blood pressure (DBP, triglyceride (TG, low density lipoprotein cholesterol (LDL-C, creatinine (Cr and fasting blood glucose (FBG. CONCLUSIONS: The APOE-ε2ε3 genotype and the APOE-ε2 allele are associated with serum uric acid levels

  17. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stimulates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins (United States)

    Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipopro...

  18. Mechanisms of cinnamon extract-induced suppression of the intestinal overproduction of apolipoprotein B48-containing lipoproteins in insulin resistant high-fructose fed animals (United States)

    We have reported previously that cinnamon extract (CE) prevents high-fructose (HF) feeding-induced whole-body insulin resistance by enhancing insulin signaling in skeletal muscle. In this study, we investigated whether intestinal apolipoprotein overproduction is inhibited by CE in this insulin-resis...

  19. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stumlates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins (United States)

    Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipopro...

  20. Apolipoprotein AV and Metabolism of Blood Lipids%载脂蛋白AV与血脂代谢研究新进展

    Institute of Scientific and Technical Information of China (English)



    新发现的载脂蛋白AV参与血脂代谢,尤其是在三酰甘油分解代谢中起重要作用.载脂蛋白AV通过减少脂蛋白的生成率、增强脂蛋白脂酶对三酰甘油的水解,促进低密度脂蛋白受体介导的富含三酰甘油的脂蛋白颗粒清除作用来调节血脂代谢.载脂蛋白AV的基因多态性与心血管疾病的发生有着密切的关系.%Apolipoprotein AV, a newly discovered apolipoprotein, has been shown to play an important role in the metabolism of lip-ids. It is especially relevant to the metabolism of triglycerides primarily through reducing the lipoprotein production rate, stimulating hydrolysis of triglycerides by lipoprotein lipase, and facilitating clearance of triglyceride-rich lipoprotein by low-density lipoprotein receptor. It has been found that the polymorphism of apolipoprotein AV is closely related with coronary heart disease. This article reviews current literature and recent findings about the role of apolipoprotein AV in lipid metabolism.

  1. The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: Findings from the Food4Me randomized controlled trial

    NARCIS (Netherlands)

    Fallaize, R.; Celis-Morales, C.; MacReady, A.L.; Marsaux, C.F.M.; Forster, H.; O'Donovan, C.; Woolhead, C.; San-Cristobal, R.; Kolossa, S.; Hallmann, J.; Mavrogianni, C.; Surwillo, A.; Livingstone, K.M.; Moschonis, G.; Navas-Carretero, S.; Walsh, M.C.; Gibney, E.R.; Brennan, L.; Bouwman, J.; Grimaldi, K.; Manios, Y.; Traczyk, I.; Drevon, C.A.; Martinez, J.A.; Daniel, H.; Saris, W.H.M.; Gibney, M.J.; Mathers, J.C.; Lovegrove, J.A.


    Background: The apolipoprotein E (APOE) risk allele (e4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether e4 carriers w

  2. Dietary Soy Protein Isolate Ameliorates Atherosclerotic Lesions in Apolipoprotein E-Deficient Mice Potentially by Inhibiting Monocyte Chemoattractant Protein-1 Expression (United States)

    Soy-based diets reportedly protect against the development of atherosclerosis; however, the underlying mechanism(s) for this protection remains unknown. In this report, the mechanism(s) contributing to the atheroprotective effects of a soy-based diet was addressed using the apolipoprotein E knockout...

  3. Photon-dominated region modeling of the [C I], [C II], and CO Line Emission From A Boundary In The Taurus molecular cloud

    Energy Technology Data Exchange (ETDEWEB)

    Orr, Matthew E. [Physics and Astronomy Department, University of Southern California, Los Angeles, CA 90089 (United States); Pineda, Jorge L.; Goldsmith, Paul F. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91109-8099 (United States)


    We present [C I] and [C II] observations of a linear edge region in the Taurus molecular cloud, and model this region as a cylindrically symmetric photon-dominated region (PDR) exposed to a low-intensity UV radiation field. The sharp, long profile of the linear edge makes it an ideal case to test PDR models and determine cloud parameters. We compare observations of the [C I], {sup 3} P {sub 1} → {sup 3} P {sub 0} (492 GHz), [C I] {sup 3} P {sub 2} → {sup 3} P {sub 1} (809 GHz), and [C II] {sup 2} P {sub 3/2} → {sup 2} P {sub 1/2} (1900 GHz) transitions, as well as the lowest rotational transitions of {sup 12}CO and {sup 13}CO, with line intensities produced by the RATRAN radiative transfer code from the results of the Meudon PDR code. We constrain the density structure of the cloud by fitting a cylindrical density function to visual extinction data. We study the effects of variation of the FUV field, {sup 12}C/{sup 13}C isotopic abundance ratio, sulfur depletion, cosmic ray ionization rate, and inclination of the filament relative to the sky-plane on the chemical network of the PDR model and resulting line emission. We also consider the role of suprathermal chemistry and density inhomogeneities. We find good agreement between the model and observations, and that the integrated line intensities can be explained by a PDR model with an external FUV field of 0.05 G {sub 0}, a low ratio of {sup 12}C to {sup 13}C ∼43, a highly depleted sulfur abundance (by a factor of at least 50), a cosmic ray ionization rate (3-6) × 10{sup –17} s{sup –1}, and without significant effects from inclination, clumping or suprathermal chemistry.

  4. Estabilidad temporal del C.I. y potencial de aprendizaje en niños superdotados: implicaciones diagnósticas

    Directory of Open Access Journals (Sweden)

    Mª Dolores Calero


    Full Text Available Tradicionalmente la determinación de la sobredotación se ha realizado con tests tradicionales de inteligencia. El principal argumento para hacerlo ha sido la estabilidad temporal de esta medida. En los últimos años algunos autores defienden una determinación temprana de la sobredotación en niños, aunque otros señalan que la determinación del C.I. en niños pequeños arroja un número importante de falsos positivos debido a la variabilidad de la medida de la inteligencia por influencia de diferentes factores tales como la plasticidad cerebral, la estimulación, etc., por lo que proponen el uso de índices complementarios para el diagnóstico de sobredotación. En este trabajo se realiza un estudio longitudinal de dos años a 49 niños de entre 5 y 9 años, -inicialmente identificados como superdotados-, para comprobar la estabilidad de su C.I. y de otras medidas tales como el potencial de aprendizaje y la memoria de trabajo. Los resultados muestran como las medidas de potencial de aprendizaje y memoria de trabajo permanecen estables en el tiempo mientras que el C.I. de un grupo de niños de menor edad no se mantiene en dicho periodo. Estos resultados señalan la utilidad de las medidas de P.A. como un índice complementario en la determinación de la sobredotación en niños pequeños.

  5. Herschel-spire Fourier transform spectrometer observations of excited CO and [C I] in the antennae (NGC 4038/39): Warm and cold molecular gas

    Energy Technology Data Exchange (ETDEWEB)

    Schirm, Maximilien R. P.; Wilson, Christine D.; Parkin, Tara J. [Department of Physics and Astronomy, McMaster University, Hamilton, ON L8S 4M1 (Canada); Kamenetzky, Julia; Glenn, Jason; Rangwala, Naseem [Center for Astrophysics and Space Astronomy, 389-UCB, University of Colorado, Boulder, CO 80303 (United States); Spinoglio, Luigi; Pereira-Santaella, Miguel [Istituto di Astrofisica e Planetologia Spaziali, INAF-IAPS, Via Fosso del Cavaliere 100, I-00133 Roma (Italy); Baes, Maarten; De Looze, Ilse [Sterrenkundig Observatorium, Universiteit Gent, Krijgslaan 281 S9, B-9000 Gent (Belgium); Barlow, Michael J. [Department of Physics and Astronomy, University College London, Gower Street, London WC1E 6BT (United Kingdom); Clements, Dave L. [Astrophysics Group, Imperial College, Blackett Laboratory, Prince Consort Road, London SW7 2AZ (United Kingdom); Cooray, Asantha [Department of Physics and Astronomy, University of California, Irvine, CA 92697 (United States); Karczewski, Oskar Ł. [Department of Physics and Astronomy, University of Sussex, Brighton BN1 9QH (United Kingdom); Madden, Suzanne C.; Rémy-Ruyer, Aurélie; Wu, Ronin, E-mail:, E-mail: [CEA, Laboratoire AIM, Irfu/SAp, Orme des Merisiers, F-91191 Gif-sur-Yvette (France)


    We present Herschel Spectral and Photometric Imaging Receiver (SPIRE) Fourier Transform Spectrometer (FTS) observations of the Antennae (NGC 4038/39), a well-studied, nearby (22 Mpc), ongoing merger between two gas-rich spiral galaxies. The SPIRE-FTS is a low spatial ( FWHM ∼ 19''-43'') and spectral (∼1.2 GHz) resolution mapping spectrometer covering a large spectral range (194-671 μm, 450-1545 GHz). We detect five CO transitions (J = 4-3 to J = 8-7), both [C I] transitions, and the [N II] 205 μm transition across the entire system, which we supplement with ground-based observations of the CO J = 1-0, J = 2-1, and J = 3-2 transitions and Herschel Photodetecting Array Camera and Spectrometer (PACS) observations of [C II] and [O I] 63 μm. Using the CO and [C I] transitions, we perform both a local thermodynamic equilibrium (LTE) analysis of [C I] and a non-LTE radiative transfer analysis of CO and [C I] using the radiative transfer code RADEX along with a Bayesian likelihood analysis. We find that there are two components to the molecular gas: a cold (T {sub kin} ∼ 10-30 K) and a warm (T {sub kin} ≳ 100 K) component. By comparing the warm gas mass to previously observed values, we determine a CO abundance in the warm gas of x {sub CO} ∼ 5 × 10{sup –5}. If the CO abundance is the same in the warm and cold gas phases, this abundance corresponds to a CO J = 1-0 luminosity-to-mass conversion factor of α{sub CO} ∼ 7 M {sub ☉} pc{sup –2} (K km s{sup –1}){sup –1} in the cold component, similar to the value for normal spiral galaxies. We estimate the cooling from H{sub 2}, [C II], CO, and [O I] 63 μm to be ∼0.01 L {sub ☉}/M {sub ☉}. We compare photon-dominated region models to the ratio of the flux of various CO transitions, along with the ratio of the CO flux to the far-infrared flux in NGC 4038, NGC 4039, and the overlap region. We find that the densities recovered from our non-LTE analysis are consistent with a

  6. Urinary peptidomics identifies potential biomarkers for major depressive disorder. (United States)

    Wang, Ying; Chen, Jianjun; Chen, Liang; Zheng, Peng; Xu, Hong-Bo; Lu, Jia; Zhong, Jiaju; Lei, Yang; Zhou, Chanjuan; Ma, Qingwei; Li, Yan; Xie, Peng


    Major depressive disorder (MDD) is a debilitating psychiatric illness with no available objective laboratory-based diagnostic test. In this study, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based peptidomics was applied to identify potential urinary diagnostic biomarkers for MDD. A training set of 42 first-episode drug-naive MDD patients and 28 age- and gender-matched healthy controls (HC) was used to develop a peptide diagnostic pattern. Then, the diagnostic efficacy of this pattern was assessed in an independent blinded test set consisting of 24 MDD patients and 13 age- and gender-matched HC. A combination of five potential biomarkers was identified, yielding a sensitivity of 91.7% and specificity of 84.6% in the test set. Moreover, the protein precursors of four of the five peptides were identified by tandem mass spectrometric analysis: serum albumin, apolipoprotein A-I, protein AMBP, and basement membrane-specific heparan sulfate proteoglycan core protein. Taken together, the peptide pattern may be valuable for establishing an objective laboratory-based diagnostic test for MDD.

