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 ...svg) (.html) (.csml) Show Regulation of endogenous apolipoprotein E secretion by macrophages. PubmedID 18388...328 Title Regulation of endogenous apolipoprotein E secretion by macrophages. Aut

Dietary Flaxseed Oil Prevents Western-Type Diet-Induced Nonalcoholic Fatty Liver Disease in Apolipoprotein-E Knockout Mice

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Hao Han

2017-01-01

Full Text Available The prevalence of nonalcoholic fatty liver disease (NAFLD has dramatically increased globally during recent decades. Intake of n-3 polyunsaturated fatty acids (PUFAs, mainly eicosapentaenoic acid (EPA, C20:5n-3 and docosahexaenoic acid (DHA, C22:6n-3, is believed to be beneficial to the development of NAFLD. However, little information is available with regard to the effect of flaxseed oil rich in α-linolenic acid (ALA, C18:3n-3, a plant-derived n-3 PUFA, in improving NAFLD. This study was to gain the effect of flaxseed oil on NAFLD and further investigate the underlying mechanisms. Apolipoprotein-E knockout (apoE-KO mice were given a normal chow diet, a western-type high-fat and high-cholesterol diet (WTD, or a WTD diet containing 10% flaxseed oil (WTD + FO for 12 weeks. Our data showed that consumption of flaxseed oil significantly improved WTD-induced NAFLD, as well as ameliorated impaired lipid homeostasis, attenuated oxidative stress, and inhibited inflammation. These data were associated with the modification effects on expression levels of genes involved in de novo fat synthesis (SREBP-1c, ACC, triacylglycerol catabolism (PPARα, CPT1A, and ACOX1, inflammation (NF-κB, IL-6, TNF-α, and MCP-1, and oxidative stress (ROS, MDA, GSH, and SOD.

Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and compromises reendothelialization impaired by oxidized HDL through SR-B1

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Dan He

2018-05-01

Full Text Available Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL oxidized by heme enzyme myeloperoxidase (MPO is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL in promoting re-endothelialization. We demonstrate that 4F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1 using human aorta endothelial cells (HAEC and SR-B1 (-/- mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS activity, Akt phosphorylation and SR-B1 expression. 4F increases NO generation and diminishes oxidative stress. In vivo, 4F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/- mice. These findings demonstrate that 4F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases.

Suppressive effects of cacao polyphenols on the development of atherosclerosis in apolipoprotein E-deficient mice.

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Natsume, Midori; Baba, Seigo

2014-01-01

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.

Serum apolipoprotein e level is not increased in Alzheimer's disease : The Rotterdam study

NARCIS (Netherlands)

Slooter, A.J.C.; Knijff, P. de; Hofman, A.; Cruts, M.; Breteler, M.M.B.; Broeckhoven, C. van; Havekes, L.M.; Duijn, C.M. van

1998-01-01

The APOE*4 allele of the apolipoprotein E gene (APOE) is an important risk factor for Alzheimer's disease. It has been suggested that levels of apolipoprotein E (apoE) in plasma are increased in Alzheimer's disease. In this population-based study, we found that serum apoE levels were lower in

Interactions of metals and Apolipoprotein E in Alzheimer’s disease

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He eXu

2014-06-01

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.

A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

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Partha S Bhattacharjee

2011-01-01

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.

IL-25 inhibits atherosclerosis development in apolipoprotein E deficient mice.

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Polyxeni T Mantani

Full Text Available IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice.Administration of 1 μg IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apoE deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 μg IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease.The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses.

Comparison of lipoprotein electrophoresis and apolipoprotein e genotyping in investigating dysbetalipoproteinemia

International Nuclear Information System (INIS)

Ahmed, F.; Kadiki, A.E.

2017-01-01

Dysbetalipoproteinemia is often associated with apolipoprotein E2E2 homozygosity; however, lipoprotein electrophoresis may also be used to assist in the diagnosis. The aim of this study was to compare apolipoprotein E (apo E) genotyping and lipoprotein electrophoresis in investigating dysbetalipoproteinemia. Data were collected over a three-year period from a lipid clinic in a tertiary referral centre and reviewed for apo E genotyping and lipoprotein electrophoresis. Sixty-two patients had both apo E genotyping and lipoprotein electrophoresis. Of these, 16 patients showed broad beta band on electrophoresis. However, only 3 of them had apo E2E2 homozygosity on genotyping. Lipoprotein electrophoresis and apo E genotyping results showed poor concordance. This was primarily due to visual interpretation error of lipoprotein electrophoresis which may over diagnose dysbetalipoproteinemia. (author)

Comparison of Lipoprotein Electrophoresis and Apolipoprotein E Genotyping in Investigating Dysbetalipoproteinemia.

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Ahmed, Farhan; El-Kadiki, Alia; Gibbons, Stephen

2017-06-01

Dysbetalipoproteinemia is often associated with apolipoprotein E2E2 homozygosity; however, lipoprotein electrophoresis may also be used to assist in the diagnosis. The aim of this study was to compare apolipoprotein E (apo E) genotyping and lipoprotein electrophoresis in investigating dysbetalipoproteinemia. Data were collected over a three-year period from a lipid clinic in a tertiary referral centre and reviewed for apo E genotyping and lipoprotein electrophoresis. Sixty-two patients had both apo E genotyping and lipoprotein electrophoresis. Of these, 16 patients showed broad beta band on electrophoresis. However, only 3 of them had apo E2E2 homozygosity on genotyping. Lipoprotein electrophoresis and apo E genotyping results showed poor concordance. This was primarily due to visual interpretation error of lipoprotein electrophoresis which may over diagnose dysbetalipoproteinemia.

Apolipoprotein E in Temporal Lobe Epilepsy: A Case-Control Study

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Amit Kumar

2006-01-01

Full Text Available Purpose: To investigate the relationship of apolipoprotein E (apoE genotype, plasma levels of apoE and lipids in temporal lobe epilepsy (TLE patients in Asian Indians. Status of plasma levels of Apo E in epilepsy patients has not been reported till date.

Equol Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice by Inhibiting Endoplasmic Reticulum Stress via Activation of Nrf2 in Endothelial Cells.

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Ting Zhang

Full Text Available The development of atherosclerosis is closely related to excessive endoplasmic reticulum stress (ERs. Equol reportedly protects against cardiovascular disease; however, the underlying mechanism for this protection remains unknown. Herein, the mechanisms contributing to the atheroprotective effect of equol were addressed using apolipoprotein E knockout (apoE-/- mice fed a high-fat diet (HFD with or without equol. Equol intervention reduced atherosclerotic lesions in the aorta in HFD-fed apoE-/- mice. Plasma lipid analysis showed that equol intervention reduced triglycerides, total cholesterol and LDL-cholesterol and increased HDL-cholesterol. Additionally, equol administration decreased lipid accumulation in the liver. Simultaneously, equol treatment inhibited cell apoptosis induced by t-BHP and thapsigargin in human umbilical vein endothelial cells (HUVECs. Furthermore, equol treatment attenuated palmitate, t-BHP or thapsigargin-induced upregulation of ER stress markers, including p-PERK, p-eIF2α, GRP78, ATF6 and CHOP proteins expression. The same tendency was also observed in aortic lysates in apoE-/- mice fed with equol plus HFD compared with HFD alone. Moreover, equol treatment dose dependently activated the Nrf2 signaling pathway under oxidative stress. Additionally, elevation of Nrf2 induction was found in aortic lysates in apoE-/- mice fed with a HFD diet containing equol compared with a HFD diet without equol. Importantly, Nrf2 siRNA interference induced CHOP and attenuated the effect of equol to inhibit t-BHP mediated CHOP induction, furthermore, abrogated cell apoptosis induced by t-BHP, suggesting a role for Nrf2 in the protective effect of equol in HUVECs. Collectively, these findings implicate that the improvement of atherosclerosis by equol through attenuation of ER stress is mediated, at least in part, by activating the Nrf2 signaling pathway.

Apolipoprotein e4 allele and cognitive decline in elderly men

NARCIS (Netherlands)

Feskens, E.J.M.; Havekes, L.M.; Kalmijn, S.; Knijff, P. de; Launer, L.J.; Kromhout, D.

1994-01-01

Objectives - To determine whether polymorphism of apolipoprotein E - notably, the e4 allele - predicts cognitive deterioration in the general population. Design - Population based cohort investigated in 1990 and in 1993. Setting - Zutphen, the Netherlands. Subjects - Representative cohort of 538

Inhibition of bacterial DD-peptidases (penicillin-binding proteins) in membranes and in vivo by peptidoglycan-mimetic boronic acids.

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Dzhekieva, Liudmila; Kumar, Ish; Pratt, R F

2012-04-03

The DD-peptidases or penicillin-binding proteins (PBPs) catalyze the final steps of bacterial peptidoglycan biosynthesis and are inhibited by the β-lactam antibiotics. There is at present a question of whether the active site structure and activity of these enzymes is the same in the solubilized (truncated) DD-peptidase constructs employed in crystallographic and kinetics studies as in membrane-bound holoenzymes. Recent experiments with peptidoglycan-mimetic boronic acids have suggested that these transition state analogue-generating inhibitors may be able to induce reactive conformations of these enzymes and thus inhibit strongly. We have now, therefore, measured the dissociation constants of peptidoglycan-mimetic boronic acids from Escherichia coli and Bacillus subtilis PBPs in membrane preparations and, in the former case, in vivo, by means of competition experiments with the fluorescent penicillin Bocillin Fl. The experiments showed that the boronic acids bound measurably (K(i) DD-peptidase inhibitors are more or less effective in vivo than in homogeneous solution.

Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function.

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Chauhan, Jay; Chen, Shen-En; Fenstermacher, Katherine J; Naser-Tavakolian, Aurash; Reingewertz, Tali; Salmo, Rosene; Lee, Christian; Williams, Emori; Raje, Mithun; Sundberg, Eric; DeStefano, Jeffrey J; Freire, Ernesto; Fletcher, Steven

2015-11-01

Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile.

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Rami A Al-Horani

Full Text Available Factor XIIIa (FXIIIa is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa's active site by using sulfated glycosaminoglycans (GAGs or non-saccharide GAG mimetics (NSGMs would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%. Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26-fold selective over two GAG-binding proteins factor Xa (efficacy of 71% and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants.

The common polymorphism of apolipoprotein E

DEFF Research Database (Denmark)

Gerdes, Ulrik

2003-01-01

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......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...

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

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Sumeet S Mitter

2012-01-01

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

Apolipoprotein E and cardiovascular disease

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Adriana Moreno Valladares

2006-01-01

Full Text Available 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 and E4 are product of three alleles e2, e3, e4 of one only gene. This factor is related with the amount of lipoproteins that contains ApoE for E/B receptors. A low concentration of lipoproteins with ApoE can increase the activity of LDL receptors and consequently downward the circulating LDL. In the other hand particles with Apo E3 or Apo E4, can cause a downward regulation of LDL and in this way produces a LDL plasma elevation. Many studies in human populations have concluded that this polymorphism of apoE and the plasma variation of lipoproteins are associated with cardiovascular risk. Cardiovascular disease is the result of different interaction between factors which are genetic factor specially ApoE polymorphism e4 allelic of ApoE can explain, in some degree, the greater frequency of cardiovascular disease in those who carries it.

Apolipoprotein E and carotid artery atherosclerosis - The Rotterdam study

NARCIS (Netherlands)

Slooter, AJC; Bots, ML; Havekes, LM; del Sol, AI; Cruts, M; Grobbee, DE; Hofman, A; Van Broeckhoven, C; Witteman, JCM; van Duijn, CM

Background and Purpose-Carotid artery atherosclerosis is a strong predictor for future stroke. It is yet unclear whether the apolipoprotein E polymorphism (APOE) is related to atherosclerosis in the carotid arteries. The aim of the present study was to investigate the role of APOE in carotid artery

[Apolipoprotein e polymorphism and cognitive function change of the elderly in a rural area, Korea].