  7. Apolipoprotein C-II Is a Potential Serum Biomarker as a Prognostic Factor of Locally Advanced Cervical Cancer After Chemoradiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Harima, Yoko, E-mail: [Department of Radiology, Takii Hospital, Kansai Medical University, Moriguchi, Osaka (Japan); Ikeda, Koshi; Utsunomiya, Keita; Komemushi, Atsushi; Kanno, Shohei; Shiga, Toshiko [Department of Radiology, Takii Hospital, Kansai Medical University, Moriguchi, Osaka (Japan); Tanigawa, Noboru [Department of Radiology, Hirakata Hospital, Kansai Medical University, Hirakata, Osaka (Japan)


    Purpose: To determine pretreatment serum protein levels for generally applicable measurement to predict chemoradiation treatment outcomes in patients with locally advanced squamous cell cervical carcinoma (CC). Methods and Materials: In a screening study, measurements were conducted twice. At first, 6 serum samples from CC patients (3 with no evidence of disease [NED] and 3 with cancer-caused death [CD]) and 2 from healthy controls were tested. Next, 12 serum samples from different CC patients (8 NED, 4 CD) and 4 from healthy controls were examined. Subsequently, 28 different CC patients (18 NED, 10 CD) and 9 controls were analyzed in the validation study. Protein chips were treated with the sample sera, and the serum protein pattern was detected by surface-enhanced laser desorption and ionization–time-of-flight mass spectrometry (SELDI-TOF MS). Then, single MS-based peptide mass fingerprinting (PMF) and tandem MS (MS/MS)-based peptide/protein identification methods, were used to identify protein corresponding to the detected peak. And then, turbidimetric assay was used to measure the levels of a protein that indicated the best match with this peptide peak. Results: The same peak 8918 m/z was identified in both screening studies. Neither the screening study nor the validation study had significant differences in the appearance of this peak in the controls and NED. However, the intensity of the peak in CD was significantly lower than that of controls and NED in both pilot studies (P=.02, P=.04) and validation study (P=.01, P=.001). The protein indicated the best match with this peptide peak at 8918 m/z was identified as apolipoprotein C-II (ApoC-II) using PMF and MS/MS methods. Turbidimetric assay showed that the mean serum levels of ApoC-II tended to decrease in CD group when compared with NED group (P=.078). Conclusion: ApoC-II could be used as a biomarker for detection in predicting and estimating the radiation treatment outcome of patients with CC.

  8. Photon-Dominated Region Modeling of the [C I],[C II], and CO Line Emission from a Boundary in the Taurus Molecular Cloud

    CERN Document Server

    Orr, Matthew; Goldsmith, Paul


    We present [Ci] and [Cii] observations of a linear edge region in the Taurus molecular cloud, and model this region as a cylindrically symmetric PDR exposed to a low-intensity UV radiation field. The sharp, long profile of the linear edge makes it an ideal case to test PDR models and determine cloud parameters. We compare observations of the [C i], 3P1 -> 3P0 (492 GHz), [C i] 3P2 -> 3P1 (809 GHz), and [Cii] 2P3/2 -> 2P1/2 (1900 GHz) transitions, as well as the lowest rotational transitions of 12CO and 13CO, with line intensities produced by the RATRAN radiative transfer code from the results of the Meudon PDR code. We constrain the density structure of the cloud by fitting a cylindrical density function to visual extinction data. We study the effects of variation of the FUV field, 12C/13C isotopic abundance ratio, sulfur depletion, cosmic ray ionization rate, and inclination of the filament relative to the sky-plane on the chemical network of the PDR model and resulting line emission. We also consider the rol...

  9. Apolipoprotein B-containing lipoprotein particle assembly: Lipid capacity of the nascent lipoprotein particle

    Energy Technology Data Exchange (ETDEWEB)

    Manchekar, Medha; Forte, Trudy M.; Datta, Geeta; Richardson, Paul E.; Segrest, Jere P.; Dashti, Nassrin


    We previously proposed that the N-terminal 1000 residue {beta}{alpha}{sub 1} domain of apolipoprotein B (apoB) forms a bulk lipid pocket homologous to that of lamprey lipovitellin (LV). In support of this ''lipid pocket'' hypothesis, apoB:1000 (residues 1-1000) was shown to be secreted by a stable transformant of McA-RH7777 cells as a monodisperse particle with HDL{sub 3} density and Stokes diameter of 112 {angstrom}. In contrast, apoB:931 (residues 1-931), missing only 69 residues of the sequence homologous to LV, was secreted as a particle considerably more dense than HDL with Stokes diameter of 110 {angstrom}. The purpose of the present study was to determine the stoichiometry of the lipid component of the apoB:931 and apoB:1000 particles. This was accomplished by metabolic labeling of cells with either [{sup 14}C]oleic acid or [{sup 3}H]glycerol followed by immunoprecipitation (IP) or nondenaturing gradient gel electrophoresis (NDGGE) of secreted lipoproteins and by immunoaffinity chromatography of secreted unlabeled lipoproteins. The [{sup 3}H]-labeled apoB:1000-containing particles, isolated by NDGGE, contained 50 phospholipids (PL) and 11 triacylglycerols (TAG) molecules per particle. In contrast, apoB:931-containing particles contained only a few molecules of PL and were devoid of TAG. The unlabeled apoB:1000-containing particles isolated by immunoaffinity chromatography and analyzed for lipid mass, contained 56 PL, 8 TAG, and 7 cholesteryl ester molecules per particle. The surface:core lipid ratio of apoB:1000-containing particles was approximately 4:1 and was not affected by incubation of cells with oleate. Although small amounts of microsomal triglyceride transfer protein (MTP) were associated with apoB:1000-containing particles, it never approached a 1:1 molar ratio of MTP to apoB. These results support a model in which: (1) the first 1000 amino acid residues of apoB are competent to complete the ''lipid pocket

  10. Hydrogen sulfide regulates vascular endoplasmic reticulum stress in apolipoprotein E knockout mice

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhi-fang; ZHAO Bin; TANG Xiu-ying; LI Wei; ZHU Lu-lu; TANG Chao-shu; DU Jun-bao; JIN Hong-fang


    Background Atherosclerosis is an important cardiovascular disease,becoming a major and increasing health problem in developed countries.However,the possible underlying mechanisms were not completely clear.In 2009,our research group first discovered that hydrogen sulfide (H2S) as a novel gastrotransmitter played an important anti-atherosclerotic role.The study was designed to examine the regulatory effect of hydrogen sulfide (H2S) on endoplasmic reticulum stress (ERS) in apolipoprotein E knockout (apoE(-/-)) mice fed a Western type diet.Methods C57BL/6 mice and homozygous apoE(-/-) mice were fed a Western type diet.C57BL/6 mice were injected intraperitoneally with normal saline (5 ml/kg per day) as control group.The apoE+ mice were treated with the same dose of normal saline as the apoE(-/-) group,injected intraperitoneally with sodium hydrosulfide (NaHS,an H2S donor,56μmol/kg per day) as the apoE(-/-)+NaHS group and injected intraperitoneally with DL-propargylglycine (PPG,a cystathionine-y-lyase inhibitor,50 mg/kg,per day) as the apoE/ +PPG group.After 10 weeks,the mice were sacrificed and the plasma lipids were detected.Sections of aortic root from these animals were examined for atherosclerotic lesions by HE and oil red O staining.The aortic ultrastructure and microstructure were analyzed with the help of light and electronic microscope.Glucose-regulated protein 78 (GRP78),caspase-12,copper-andzinc-containing superoxide dismutase (Cu/ZnSOD) and Mn-containing superoxide dismutase (MnSOD) protein expression in aortic tissues were detected with immunohistochemistry.The level of intracellular reactive oxygen species (ROS) were measured by using a commercial assay kit.Results Compared with control mice,apoE(-/-) mice showed increased plasma levels of total cholesterol (TC),triglyceride (TG) and low density lipoprotein (LDL),decreased high density lipoprotein (HDL),increased aortic plaque size,destroyed ultra-structure of aortic tissue,and increased expression of GRP

  11. APOLIPOPROTEÍNA E Y ENFERMEDAD CARDIOVASCULAR Apolipoprotein E and cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Adriana Moreno Valladares


    Full Text Available La apolipoproteína E es una glicoproteína polimórfica que interactúa con los receptores de lipoproteínas (LRP-Receptor Related Protein o receptores ApoE y los receptores de lipoproteínas de baja densidad (receptores LDL. Cuando las lipoproteínas se unen al receptor comienza la captación y degradación de lípidos por parte de la célula, lo que permite la utilización del colesterol contenido en las lipoproteínas, produciéndose una autorregulación intracelular La tres isoformas de mayor importancia de ApoE se denominan Apo E2, E3 y E4 y son producto de tres alelos e2, e3, e4 de un gen único. Este factor está relacionado con la cantidad de lipoproteínas que contienen ApoE para receptores E⁄B. El menor contenido de lipoproteínas con ApoE puede aumentar la actividad del receptor LDL y consecuentemente, bajar la concentración de LDL en circulación. De otra parte, las partículas con Apo E3 o Apo E4, causan disminución de la regulación de receptores LDL y producen elevación del LDL plasmático. Muchos estudios en poblaciones humanas han demostrado la relación entre este polimorfismo de apoE y la variación en los niveles plasmáticos de lípidos y de lipoproteínas y el riesgo de desarrollar enfermedad cardiovascular. La enfermedad cardiovascular es el resultado de la interacción de diferentes factores entre los que se encuentra el factor genético y específicamente el polimorfismo de la ApoE. La presencia del alelo e4 de la ApoE puede explicar, en parte, la mayor frecuencia de enfermedad cardiovascular en quienes lo portan.Apolipoprotein E is a polymorphic glycoprotein who interacts with the lipoprotein receptors (LRP-Receptor Related Protein and the receptors for low density lipoproteins of (LDL receptors. When lipoproteins bring up the receptors begins lipids captation and degradation which allows cholesterol utilization, taking place an intracellular auto regulation. The three isoforms of greater importance: Apo E2, E3

  12. Expression of human apolipoprotein E4 reduces insulin-receptor substrate 1 expression and Akt phosphorylation in the ageing liver

    Directory of Open Access Journals (Sweden)

    Qi-Rui Ong


    Full Text Available The diabetic drug rosiglitazone was reported to improve glucose tolerance in insulin-resistant ApoE3 but not ApoE4 knock-in mice. We therefore examined whether apolipoprotein E (ApoE has genotype-specific effects on liver insulin function. At 12 weeks, no difference in liver insulin signaling was detected between fasting ApoE3 and ApoE4 mice. At 72 weeks however, ApoE4 mice had lower IRS-1 and PI3K expression, and reduced Akt phosphorylation. This decline was associated with lower insulin and higher glucose in ApoE4 mouse liver. Liver cholesterol was not affected. These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

  13. Apolipoprotein E polymorphism as a predictor for cognitive decline and dementia in the Saudi general population over 65 years

    Directory of Open Access Journals (Sweden)

    Abdulaziz Ali A. Al-Khedhairy


    Full Text Available Specific Apolipoprotein E (ApoE genotypes are thought to be associated with risk for Alzheimer's disease (AD. It is essential to understand how this genetic factor affects cognitive decline and dementia in the general population. One hundred and fifty elderly persons residing at social nursing centers in different provinces of Saudi Arabia were tested for ApoE genotypes, using PCR amplification of genomic DNA followed by DNA digestion with Cfo I. All subjects were diagnosed with regard to cognitive decline and dementia. In the general Saudi population, the ApoE4 allele was found to be a weaker predictor for dementia than for AD. This may be a result of non-AD pathological processes and/or of most prevalent dementia at an age when the ApoE4 effect on the AD/dementia risk has decreased.

  14. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan


    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  15. Apolipoprotein E gene polymorphism and dyslipidaemia in adult Asian Indians: A population based study from calcutta, India

    Directory of Open Access Journals (Sweden)

    Das Mithun


    Full Text Available Aim : The study was aimed to determine the association of Apolipoprotein E (apo E gene polymorphisms on lipid levels in Asian Indian population. Methods : A total of 350 (184 males and 166 females adult (30 years and above Asian Indians of Calcutta and suburb participated in the study. Anthropometric measures, lipids profiles, and blood glucose measures were collected. Out of 350 subjects, a sample of 70 individuals was selected randomly for genotyping after adjusting for age and sex. The apo E gene polymorphisms were determined by agarose gel electrophoresis. Results : The apo E polymorphism showed significant association with dyslipidaemia (P=0.0135 with e3/4 combination has had the highest occurrence of dyslipidaemia and metabolic syndrome (MS followed by ε4/4 Conclusions : The ε4 allele of apo E gene independent of other risk factors is associated with dyslipidaemia in particular with low HDLc and high TC: HDLc ratio.

  16. Evidence for apolipoprotein E {epsilon}4 association in early-onset Alzheimer`s patients with late-onset relatives

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Tur, J.; Delacourte, A.; Chartier-Harlin, M.C. [INSERM, Rouen (France)] [and others


    Recently several reports have extended the apolipoprotein E (APOE) {epsilon}4 association found in late-onset Alzheimer`s disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset {<=}60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE {epsilon}A allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that, for an individual, bearing at least one {epsilon}4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases. 19 refs., 3 tabs.

  17. Plasma clearance of human low-density lipoprotein in human apolipoprotein B transgenic mice is related to particle diameter. (United States)

    Berneis, Kaspar; Shames, David M; Blanche, Patricia J; La Belle, Michael; Rizzo, Manfredi; Krauss, Ronald M


    To test for intrinsic differences in metabolic properties of low-density lipoprotein (LDL) as a function of particle size, we examined the kinetic behavior of 6 human LDL fractions ranging in size from 251 to 265 A injected intravenously into human apolipoprotein (apo) B transgenic mice. A multicompartmental model was formulated and fitted to the data by standard nonlinear regression using the Simulation, Analysis and Modeling (SAAM II) program. Smaller sized LDL particles (251 to 257 A) demonstrated a significantly slower fractional catabolic rate (FCR) (0.050 +/- 0.045 h(-1)) compared with particles of larger size (262 to 265 A) (0.134 +/- -0.015 h(-1), P particles are cleared more slowly from plasma than larger LDL and are exchanged more slowly with the extravascular space. This might be due to compositional or structural features of smaller LDL that lead to retarded clearance.

  18. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice

    DEFF Research Database (Denmark)

    Bentzon, Jacob F; Sondergaard, Claus S; Kassem, Mustafa;


    circulating bone marrow-derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE-/-) mice. METHODS AND RESULTS: To determine the origin of SMCs after spontaneous plaque disruption......, irradiated 18-month-old apoE-/- mice were reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE-/- mice and examined when they died up to 9 months later. Plaque hemorrhage, indicating previous plaque disruption, was widely present, but no bone marrow-derived e......GFP+ SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE-/- mice. Mechanical...

  19. Cloning and Expression of Apolipoprotein E3 and Its Variant apoE2 and apoE4

    Institute of Scientific and Technical Information of China (English)


    In order to obtain three isoforms of apolipoprotein E (apoE), the cDNA encoding apoE3 was obtained by RT-PCR from normal human liver tissue. Site-directed mutagenesis was used to obtain the cDNAs encoding apoE2 and apoE4 isoforms. The 3 cDNAs were subcloned into vector pGEM-3Z and verified by DNA sequencing. The expression recombinant which can express the target protein as a (His) 6-tagged fusion was constructed by subcloning apoE cDNA into vector pT7-PL. The purified proteins were gained by Ni-NTA column. The SDS-PAGE results revealed the 6 His fusion proteins (apoE2, apoE3 and apoE4) were correctly expressed and purified successfully.

  20. The Immune-Modulatory Role of Apolipoprotein E with Emphasis on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Hong-Liang Zhang


    Full Text Available Apolipoprotein E (apoE is a 34.2 kDa glycoprotein characterized by its wide tissue distribution and multiple functions. The nonlipid-related properties of apoE include modulating inflammation and oxidation, suppressing T cell proliferation, regulating macrophage functions, and facilitating lipid antigen presentation by CD1 molecules to natural killer T (NKT cells, and so forth. Increasing studies have revealed that APOE ε allele might be associated with multiple sclerosis (MS, although evidence is still not sufficient enough. In this review, we summarized the current progress of the immunomodulatory functions of apoE, with special focus on the association of APOE ε allele with the clinical features of MS and of its animal model experimental autoimmune encephalomyelitis (EAE.

  1. Are men carrying the apolipoprotein epsilon 4- or epsilon 2 allele less fertile than epsilon 3 epsilon 3 genotypes?

    DEFF Research Database (Denmark)

    Gerdes, Lars Ulrik; Gerdes, C; Hansen, P S;


    The epsilon 3 allele in the human gene coding for apolipoprotein E (apoE) is the most common worldwide, but epsilon 4 is probably the ancestral allele. Since apoE is involved in many important biological processes, selection forces could have favoured epsilon 3. We hypothesized that apoE genotypes...... may affect reproductive efficiency, and we therefore compared the distributions of 40-year-old married men with known genotypes by the numbers of their biological children. The distributions were statistically significantly different (P = 0.0026). On average, men with the epsilon 3 epsilon 3 genotype...... (n = 212) had 1.93 children, men with the epsilon 3 epsilon 4 or epsilon 4 epsilon 4 genotype (n = 105) had 1.50, and men with the epsilon 3 epsilon 2 or epsilon 2 epsilon 2 genotypes (n = 53) had 1.66 children. Of the men in the three groups, 6%, 26% and 19%, respectively, reported being childless...

  2. Recombinant Neural Protein PrP Can Bind with Both Recombinant and Native Apolipoprotein E In Vitro

    Institute of Scientific and Technical Information of China (English)

    Chen GAO; Wei ZHOU; Xiao-Ping DONG; Yan-Jun LEI; Jun HAN; Qi SHI; Lan CHEN; Yan GUO; Yong-Jun GAO; Jian-Ming CHEN; Hui-Ying JIANG


    The most essential and crucial step during the pathogenesis of transmissible spongiform encephalopathy is the conformational change of cellular prion protein (PrPC) to pathologic isoform (prpSc). A lot of data revealed that caveolae-like domains (CLDs) in the cell surface were the probable place where the conversion of PrP proteins happened. Apolipoprotein E (ApoE) is an apolipoprotein which is considered to play an important role in the development of Alzheimer's disease and other neurodegenerative diseases by forming protein complex through binding to the receptor located in the clathrin-coated pits of the cell surface.In this study, a 914-bp cDNA sequence encoding human ApoE3 was amplified from neuroblastoma cell line SH-SY5Y. Three human ApoE isomers were expressed and purified from Escherichia coli. ApoE-specific antiserum was prepared by immunizing rabbits with the purified ApoE3. GST/His pull-down assay,immunoprecipitation and ELISA revealed that three full-length ApoE isomers interact with the recombinant full-length PrP protein in vitro. The regions corresponding to protein binding were mapped in the N-terminal segment of ApoE (amino acid 1-194) and the N-terminal of PrP (amino acid 23-90). Moreover, the recombinant PrP showed the ability to form a complex with the native ApoE from liver tissues. Our data provided direct evidence of molecular interaction between ApoE and PrP. It also supplied scientific clues for assessing the significance of CLDs on the surface of cellular membrane in the process of conformational conversion from PrPC to PrPSc and probing into the pathogenesis of transmissible spongiform encephalopathy.

  3. Statistical validation of GCM-simulated climates for the U.S. Great Lakes and the C.I.S. Emba and Ural River basins (United States)

    Privalsky, V.; Croley, T. E.


    Many researchers use outputs from large-scale global circulation models of the atmosphere to assess hydrological and other impacts associated with climate change. However, these models cannot capture all climate variations since the physical processes are imperfectly understood and are poorly represented at smaller regional scales. This paper statistically compares model outputs from the global circulation model of the Geophysical Fluid Dynamics Laboratory to historical data for the United States' Laurentian Great Lakes and for the Emba and Ural River basins in the Commonwealth of Independent States (C.I.S.). We use maximum entropy spectral analysis to compare model and data time series, allowing us to both assess statistical predictabilities and to describe the time series in both time and frequency domains. This comparison initiates assessments of the model's representation of the real world and suggests areas of model improvement.

  4. Analysing Java Identifier Names


    Butler, Simon


    Identifier names are the principal means of recording and communicating ideas in source code and are a significant source of information for software developers and maintainers, and the tools that support their work. This research aims to increase understanding of identifier name content types - words, abbreviations, etc. - and phrasal structures - noun phrases, verb phrases, etc. - by improving techniques for the analysis of identifier names. The techniques and knowledge acquired can be appl...

  5. Identifiability in stochastic models

    CERN Document Server


    The problem of identifiability is basic to all statistical methods and data analysis, occurring in such diverse areas as Reliability Theory, Survival Analysis, and Econometrics, where stochastic modeling is widely used. Mathematics dealing with identifiability per se is closely related to the so-called branch of ""characterization problems"" in Probability Theory. This book brings together relevant material on identifiability as it occurs in these diverse fields.

  6. Alterations in amyloid beta-protein and apolipoprotein E in cerebrospinal fluid after subarachnoid hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Xinzhong Wen; Yonghong Zhang; Leiming Huo


    BACKGROUND: The findings about the alterations in cerebrospinal fluid beta-amyloid protein (Aβ) and apolipoprotein E (ApoE) after subarachnoid hemorrhage indicate that they have significant correlation with prognosis of patients.OBJECTIVE: To observe the alterations in cerebrospinal fluid Aβ and ApoE after subarachnoid hemorrhage (SAH).DESIGN: Contrast observation.SETTING: Department of Neurosurgery, the First Hospital of Lanzhou University.PARTICIPANTS: A total of 25 SAH patients including 16 males and 9 females aged from 13 to 72 years were selected form Department of Neurosurgery, the First Affiliated Hospital of Lanzhou University from October 2003 to February 2004. The Hunt-Hess grade ranged from Ⅰ to Ⅳ, and patients admitted hospital in 24 hours after invasion, affirmed by the brain CT scan and lumbar vertebra puncture, no other severe complications and important organs' functional defect and severe infection, no hematological system disease.METHODS: All admitted patients were collected CSF by lumbar vertebra puncture in 24 hours. The cerebrospinal fluid (CSF) of control group came from the admitted 15 patients of our hospital that have no nervous system disease. Aβ content was detected by enzyme linked immunosorbent assay (ELISA), the kit was provided by the Central Laboratory of the First Hospital of Lanzhou University; ApoE concentration was detected by monoclone enzyme linked immunosorbent assay (ELISA), the kit was provided by the Immunotechnique Research Institute of the Fourth Military Medical University. S100B concentration was detected by enzyme linked immunosorbent assay double antibody sandwich method, the kit was provided by the Physiological Research Room of the Fourth Military Medical University. The data were indicated on Mean±SD and were analyzed by SPSS 10.0 statistical package. All data were handled through test of significance variance analysis, and groups were compared through independent sampler t test. The concentration was

  7. Lipoprotein lipase-catalyzed hydrolysis of phosphatidylcholine of guinea pig very low density lipoproteins and discoidal complexes of phospholipid and apolipoprotein: effect of apolipoprotein C-II on the catalytic mechanism. (United States)

    Shirai, K; Fitzharris, T J; Shinomiya, M; Muntz, H G; Harmony, J A; Jackson, R L; Quinn, D M