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Kim, Sang Kyu; Hwang, Tae Yoon; Lee, Kyeong Soo; Kang, Pock Soo; Cho, Hee Soon; Bae, Young Kyung

2009-07-01

The aim of this study is to examine the cognitive function change related to aging, the incidence of cognitive impairment, and the association between apolipoprotein E polymorphism and cognitive impairment through a follow-up of the elderly with normal cognitive ability at baseline. Two hundred and fifteen subjects aged 65 and over were surveyed in February, 1998 (baseline survey), and their cognitive function was assessed again in 2003 (1st follow-up) and the once again in 2006 (2nd follow-up). Ninety one subjects completed all surveys up through the 2nd follow-up and their cognitive function scores using MMSE-K (Korean Version of the Mini-Mental State Examination) and the distribution of apolipoprotein E allele were analyzed. The cognitive function scores decreased with aging and the difference between baseline and the 2nd follow-up scores of the study increased with the age group. The incidence rate of cognitive impairment through an 8-year follow-up was 38.5% and higher in older age groups. Age was the only significant factor for incidence of cognitive impairment, but there was no significant association between apolipoprotein E genotype and incidence of cognitive impairment. The cognition of the elderly decreased with aging and the association of apolipoprotein E genotype with incidence of cognitive impairment was not significant in this study. To confirm the association between apolipoprotein E polymorphism and incidence of cognitive impairment further studies will be needed.

Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke

DEFF Research Database (Denmark)

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

2013-01-01

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 c...

Apolipoprotein E*3-Leiden transgenic mice mode for hypolipidaemic drugs

NARCIS (Netherlands)

Vlijmen, B.J.M. van; Pearce, N.J.; Bergö, M.; Staels, B.; Yates, J.W.; Gribble, A.D.; Bond, B.C.; Hofker, M.H.; Havekes, L.M.; Groot, P.H.E.

1998-01-01

Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5)

Apolipoprotein E in Temporal Lobe Epilepsy: A Case-Control Study

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Kumar, Amit; Tripathi, Manjari; Pandey, Ravindra M.; Ramakrishnan, Lakshmy; Srinivas, M.; Luthra, Kalpana

2006-01-01

Purpose: To investigate the relationship of apolipoprotein E (apoE) genotype, plasma levels of apoE and lipids in temporal lobe epilepsy (TLE) patients in Asian Indians. Status of plasma levels of Apo E in epilepsy patients has not been reported till date. Methods: ApoE gene polymorphism was analyzed in 58 patients with temporal lobe epilepsy (TLE) and 57 age and sex approximated controls using Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Levels of plasma apoE and lipids were measured using ELISA and enzymatic kits respectively. Results: The distribution of ApoE genotype in epilepsy patients and controls was comparable. Higher levels of plasma ApoE were observed in TLE patients as compared to controls (p = 0.0001). Individuals with plasma levels of apoE > 190 mg/L were at 20 times higher odds (95%CI = 2.46–163.34, p = 0.005), while those with levels of apoE between 150–190 mg/L were at 4.9 times higher odds (95% CI = 1.85–13.9, p = 0.001), to develop TLE. Conclusions: We have observed for the first time, high levels of plasma apoE in epilepsy patients. The findings of this case-control study suggest that apolipoprotein E may play an important role in epilepsy. PMID:17264404

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

Czech Academy of Sciences Publication Activity Database

Dolejší, Eva; Liraz, O.; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; Michaelson, D. M.

2016-01-01

Roč. 136, č. 3 (2016), s. 503-509 ISSN 0022-3042 R&D Projects: GA MŠk(CZ) LH13269 Institutional support: RVO:67985823 Keywords : acetylcholine release * Alzheimer's disease (AD) * apolipoprotein E4 (apoE4) * hippocampus Subject RIV: FH - Neurology Impact factor: 4.083, year: 2016

Class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion.

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Dresselhaus, Erica; Duerr, James M; Vincent, Fabien; Sylvain, Emily K; Beyna, Mercedes; Lanyon, Lorraine F; LaChapelle, Erik; Pettersson, Martin; Bales, Kelly R; Ramaswamy, Gayathri

2018-01-01

Despite the important role of apolipoprotein E (apoE) secretion from astrocytes in brain lipid metabolism and the strong association of apoE4, one of the human apoE isoforms, with sporadic and late onset forms of Alzheimer's disease (AD) little is known about the regulation of astrocytic apoE. Utilizing annotated chemical libraries and a phenotypic screening strategy that measured apoE secretion from a human astrocytoma cell line, inhibition of pan class I histone deacetylases (HDACs) was identified as a mechanism to increase apoE secretion. Knocking down select HDAC family members alone or in combination revealed that inhibition of the class I HDAC family was responsible for enhancing apoE secretion. Knocking down LXRα and LXRβ genes revealed that the increase in astrocytic apoE in response to HDAC inhibition occurred via an LXR-independent pathway. Collectively, these data suggest that pan class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion.

A simple approach for human recombinant apolipoprotein E4 expression and purification.

Science.gov (United States)

Argyri, Letta; Skamnaki, Vassiliki; Stratikos, Efstratios; Chroni, Angeliki

2011-10-01

We report a simple expression and purification procedure for the production of recombinant apolipoprotein E4 (apoE4), an important protein for the lipid homeostasis in humans that plays critical roles in the pathogenesis of cardiovascular and neurodegenerative diseases. Our approach is based on the expression of a thioredoxin-apoE4 fusion construct in bacterial cells and subsequent removal of the fused thioredoxin using the highly specific 3C protease, avoiding costly and laborious lipidation-delipidation steps used before. Our approach results in rapid, high-yield production of structurally and functionally competent apoE4 as evidenced by secondary structure measurements, thermal and chemical melting profiles and the kinetic profile of solubilization of dimyristoyl-phosphatidylcholine (DMPC) vesicles. This protocol is appropriate for laboratories with little experience in apolipoprotein biochemistry and will facilitate future studies on the role of apoE4 in the pathogenesis of cardiovascular disease and neurodegenerative diseases, including Alzheimer's disease. Copyright © 2011 Elsevier Inc. All rights reserved.

Mimetic Learning

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Christoph Wulf

2008-03-01

Full Text Available Mimetic learning, learning by imitation, constitutes one of the most important forms of learning. Mimetic learning does not, however, just denote mere imitation or copying: Rather, it is a process by which the act of relating to other persons and worlds in a mimetic way leads to an en-hancement of one’s own world view, action, and behaviour. Mimetic learning is productive; it is related to the body, and it establishes a connection between the individual and the world as well as other persons; it creates practical knowledge, which is what makes it constitutive of social, artistic, and practical action. Mimetic learning is cultural learning, and as such it is crucial to teaching and education (Wulf, 2004; 2005.

Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice

DEFF Research Database (Denmark)

Yao, Xianglan; Dai, Cuilian; Fredriksson, Karin

2012-01-01

Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (e2, e3, and e4) reflecting single ...

Rescuing cholinergic neurons from apoptotic degeneration by targeting of serotonin modulator- and apolipoprotein E-conjugated liposomes to the hippocampus

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Kuo YC

2016-12-01

Full Text Available Yung-Chih Kuo, Yin-Jung Lee Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China Abstract: β-Amyloid (Aβ-targeting liposomes (LIP with surface serotonin modulator (SM and apolipoprotein E (ApoE were utilized to facilitate the delivery of nerve growth factor (NGF across the blood–brain barrier (BBB for neuroprotection in the hippocampus. The therapeutic efficacy of SM- and ApoE-grafted LIP carrying NGF (NGF-SM-ApoE-LIP was assessed by an in vitro Alzheimer’s disease (AD model of degenerated SK-N-MC cells and an in vivo AD model of Aβ-insulted Wistar rats. The experimental evidences revealed that the modified SM and ApoE on the surface of LIP increased the permeation of NGF across the BBB without serious damage to structural integrity of tight junction. When compared with free NGF, NGF-SM-ApoE-LIP upregulated the expression of phosphorylated neurotrophic tyrosine kinase receptor type 1 on cholinergic neurons and significantly improved their survival. In addition, NGF-SM-ApoE-LIP could reduce the secretion of acetylcholinesterase and malondialdehyde and rescue hippocampal neurons from apoptosis in rat brains. The synergistic effect of SM and ApoE is promising in the induction of NGF to inhibit the neurotoxicity of Aβ and NGF-SM-ApoE-LIP can be a potent antiapoptotic pharmacotherapy for clinical care of patients with AD. Keywords: Alzheimer’s disease, blood–brain barrier, serotonin modulator, apolipoprotein E, nerve growth factor, liposome

Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation.

Science.gov (United States)

Hatziri, Aikaterini; Kalogeropoulou, Christina; Xepapadaki, Eva; Birli, Eleni; Karavia, Eleni A; Papakosta, Eugenia; Filou, Serafoula; Constantinou, Caterina; Kypreos, Kyriakos E

2018-02-01

Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity. In our studies APOE3 knock-in (Apoe3 knock-in ), Apoe-deficient (apoe -/- ) and brain-specific expressing APOE3 (Apoe3 brain ) mice were fed western-type diet for 12week and biochemical analyses were performed. Moreover, AAV-mediated gene transfer of APOE3 to apoe -/- mice was employed, as a means to achieve APOE3 expression selectively in periphery, since peripherally expressed APOE does not cross blood brain barrier (BBB) or blood-cerebrospinal fluid barrier (BCSFB). Our data suggest a bimodal role of APOE3 in visceral white adipose tissue (WAT) mitochondrial metabolic activation that is highly dependent on its site of expression and independent of postprandial dietary lipid deposition. Our findings indicate that brain APOE3 expression is associated with a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation, leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, peripherally expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. Copyright © 2017 Elsevier B.V. All rights reserved.

Mimetic discretization methods

CERN Document Server

Castillo, Jose E

2013-01-01

To help solve physical and engineering problems, mimetic or compatible algebraic discretization methods employ discrete constructs to mimic the continuous identities and theorems found in vector calculus. Mimetic Discretization Methods focuses on the recent mimetic discretization method co-developed by the first author. Based on the Castillo-Grone operators, this simple mimetic discretization method is invariably valid for spatial dimensions no greater than three. The book also presents a numerical method for obtaining corresponding discrete operators that mimic the continuum differential and

Influence of apolipoprotein-E gene on lipid profile, physical activity and body fat relationship. DOI:10.5007/1980-0037.2012v14n2p221

Directory of Open Access Journals (Sweden)

Thales Boaventura Rachid Nascimento

2012-02-01

Full Text Available Physical activity and body fat modify lipemia, and this effect seems to be influenced by apolipoprotein-E (APOE gene polymorphism. Thus, the purpose of this article was to review main results of studies that have analyzed the relation of APOE gene with physical activity and body fat on triglycerides, total cholesterol and low (LDL and high density lipoprotein (HDL concentrations. The Scientific Electronic Library Online – SciELO, Web of Science and PubMed database were used to locate the articles. The keywords used in combination were: apoe genotype, apolipoprotein-E polymorphism, physical exercise, physical activity, aerobic exercise, body fat and obesity. Originals scientific investigations performed with humans were included, and excluded those ones which involved samples with diseases, except obesity and/or lipemic disorders. It was observed a trend, that ε2 allele carriers are the ones with the greater improvements on lipemia from physical exercise. In addition, the body fat impact on the elevation of triglycerides and LDL are stronger in carriers of the ε2 and ε4 allele, respectively. Considering the small number of originals scientific investigations and their divergent results, reliable inferences can not be made about the APOE gene polymorphism influences on physical activity and body fat effect on lipemia. Thus, further studies with others populations and more volunteers for allele, as well as others exercise modalities and intensities, are necessary.