    To elucidate the mechanism by which apolipoprotein C-II (apoC-II) enhances the activity of lipoprotein lipase (LpL), discoidal phospholipid complexes were prepared with apoC-III and di[(14)C]palmitoyl phosphatidylcholine (DPPC) and containing various amounts of apoC-II. The rate of DPPC hydrolysis catalyzed by purified bovine milk LpL was determined on the isolated complexes. The rate of hydrolysis was optimal at pH 8.0. Analysis of enzyme kinetic data over a range of phospholipid concentrations revealed that the major effect of apoC-II was to increase the maximal velocity (V(max)) some 50-fold with a limited effect on the Michaelis constant (K(m)). V(max) of the apoC-III complex containing no apoC-II was 9.2 nmol/min per mg LpL vs. 482 nmol/min per mg LpL for the complex containing only apoC-II. The effect of apoC-II on enzyme kinetic parameters for LpL-catalyzed hydrolysis of DPPC complexes was compared to that on the parameters for hydrolysis of DPPC and trioleoylglycerol incorporated into guinea pig very low density lipoproteins (VLDL(p)) which lack the equivalent of human apoC-II. Tri[(3)H]oleoylglycerol-labeled VLDL(p) were obtained by perfusion of guinea pig liver with [(3)H]oleic acid. Di[(14)C]palmitoyl phosphatidylcholine was incorporated into the VLDL(p) by incubation of VLDL(p) with sonicated vesicles of di[(14)C]palmitoyl phosphatidylcholine and purified bovine liver phosphatidylcholine exchange protein. The rates of LpL-catalyzed hydrolysis of trioleoylglycerol and DPPC were determined at pH 7.4 and 8.5 in the presence and absence of apoC-II. In the presence of apoC-II, the V(max) for DPPC hydrolysis in guinea pig VLDL(p) increased at both pH 7.4 and pH 8.5 (2.4- and 3.2-fold, respectively); the value of K(m) did not change at either pH (0.23 mm). On the other hand, the kinetic value of K(m) for triacylglycerol hydrolysis in the presence of apoC-II decreased at both pH 7.4 (3.05 vs. 0.54 mm) and pH 8.5 (2.73 vs. 0.62 mm). These kinetic studies suggest

  8. On-treatment non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipid ratios in relation to residual vascular risk after treatment with potent statin therapy

    DEFF Research Database (Denmark)

    Mora, Samia; Glynn, Robert J; Boekholdt, S Matthijs;


    The goal of this study was to determine whether residual risk after high-dose statin therapy for primary prevention individuals with reduced levels of low-density lipoprotein cholesterol (LDL-C) is related to on-treatment apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL......-C), trigylcerides, or lipid ratios, and how they compare with on-treatment LDL-C....

  9. Impact of psychological stress on the associations between apolipoprotein E variants and metabolic traits: findings in an American sample of caregivers and controls

    DEFF Research Database (Denmark)

    Kring, Sofia Iqbal; Brummett, Beverly H; Barefoot, John


    To examine the association between apolipoprotein E (APOE) gene variants and waist circumference, fasting plasma glucose, serum insulin, serum high-density lipoprotein cholesterol, and serum triglycerides, all metabolic traits known as cardiovascular disease (CVD) endophenotypes, in a population ...... of stressed individuals and controls. Abdominal obesity, insulin resistance, elevated serum lipid concentration, and APOE polymorphisms have been associated with CVD risk. Current evidence supports the hypothesis that gene-environment interactions modulate serum lipid concentrations....

  10. Metabolic hormones, apolipoproteins, adipokines, and cytokines in the alveolar lining fluid of healthy adults: compartmentalization and physiological correlates.

    Directory of Open Access Journals (Sweden)

    Carlos O Mendivil

    Full Text Available Our current understanding of hormone regulation in lung parenchyma is quite limited. We aimed to quantify a diverse array of biologically relevant protein mediators in alveolar lining fluid (ALF, compared to serum concentrations, and explore factors associated with protein compartmentalization on either side of the air-blood barrier.Participants were 24 healthy adult non-smoker volunteers without respiratory symptoms or significant medical conditions, with normal lung exams and office spirometry. Cell-free bronchoalveolar lavage fluid and serum were analyzed for 24 proteins (including enteric and metabolic hormones, apolipoproteins, adipokines, and cytokines using a highly sensitive multiplex ELISA. Measurements were normalized to ALF concentrations. The ALF:serum concentration ratios were examined in relation to measures of protein size, hydrophobicity, charge, and to participant clinical and spirometric values.ALF measurements from 24 individuals detected 19 proteins, including adiponectin, adipsin, apoA-I, apoA-II, apoB, apoC-II, apoC-III, apoE, C-reactive protein, ghrelin, glucose-dependent insulinotropic peptide (GIP, glucagon-like peptide-1 (GLP-1, glucagon, insulin, leptin, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, resistin, and visfatin. C-peptide and serpin E1 were not detected in ALF for any individual, and IL-6, IL-10, and TNF-alpha were not detected in either ALF or serum for any individual. In general, ALF levels were similar or lower in concentration for most proteins compared to serum. However, ghrelin, resistin, insulin, visfatin and GLP-1 had ALF concentrations significantly higher compared to serum. Importantly, elevated ALF:serum ratios of ghrelin, visfatin and resistin correlated with protein net charge and isoelectric point, but not with molecular weight or hydrophobicity.Biologically relevant enteric and metabolic hormones, apolipoproteins, adipokines, and cytokines can be detected in the ALF of

  11. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuehai [Cardiovascular Department, Liaocheng People’s Hospital of Shandong University, Liaocheng, Shandong 252000 (China); Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lu, Huixia [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Huang, Ziyang, E-mail: [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Huili [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lei, Zhenmin [Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Chen, Xiaoqing [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Tang, Mengxiong; Gao, Fei; Dong, Mei [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Li, Rongda [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Ling, E-mail: [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China)


    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • The spleen weights and glomerular areas were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE{sup −/−} mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE{sup −/−}) mice is a classic model of atherosclerosis. We have found that ApoE{sup −/−} mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE{sup −/−} mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE{sup −/−}, Fas{sup −/−} and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas{sup −/−} mice, a model of systemic lupus erythematosus (SLE), ApoE{sup −/−} mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE{sup −/−} mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE{sup −/−} mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

  12. Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle. (United States)

    Sapkota, Shraddha; Bäckman, Lars; Dixon, Roger A


    Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.

  13. Identifying Knowledge and Communication

    Directory of Open Access Journals (Sweden)

    Eduardo Coutinho Lourenço de Lima


    Full Text Available In this paper, I discuss how the principle of identifying knowledge which Strawson advances in ‘Singular Terms and Predication’ (1961, and in ‘Identifying Reference and Truth-Values’ (1964 turns out to constrain communication. The principle states that a speaker’s use of a referring expression should invoke identifying knowledge on the part of the hearer, if the hearer is to understand what the speaker is saying, and also that, in so referring, speakers are attentive to hearers’ epistemic states. In contrasting it with Russell’s Principle (Evans 1982, as well as with the principle of identifying descriptions (Donnellan 1970, I try to show that the principle of identifying knowledge, ultimately a condition for understanding, makes sense only in a situation of conversation. This allows me to conclude that the cooperative feature of communication (Grice 1975 and reference (Clark andWilkes-Gibbs 1986 holds also at the understanding level. Finally, I discuss where Strawson’s views seem to be unsatisfactory, and suggest how they might be improved.

  14. Identifying learning styles. (United States)

    Hughes, Grace


    What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article explored different learning styles and outlined some of the models that can be used to identify them. It discussed the limitations of these models, indicating that although they can be helpful in identifying a student's preferred learning style, this is not 'fixed' and might change over time. Learning is also influenced by other factors, such as culture and age.

  15. Performance Improvement of Microcrystalline p-SiC/i-Si/n-Si Thin Film Solar Cells by Using Laser-Assisted Plasma Enhanced Chemical Vapor Deposition

    Directory of Open Access Journals (Sweden)

    Hsin-Ying Lee


    Full Text Available The microcrystalline p-SiC/i-Si/n-Si thin film solar cells treated with hydrogen plasma were fabricated at low temperature using a CO2 laser-assisted plasma enhanced chemical vapor deposition (LAPECVD system. According to the micro-Raman results, the i-Si films shifted from 482 cm−1 to 512 cm−1 as the assisting laser power increased from 0 W to 80 W, which indicated a gradual transformation from amorphous to crystalline Si. From X-ray diffraction (XRD results, the microcrystalline i-Si films with (111, (220, and (311 diffraction were obtained. Compared with the Si-based thin film solar cells deposited without laser assistance, the short-circuit current density and the power conversion efficiency of the solar cells with assisting laser power of 80 W were improved from 14.38 mA/cm2 to 18.16 mA/cm2 and from 6.89% to 8.58%, respectively.

  16. Low-Cost Biodegradation and Detoxification of Textile Azo Dye C.I. Reactive Blue 172 by Providencia rettgeri Strain HSL1

    Directory of Open Access Journals (Sweden)

    Harshad Lade


    Full Text Available Present study focuses on exploitation of agricultural waste wheat bran (WB as growth medium for degradation of textile azo dye C.I. Reactive Blue 172 (RB 172 using a single bacterium P. rettgeri strain HSL1 (GenBank accession number JX853768.1. The bacterium was found to completely decolorize 50 mg L−1 of dye RB 172 within 20 h at 30 ± 0.2°C under microaerophilic incubation conditions. Additionally, significant reduction in COD (85% and TOC (52% contents of dye decolorized medium was observed which suggested its mineralization. Induction in the activities of azoreductase (159% and NADH-DCIP reductase (88% provided an evidence for reductive cleavage of dye RB 172. The HPLC, FTIR, and GC-MS analysis of decolorized products confirmed the degradation of dye into various metabolites. The proposed metabolic pathway for biodegradation of RB 172 has been elucidated which showed the formation of 2 intermediate metabolites, namely, 4-(ethenylsulfonyl aniline and 1-amino-1-(4-aminophenyl propan-2-one. The acute and phytotoxicity evaluation of degraded metabolites suggests that bacterial strain favors the detoxification of dye RB 172. Thus, WB could be utilized as a low-cost growth medium for the enrichment of bacteria and their further use for biodegradation of azo dyes and its derivatives containing wastes into nontoxic form.

  17. Improvement on Synthesis Process of C. I. Direct Blue 199%C.I.直接蓝199工艺改进

    Institute of Scientific and Technical Information of China (English)

    王雪梅; 郑玉安


    The Synthesis Process of C. I. Direct Blue 199 was improved. The reaction temperature of CuPc and chtorosulfonic acid was raised from 130℃ to 140 ℃, then the reaction temperature of the product with thionyl chloride was raised from 60 - 65 ℃ to 80 ℃ ; the dropping time of thionyl chloride was prolonged from 2 - 2. 5 hours to 4 hours; and ammonia was replaced by organic base in ammonolysis. By this new technology, the difficult problem in membrane filtration before salting out was resolved when the dye was applied in ink.%对C.I.直接蓝199的老工艺进行了改进。使铜酞菁与氯磺酸的反应温度由原来的130℃升至140℃左右,之后与氯化亚砜的反应温度由60~65℃提高到80℃,而且滴加氯化亚砜的时间从2~2.5延长至4小时,同时氨解用的氨水用有机碱替代。新工艺解决了此染料用于墨水时在盐析前膜过滤困难的问题。

  18. Effect of operational parameters on the decolorization of C.I. Reactive Blue 19 in aqueous solution by ozone-enhanced electrocoagulation

    Energy Technology Data Exchange (ETDEWEB)

    Song Shuang; Yao Jie [College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China); He Zhiqiao [College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China)], E-mail:; Qiu Jianping; Chen Jianmeng [College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032 (China)


    The aim of this paper was to investigate the efficiency of the ozone-enhanced electrocoagulation (EC) process in the decolorization of C.I. Reactive Blue 19 in water using iron electrodes. We determined the effects of various operating parameters such as initial pH, initial dye concentration, current density, salt concentration, temperature, ozone flow rate, and distance between electrodes on decolorization efficiency in a laboratory-scale reactor. Increasing the initial dye concentration decreased the decolorization efficiency, whereas increasing the distance between electrodes increased it. The other operating factors had both positive and negative effects. With an initial pH of 10.0, an initial dye concentration of 100 mg/L, current density of 10 mA/cm{sup 2}, salt concentration of 3000 mg/L, temperature of 30 deg. C, ozone flow rate of 20 mL/min, and distance between electrodes of 3 cm, over 96% of the color was removed after 10 min. As a consequence, removal of total organic carbon (TOC) was over 80%.

  19. The use of artificial neural networks (ANN) for modeling of decolorization of textile dye solution containing C. I. Basic Yellow 28 by electrocoagulation process

    Energy Technology Data Exchange (ETDEWEB)

    Daneshvar, N. [Water and Wastewater Treatment Research Laboratory, Department of Applied Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz (Iran, Islamic Republic of)]. E-mail:; Khataee, A.R. [Water and Wastewater Treatment Research Laboratory, Department of Applied Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz (Iran, Islamic Republic of)]. E-mail:; Djafarzadeh, N. [Water and Wastewater Treatment Research Laboratory, Department of Applied Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz (Iran, Islamic Republic of)]. E-mail:


    In this paper, electrocoagulation has been used for removal of color from solution containing C. I. Basic Yellow 28. The effect of operational parameters such as current density, initial pH of the solution, time of electrolysis, initial dye concentration, distance between the electrodes, retention time and solution conductivity were studied in an attempt to reach higher removal efficiency. Our results showed that the increase of current density up to 80 A m{sup -2} enhanced the color removal efficiency, the electrolysis time was 7 min and the range of pH was determined 5-8. It was found that for achieving a high color removal percent, the conductivity of the solution and the initial concentration of dye should be 10 mS cm{sup -1} and 50 mg l{sup -1}, respectively. An artificial neural networks (ANN) model was developed to predict the performance of decolorization efficiency by EC process based on experimental data obtained in a laboratory batch reactor. A comparison between the predicted results of the designed ANN model and experimental data was also conducted. The model can describe the color removal percent under different conditions.

  20. Fibrinogen assays: a collaborative study of six different methods. C.I.S.M.E.L. Comitato Italiano per la Standardizzazione dei Metodi in Ematologia e Laboratorio. (United States)

    Palareti, G; Maccaferri, M; Manotti, C; Tripodi, A; Chantarangkul, V; Rodeghiero, F; Ruggeri, M; Mannucci, P M


    This collaborative study, organized by the Hemostasis Subcommittee of C.I.S.M.E.L., evaluated the accuracy, precision, and comparability of the following six widely used fibrinogen assays: total clottable fibrinogen (Blombäck and Blombäck), clotting time (Von Clauss), turbidimetry (Ellis and Stransky), Chromotime System, prothrombin time (PT)-derived, and radial immunodiffusion (RID). The same frozen samples, with normal and high contents of fibrinogen, were examined in four laboratories. The methods were calibrated with an internal standard whose fibrinogen content was determined gravimetrically. Both the Von Clauss and the RID methods were reliable, accurate, and precise, if adequate calibration was used. The PT-derived method was highly reproducible, but had some problems with accuracy. We demonstrate that an adequate calibration procedure is indispensable for reliable fibrinogen measurements whatever method is used. Because neither the calibration procedures proposed by the manufacturers nor the use of lyophilized commercial plasmas is adequate for this purpose, we urge that an international standard for fibrinogen measurement be promptly established.

  1. Bioaugmentation on decolorization of C.I. Direct Blue 71 by using genetically engineered strain Escherichia coli JM109 (pGEX-AZR)

    Energy Technology Data Exchange (ETDEWEB)

    Jin Ruofei; Yang Hua; Zhang Aili; Wang Jing [School of Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116023 (China); Liu Guangfei [School of Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116023 (China)], E-mail:


    The study showed that Escherichia coli JM109 (pGEX-AZR), the genetically engineered microorganism (GEM) with higher ability to decolorize azo dyes, bioaugmented successfully the dye wastewater bio-treatment systems to enhance C.I. Direct Blue 71 (DB 71) decolorization. The control and bioaugmented reactors failed at a around pH 5.0. However, the bioaugmented one succeeded at around pH 9.0, the influent DB 71 concentration was 150 mg/L, DB 71 concentration was decreased to 27.4 mg/L in 12 h. The 1-3% NaCl concentration of bioaugmented reactors had no definite influence on decolorization, DB 71 concentration was decreased to 12.6 mg/L in 12 h. GEM was added into anaerobic sequencing batch reactors (AnSBRs) to enhance DB 71 decolorization. Continuous operations of the control and bioaugmented AnSBRs showed that E. coli JM109 (pGEX-AZR) could bioaugment decolorization. The concentrations of activated sludge and GEM were still more than 2.80 g/L and 1.5 x 10{sup 6} cells/mL, respectively, in the bioaugmented AnSBR. All the microbial communities changed indistinctively with time. The microbial community structures of the control AnSBR were similar to those of the bioaugmented one.

  2. Enzyme-mediated bacterial biodegradation of an azo dye (C.I. Acid blue 113): reuse of treated dye wastewater in post-tanning operations. (United States)

    Senthilvelan, T; Kanagaraj, J; Panda, R C


    "Dyeing" is a common practice used to color the hides during the post-tanning operations in leather processing generating plenty of wastewater. The waste stream containing dye as pollutant is severely harmful to living beings. An azo dye (C.I. Acid Blue 113) has been biodegraded effectively by bacterial culture mediated with azoreductase enzyme to reduce the pollution load in the present investigation. The maximum rate of dye degradation was found to be 96 ± 4 and 92 ± 4 % for the initial concentrations of 100 and 200 mg/l, respectively. The enzyme activity was measured using NADH as a substrate. Fourier transform infrared spectroscopy (FT-IR) analysis was confirmed that the transformation of azo linkage could be transformed into N2 or NH3 or incorporated into complete biomass. Breaking down of dye molecules to various metabolites (such as aniline, naphthalene-1,4-diamine, 3-aminobenzenesulfonic acid, naphthalene-1-sulfonic acid, 8-aminonaphthalene-1-sulfonic acid, 5,8-diaminonaphthalene-1-sulfonic acid) was confirmed by gas chromatography and mass spectra (GC-MS) and mass (electrospray ionization (ESI)) spectra analysis. The treated wastewater could be reused for dyeing operation in the leather processing, and the properties of produced leather were evaluated by conventional methods that revealed to have improved dye penetration into the grain layer of experimental leather sample and resulted in high levelness of dyeing, which helps to obtain the desired smoothness and soft leather properties.

  3. Identifying Nursing's Future Leaders. (United States)

    Gunning, Carolyn S.; Hawken, Patty L.


    A study determined that encouraging and supporting students in professional activities while they were still in school would lead those students to participate in professional nursing organizations after they graduated. Organized nursing needs to identify the factors that influence nurses to join organizations and concentrate on these factors to…

  4. Identifying and Managing Risk. (United States)

    Abraham, Janice M.


    The role of the college or university chief financial officer in institutional risk management is (1) to identify risk (physical, casualty, fiscal, business, reputational, workplace safety, legal liability, employment practices, general liability), (2) to develop a campus plan to reduce and control risk, (3) to transfer risk, and (4) to track and…

  5. Primary Genetic Investigation of a Hyperlipidemia Model: Molecular Characteristics and Variants of the Apolipoprotein E Gene in Mongolian Gerbil

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    Yuehuan Liu


    Full Text Available The objective of this work was to establish a novel Mongolian gerbil (Meriones unguiculatus hyperlipidemia model and to investigate its susceptibility genetic basis. Two rodent (gerbil and rat hyperlipidemia models were induced by feeding a high fat/high-cholesterol (HF/HC diet. There were significant increases of serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C, and high-density lipoprotein cholesterol (HDL-C in gerbils within a 4-week modeling period. About 10–30% of >8-month-old individuals developed hyperlipidemia spontaneously. The apolipoprotein E (ApoE gene was cloned by merging a sequence of rapid amplification of cDNA ends (RACE and nested polymerase chain reaction products. The results revealed an open reading frame of 948 bp, encoding a protein of 298 amino acids. The gene without a 5′-UTR region in the first intron was highly homologous to human Apo-A-I and rat Apo-A-IV. The distribution of expression of the ApoE gene in liver, brain, heart, lung, kidney, and adrenal gland was detected by an ABC immunohistochemical procedure. Three single nucleotide polymorphisms (SNPs; C97T, G781T, and A1774T were first found using PCR-single-strand conformation polymorphism (PCR-SSCP in a closed population containing 444 animals. Correlation analysis confirmed that new SNPs , age, and gender were associated significantly (P<0.05 with hyperlipidemia.

  6. Molecular characterization and developmental expression pattern of the chicken apolipoprotein D gene: implications for the evolution of vertebrate lipocalins. (United States)

    Ganfornina, María D; Sánchez, Diego; Pagano, Aldo; Tonachini, Laura; Descalzi-Cancedda, Fiorella; Martínez, Salvador


    The insect Lazarillo and the mammalian apolipoprotein D (ApoD) are orthologous members of the lipocalin protein family. We report the cloning and embryonic expression of chicken ApoD, the first molecularly characterized nonmammalian ApoD. We also report the ApoD expression in mouse during postnatal development and some novel aspects of the expression of the paralogous lipocalin prostaglandin D-synthase (PGDS) and discuss these results in view of the lipocalin family evolution in vertebrates. ApoD is expressed in subsets of central nervous system (CNS) neurons and glia during late chicken embryogenesis. Contrary to mouse ApoD, no expression appears in neural crest-derived cephalic mesenchyme and blood vessel pericytes. Also, ApoD is expressed in developing chicken feathers. These expressions are corroborated by quantitative reverse transcriptase-polymerase chain reaction profiles. ApoD is expressed during mouse postnatal development in a subset of CNS neurons, astrocytes and oligodendrocytes, but also in meninges and pericytes. Chicken PGDS is expressed in brain meninges and perivascular cells. Our results suggest that the amniote last common ancestor expressed ApoD and PGDS in the brain during embryogenesis. ApoD appears restricted to ectodermal derivatives, whereas PGDS is expressed by derivatives of the three germ layers.

  7. The locus for apolipoprotein E (apoE) is close to the Lutheran (Lu) blood group locus on chromosome 19. (United States)

    Gedde-Dahl, T; Olaisen, B; Teisberg, P; Wilhelmy, M C; Mevåg, B; Helland, R


    Linkage has been described between the loci for apolipoprotein E (apoE) and the complement C3 (C3) on chromosome 19. C3 is known to belong to a linkage group with gene order C3-Se-Lu. The present study revealed linkage between Se and apoE with peak lod score +3.3 at recombination fraction 0.08 in males and +1.36 at 0.22 in females, and linkage between apoE and Lu with lod score +4.52 at zero recombination in sexes combined. The C3-apoE linkage gives lod score +4.00 at theta = 0.18 in males, but +0.04 at theta = 0.45 in females. Triple heterozygote families confirm that apoE is on the Se side and on the Lu side of C3. Allelic association between apoE and Lu has not been ruled out. Combining our data with published data on C3-Se and Se-Lu, this segment of chromosome 19 has an average age sex ratio of female/male recombination of 2.3.

  8. Apolipoprotein CIII Reduces Proinflammatory Cytokine-Induced Apoptosis in Rat Pancreatic Islets via the Akt Prosurvival Pathway

    DEFF Research Database (Denmark)

    Størling, Joachim; Juntti-Berggren, Lisa; Olivecrona, Gunilla;


    Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic ß-cells in the absence of inflammatory stress...... µg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1ß + interferon-¿, ApoCIII reduced cytokine-mediated islet cell death and impairment of ß-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had...... of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces...