Is Apolipoprotein E4 an Important Risk Factor for Dementia in Persons with Down Syndrome?

Science.gov (United States)

Rohn, Troy T; McCarty, Katie L; Love, Julia E; Head, Elizabeth

2014-12-08

Down syndrome is one of the most common genetic causes of intellectual disability and is characterized by a number of behavioral as well as cognitive symptoms. Triplication of all or part of human chromosome 21 has been considered as the main cause of Down syndrome. Due to the location of the amyloid precursor protein on chromosome 21, many of the neuropathological features of early-onset Alzheimer's disease including senile plaques and neurofibrillary tangles are also present in Down syndrome patients who are either demented or nondemented. Significant advances in medical treatment have increased longevity in people with Down syndrome resulting in an increased population that may be subjected to many of the same risk factors as those with Alzheimer's disease. It is well established that harboring one or both apolipoprotein E4 alleles greatly increases the risk for Alzheimer's disease. However, whether apolipoprotein E4 contributes to an earlier onset of dementia or increased mortality in Down syndrome patients is still a matter of debate. The purpose of this mini review is to provide an updated assessment on apolipoprotein E4 status and risk potential of developing dementia and mortality associated with Down syndrome.

Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse.

Science.gov (United States)

Chew, Phyllis; Yuen, Derek Y C; Stefanovic, Nada; Pete, Josefa; Coughlan, Melinda T; Jandeleit-Dahm, Karin A; Thomas, Merlin C; Rosenfeldt, Franklin; Cooper, Mark E; de Haan, Judy B

2010-12-01

To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress. The study was performed using diabetic apolipoprotein E/GPx1 (ApoE(-/-)GPx1(-/-))-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks. Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways. Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.

Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

Science.gov (United States)

Shaginian, Alex; Whitby, Landon R; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K; Boger, Dale L

2009-04-22

The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

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 (Cornelia); D.E. Grobbee (Diederick); M.M.B. Breteler (Monique); C. van Broeckhoven (Christine); A. Hofman (Albert)

1997-01-01

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

Bio-mimetic Flow Control

Science.gov (United States)

Choi, Haecheon

2009-11-01

Bio-mimetic engineering or bio-mimetics is the application of biological methods and systems found in nature to the study and design of engineering systems and modern technology (from Wikipedia). The concept itself is old, but successful developments have been made recently, especially in the research field of flow control. The objective of flow control based on the bio-mimetic approach is to develop novel concepts for reducing drag, increasing lift and enhancing aerodynamic performance. For skin friction reduction, a few ideas have been suggested such as the riblet from shark, compliant surface from dolphin, microbubble injection and multiple front-body curvature from penguin, and V-shaped protrusion from sailfish. For form drag reduction, several new attempts have been also made recently. Examples include the V-shaped spanwise grooves from saguaro cactus, overall shape of box fish, longitudinal grooves on scallop shell, bill of swordfish, hooked comb on owl wing, trailing-edge protrusion on dragonfly wing, and fillet. For the enhancement of aerodynamic performance, focuses have been made on the birds, fish and insects: e.g., double layered feather of landing bird, leading-edge serration of humpback-whale flipper, pectoral fin of flying fish, long tail on swallowtail-butterfly wing, wing flapping motion of dragonfly, and alula in birds. Living animals adapt their bodies to better performance in multi purposes, but engineering requires single purpose in most cases. Therefore, bio-mimetic approaches often produce excellent results more than expected. However, they are sometimes based on people's wrong understanding of nature and produce unwanted results. Successes and failures from bio-mimetic approaches in flow control will be discussed in the presentation.

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

DEFF Research Database (Denmark)

Jacobsen, Nana; Bentzen, Joan; Meldgaard, Michael

2002-01-01

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...... was applied to a panel of patient samples with simultaneous genotyping of the patients by DNA sequencing. The apoE genotyping assays for the codons 112 and 158 SNPs resulted in unambiguous results for all patient samples, concurring with those obtained by DNA sequencing....

Unimodular-mimetic cosmology

International Nuclear Information System (INIS)

Nojiri, S; Odintsov, S D; Oikonomou, V K

2016-01-01

We combine the unimodular gravity and mimetic gravity theories into a unified theoretical framework, which is proposed to provide a suggestive proposal for a framework that may assist in the discussion and search for a solution to the cosmological constant problem and the dark matter issue. After providing the formulation of the unimodular mimetic gravity and investigating all the new features that the vacuum unimodular gravity implies, by using the underlying reconstruction method, we realize some well known cosmological evolutions, with some of these being exotic for the ordinary Einstein–Hilbert gravity. Specifically we provide the vacuum unimodular mimetic gravity description of the de Sitter cosmology and of the perfect fluid with constant equation of state cosmology. As we demonstrate, these cosmologies can be realized by vacuum mimetic unimodular gravity, without the existence of any matter fluid source. Moreover, we investigate how cosmologically viable cosmologies, which are compatible with the recent observational data, can be realized by the vacuum unimodular mimetic gravity. Since in some cases, a graceful exit from inflation problem might exist, we provide a qualitative description of the mechanism that can potentially generate the graceful exit from inflation in these theories, by searching for the unstable de Sitter solutions in the context of unimodular mimetic theories of gravity. (paper)

Fibronectin- and collagen-mimetic ligands regulate bone marrow stromal cell chondrogenesis in three-dimensional hydrogels

Directory of Open Access Journals (Sweden)

JT Connelly

2011-09-01

Full Text Available Modification of tissue engineering scaffolds with bioactive molecules is a potential strategy for modulating cell behavior and guiding tissue regeneration. While adhesion to RGD peptides has been shown to inhibit in vitro chondrogenesis, the effects of extracellular matrix (ECM-mimetic ligands with complex secondary and tertiary structures are unknown. This study aimed to determine whether collagen- and fibronectin-mimetic ligands would retain biologic functionality in three-dimensional (3D hydrogels, whether different ECM-mimetic ligands differentially influence in vitro chondrogenesis, and if effects of ligands on differentiation depend on soluble biochemical stimuli. A linear RGD peptide, a recombinant fibronectin fragment containing the seven to ten Type III repeats (FnIII7-10 and a triple helical, collagen mimetic peptide with the GFOGER motif were covalently coupled to agarose gels using the sulfo-SANPAH crosslinker, and bone marrow stromal cells (BMSCs were cultured within the 3D hydrogels. The ligands retained biologic functionality within the agarose gels and promoted density-dependent BMSC spreading. Interactions with all adhesive ligands inhibited stimulation by chondrogenic factors of collagen Type II and aggrecan mRNA levels and deposition of sulfated glycosaminoglycans. In medium containing fetal bovine serum, interactions with the GFOGER peptide enhanced mRNA expression of the osteogenic gene osteocalcin whereas FnIII7-10 inhibited osteocalcin expression. In conclusion, modification of agarose hydrogels with ECM-mimetic ligands can influence the differentiation of BMSCs in a manner that depends strongly on the presence and nature of soluble biochemical stimuli.

Curcumin Protects against Atherosclerosis in Apolipoprotein E-Knockout Mice by Inhibiting Toll-like Receptor 4 Expression.

Science.gov (United States)

Zhang, Shanshan; Zou, Jun; Li, Peiyang; Zheng, Xiumei; Feng, Dan

2018-01-17

Toll-like receptor 4 (TLR4) has been reported to play a critical role in the pathogenesis of atherosclerosis, the current study aimed to investigate whether curcumin suppresses atherosclerosis development in ApoE-knockout (ApoE -/- ) mice by inhibiting TLR4 expression. ApoE -/- mice were fed a high-fat diet supplemented with or without curcumin (0.1% w/w) for 16 weeks. Curcumin supplementation significantly reduced TLR4 expression and macrophage infiltration in atherosclerotic plaques. Curcumin also reduced aortic interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, nuclear factor-κB (NF-κB) activity, and plasma IL-1β, TNF-α, soluble VCAM-1 and ICAM-1 levels. In addition, aortic sinus sections revealed that curcumin treatment reduced the extent of atherosclerotic lesions and inhibited atherosclerosis development. In vitro, curcumin inhibited NF-κB activation in macrophages and reduced TLR4 expression induced by lipopolysaccharide. Our results indicate that curcumin protects against atherosclerosis at least partially by inhibiting TLR4 expression and its related inflammatory reaction.

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

2009-01-01

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...

Hypoxia-mimetic agents inhibit proliferation and alter the morphology of human umbilical cord-derived mesenchymal stem cells

Directory of Open Access Journals (Sweden)

Zeng Hui-Lan

2011-08-01

Full Text Available Abstract Background The therapeutic efficacy of human mesenchymal stem cells (hMSCs for the treatment of hypoxic-ischemic diseases is closely related to level of hypoxia in the damaged tissues. To elucidate the potential therapeutic applications and limitations of hMSCs derived from human umbilical cords, the effects of hypoxia on the morphology and proliferation of hMSCs were analyzed. Results After treatment with DFO and CoCl2, hMSCs were elongated, and adjacent cells were no longer in close contact. In addition, vacuole-like structures were observed within the cytoplasm; the rough endoplasmic reticulum expanded, and expanded ridges were observed in mitochondria. In addition, DFO and CoCl2 treatments for 48 h significantly inhibited hMSCs proliferation in a concentration-dependent manner (P Conclusions The hypoxia-mimetic agents, DFO and CoCl2, alter umbilical cord-derived hMSCs morphology and inhibit their proliferation through influencing the cell cycle.

Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

Energy Technology Data Exchange (ETDEWEB)

Lucotte, G.; David, F.; Berriche, S. [Regional Center of Neurogenetics, Reims (France)] [and others

1994-09-15

Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice.

NARCIS (Netherlands)

Mensenkamp, A.R.; Luyn, M.J.A. van; Havinga, R.; Teusink, B.; Waterman, I.J.; Mann, C.J.; Elzinga, B.M.; Verkade, H.J.; Zammit, V.A.; Havekes, L.M.; Shoulders, C.C.; Kuipers, F.

2004-01-01

BACKGROUND/AIMS: Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and secrete reduced levels of VLDL-TG. METHODS AND RESULTS: We examined the effects of apoE-deficiency on intracellular lipid homeostasis and secretion of triglycerides (TG). We show that intracellular TG turnover and

The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice

NARCIS (Netherlands)

Mensenkamp, AR; van Luyn, MJA; Havinga, R; Teusink, B; Waterman, IJ; Mann, CJ; Elzinga, BM; Verkade, HJ; Zammit, VA; Havekes, LM; Shoulders, CC; Kuipers, F

Background/Aims: Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and secrete reduced levels of VLDL-TG. Methods and results: We examined the effects of apoE-deficiency on intracellular lipid homeostasis and secretion of triglycerides (TG). We show that intracellular TG turnover and

HDL mimetic CER-001 targets atherosclerotic plaques in patients.