  9. Transcriptional regulation of the apolipoprotein F (ApoF) gene by ETS and C/EBPα in hepatoma cells. (United States)

    Shen, Xue-Bin; Huang, Ling; Zhang, Shao-Hong; Wang, De-Ping; Wu, Yun-Li; Chen, Wan-Nan; Xu, Shang-Hua; Lin, Xu


    Apolipoprotein F (ApoF) inhibits cholesteryl ester transfer protein (CETP) activity and plays an important role in lipid metabolism. In the present study, the full-length human ApoF promoter was cloned, and the molecular mechanism of the regulation of ApoF was investigated. The ApoF promoter displayed higher activities in hepatoma cell lines, and the -198 nt to +79 nt promoter region contained the maximum promoter activity. In the promoter region of -198 nt to -2 nt there were four putative binding sites for transcription factors ETS-1/ETS-2 (named EBS-1 to EBS-4) and one for C/EBP. Mutation of EBS-2, EBS4 and the C/EBP binding site abolished the promoter activity, and ETS-1/ETS-2 and C/EBPα could interact with corresponding binding sites. In addition, overexpression of ETS-1/2 or C/EBPα enhanced, while dominant-negative mutants of ETS-1/2 and knockdown of C/EBPα decreased, ApoF promoter activities. ETS-1 and C/EBPα associated physically, and acted synergistically to activate ApoF transcription. These results demonstrated combined activation of the ApoF promoter by liver-enriched and ubiquitous transcription factors. Direct interactions between C/EBPα and ETS-1 were important for high liver-specific expression of ApoF.

  10. Apolipoprotein E gene polymorphism and its effect on anthropometric measures in normoglycemic subjects and type 2 diabetes

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    Tabatabaei-Malazy Ozra


    Full Text Available Abstract Background Apolipoprotein E (apo E plays a major role in lipid metabolism, obesity and accordingly in development of diabetes and coronary heart disease (CHD. Our main objective was to evaluate the association between apo E gene polymorphism with anthropometric measures. Methods Participants were selected from zone 17 Tehran/Iran. We assessed height, weight, body mass index (BMI, waist circumference (WC, blood pressure, serum fasting blood sugar, total cholesterol and triglycerides. Genotyping for apo E gene polymorphism was carried out using PCR-RFLP technique. Results Among total study population (n=311, 156 subjects were diabetic. The apo E3/E3 was the most common genotype in our population while E2 and E4 alleles had lower frequencies, respectively. After adjustment for diabetes, the apo E2 and E4 alleles were significantly associated with hypercholesterolemia and WC, respectively (p= 0.009, 0.034. This association was also related to sex and age. The probability of having abdominal obesity in E4 allele carriers was increased from 0.22 to 8.12 in women and to 3.08 in age ≥ 50 years. Conclusions Apo E polymorphism had significant influences on WC and total cholesterol level in patients with type 2 diabetes. This study highlights the importance of lifestyle modifications which may be more beneficial in hypercholesterolemic women carriers of E2 and E4 alleles concomitant central obesity.

  11. In situ delipidation of low-density lipoproteins in capillary electrochromatography yields apolipoprotein B-100-coated surfaces for interaction studies. (United States)

    D'Ulivo, Lucia; Chen, Jie; Meinander, Kristoffer; Oörni, Katariina; Kovanen, Petri T; Riekkola, Marja-Liisa


    An electrochromatographic method was developed for the in situ delipidation of intact low-density lipoprotein (LDL) particles immobilized on the inner wall of a 50-microm inner diameter silica capillary. In this method, the immobilized LDL particles were delipidated with nonionic surfactant Nonidet P-40 at pH 7.4 and 25 degrees C, resulting in an apolipoprotein B-100 (apoB-100)-coated capillary surface. The mobility of the electroosmotic flow marker dimethyl sulfoxide gave information about the surface charge, and the retention factors of beta-estradiol, testosterone, and progesterone were informative of the surface hydrophobicity. The calculated distribution coefficients of the steroids produced specific information about the affinity interactions of the steroids, with capillary surfaces coated either with intact LDL particles or with apoB-100. Delipidation with Nonidet P-40 resulted in a strong decrease in the hydrophobicity of the LDL coating. Atomic force microscopy images confirmed the loss of lipids from the LDL particles and the presence of apoB-100 protein coating. The in situ delipidation of LDL particles in capillaries represents a novel approach for the isolation of immobilized apoB-100 and for the determination of its pI value. The technique requires extremely low quantities of LDL particles, and it is simple and fast.

  12. Impact of Apolipoprotein B on Hepatosteatosis in a Population Infected with Hepatitis C Virus: A Cross-Sectional Observational Study

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    Ming-Shyan Lin


    Full Text Available Objective: Non-alcoholic fatty liver disease (NAFLD is an established risk factor for diabetes, cardiovascular disease, antiviral treatment resistance, and progression of chronic hepatitis C virus (HCV infection to fibrosis. Apolipoprotein-B 100 (ApoB-100 is a dyslipidemia marker and steatosis predictor. We assess the correlation between ApoB-100 and hepatosteatosis. Methods: This cross-sectional study enrolled 1,218 HCV-seropositive participants from a 2012-2013 health checkup in Taiwan. NAFLD was detected using ultrasound. All anthropometric and laboratory studies that included ApoB-100 were evaluated whether or not ApoB-100 predicts NAFLD. Logistic regression was also used to examine the association between ApoB-100 and NAFLD. Results: Participants were 47.16 ± 16.08 years old (mean age. The overall prevalence of NAFLD was 35.8% (n = 436; 32.8% men, 38.1% women. Participants with ApoB-100 ≥ 8 had a significantly higher incidence of NAFLD (39.4 vs. 29.4%; 95% CI 0.044-0.156; p Conclusion: ApoB-100 is strongly associated with NAFLD in people with non-genotype 3 HCV; greater ApoB-100 content is significantly correlated with higher-grade hepatosteatosis.

  13. Lactobacillus acidophilus ATCC 4356 prevents atherosclerosis via inhibition of intestinal cholesterol absorption in apolipoprotein E-knockout mice. (United States)

    Huang, Ying; Wang, Jinfeng; Quan, Guihua; Wang, Xiaojun; Yang, Longfei; Zhong, Lili


    The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Eight-week-old ApoE(-/-) mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE(-/-) mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P acidophilus ATCC 4356 treatment groups than in the control groups. Furthermore, L. acidophilus ATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration of L. acidophilus ATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore, L. acidophilus ATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis.

  14. High-density Lipoproteins and Apolipoprotein A-I: Potential New Players in the Prevention and Treatment of Lung Disease

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    Elizabeth M. Gordon


    Full Text Available Apolipoprotein A-I (apoA-I and high-density lipoproteins (HDL mediate reverse cholesterol transport out of cells. Furthermore, HDL has additional protective functions, which include anti-oxidative, anti-inflammatory, anti-apoptotic, and vasoprotective effects. In contrast, HDL can become dysfunctional with a reduction in both cholesterol efflux and anti-inflammatory properties in the setting of disease or the acute phase response. These paradigms are increasingly being recognized to be active in the pulmonary system, where apoA-I and HDL have protective effects in normal lung health, as well as in a variety of disease states, including acute lung injury, asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary arterial hypertension, pulmonary fibrosis, and viral pneumonia. Similar to observations in cardiovascular disease, however, HDL may become dysfunctional and contribute to disease pathogenesis in respiratory disorders. Furthermore, synthetic apoA-I mimetic peptides have been shown to have protective effects in animal models of acute lung injury, asthma, pulmonary hypertension, and influenza pneumonia. These findings provide evidence to support the concept that apoA-I mimetic peptides might be developed into a new treatment that can either prevent or attenuate the manifestations of lung diseases, such as asthma. Thus, the lung is positioned to take a page from the cardiovascular disease playbook and utilize the protective properties of HDL and apoA-I as a novel therapeutic approach.

  15. Interleukin-8-251T > a, interleukin-1α-889C > t and apolipoprotein e polymorphisms in Alzheimer's disease

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    Alex Augusto Vendramini


    Full Text Available An inflammatory process has been involved in numerous neurodegenerative disorders such as Parkinson's disease, stroke and Alzheimer's disease (AD. In AD, the inflammatory response is mainly located in the vicinity of amyloid plaques. Cytokines, such as interleukin-8 (IL-8 and interleukin-1α (IL-1α, have been clearly involved in this inflammatory process. Polymorphisms of several interleukin genes have been correlated to the risk of developing AD. The present study investigated the association of AD with polymorphisms IL-8 -251T > A (rs4073 and IL-1α-889C > T (rs1800587 and the interactive effect of both, adjusted by the Apolipoprotein E genotype. 199 blood samples from patients with AD, 146 healthy elderly controls and 95 healthy young controls were obtained. DNA samples were isolated from blood cells, and the PCR-RFLP method was used for genotyping. The genotype distributions of polymorphisms IL-8, IL-1α and APOE were as expected under Hardy-Weinberg equilibrium. The allele frequencies did not differ significantly among the three groups tested. As expected, the APOE4 allele was strongly associated with AD (p A and IL-1α-889C > T were not found to be risk factors for AD.

  16. Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer’s Disease Therapy from Traditional Chinese Medicine

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    Hung-Jin Huang


    Full Text Available Apolipoprotein E4 (Apo E4 is the major genetic risk factor in the causation of Alzheimer’s disease (AD. In this study we utilize virtual screening of the world’s largest traditional Chinese medicine (TCM database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.

  17. Mass spectrometry quantification revealed accumulation of C-terminal fragment of apolipoprotein E in the Alzheimer's frontal cortex.

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    Meiyao Wang

    Full Text Available Polymorphic variation in the apolipoprotein E (apoE gene is the major genetic susceptibility factor for late-onset Alzheimer's disease (AD and likely contributes to neuropathology through various pathways. It is also recognized that apoE undergoes proteolytic cleavage in the brain and the resultant apoE fragments likely have a variety of bioactive properties that regulate neuronal signaling and may promote neurodegeneration. ApoE fragmentation in the human brain has been intensively studied using different immunochemical methods, but has never been analyzed in a quantitative manner to establish preferably accumulated fragments. Here we report quantification using multiple reaction monitoring mass spectrometry (MRM MS with (15N-labeled full-length apoE4 as an internal standard. Measurements were performed on frontal cortex from control and severe AD donors. Our data point to a preferable accumulation of C-terminal apoE fragment in the insoluble fraction of tissue homogenate in the severe AD group versus the control group. Further insight into the biological consequences of this accumulation may lead to a better understanding of the basic mechanism of AD pathology.

  18. Increased prothrombin, apolipoprotein A-IV, and haptoglobin in the cerebrospinal fluid of patients with Huntington's disease.

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    Yen-Chu Huang

    Full Text Available Huntington's disease (HD is a progressive neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion. The need for biomarkers of onset and progression in HD is imperative, since currently reliable outcome measures are lacking. We used two-dimensional electrophoresis and mass spectrometry to analyze the proteome profiles in cerebrospinal fluid (CSF of 6 pairs of HD patients and controls. Prothrombin, apolipoprotein A-IV (Apo A-IV and haptoglobin were elevated in CSF of the HD patients in comparison with the controls. We used western blot as a semi-quantified measurement for prothrombin and Apo A-IV, as well as enzyme linked immunosorbent assay (ELISA for measurement of haptoglobin, in 9 HD patients and 9 controls. The albumin quotient (Qalb, a marker of blood-brain barrier (BBB function, was not different between the HD patients and the controls. The ratios of CSF prothrombin/albumin (prothrombin/Alb and Apo A-IV/albumin (Apo A-IV/Alb, and haptoglobin level were significantly elevated in HD. The ratio of CSF prothrombin/Alb significantly correlated with the disease severity assessed by Unified Huntington's Disease Rating Scale (UHDRS. The results implicate that increased CSF prothrombin, Apo A-IV, and haptoglobin may be involved in pathogenesis of HD and may serve as potential biomarkers for HD.

  19. Studies on the Effects of Steroid Hormone Contraceptives on Lipid, Lipoprotein and Apolipoprotein Metabolism in Chinese Women

    Institute of Scientific and Technical Information of China (English)

    杨培娟; 宋思; 杨秋英; 桂幼伦; 贺昌海


    Objective To explore the effects of steroid hormone contraceptives (SHCs), such as Mercilon, Chinese No. 1 pill, Post-coital pill, Mesigyna, and Cyclofem, on lipid metabolism in Chinese women during the last decade.Materials & Methods A total of 122 healthy volunteers who requested contraception were recruited in the study and one of the above-mentioned SHCs was administered.Fasting serum samples were taken from each subject before, during and after treatments. Triglycerides ( TG ) , total cholesterol ( TC ) , high density lipoprotein-cholesterol (HDL-c ) , low density lipoprotein-cholesterol (LDL-c ) , Apolipoprotein A I, A II and B were measured. The changes in the ratios of TC/HDL-c, Apo A I/Apo B were also observed.Results Although the levels of lipid were either increased or decreased by any one of the 5 contraceptives, these changes recovered after withdrawal of the drug administration. No significant changes were detected in the ratios of TC/HDL-c, Apo A I/Apo B during treatments.Conclusion The results suggest that there is no obvious impact on lipid profile induced by any of the 5 contraceptives within one year. The induced effects on lipid metabolism could be reduced by alternate use of 2 contraceptives with different biological activities.

  20. Apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging. (United States)

    Roussotte, Florence F; Gutman, Boris A; Madsen, Sarah K; Colby, John B; Narr, Katherine L; Thompson, Paul M


    The apolipoprotein E epsilon 4 allele (ApoE-ε4) is the strongest known genetic risk factor for late onset Alzheimer's disease. Expansion of the lateral ventricles occurs with normal aging, but dementia accelerates this process. Brain structure and function depend on ApoE genotype not just for Alzheimer's disease patients but also in healthy elderly individuals, and even in asymptomatic young individuals. Therefore, we hypothesized that the ApoE-ε4 allele is associated with altered patterns of longitudinal ventricular expansion, in dementia and normal aging. We tested this hypothesis in a large sample of elderly participants, using a linear discriminant analysis-based approach. Carrying more ApoE-ε4 alleles was associated with faster ventricular expansion bilaterally and with regional patterns of lateral ventricle morphology at 1- and 2-year follow up, after controlling for sex, age, and dementia status. ApoE genotyping is considered critical in clinical trials of Alzheimer's disease. These findings, combined with earlier investigations showing that ApoE is also directly implicated in other conditions, suggest that the selective enrollment of ApoE-ε4 carriers may empower clinical trials of other neurological disorders.

  1. Demographic and Lifestyle Characteristics, but Not Apolipoprotein E Genotype, Are Associated with Intelligence among Young Chinese College Students.

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    Xiao-Fen Chen

    Full Text Available Intelligence is an important human feature that strongly affects many life outcomes, including health, life-span, income, educational and occupational attainments. People at all ages differ in their intelligence but the origins of these differences are much debated. A variety of environmental and genetic factors have been reported to be associated with individual intelligence, yet their nature and contribution to intelligence differences have been controversial.To investigate the contribution of apolipoprotein E (APOE genotype, which is associated with the risk for Alzheimer's disease, as well as demographic and lifestyle characteristics, to the variation in intelligence.A total of 607 Chinese college students aged 18 to 25 years old were included in this prospective observational study. The Chinese revision of Wechsler Adult Intelligence Scale (the fourth edition, short version was used to determine the intelligence level of participants. Demographic and lifestyle characteristics data were obtained from self-administered questionnaires.No significant association was found between APOE polymorphic alleles and different intelligence quotient (IQ measures. Interestingly, a portion of demographic and lifestyle characteristics, including age, smoking and sleep quality were significantly associated with different IQ measures.Our findings indicate that demographic features and lifestyle characteristics, but not APOE genotype, are associated with intelligence measures among young Chinese college students. Thus, although APOE ε4 allele is a strong genetic risk factor for Alzheimer's disease, it does not seem to impact intelligence at young ages.

  2. An Improved RSP Method to Detect HpaI Polymorphism in the Apolipoprotein C-1 Gene Promoter

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    Lavoie Tera


    Full Text Available Abstract Background An apolipoprotein C1 gene promoter polymorphism (CGTT insertion at position -317 is associated with familial dysbetalipoprotemia, cardiovascular diseases, and Alzheimer's disease. Restriction site polymorphism (RSP assays were previously established to detect this polymorphism. In this study, we introduce an improved RSP assay to detect this polymorphism. Methods This method included newly designed primers and only one round of PCR amplification which yields one short and specific APOC1 fragment followed by HpaI digestion. Briefly, It consists of three steps: 1 one round of PCR amplification of DNA sample, 2 HpaI enzyme digestion of PCR products, and 3 electrophoresis on an agarose gel to visualize the genotypes. This improved RSP method was applied to genotype 92 human samples collected from The Johns Hopkins Hospital. Results The observed allele frequencies for H1 and H2 from 92 genotyped human subjects were 0.707 and 0.293 respectively. The H2 allele frequency in the black subjects (0.350 was significantly (p = 0.024 higher than that in the white subjects (0.177. This method was more economical and convenient than the methods previously reported to detect this mutation in the APOC1 gene. Conclusions This assay will be readily applied to screen large sample sizes for population studies in a simple and cost effective way.

  3. Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes.

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    Casey R Dorr

    Full Text Available Apolipoprotein L1 gene (APOL1 G1 and G2 renal-risk variants, common in populations with recent African ancestry, are strongly associated with non-diabetic nephropathy, end-stage kidney disease, and shorter allograft survival in deceased-donor kidneys (autosomal recessive inheritance. Circulating APOL1 protein is synthesized primarily in the liver and hydrodynamic gene delivery of APOL1 G1 and G2 risk variants has caused hepatic necrosis in a murine model.To evaluate the impact of these variants in liver transplantation, this multicenter study investigated the association of APOL1 G1 and G2 alleles in deceased African American liver donors with allograft survival. Transplant recipients were followed for liver allograft survival using data from the Scientific Registry of Transplant Recipients.Of the 639 liver donors evaluated, 247 had no APOL1 risk allele, 300 had 1 risk allele, and 92 had 2 risk alleles. Graft failure assessed at 15 days, 6 months, 1 year and total was not significantly associated with donor APOL1 genotype (p-values = 0.25, 0.19, 0.67 and 0.89, respectively.In contrast to kidney transplantation, deceased-donor APOL1 G1 and G2 risk variants do not significantly impact outcomes in liver transplantation.

  4. Interactions of the apolipoprotein C-III 3238C>G polymorphism and alcohol consumption on serum triglyceride levels

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    Ruixing Yin


    Full Text Available Abstract Background Both apolipoprotein (Apo C-III gene polymorphism and alcohol consumption have been associated with increased serum triglyceride (TG levels, but their interactions on serum TG levels are not well known. The present study was undertaken to detect the interactions of the ApoC-III 3238C>G (rs5128 polymorphism and alcohol consumption on serum TG levels. Methods A total of 516 unrelated nondrinkers and 514 drinkers aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoC-III 3238C>G was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Interactions of the ApoC-III 3238C>G genotype and alcohol consumption was assessed by using a cross-product term between genotypes and the aforementioned factor. Results Serum total cholesterol (TC, TG, high-density lipoprotein cholesterol (HDL-C, ApoA-I and ApoB levels were higher in drinkers than in nondrinkers (P P P P P P P P Conclusions This study suggests that the ApoC-III 3238CG heterozygotes benefited more from alcohol consumption than CC and GG homozygotes in increasing serum levels of HDL-C, ApoA-I, and the ratio of ApoA-I to ApoB, and lowering serum levels of TC and TG.

  5. An ABCA1-independent pathway for recycling a poorly lipidated 8.1 nm apolipoprotein E particle from glia (United States)

    Fan, Jianjia; Stukas, Sophie; Wong, Charmaine; Chan, Jennifer; May, Sharon; DeValle, Nicole; Hirsch-Reinshagen, Veronica; Wilkinson, Anna; Oda, Michael N.; Wellington, Cheryl L.


    Lipid transport in the brain is coordinated by glial-derived lipoproteins that contain apolipoprotein E (apoE) as their primary protein. Here we show that apoE is secreted from wild-type (WT) primary murine mixed glia as nascent lipoprotein subspecies ranging from 7.5 to 17 nm in diameter. Negative-staining electron microscropy (EM) revealed rouleaux, suggesting a discoidal structure. Potassium bromide (KBr) density gradient ultracentrifugation showed that all subspecies, except an 8.1 nm particle, were lipidated. Glia lacking the cholesterol transporter ABCA1 secreted only 8.1 nm particles, which were poorly lipidated and nondiscoidal but could accept lipids to form the full repertoire of WT apoE particles. Receptor-associated-protein (RAP)-mediated inhibition of apoE receptor function blocked appearance of the 8.1 nm species, suggesting that this particle may arise through apoE recycling. Selective deletion of the LDL receptor (LDLR) reduced the level of 8.1 nm particle production by approximately 90%, suggesting that apoE is preferentially recycled through the LDLR. Finally, apoA-I stimulated secretion of 8.1 nm particles in a dose-dependent manner. These results suggest that nascent glial apoE lipoproteins are secreted through multiple pathways and that a greater understanding of these mechanisms may be relevant to several neurological disorders. PMID:21705806

  6. Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPARβ/δ in HepG2 cells. (United States)

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua; Berggren-Söderlund, Maria; Nilsson-Ehle, Peter; Zhang, Xiaoying; Xu, Ning


    It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPARβ/δ pathway.

  7. Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment. (United States)

    Genis, I; Fisher, A; Michaelson, D M


    Apolipoprotein E (apoE)-deficient mice have memory deficits that are associated with synaptic loss of basal forebrain cholinergic projections and with hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. Furthermore, treatment of apoE-deficient mice with the M1 selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline) [AF150(S)] abolishes their memory deficits and results in recovery of their brain cholinergic markers. In the present study, we used a panel of anti-tau monoclonal antibodies to further map the tau epitopes that are hyperphosphorylated in apoE-deficient mice and examined the effects of prolonged treatment with AF150(S). This revealed that tau of apoE-deficient mice contains a distinct, hyperphosphorylated "hot spot" domain which is localized N-terminally to the microtubule binding domain of tau, and that AF150(S) has an epitope-specific tau dephosphorylating effect whose magnitude is affected by apoE deficiency. Accordingly, epitopes which reside in the hyperphosphorylated "hot spot" are dephosphorylated by AF150(S) in apoE-deficient mice but are almost unaffected in the controls, whereas epitopes which flank this tau domain are dephosphorylated by AF150(S) in both mice groups. In contrast, epitopes located at the N and C terminals of tau are unaffected by AF150(S) in both groups of mice. These findings suggest that apoE deficiency results in hyperphosphorylation of a distinct tau domain whose excess phosphorylation can be reduced by muscarinic treatment.