Science.gov (United States)

Zheng, Kang He; van der Valk, Fleur M; Smits, Loek P; Sandberg, Mara; Dasseux, Jean-Louis; Baron, Rudi; Barbaras, Ronald; Keyserling, Constance; Coolen, Bram F; Nederveen, Aart J; Verberne, Hein J; Nell, Thijs E; Vugts, Danielle J; Duivenvoorden, Raphaël; Fayad, Zahi A; Mulder, Willem J M; van Dongen, Guus A M S; Stroes, Erik S G

2016-08-01

Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Plasma lipoproteins in familial dysbetalipoproteinemia associated with apolipoproteins E2 (Arg158 -->Cys), E3-Leiden, and E2 (Lys146-->Gln), and effects of treatment with simvastatin

NARCIS (Netherlands)

Zhao, S.P.; Smelt, A.H.; Maagdenberg, A.M. van den; Tol, A. van; Vroom T.F.; Gevers Leuven, J.A.; Frants, R.R.; Havekes, L.M.; Laarse, A. van der; Hooft, F.M. van 't

1994-01-01

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden

Mimetic finite difference method

Science.gov (United States)

Lipnikov, Konstantin; Manzini, Gianmarco; Shashkov, Mikhail

2014-01-01

The mimetic finite difference (MFD) method mimics fundamental properties of mathematical and physical systems including conservation laws, symmetry and positivity of solutions, duality and self-adjointness of differential operators, and exact mathematical identities of the vector and tensor calculus. This article is the first comprehensive review of the 50-year long history of the mimetic methodology and describes in a systematic way the major mimetic ideas and their relevance to academic and real-life problems. The supporting applications include diffusion, electromagnetics, fluid flow, and Lagrangian hydrodynamics problems. The article provides enough details to build various discrete operators on unstructured polygonal and polyhedral meshes and summarizes the major convergence results for the mimetic approximations. Most of these theoretical results, which are presented here as lemmas, propositions and theorems, are either original or an extension of existing results to a more general formulation using polyhedral meshes. Finally, flexibility and extensibility of the mimetic methodology are shown by deriving higher-order approximations, enforcing discrete maximum principles for diffusion problems, and ensuring the numerical stability for saddle-point systems.

Nanobody-Based Apolipoprotein E Immunosensor for Point-of-Care Testing.

Science.gov (United States)

Ren, Xiang; Yan, Junrong; Wu, Dan; Wei, Qin; Wan, Yakun

2017-09-22

Alzheimer's disease (AD) biomarkers can reflect the neurochemical indicators used to estimate the risk in clinical nephrology. Apolipoprotein E (ApoE) is an early biomarker for AD in clinical diagnosis. In this research, through bactrian camel immunization, lymphocyte isolation, RNA extraction, and library construction, ApoE-specific Nbs with high affinity were successfully separated from an immune phage display nanobody library. Herein, a colorimetric immunosensor was developed for the point-of-care testing of ApoE by layer-by-layer nanoassembly techniques and novel nanobodies (Nbs). Using highly oriented Nbs as the capture and detection antibodies, an on-site immunosensor was developed by detecting the mean gray value of fade color due to the glutaraldehyde@3-aminopropyltrimethoxysilane oxidation by H 2 O 2 . The detection limit of AopE is 0.42 pg/mL, and the clinical analysis achieves a good performance. The novel easily operated immunosensor may have potential application in the clinical diagnosis and real-time monitoring for AD.

Possible Alzheimer’s Disease in an Apolipoprotein E2 Homozygote

Science.gov (United States)

Ignatov, Ignat; Belden, Christine; Jacobson, Sandra; Connor, Donald; Sabbagh, Marwan N.

2010-01-01

The objective of this study was to describe a case of Alzheimer’s disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer’s disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer’s disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer’s disease is rare in Apo E2 homozygotes but can occur. PMID:19158419

Apolipoprotein E e4 allele does not increase the risk of early postoperative delirium after major surgery.

Science.gov (United States)

Abelha, Fernando José; Fernandes, Vera; Botelho, Miguela; Santos, Patricia; Santos, Alice; Machado, J C; Barros, Henrique

2012-02-01

BACKGROUND: A relationship between patients with a genetic predisposition to and those who develop postoperative delirium has not been yet determined. The aim of this study was to determine whether there is an association between apolipoprotein E epsilon 4 allele (APOE4) and delirium after major surgery. METHODS: Of 230 intensive care patients admitted to the post anesthesia care unit (PACU) over a period of 3 months, 173 were enrolled in the study. Patients' demographics and intra- and postoperative data were collected. Patients were followed for the development of delirium using the Intensive Care Delirium Screening Checklist, and DNA was obtained at PACU admission to determine apolipoprotein E genotype. RESULTS: Fifteen percent of patients developed delirium after surgery. Twenty-four patients had one copy of APOE4. The presence of APOE4 was not associated with an increased risk of early postoperative delirium (4% vs. 17%; P = 0.088). The presence of APOE4 was not associated with differences in any studied variables. Multivariate analysis identified age [odds ratio (OR) 9.3, 95% confidence interval (CI) 2.0-43.0, P = 0.004 for age ≥65 years), congestive heart disease (OR 6.2, 95% CI 2.0-19.3, P = 0.002), and emergency surgery (OR 59.7, 95% CI 6.7-530.5, P < 0.001) as independent predictors for development of delirium. The Simplified Acute Physiology Score II (SAPS II) and The Acute Physiology and Chronic Health Evaluation II (APACHE II) were significantly higher in patients with delirium (P < 0.001 and 0.008, respectively). Hospital mortality rates of these patients was higher and they had a longer median PACU stay. CONCLUSIONS: Apolipoprotein e4 carrier status was not associated with an increased risk for early postoperative delirium. Age, congestive heart failure, and emergency surgery were independent risk factors for the development of delirium after major surgery.

Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages

Energy Technology Data Exchange (ETDEWEB)

Stavri, Simona; Trusca, Violeta G.; Simionescu, Maya; Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro

2015-05-29

The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis. - Highlights: • High doses of metformin slightly increase apoE expression in macrophages. • Low doses of metformin up-regulate apoE gene in endotoxin-stressed macrophages. • Metformin reduces the negative effect of LPS on apoE expression by NF-κB inhibition.

Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages

International Nuclear Information System (INIS)

Stavri, Simona; Trusca, Violeta G.; Simionescu, Maya; Gafencu, Anca V.

2015-01-01

The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis. - Highlights: • High doses of metformin slightly increase apoE expression in macrophages. • Low doses of metformin up-regulate apoE gene in endotoxin-stressed macrophages. • Metformin reduces the negative effect of LPS on apoE expression by NF-κB inhibition

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid.

Science.gov (United States)

Mateuszuk, Lukasz; Jasztal, Agnieszka; Maslak, Edyta; Gasior-Glogowska, Marlena; Baranska, Malgorzata; Sitek, Barbara; Kostogrys, Renata; Zakrzewska, Agnieszka; Kij, Agnieszka; Walczak, Maria; Chlopicki, Stefan

2016-02-01

1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/LDLR(-/-) mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F1 α and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR(-/-) mice, an effect associated with an improvement in prostacyclin- and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA. Copyright © 2016 by The American Society for Pharmacology and Experimental

Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease.

OpenAIRE

Harrington, C. R.; Louwagie, J.; Rossau, R.; Vanmechelen, E.; Perry, R. H.; Perry, E. K.; Xuereb, J. H.; Roth, M.; Wischik, C. M.

1994-01-01

Alzheimer's disease (AD) is associated with an increased frequency of the apolipoprotein E type epsilon 4 allele. To address both the disease and the allele specificity of this association, we have examined the apolipoprotein E allele distribution in 255 elderly persons including those with autopsy-confirmed AD, senile dementia of the Lewy body type (SDLT), vascular dementia, Parkinson's disease (PD) or Huntington's disease and in nondemented controls either with or without coronary complicat...

Selection on alleles affecting human longevity and late-life disease: the example of apolipoprotein E.

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Fotios Drenos

2010-04-01

Full Text Available It is often claimed that genes affecting health in old age, such as cardiovascular and Alzheimer diseases, are beyond the reach of natural selection. We show in a simulation study based on known genetic (apolipoprotein E and non-genetic risk factors (gender, diet, smoking, alcohol, exercise that, because there is a statistical distribution of ages at which these genes exert their influence on morbidity and mortality, the effects of selection are in fact non-negligible. A gradual increase with each generation of the epsilon2 and epsilon3 alleles of the gene at the expense of the epsilon4 allele was predicted from the model. The epsilon2 allele frequency was found to increase slightly more rapidly than that for epsilon3, although there was no statistically significant difference between the two. Our result may explain the recent evolutionary history of the epsilon 2, 3 and 4 alleles of the apolipoprotein E gene and has wider relevance for genes affecting human longevity.

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.

Science.gov (United States)

Liu, Chia-Chen; Liu, Chia-Chan; Kanekiyo, Takahisa; Xu, Huaxi; Bu, Guojun

2013-02-01

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

Influence of Peripheral Artery Disease and Statin Therapy on Apolipoprotein Profiles

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Andrew W. Gardner

2013-01-01

Full Text Available Apolipoprotein B is a stronger predictor of myocardial infarction than LDL cholesterol, and it is inversely related to physical activity and modifiable with exercise training. As such, apolipoprotein measures may be of particular relevance for subjects with PAD and claudication. We compared plasma apolipoprotein profiles in 29 subjects with peripheral artery disease (PAD and intermittent claudication and in 39 control subjects. Furthermore, we compared the plasma apolipoprotein profiles of subjects with PAD either treated (n=17 or untreated (n=12 with statin medications. For the apolipoprotein subparticle analyses, subjects with PAD had higher age-adjusted Lp-B:C (P<0.05 and lower values of Lp-A-I:A-II (P<0.05 than controls. The PAD group taking statins had lower age-adjusted values for apoB (P<0.05, Lp-A-II:B:C:D:E (P<0.05, Lp-B:E + Lp-B:C:E (P<0.05, Lp-B:C (P<0.05, and Lp-A-I (P<0.05 than the untreated PAD group. Subjects with PAD have impaired apolipoprotein profiles than controls, characterized by Lp-B:C and Lp-A-I:A-II. Furthermore, subjects with PAD on statin medications have a more favorable risk profile, particularly noted in multiple apolipoprotein subparticles. The efficacy of statin therapy to improve cardiovascular risk appears more evident in the apolipoprotein sub-particle profile than in the more traditional lipid profile of subjects with PAD and claudication. This trial is registered with ClinicalTrials.gov NCT00618670.

Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer's disease (APP/PS1) mice by inhibiting TGF-β/Smad2/STAT3 signaling.

Science.gov (United States)

Zheng, Jin-Yu; Sun, Jian; Ji, Chun-Mei; Shen, Lin; Chen, Zhong-Jun; Xie, Peng; Sun, Yuan-Zhao; Yu, Ru-Tong

2017-06-01

Astrocytes and apolipoprotein E (apoE) play critical roles in cognitive function, not only under physiological conditions but also in some pathological situations, particularly in the pathological progression of Alzheimer's disease (AD). The regulatory mechanisms underlying the effect of apoE, derived from astrocytes, on cognitive deficits during AD pathology development are unclear. In this study, we generated amyloid precursor protein/apoE knockout (APP/apoE KO ) and APP/glial fibrillary acidic protein (GFAP)-apoE KO mice (the AD mice model used in this study was based on the APP-familial Alzheimer disease overexpression) to investigate the role of apoE, derived from astrocytes, in AD pathology and cognitive function. To explore the mechanism, we investigated the amyloidogenic process related transforming growth factor β/mothers against decapentaplegic homolog 2/signal transducer and activator of transcription 3 (TGF-β/Smad2/STAT3) signaling pathway and further confirmed by administering TGF-β-overexpression adeno-associated virus (specific to astrocytes) to APP/GFAP-apoE KO mice and TGF-β-inhibition adeno-associated virus (specific to astrocytes) to APP/WT mice. Whole body deletion of apoE significantly ameliorated the spatial learning and memory impairment, reduced amyloid β-protein production and inhibited astrogliosis in APP/apoE KO mice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoE KO mice. Moreover, amyloid β-protein accumulation was increased due to promotion of amyloidogenesis of APP, and astrogliosis was upregulated by activation of TGF-β/Smad2/STAT3 signaling. Furthermore, the overexpression of TGF-β in astrocytes in APP/GFAP-apoE KO mice abrogated the effects of apoE knockout. In contrast, repression of TGF-β in astrocytes of APP/WT mice exerted a therapeutic effect similar to apoE knockout. These data suggested that apoE derived from astrocytes contributes to the risk of AD through TGF-β/Smad2/STAT3 signaling activation

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

DEFF Research Database (Denmark)

Rune, Ida; Rolin, Bidda; Lykkesfeldt, Jens

2018-01-01

In the apolipoprotein E-deficient mouse, the gut microbiota has an impact on the development of atherosclerosis, but whether such correlations are also present in rats requires investigation. Therefore, we studied female SD-Apoe tm1sage (Apoe -/-) rats fed either a Western diet or a low-fat control...

Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment Cells

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Guillaume van Niel

2015-10-01

Full Text Available Accumulation of toxic amyloid oligomers is a key feature in the pathogenesis of amyloid-related diseases. Formation of mature amyloid fibrils is one defense mechanism to neutralize toxic prefibrillar oligomers. This mechanism is notably influenced by apolipoprotein E variants. Cells that produce mature amyloid fibrils to serve physiological functions must exploit specific mechanisms to avoid potential accumulation of toxic species. Pigment cells have tuned their endosomes to maximize the formation of functional amyloid from the protein PMEL. Here, we show that ApoE is associated with intraluminal vesicles (ILV within endosomes and remain associated with ILVs when they are secreted as exosomes. ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. This process secures the physiological formation of amyloid fibrils by exploiting ILVs as amyloid nucleating platforms.

Apolipoprotein E-epsilon 4 frequency in affective disorder

DEFF Research Database (Denmark)

Kessing, L V; Jørgensen, O S

1999-01-01

-Bråne-Steen Dementia Rating Scale, and the Global Deterioration Scale. RESULTS: The frequency of APOE-epsilon 4 allele was approximately the same in unipolar patients (.189) and in bipolar patients (.167). Although patients showed more cognitive impairment than controls, no significant overall difference was found...... was found with gender, age at onset, the number of affective episodes, the presence of psychotic features, or the prevalence of familial affective disorder. CONCLUSIONS: It seems that cognitive impairment in affective disorder can be attributed to pathways other than the APOE genotype.......BACKGROUND: The epsilon 4 allele of apolipoprotein E (APOE) as well as affective disorder have been found to be associated with Alzheimer's disease, but it is unclear whether cognitive impairment in affective disorder or subtypes of affective disorder is mediated by the epsilon 4 allele of APOE...

Function and Comorbidities of Apolipoprotein E in Alzheimer's Disease

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Valérie Leduc

2011-01-01

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.

NEC violation in mimetic cosmology revisited

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Anna Ijjas

2016-09-01

Full Text Available In the context of Einstein gravity, if the null energy condition (NEC is satisfied, the energy density in expanding space–times always decreases while in contracting space–times the energy density grows and the universe eventually collapses into a singularity. In particular, no non-singular bounce is possible. It is, though, an open question if this energy condition can be violated in a controlled way, i.e., without introducing pathologies, such as unstable negative-energy states or an imaginary speed of sound. In this letter, we will re-examine the claim that the recently proposed mimetic scenario can violate the NEC without pathologies. We show that mimetic cosmology is prone to gradient instabilities even in cases when the NEC is satisfied (except for trivial examples. Most interestingly, the source of the instability is always the Einstein–Hilbert term in the action. The matter stress-energy component does not contribute spatial gradient terms but instead makes the problematic curvature modes dynamical. We also show that mimetic cosmology can be understood as a singular limit of known, well-behaved theories involving higher-derivative kinetic terms and discuss ways of removing the instability.

Serum apolipoprotein E concentration and polymorphism influence serum lipid levels in Chinese Shandong Han population.

Science.gov (United States)

Han, ShuYi; Xu, YiHui; Gao, MeiHua; Wang, YunShan; Wang, Jun; Liu, YanYan; Wang, Min; Zhang, XiaoQian

2016-12-01

Apolipoprotein E (ApoE), which has been shown to influence serum lipid parameters, can bind to multiple types of lipids and plays an important role in the metabolism and homeostasis of lipids and lipoproteins. A previous study showed that ApoE concentration significantly affects serum lipid levels independently of ApoE polymorphism. The serum lipid levels were also closely correlated with dietary habits, and Shandong cuisine is famous for its high salt and oil contents, which widely differ among the different areas in China. Therefore, studying the effect of ApoE polymorphism on ApoE concentration and serum lipid levels in Shandong province is very important.A total of 815 subjects including 285 men and 530 women were randomly selected and studied from Jinan, Shandong province. In order to evaluate the association of ApoE polymorphism and serum level on lipid profiles, the ApoE genotypes, as well as levels of fasting serum ApoE and other lipid parameters, were detected in all subjects.The frequency of the ApoE E3 allele was highest (83.1%), while those of E2 and E4 were 9.4% and 7.5%, respectively, which are similar to those in other Asian populations. ApoE2 allele carriers showed significantly increased ApoE levels but lower levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and Apolipoprotein B (ApoB).We found that ApoE level is influenced by ApoE polymorphism in a gene-dependent manner. The ApoE polymorphism showed different influences on serum lipid parameters with increasing age and body mass index (BMI) in our Shandong Han population.

Association between apolipoprotein E genotype, serum lipids, and colorectal cancer in Brazilian individuals

OpenAIRE

Souza, D.R.S.; Nakazone, M.A.; Pinhel, M.A.S.; Alvares, R.M.; Monaco, A.C.; Pinheiro, A.; Barros, C.F.D.C.; Cury, P.M.; Cunrath, G.S.; Netinho, J.G.

2009-01-01

We evaluated genetic variants of apolipoprotein E (APOE HhaI) and their association with serum lipids in colorectal cancer (CRC), together with eating habits and personal history. Eight-seven adults with CRC and 73 controls were studied. APOE*2 (rs7412) and APOE*4 (rs429358) were identified by polymerase chain reaction-restriction fragment length polymorphism. APOE gene polymorphisms were similar in both groups, but the ε4/ε4 genotype (6%) was present only in controls. The patients ...

The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study.

Science.gov (United States)

Hovingh, G Kees; Smits, Loek P; Stefanutti, Claudia; Soran, Handrean; Kwok, See; de Graaf, Jacqueline; Gaudet, Daniel; Keyserling, Constance H; Klepp, Heather; Frick, Jennifer; Paolini, John F; Dasseux, Jean-Louis; Kastelein, John J P; Stroes, Erik S

2015-05-01

Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)-containing high-density lipoprotein-mimetic particle, on carotid artery wall dimensions in patients with HoFH. Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm(2) (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). In HoFH, 12 biweekly infusions with an apoA-I-containing high-density lipoprotein-mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein-lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in patients with HoFH. Copyright © 2015 Mosby, Inc. All rights reserved.

Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis

Science.gov (United States)

Liu, Mengying; Bian, Chen; Zhang, Jiqiang; Wen, Feng

2014-03-01

The relationship between Apolipoprotein E (ApoE) genotype and the risk of Alzheimer's disease (AD) is relatively well established in Caucasians, but less established in other ethnicities. To examine the association between ApoE polymorphism and the onset of AD in Chinese population, we searched the commonly used electronic databases between January 2000 and November 2013 for relevant studies. Total 20 studies, including 1576 cases and 1741 controls, were retrieved. The results showed statistically significant positive association between risk factor ɛ4 allele carriers and AD in Chinese population (OR = 3.93, 95% CI = 3.37-4.58, P risk suffering from AD than controls in Chinese population. The results also provide a support for the protection effect of ApoE ɛ3 allele in developing AD.

Atorvastatin decreases apolipoprotein C-III in apolipoprotein B-containing lipoprotein and HDL in type 2 diabetes: a potential mechanism to lower plasma triglycerides

NARCIS (Netherlands)

Dallinga-Thie, Geesje M.; Berk-Planken, Ingrid I. L.; Bootsma, Aart H.; Jansen, Hans

2004-01-01

Apolipoprotein (apo)C-III is a constituent of HDL (HDL apoC-III) and of apoB-containing lipoproteins (LpB:C-III). It slows the clearance of triglyceride-rich lipoproteins (TRLs) by inhibition of the activity of the enzyme lipoprotein lipase (LPL) and by interference with lipoprotein binding to

Enriched environment reduces apolipoprotein E (ApoE) in reactive astrocytes and attenuates inflammation of the peri-infarct tissue after experimental stroke

DEFF Research Database (Denmark)

Ruscher, Karsten; Johannesson, Emelie; Brugiere, Elena

2009-01-01

Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after experimental stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after experimental stroke, by using animal housing conditions...... lower in animals housed in an enriched environment. We propose that during the subacute phase after experimental stroke a zone for tissue reorganization with low cellular ApoE levels is formed. We conclude that the strong sensori-motor stimulation provided by enriched housing conditions mitigates...

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

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García-Arias Carlota

2009-06-01

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.

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

Science.gov (United States)

2009-01-01

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. PMID:19534808

Leisure activities, apolipoprotein E e4 status, and the risk of dementia.

Science.gov (United States)

Yang, Sheng-Ying; Weng, Pei-Hsuan; Chen, Jen-Hau; Chiou, Jeng-Min; Lew-Ting, Chih-Yin; Chen, Ta-Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen-Ching

2015-12-01

Leisure activities have been associated with a decreased risk of dementia. However, to date, no study has explored how apolipoprotein E (ApoE) e4 status or vascular risk factors modified the association between leisure activities and dementia risks. This case-control study recruited patients (age ≥ 60 years) with Alzheimer's disease (AD; n = 292) and vascular dementia (VaD; n = 144) and healthy controls (n = 506) from three teaching hospitals in Taiwan between 2007 and 2010. Information on patient's leisure activities were obtained through a questionnaire. Conditional logistic regression models were used to assess the association of leisure activities and ApoE e4 status with the risk of dementia. High-frequency physical activity was associated with a decreased risk of AD [adjusted odds ratio (AOR) = 0.45], and the results become more evident among ApoE e4 carriers with AD (AOR = 0.30) and VaD (AOR = 0.26). Similar findings were observed for cognitive (AOR = 0.42) and social activities (AOR = 0.55) for AD. High-frequency physical, cognitive, and social activities were associated with a decreased risk of VaD (AOR = 0.29-0.60). Physical and social activities significantly interacted with each other on the risk of VaD (pinteraction = 0.04). Physical activity consistently protects against AD and VaD. Significant interactions were identified across different types of leisure activities in lowering dementia risk. Copyright © 2014. Published by Elsevier B.V.

C. pneumoniae CdsL regulates CdsN ATPase activity, and disruption with a peptide mimetic prevents bacterial invasion

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Chris Blair Stone

2011-02-01

Full Text Available Chlamydiae are obligate intracellular pathogens that likely require type III secretion (T3S to invade cells and replicate intracellulary within a cytoplasmic vacuole called an inclusion body. C. pneumoniae possess a YscL ortholog, CdsL, that has been shown to interact with the T3S ATPase (CdsN. In this report we demonstrate that CdsL down-regulates CdsN enzymatic activity in a dose-dependent manner. Using PepScan epitope mapping we identified two separate binding domains to which CdsL binds viz. CdsN 221-229 and CdsN265-270. We confirmed the binding domains using a pull-down assay and showed that GST-CdsN221-270, which encompasses these peptides, co-purified with His-CdsL. Next, we used orthology modeling based on the crystal structure of a T3S ATPase ortholog from E. coli, EscN, to map the binding domains on the predicted three dimensional structure of CdsN. The CdsL binding domains mapped to the catalytic domain of the ATPase, one in the central channel of the ATPase hexamer and one on the outer face. Since peptide mimetics have been used to disrupt essential protein interactions of the chlamydial T3S system and inhibit T3S-mediated invasion of HeLa cells, we hypothesized that if CdsL – CdsN binding is essential for regulating T3S then a CdsN peptide mimetic could be used to potentially block T3S and Chlamydial invasion. Treatment of EBs with a CdsN peptide mimetic inhibited C. pneumoniae invasion into HeLa cells in a dose-dependent fashion. This report represents the first use of Pepscan technology to identify binding domains for specific T3S proteins viz. CdsL on the ATPase, CdsN, and demonstrates that peptide mimetics can be used as anti-virulence factors to block bacterial invasion.