  8. High-density cholesterol and apolipoprotein AI as modifiers of plasma fibrin clot properties in apparently healthy individuals. (United States)

    Ząbczyk, Michał; Hońdo, Łukasz; Krzek, Marzena; Undas, Anetta


    Low high-density lipoprotein cholesterol (HDL-C) increases cardiovascular risk, whereas its high levels protect against atherosclerosis via multiple beneficial effects. Dense and poorly lysable fibrin clot formation is observed in cardiovascular disease. We sought to investigate whether HDL-C and its major component apolipoprotein A (Apo A)-I affect fibrin clot properties. In 136 apparently healthy individuals (99 men, 37 women, aged 49-69 years) we determined plasma fibrin clot permeability (Ks coefficient) and lysis time (t50%) together with Apo A-I and lipoprotein (a) [Lp(a)] levels. The median HDL-C level was 1.33  mmol/l (range from 0.77 to 2.19  mmol/l). HDL-C was positively associated with Apo A-I (r = 0.62, P Ks (r = 0.52, P Ks and t50% were associated with Lp(a) (r = -0.42, P Ks (P = 0.00016) and 17% shorter t50% (P = 0.0012) than the remainder. After adjustment for age, fibrinogen, and Lp(a), HDL-C was the independent predictor of Ks (β = 0.7, P < 0.00001) and t50% (β = -0.62, P < 0.00001). This study shows that elevated HDL-C levels are associated with improved fibrin clot permeability and lysis, indicating a novel antithrombotic mechanism underlying the postulated beneficial effects of therapy targeted at HDL-C.

  9. Expression and purification of recombinant apolipoprotein A-I Zaragoza (L144R) and formation of reconstituted HDL particles. (United States)

    Fiddyment, Sarah; Barceló-Batllori, Sílvia; Pocoví, Miguel; García-Otín, Angel-Luis


    Apolipoprotein A-I Zaragoza (L144R) (apo A-I Z), has been associated with severe hypoalphalipoproteinemia and an enhanced effect of high density lipoprotein (HDL) reverse cholesterol transport. In order to perform further studies with this protein we have optimized an expression and purification method of recombinant wild-type apo A-I and apo A-I Z and produced mimetic HDL particles with each protein. An pET-45 expression system was used to produce N-terminal His-tagged apo A-I, wild-type or mutant, in Escherichia coli BL21 (DE3) which was subsequently purified by affinity chromatography in non-denaturing conditions. HDL particles were generated via a modified sodium cholate method. Expression and purification of both proteins was verified by SDS-PAGE, MALDI-TOF MS and immunochemical procedures. Yield was 30mg of purified protein (94% purity) per liter of culture. The reconstituted HDL particles checked via non-denaturing PAGE showed high homogeneity in their size when reconstituted both with wild-type apo A-I and apo A-I Z. An optimized system for the expression and purification of wild-type apo A-I and apo A-I Z with high yield and purity grade has been achieved, in addition to their use in reconstituted HDL particles, as a basis for further studies.

  10. A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

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    Partha S Bhattacharjee

    Full Text Available Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp derived from the receptor binding region of human apolipoprotein E (apoE inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

  11. Structural and functional characterization of human apolipoprotein E 72-166 peptides in both aqueous and lipid environments

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    Chou Chi-Yuan


    Full Text Available Abstract Backgrounds There are three apolipoprotein E (apoE isoforms involved in human lipid homeostasis. In the present study, truncated apoE2-, apoE3- and apoE4-(72-166 peptides that are tailored to lack domain interactions are expressed and elucidated the structural and functional consequences. Methods & Results Circular dichroism analyses indicated that their secondary structure is still well organized. Analytical ultracentrifugation analyses demonstrated that apoE-(72-166 produces more complicated species in PBS. All three isoforms were significantly dissociated in the presence of dihexanoylphosphatidylcholine. Dimyristoylphosphatidylcholine turbidity clearance assay showed that apoE4-(72-166 maintains the highest lipid-binding capacity. Finally, only apoE4-(72-166 still maintained significant LDL receptor binding ability. Conclusions Overall, apoE4-(72-166 peptides displayed a higher lipid-binding and comparable receptor-binding ability as to full-length apoE. These findings provide the explanation of diverged functionality of truncated apoE isoforms.

  12. Segregation analysis of apolipoprotein A1 levels in families of adolescents: A community-based study in Taiwan

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    Su Ta-Chen


    Full Text Available Background Apolipoprotein (Apo A1 is a protective factor for cardiovascular events. This study aimed to perform complex segregation analyses of Apo A1 levels in families of adolescents systematically ascertained from the junior high school students in a rural community. Both siblings and parents of the adolescent probands were recruited for the study. Apo A1 concentrations were measured by turbidimetric immunoassay methods. After adjustment for gender, age, body mass index, smoking and drinking status, residual values of Apo A1 were subjected to subsequent analyses. Results Significant mother-father and parent-offspring correlations were found. Commingling analyses indicated that a four-component distribution model was needed to account for the Apo A1 variation. Segregation analysis using regressive models revealed that the best-fit model of Apo A1 was a model of environmental effect plus familial correlation (heritability = 23.9%, in which a significant mother-father correlation existed. Models containing major gene effect could be rejected. Conclusion These results suggest that variations of Apo A1 levels in the normal range, especially during adolescence, are likely to be influenced by multiple factors without significant contribution from major genes.

  13. Epigenetic effectiveness of complete carcinogens: specific interactions of polycyclic aromatic hydrocarbons and aminoazo dyes with cholesterol and apolipoprotein A - I

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    Contag, B. [Technische Fachhochschule Berlin (Germany). Fachbereich II - Pharma- und Chemietechnik


    During a co-precipitation of cholesterol (Chol) and slight amounts of polycyclic aromatic hydrocarbons (PAHs) or aminoazo dyes (AZOs) in aqueous albumin solution, complex particles are formed; on their surfaces apolipoproteins with an amphipathic {alpha}-helix (e.g. apoA-I) are more or less firmly adsorbed. An efficacy index can be calculated from the strength of the hydrophobic interactions between apoA-I and the [Chol/PAH]- or [Chol/AZO]-complex, and the solubility of the PAH or AZO in an aqueous medium, which correlates to the carcinogenicity of these compounds. A short-term test for PAHs and AZOs is described, in which the efficacy index can be determined in the simplest manner without any great expenditure on equipment. The previous results suggest that the parent compounds of the PAHs and AZOs can be involved in a specific interaction with cholesterol-domains of the plasma membrane of a cell. The changes in membrane fluidity and architecture caused by these specific interactions could modulate the distribution and/or activity of membrane proteins which are critical to the regulation of cellular proliferation. (orig.)

  14. Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy? (United States)

    Jasienska, Grazyna; Ellison, Peter T; Galbarczyk, Andrzej; Jasienski, Michal; Kalemba-Drozdz, Malgorzata; Kapiszewska, Maria; Nenko, Ilona; Thune, Inger; Ziomkiewicz, Anna


    The alleles that are detrimental to health, especially in older age, are thought to persist in populations because they also confer some benefits for individuals (through antagonistic pleiotropy). The ApoE4 allele at the ApoE locus, encoding apolipoprotein E (ApoE), significantly increases risk of poor health, and yet it is present in many populations at relatively high frequencies. Why has it not been replaced by natural selection with the health-beneficial ApoE3 allele? ApoE is a major supplier of cholesterol precursor for the production of ovarian oestrogen and progesterone, thus ApoE has been suggested as the potential candidate gene that may cause variation in reproductive performance. Our results support this hypothesis showing that in 117 regularly menstruating women those with genotypes with at least one ApoE4 allele had significantly higher levels of mean luteal progesterone (144.21 pmol l(-1)) than women with genotypes without ApoE4 (120.49 pmol l(-1)), which indicates higher potential fertility. The hormonal profiles were based on daily data for entire menstrual cycles. We suggest that the finding of higher progesterone in women with ApoE4 allele could provide first strong evidence for an evolutionary mechanism of maintaining the ancestral and health-worsening ApoE4 allele in human populations.

  15. Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples. (United States)

    Gillespie, Anna K; Jones, Emily A; Lin, Yuan-Hung; Karlsson, Mattias P; Kay, Kenneth; Yoon, Seo Yeon; Tong, Leslie M; Nova, Philip; Carr, Jessie S; Frank, Loren M; Huang, Yadong


    Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT.

  16. Angiotensin converting enzyme inhibitors and the reduced risk of Alzheimer's disease in the absence of apolipoprotein E4 allele. (United States)

    Qiu, Wei Qiao; Mwamburi, Mkaya; Besser, Lilah M; Zhu, Haihao; Li, Huajie; Wallack, Max; Phillips, Leslie; Qiao, Liyan; Budson, Andrew E; Stern, Robert; Kowall, Neil


    Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer's disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer's Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 test: 13% versus 27%, p ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype.

  17. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. (United States)

    Halliday, Matthew R; Rege, Sanket V; Ma, Qingyi; Zhao, Zhen; Miller, Carol A; Winkler, Ethan A; Zlokovic, Berislav V


    The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

  18. Human apolipoprotein E ɛ4 expression impairs cerebral vascularization and blood-brain barrier function in mice. (United States)

    Alata, Wael; Ye, Yue; St-Amour, Isabelle; Vandal, Milène; Calon, Frédéric


    Human apolipoprotein E (APOE) exists in three isoforms ɛ2, ɛ3, and ɛ4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood-brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [(3)H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [(3)H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.

  19. Apolipoprotein A-I configuration and cell cholesterol efflux activity of discoidal lipoproteins depend on the reconstitution process. (United States)

    Cuellar, Luz Ángela; Prieto, Eduardo Daniel; Cabaleiro, Laura Virginia; Garda, Horacio Alberto


    Discoidal high-density lipoproteins (D-HDL) are critical intermediates in reverse cholesterol transport. Most of the present knowledge of D-HDL is based on studies with reconstituted lipoprotein complexes of apolipoprotein A-I (apoA-I) obtained by cholate dialysis (CD). D-HDL can also be generated by the direct microsolubilization (DM) of phospholipid vesicles at the gel/fluid phase transition temperature, a process mechanistically similar to the "in vivo" apoAI lipidation via ABCA1. We compared the apoA-I configuration in D-HDL reconstituted with dimyristoylphosphatidylcholine by both procedures using fluorescence resonance energy transfer measurements with apoA-I tryptophan mutants and fluorescently labeled cysteine mutants. Results indicate that apoA-I configuration in D-HDL depends on the reconstitution process and are consistent with a "double belt" molecular arrangement with different helix registry. As reported by others, a configuration with juxtaposition of helices 5 of each apoAI monomer (5/5 registry) predominates in D-HDL obtained by CD. However, a configuration with helix 5 of one monomer juxtaposed with helix 2 of the other (5/2 registry) would predominate in D-HDL generated by DM. Moreover, we also show that the kinetics of cholesterol efflux from macrophage cultures depends on the reconstitution process, suggesting that apoAI configuration is important for this HDL function.

  20. Amyloidogenic propensity of a natural variant of human apolipoprotein A-I: stability and interaction with ligands.

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    Silvana A Rosú

    Full Text Available A number of naturally occurring mutations of human apolipoprotein A-I (apoA-I have been associated with hereditary amyloidoses. The molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here we examined the effects of the Arg173Pro point mutation in apoA-I on the structure, stability, and aggregation propensity, as well as on the ability to bind to putative ligands. Our results indicate that the mutation induces a drastic loss of stability, and a lower efficiency to bind to phospholipid vesicles at physiological pH, which could determine the observed higher tendency to aggregate as pro-amyloidogenic complexes. Incubation under acidic conditions does not seem to induce significant desestabilization or aggregation tendency, neither does it contribute to the binding of the mutant to sodium dodecyl sulfate. While the binding to this detergent is higher for the mutant as compared to wt apoA-I, the interaction of the Arg173Pro variant with heparin depends on pH, being lower at pH 5.0 and higher than wt under physiological pH conditions. We suggest that binding to ligands as heparin or other glycosaminoglycans could be key events tuning the fine details of the interaction of apoA-I variants with the micro-environment, and probably eliciting the toxicity of these variants in hereditary amyloidoses.