Instabilities in mimetic matter perturbations

Energy Technology Data Exchange (ETDEWEB)

Firouzjahi, Hassan; Gorji, Mohammad Ali [School of Astronomy, Institute for Research in Fundamental Sciences (IPM), P.O. Box 19395-5531, Tehran (Iran, Islamic Republic of); Mansoori, Seyed Ali Hosseini, E-mail: firouz@ipm.ir, E-mail: gorji@ipm.ir, E-mail: shosseini@shahroodut.ac.ir, E-mail: shossein@ipm.ir [Physics Department, Shahrood University of Technology, P.O. Box 3619995161 Shahrood (Iran, Islamic Republic of)

2017-07-01

We study cosmological perturbations in mimetic matter scenario with a general higher derivative function. We calculate the quadratic action and show that both the kinetic term and the gradient term have the wrong sings. We perform the analysis in both comoving and Newtonian gauges and confirm that the Hamiltonians and the associated instabilities are consistent with each other in both gauges. The existence of instabilities is independent of the specific form of higher derivative function which generates gradients for mimetic field perturbations. It is verified that the ghost instability in mimetic perturbations is not associated with the higher derivative instabilities such as the Ostrogradsky ghost.

Amphipathic α-Helices in Apolipoproteins Are Crucial to the Formation of Infectious Hepatitis C Virus Particles

Science.gov (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

2014-01-01

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

Hippocampal infusions of apolipoprotein E peptides induce long-lasting cognitive impairment.

Science.gov (United States)

Eddins, Donnie; Klein, Rebecca C; Yakel, Jerrel L; Levin, Edward D

2009-04-29

The inheritance of the varepsilon4 allele of apolipoprotein E (ApoE4) and cholinergic system dysfunction have long been associated with the pathology of Alzheimer's disease (AD). Recently, in vitro studies have established a direct link between ApoE and cholinergic function in that synthetic peptides containing segments of the ApoE protein (ApoE(133-149) and ApoE(141-148)) interact with alpha7 nicotinic acetylcholine receptors (nAChRs) in the hippocampus. This raises the possibility that ApoE peptides may contribute to cognitive impairment in AD in that the hippocampus plays a key role in cognitive functioning. To test this, we acutely infused ApoE peptides into the ventral hippocampus of female Sprague-Dawley rats and assessed the resultant effects on radial-arm maze choice accuracy over a period of weeks after the infusion. Local ventral hippocampal infusion of ApoE peptides caused significant cognitive impairment in radial-arm maze learning that persisted several weeks after the acute infusion. This persisting deficit may be an important model for understanding the relationship between ApoE protein-induced neurotoxicity and cognitive impairment as well as serve as a platform for the development of new therapies to avoid neurotoxicity and cognitive decline.

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.

1998-01-01

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

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.

1998-01-01

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)

Apolipoprotein E deficiency increases remnant lipoproteins and accelerates progressive atherosclerosis, but not xanthoma formation, in gene modified minipigs

DEFF Research Database (Denmark)

Shim, Jeong; Poulsen, Christian Bo; Hagensen, Mette K.

2017-01-01

Summary: Deficiency of apolipoprotein E (APOE) causes familial dysbetalipoproteinemia in humans resulting in a higher risk of atherosclerotic disease. In mice, APOE deficiency results in a severe atherosclerosis phenotype, but it is unknown to what extent this is unique to mice. In this study, AP...

Apolipoprotein e4 Is Associated with More Rapid Decline in Odor Identification than in Odor Threshold or Dementia Rating Scale Scores

Science.gov (United States)

Calhoun-Haney, R.; Murphy, C.

2005-01-01

Individuals with the apolipoprotein E e4 genetic risk factor for Alzheimer's disease (AD) show deficits in olfactory function. The purpose of the present study was to examine longitudinally odor identification (odor ID), odor threshold, picture identification, and global cognitive status in allele positive (e4+) and negative (e4-) persons.…

Black hole solutions in mimetic Born-Infeld gravity.

Science.gov (United States)

Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

2018-01-01

The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite.

Black hole solutions in mimetic Born-Infeld gravity

Energy Technology Data Exchange (ETDEWEB)

Chen, Che-Yu [National Taiwan University, Department of Physics and Center for Theoretical Sciences, Taipei (China); LeCosPA, National Taiwan University, Taipei (China); Bouhmadi-Lopez, Mariam [University of the Basque Country UPV/EHU, Department of Theoretical Physics, Bilbao (Spain); IKERBASQUE, Basque Foundation for Science, Bilbao (Spain); Chen, Pisin [National Taiwan University, Department of Physics and Center for Theoretical Sciences, Taipei (China); LeCosPA, National Taiwan University, Taipei (China); Stanford University, Kavli Institute for Particle Astrophysics and Cosmology, SLAC National Accelerator Laboratory, Stanford, CA (United States)

2018-01-15

The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite. (orig.)

Cosmological dynamics of mimetic gravity

Science.gov (United States)

Dutta, Jibitesh; Khyllep, Wompherdeiki; Saridakis, Emmanuel N.; Tamanini, Nicola; Vagnozzi, Sunny

2018-02-01

We present a detailed investigation of the dynamical behavior of mimetic gravity with a general potential for the mimetic scalar field. Performing a phase-space and stability analysis, we show that the scenario at hand can successfully describe the thermal history of the universe, namely the successive sequence of radiation, matter, and dark-energy eras. Additionally, at late times the universe can either approach a de Sitter solution, or a scaling accelerated attractor where the dark-matter and dark-energy density parameters are of the same order, thus offering an alleviation of the cosmic coincidence problem. Applying our general analysis to various specific potential choices, including the power-law and the exponential ones, we show that mimetic gravity can be brought into good agreement with the observed behavior of the universe. Moreover, with an inverse square potential we find that mimetic gravity offers an appealing unified cosmological scenario where both dark energy and dark matter are characterized by a single scalar field, and where the cosmic coincidence problem is alleviated.

Apolipoprotein C3 polymorphism is associated with cognitive function in Caribbean Hispanics

Science.gov (United States)

Background: 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 ...

Apolipoprotein B is a calcium binding protein

International Nuclear Information System (INIS)

Dashti, N.; Lee, D.M.; Mok, T.

1986-01-01

Human hepatocarcinoma Hep G2 cells were grown in culture medium containing [ 45 Ca 2+ ]. The secreted lipoproteins of d 45 Ca] from the gels showed that the peak of radioactivity corresponded to the apolipoprotein B band. The molar ratio of the incorporated [ 45 Ca 2+ ] and apolipoprotein B was close to unity. No radioactivity was found associated with any other secreted apolipoproteins. To confirm these findings, apolipoprotein B-containing lipoproteins were precipitated with anti-apolipoprotein B and high density lipoproteins were precipitated with anti-apolipoprotein A-I. Only the former precipitate was radioactive. These results suggest that apolipoprotein B is a calcium binding protein

Antibody mimetics: promising complementary agents to animal-sourced antibodies.

Science.gov (United States)

Baloch, Abdul Rasheed; Baloch, Abdul Wahid; Sutton, Brian J; Zhang, Xiaoying

2016-01-01

Despite their wide use as therapeutic, diagnostic and detection agents, the limitations of polyclonal and monoclonal antibodies have inspired scientists to design the next generation biomedical agents, so-called antibody mimetics that offer many advantages over conventional antibodies. Antibody mimetics can be constructed by protein-directed evolution or fusion of complementarity-determining regions through intervening framework regions. Substantial progress in exploiting human, butterfly (Pieris brassicae) and bacterial systems to design and select mimetics using display technologies has been made in the past 10 years, and one of these mimetics [Kalbitor® (Dyax)] has made its way to market. Many challenges lie ahead to develop mimetics for various biomedical applications, especially those for which conventional antibodies are ineffective, and this review describes the current characteristics, construction and applications of antibody mimetics compared to animal-sourced antibodies. The possible limitations of mimetics and future perspectives are also discussed.

Large-scale structure in mimetic Horndeski gravity

Science.gov (United States)

Arroja, Frederico; Okumura, Teppei; Bartolo, Nicola; Karmakar, Purnendu; Matarrese, Sabino

2018-05-01

In this paper, we propose to use the mimetic Horndeski model as a model for the dark universe. Both cold dark matter (CDM) and dark energy (DE) phenomena are described by a single component, the mimetic field. In linear theory, we show that this component effectively behaves like a perfect fluid with zero sound speed and clusters on all scales. For the simpler mimetic cubic Horndeski model, if the background expansion history is chosen to be identical to a perfect fluid DE (PFDE) then the mimetic model predicts the same power spectrum of the Newtonian potential as the PFDE model with zero sound speed. In particular, if the background is chosen to be the same as that of LCDM, then also in this case the power spectrum of the Newtonian potential in the mimetic model becomes indistinguishable from the power spectrum in LCDM on linear scales. A different conclusion may be found in the case of non-adiabatic perturbations. We also discuss the distinguishability, using power spectrum measurements from LCDM N-body simulations as a proxy for future observations, between these mimetic models and other popular models of DE. For instance, we find that if the background has an equation of state equal to ‑0.95 then we will be able to distinguish the mimetic model from the PFDE model with unity sound speed. On the other hand, it will be hard to do this distinction with respect to the LCDM model.

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

Science.gov (United States)

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

2015-09-08

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.

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

2015-01-01

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...... 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...... adjustment for ε2/ε3/ε4 APOE genotype, plasma apoE tertiles remained associated with Alzheimer disease (p for trend = 0.007) and all dementia (p for trend = 0.04). Plasma apoE tertiles did not interact with ε2/ε3/ε4 APOE genotype on risk of Alzheimer disease (p = 0.53) or all dementia (p = 0...

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.

1998-01-01

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)

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease

DEFF Research Database (Denmark)

Mattsson, Niklas; Groot, Colin; Jansen, Willemijn J

2018-01-01

INTRODUCTION: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. METHODS: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cog...

Apolipoprotein E and presenilin-1 genotypes in Huntington's disease.

Science.gov (United States)

Panas, M; Avramopoulos, D; Karadima, G; Petersen, M B; Vassilopoulos, D

1999-07-01

Huntington's disease (HD) is an autosomal dominant degenerative disease of the central nervous system manifested by involuntary movements (chorea), psychiatric manifestations, and cognitive impairment with a variable age at onset. This variability is mainly attributed to genetic factors. The so-called aging genes [e.g., those for apolipoprotein E (APOE) and presenilin-1 (PS-1) have been implicated in determining the age at onset of Alzheimer's disease, a disease sharing common clinical features with HD. In 60 unrelated patients suffering from HD (mean age at onset 40.1 years, range 20-65) we determined number of CAG repeats and the distribution of the APOE alleles (epsilon2, epsilon3, epsilon4) and PS-1 alleles. The results showed that: (a) The age at onset was higher in the group of patients with the epsilon4 allele (51.6 vs. 38.0 P<0.002), (b) The correlation between the age at onset and the number of CAG repeats was strong in patients with the epsilon3/epsilon3 genotype while it was not detected in patients with epsilon3/epsilon4 genotype. (c) No correlation was found between age at onset and PS-1 alleles. In conclusion, APOE seems to be a significant factor influencing the age at onset of Huntington's disease.

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.

Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.

Science.gov (United States)

Graham, Mark J; Lee, Richard G; Bell, Thomas A; Fu, Wuxia; Mullick, Adam E; Alexander, Veronica J; Singleton, Walter; Viney, Nick; Geary, Richard; Su, John; Baker, Brenda F; Burkey, Jennifer; Crooke, Stanley T; Crooke, Rosanne M

2013-05-24

Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels. Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations. Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

Roles of high apolipoprotein E blood levels and HDL in development of familial dysbetalipoproteinemia in ε2ε2 subjects

NARCIS (Netherlands)

Corsetti, James P; Sparks, Charles E; Bakker, Stephan J L; Gruppen, Eke G; Dullaart, Robin P F

2017-01-01

OBJECTIVE: Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is a mixed hyperlipidemia closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all homozygotes progress to FD. Unlike the polymorphism, few studies explore effects of apolipoprotein E

Effect of tocopherol on atherosclerosis, vascular function, and inflammation in apolipoprotein E knockout mice with subtotal nephrectomy.

Science.gov (United States)

Shing, Cecilia M; Fassett, Robert G; Peake, Jonathan M; Coombes, Jeff S

2014-12-01

Inflammation and endothelial dysfunction contribute to cardiovascular disease, prevalent in chronic kidney disease (CKD). Antioxidant supplements such as tocopherols may reduce inflammation and atherosclerosis. This study aimed to investigate the effect of tocopherol supplementation on vascular function, aortic plaque formation, and inflammation in apolipoprotein E(-/-) mice with 5/6 nephrectomy as a model of combined cardiovascular and kidney disease. Nephrectomized mice were assigned to a normal chow diet group (normal chow), a group receiving 1000 mg/kg diet of α-tocopherol supplementation or a group receiving 1000 mg/kg diet mixed-tocopherol (60% γ-tocopherol). Following 12 weeks, in vitro aortic endothelial-independent relaxation was enhanced with both α-tocopherol and mixed-tocopherol (P tocopherol enhanced aortic contraction at noradrenaline concentrations of 3 × 10(-7) M to 3 × 10(-5) M (P tocopherol reduced systemic concentrations of IL-6 (P tocopherol also reduced MCP-1 (P tocopherol supplementation when compared to normal chow (P Tocopherol supplementation favorably influenced vascular function and cytokine profile, while it was also effective in reducing atherosclerosis in the apolipoprotein E(-/-) mouse with CKD. © 2014 John Wiley & Sons Ltd.

Subcellular distribution of apolipoprotein E along the lipoprotein synthetic pathway of rat liver

International Nuclear Information System (INIS)

Cole, T.G.; Stockhausen, D.C.

1986-01-01

Apolipoprotein E (apoE) is synthesized by the liver and is secreted as a component of VLDL. To define the intracellular locations of apoE, liver from 10 nonfasted male rats were removed and subcellular organelles prepared by differential pelleting through sucrose gradients. Mass of apoE was measured by radioimmunoassay. Approximately 10% of total hepatic apoE was recovered in rough endoplasmic reticulum (RER), smooth endoplasmic reticulum (SER) and Golgi fractions. Concentrations of apoE (ng/mg protein) were: homogenate, 302 +/- 59; RER, 653 +/- 251; SER, 1250 +/- 471; Golgi, 11,044 +/- 4291. Total apoE content of each reaction (μg/organelle) was: homogenate (whole liver), 517 +/- 103; RER, 15 +/- 3; SER, 9 +/- 3; Golgi, 28 +/- 8. These data indicate that along the putative pathway of lipoprotein synthesis (RER->SER->Golgi), apoE concentration increases in each successive organelle and that flux of apoE is apparently most rapid through SER. Furthermore, the majority of apoE in the rat liver is apparently not directly associated with the lipoprotein synthetic pathway and may be associated with internalized lipoproteins or may be involved in non-lipoprotein related functions

Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes

Energy Technology Data Exchange (ETDEWEB)

Roman, Corina; Fuior, Elena V.; Trusca, Violeta G. [Institute of Cellular Biology and Pathology “Nicolae Simionescu”, Bucharest (Romania); Kardassis, Dimitris [University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Crete (Greece); Simionescu, Maya [Institute of Cellular Biology and Pathology “Nicolae Simionescu”, Bucharest (Romania); Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro [Institute of Cellular Biology and Pathology “Nicolae Simionescu”, Bucharest (Romania)

2015-12-04

Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341–488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5′- and 3′-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. - Highlights: • T3 induce a dose-dependent increase of apoE expression in astrocytes. • Thyroid hormones activate apoE promoter in a cell specific manner. • Ligand activated TRβ/RXRα bind on the distal regulatory element ME.2 to modulate apoE. • The binding site of TRβ/RXRα heterodimer is located at 409 bp on ME.2.

Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes

International Nuclear Information System (INIS)

Roman, Corina; Fuior, Elena V.; Trusca, Violeta G.; Kardassis, Dimitris; Simionescu, Maya; Gafencu, Anca V.

2015-01-01

Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341–488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5′- and 3′-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. - Highlights: • T3 induce a dose-dependent increase of apoE expression in astrocytes. • Thyroid hormones activate apoE promoter in a cell specific manner. • Ligand activated TRβ/RXRα bind on the distal regulatory element ME.2 to modulate apoE. • The binding site of TRβ/RXRα heterodimer is located at 409 bp on ME.2.

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

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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.

Functional blockage of EMMPRIN ameliorates atherosclerosis in apolipoprotein E-deficient mice.

Science.gov (United States)

Liu, Hong; Yang, Li-xia; Guo, Rui-wei; Zhu, Guo-Fu; Shi, Yan-Kun; Wang, Xian-mei; Qi, Feng; Guo, Chuan-ming; Ye, Jin-shan; Yang, Zhi-hua; Liang, Xing

2013-10-09

Extracellular matrix metalloproteinase inducer (EMMPRIN), a 58-kDa cell surface glycoprotein, has been identified as a key receptor for transmitting cellular signals mediating metalloproteinase activities, as well as inflammation and oxidative stress. Clinical evidence has revealed that EMMPRIN is expressed in human atherosclerotic plaque; however, the relationship between EMMPRIN and atherosclerosis is unclear. To evaluate the functional role of EMMPRIN in atherosclerosis, we treated apolipoprotein E-deficient (ApoE(-/-)) mice with an EMMPRIN function-blocking antibody. EMMPRIN was found to be up-regulated in ApoE(-/-) mice fed a 12-week high-fat diet in contrast to 12 weeks of normal diet. Administration of a function-blocking EMMPRIN antibody (100 μg, twice per week for 4 weeks) to ApoE(-/-) mice, starting after 12 weeks of high-fat diet feeding caused attenuated and more stable atherosclerotic lesions, less reactive oxygen stress generation on plaque, as well as down-regulation of circulating interleukin-6 and monocyte chemotactic protein-1 in ApoE(-/-) mice. The benefit of EMMPRIN functional blockage was associated with reduced metalloproteinases proteolytic activity, which delayed the circulating monocyte transmigrating into atherosclerotic lesions. EMMPRIN antibody intervention ameliorated atherosclerosis in ApoE(-/-) mice by the down-regulation of metalloproteinase activity, suggesting that EMMPRIN may be a viable therapeutic target in atherosclerosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

LENUS (Irish Health Repository)

Trompet, Stella

2009-12-01

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.

Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo. Carboxyl-terminal region 203-299 promotes hepatic very low density lipoprotein-triglyceride secretion

NARCIS (Netherlands)

Kypreos, K.E.; Dijk, K.W. van; Zee, A. van der; Havekes, L.M.; Zannis, V.I.

2001-01-01

Apolipoprotein (apo) E has been implicated in cholesterol and triglyceride homeostasis in humans. At physiological concentration apoE promotes efficient clearance of apoE-containing lipoprotein remnants. However, high apoE plasma levels correlate with high plasma triglyceride levels. We have used

Association between iris constitution and apolipoprotein e gene polymorphism in hypertensives.

Science.gov (United States)

Um, Jae-Young; Hwang, Chung-Yeon; Hwang, Woo-Jun; Kang, Sung-Do; Do, Keum-Rok; Cho, Ju-Jang; Cho, Jae-Woon; Kim, Sung-Hoon; Shin, Tae-Yong; Kim, Yun-Kyung; Kim, Hyung-Min; Hong, Seung-Heon

2004-12-01

Iridology is a complementary and alternative medicine (CAM) that involves the diagnosis of medical conditions by noting irregularities of the pigmentation in the iris. Iris constitution has a strong familial aggregation and heredity is implicated. Apolipoprotein E (apoE) gene polymorphism is one of the most well-studied genetic markers for vascular diseases, including hypertension. In this study, we investigated the relationship between iris constitution and apoE polymorphism in hypertensives. We classified 87 hypertensives and 79 controls according to iris constitution and determined the apoE genotype of each individual. A significantly higher percentage of individuals with neurogenic constitutions was found in the hypertensive group when compared with the control group (chi(2) = 40.244, p < 0.001). In addition, a neurogenic constitution increased the relative risk for hypertension for subjects with an apo epsilon2 or an epsilon4 allele (chi(2) = 4.086, p = 0.049, odds ratio = 2.633, confidence interval = 1.004-6.905). Our results imply that a neurogenic iris constitution enhances the relative risk for hypertension in subjects with the apo epsilon2 or epsilon4 allele. Furthermore, we attempted to evaluate the efficacy of iris constitutional medicine and to find an association with hypertension.

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.

Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

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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: huangziyang666@126.com [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: qzlinl@163.com [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China)

2014-07-18

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.

Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

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Wang, Yuehai; Lu, Huixia; Huang, Ziyang; Lin, Huili; Lei, Zhenmin; Chen, Xiaoqing; Tang, Mengxiong; Gao, Fei; Dong, Mei; Li, Rongda; Lin, Ling

2014-01-01

Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE −/− and Fas −/− mice. • The spleen weights and glomerular areas were similar in ApoE −/− and Fas −/− mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE −/− and Fas −/− mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE −/− mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE −/− ) mice is a classic model of atherosclerosis. We have found that ApoE −/− mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE −/− mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE −/− , Fas −/− 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 −/− mice, a model of systemic lupus erythematosus (SLE), ApoE −/− 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 −/− mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE −/− mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

Influence of depleted uranium on hepatic cholesterol metabolism in apolipoprotein E-deficient mice.

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Souidi, M; Racine, R; Grandcolas, L; Grison, S; Stefani, J; Gourmelon, P; Lestaevel, P

2012-04-01

Depleted uranium (DU) is uranium with a lower content of the fissile isotope U-235 than natural uranium. It is a radioelement and a waste product from the enrichment process of natural uranium. Because of its very high density, it is used in the civil industry and for military purposes. DU exposure can affect many vital systems in the human body, because in addition to being weakly radioactive, uranium is a toxic metal. It should be emphasized that, to be exposed to radiation from DU, you have to eat, drink, or breathe it, or get it on your skin. This particular study is focusing on the health effects of DU for the cholesterol metabolism. Previous studies on the same issue have shown that the cholesterol metabolism was modulated at molecular level in the liver of laboratory rodents contaminated for nine months with DU. However, this modulation was not correlated with some effects at organs or body levels. It was therefore decided to use a "pathological model" such as hypercholesterolemic apolipoprotein E-deficient laboratory mice in order to try to clarify the situation. The purpose of the present study is to assess the effects of a chronic ingestion (during 3 months) of a low level DU-supplemented water (20 mg L(-1)) on the above mentioned mice in order to determine a possible contamination effect. Afterwards the cholesterol metabolism was studied in the liver especially focused on the gene expressions of cholesterol-catabolising enzymes (CYP7A1, CYP27A1 and CYP7B1), as well as those of associated nuclear receptors (LXRα, FXR, PPARα, and SREBP 2). In addition, mRNA levels of other enzymes of interest were measured (ACAT 2, as well as HMGCoA Reductase and HMGCoA Synthase). The gene expression study was completed with SRB1 and LDLr, apolipoproteins A1 and B and membrane transporters ABC A1, ABC G5. The major effect induced by a low level of DU contamination in apo-E deficient mice was a decrease in hepatic gene expression of the enzyme CYP7B1 (-23%) and nuclear

Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis

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Mobaswar Hossain Chowdhury

2018-02-01

Full Text Available Invasive candidiasis caused by Candida albicans and non-albicans Candida (NAC present a serious disease threat. Although the echinocandins are recommended as the first line of antifungal drug class, resistance to these agents is beginning to emerge, demonstrating the need for new antifungal agents. Host defense peptides (HDP exhibit potent antifungal activity, but as drugs they are difficult to manufacture efficiently, and they are often inactivated by serum proteins. HDP mimetics are low molecular weight non-peptide compounds that can alleviate these problems and were shown to be membrane-active against C. albicans and NAC. Here, we expand upon our previous works to describe the in vitro and in vivo activity of 11 new HDP mimetics that are active against C. albicans and NAC that are both sensitive and resistant to standard antifungal drugs. These compounds exhibit minimum inhibitory/fungicidal concentration (MIC/MFC in the µg/mL range in the presence of serum and are inhibited by divalent cations. Rapid propidium iodide influx into the yeast cells following in vitro exposure suggested that these HDP mimetics were also membrane active. The lead compounds were able to kill C. albicans in an invasive candidiasis CD-1 mouse model with some mimetic candidates decreasing kidney burden by 3–4 logs after 24 h in a dose-dependent manner. The data encouraged further development of this new anti-fungal drug class for invasive candidiasis.

Synergistic associations of depression and apolipoprotein E genotype with incidence of dementia.

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Kim, Jae-Min; Stewart, Robert; Kim, Seon-Young; Kim, Sung-Wan; Bae, Kyung-Yeol; Yang, Su-Jin; Shin, Il-Seon; Yoon, Jin-Sang

2011-09-01

A cohort study of Japanese-American men suggested interactive effects of depression and apolipoprotein E (APOE) e4 allele on risk of incident dementia. In another sample of East Asian origin, we sought to replicate the findings and to explore individual depressive symptoms where this interaction was most evident. Of 625 Korean community elders without dementia at baseline, 518 (83%) were followed over a 2.4-year period and were clinically assessed for incident dementia. Depression was identified by the Geriatric Mental State Schedule (GMS), and nine individual depressive symptoms relevant to DSM-IV major depressive episode criteria were extracted. APOE genotype was ascertained. Covariates included age, gender, education, and disability. There were synergistic interactions between depression and APOE e4 on incident dementia independent of covariates. This interaction was particularly strong for four depressive symptoms: depressed mood, worthlessness, concentration difficulty, and suicidal ideation. We were able to replicate the previous study, finding that, at least in East Asian origin populations, the APOE e4 allele is a stronger predictor of incident dementia in the presence of depressive syndrome, and particular depressive symptoms. Copyright © 2010 John Wiley & Sons, Ltd.

The mimetic finite difference method for elliptic problems

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Veiga, Lourenço Beirão; Manzini, Gianmarco

2014-01-01

This book describes the theoretical and computational aspects of the mimetic finite difference method for a wide class of multidimensional elliptic problems, which includes diffusion, advection-diffusion, Stokes, elasticity, magnetostatics and plate bending problems. The modern mimetic discretization technology developed in part by the Authors allows one to solve these equations on unstructured polygonal, polyhedral and generalized polyhedral meshes. The book provides a practical guide for those scientists and engineers that are interested in the computational properties of the mimetic finite difference method such as the accuracy, stability, robustness, and efficiency. Many examples are provided to help the reader to understand and implement this method. This monograph also provides the essential background material and describes basic mathematical tools required to develop further the mimetic discretization technology and to extend it to various applications.

A recombinant mimetics of the HIV-1 gp41 prehairpin fusion intermediate fused with human IgG Fc fragment elicits neutralizing antibody response in the vaccinated mice

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Qi, Zhi; Pan, Chungen; Lu, Hong; Shui, Yuan; Li, Lin; Li, Xiaojuan; Xu, Xueqing; Liu, Shuwen; Jiang, Shibo

2010-01-01

Research highlights: → One recombinant mimetics of gp41 prehairpin fusion intermediate (PFI) consisting of gp41 N46 sequence, foldon and IgG Fc, designated N46FdFc, was expressed. → N46FdFc-induced antibodies in mice that neutralized HIV-1 infection, inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. → These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines. -- Abstract: HIV-1 gp41 prehairpin fusion intermediate (PFI) composed of three N-terminal heptad repeats (NHR) plays a crucial role in viral fusion and entry and represents an attractive target for anti-HIV therapeutics (e.g., enfuvirtide) and vaccines. In present study, we constructed and expressed two recombinant gp41 PFI mimetics, designated N46Fd and N46FdFc. N46Fd consists of N46 (residues 536-581) in gp41 NHR and foldon (Fd), a trimerization motif. N46FdFc is composed of N46Fd fused with human IgG Fc fragment as an immunoenhancer. We immunized mice with N46 peptide, N46Fd and N46FdFc, respectively, and found that only N46FdFc elicited neutralizing antibody response in mice against infection by HIV-1 strains IIIB (clade B, X4), 92US657 (clade B, R5), and 94UG103 (clade A, X4R5). Anti-N46FdFc antibodies inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines.

Progress of Mimetic Enzymes and Their Applications in Chemical Sensors.

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Yang, Bin; Li, Jianping; Deng, Huan; Zhang, Lianming

2016-11-01

The need to develop innovative and reformative approaches to synthesize chemical sensors has increased in recent years because of demands for selectivity, stability, and reproducibility. Mimetic enzymes provide an efficient and convenient method for chemical sensors. This review summarizes the application of mimetic enzymes in chemical sensors. Mimetic enzymes can be classified into five categories: hydrolases, oxidoreductases, transferases, isomerases, and induced enzymes. Potential and recent applications of mimetic enzymes in chemical sensors are reviewed in detail, and the outlook of profound development has been illustrated.

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

2016-09-01

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.

Research progress of nanoparticles as enzyme mimetics

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Hu, XiaoNa; Liu, JianBo; Hou, Shuai; Wen, Tao; Liu, WenQi; Zhang, Ke; He, WeiWei; Ji, YingLu; Ren, HongXuan; Wang, Qi; Wu, XiaoChun

2011-10-01

Natural enzymes as biological catalysts possess remarkable advantages, especially their highly efficient and selective catalysis under mild conditions. However, most natural enzymes are proteins, thus exhibiting an inherent low durability to harsh reaction conditions. Artificial enzyme mimetics have been pursued extensively to avoid this drawback. Quite recently, some inorganic nanoparticles (NPs) have been found to exhibit unique enzyme mimetics. In addition, their much higher stability overcomes the inherent disadvantage of natural enzymes. Furthermore, easy mass-production and low cost endow them more benefits. As a new member of artificial enzyme mimetics, they have received intense attention. In this review article, major progress in this field is summarized and future perspectives are highlighted.

Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/- Mice.

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Rinne, Petteri; Kadiri, James J; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

2018-02-01

The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Apoe -/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r e/e ) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe -/- Mc1r e/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe -/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe -/- Mc1r e/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C high monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C high monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. © 2017 The Authors.

Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics.

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Dennie T Frederick

Full Text Available While response rates to BRAF inhibitiors (BRAFi are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA, significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720 and BCL2 (navitoclax inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.

Age-Related Effects of the Apolipoprotein E Gene on Brain Function.

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Matura, Silke; Prvulovic, David; Hartmann, Daniel; Scheibe, Monika; Sepanski, Beate; Butz, Marius; Oertel-Knöchel, Viola; Knöchel, Christian; Karakaya, Tarik; Fußer, Fabian; Hattingen, Elke; Pantel, Johannes

2016-03-16

The apolipoprotein E (ApoE) ɛ4 allele is a well-established genetic risk factor for sporadic Alzheimer's disease. Some evidence suggests a negative role of the ApoE ɛ4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4±4.6 years, 25 ɛ4 carriers) and old (n = 40; age 66.1±7.0 years, 20 ɛ4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ4 carriers. The increased BOLD response in old ɛ4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

Synthesis and evaluation of di- and trimeric hydroxylamine-based β-(1→3)-glucan mimetics.

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Ferry, Angélique; Malik, Gaëlle; Guinchard, Xavier; Vĕtvička, Václav; Crich, David

2014-10-22

Di- and trimeric hydroxylamine-based mimetics of β-(1→3)-glucans have been accessed by an asymmetric synthesis route featuring an iterative double ring-closing reductive amination reaction. These oligomeric hydroxylamines are demonstrated to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-dectin-1 antibodies, respectively, and to stimulate phagocytosis, all in a linkage-dependent manner suggestive of binding to the lectin domains of complement receptor 3 (CR3) and dectin-1. The ability of these relatively short mimetics to bind to CR3 and dectin-1, as compared to the greater degree of polymerization required in β-(1→3)-glucans, is discussed in terms of the increased hydrophobicity of the α-face on replacement of the glycosidic bond by the hydroxylamine linkage.

Apolipoprotein E epsilon 4 (APOE-ε4) genotype is associated with decreased 6-month verbal memory performance after mild traumatic brain injury

NARCIS (Netherlands)

J.K. Yue (John); Robinson, C.K. (Caitlin K.); J.F. Burke (John F.); E.A. Winkler (Ethan A.); Deng, H. (Hansen); M.C. Cnossen (Maryse); H.F. Lingsma (Hester); A.R. Ferguson (Adam); McAllister, T.W. (Thomas W.); J. Rosand (Jonathan); E.G. Burchard (Esteban); M.D. Sorani (Marco); S. Sharma (Sourabh); J.L. Nielson (Jessica L.); G.G. Satris (Gabriela G.); Talbott, J.F. (Jason F.); P.E. Tarapore (Phiroz E.); F.K. Korley (Frederick K.); Wang, K.K.W. (Kevin K.W.); E.L. Yuh (Esther); P. Mukherjee (Pratik); R. Diaz-Arrastia (Ramon); A.B. Valadka (Alex); D. Okonkwo (David); G. Manley (Geoffrey)

2017-01-01

textabstractIntroduction: The apolipoprotein E (APOE) ε4 allele associates with memory impairment in neurodegenerative diseases. Its association with memory after mild traumatic brain injury (mTBI) is unclear. Methods: mTBI patients (Glasgow Coma Scale score 13–15, no neurosurgical intervention,

BH3-mimetics- and cisplatin-induced cell death proceeds through different pathways depending on the availability of death-related cellular components.

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Vicente Andreu-Fernández

Full Text Available BACKGROUND: Owing to their important function in regulating cell death, pharmacological inhibition of Bcl-2 proteins by dubbed BH3-mimetics is a promising strategy for apoptosis induction or sensitization to chemotherapy. However, the role of Apaf-1, the main protein constituent of the apoptosome, in the process has yet not been analyzed. Furthermore as new chemotherapeutics develop, the possible chemotherapy-induced toxicity to rapidly dividing normal cells, especially sensitive differentiated cells, has to be considered. Such undesirable effects would probably be ameliorated by selectively and locally inhibiting apoptosis in defined sensitive cells. METHODOLOGY AND PRINCIPAL FINDINGS: Mouse embryonic fibroblasts (MEFS from Apaf-1 knock out mouse (MEFS KO Apaf-1 and Bax/Bak double KO (MEFS KO Bax/Bak, MEFS from wild-type mouse (MEFS wt and human cervix adenocarcinoma (HeLa cells were used to comparatively investigate the signaling cell death-induced pathways of BH3-mimetics, like ABT737 and GX15-070, with DNA damage-inducing agent cisplatin (cis-diammineplatinum(II dichloride, CDDP. The study was performed in the absence or presence of apoptosis inhibitors namely, caspase inhibitors or apoptosome inhibitors. BH3-mimetic ABT737 required of Apaf-1 to exert its apoptosis-inducing effect. In contrast, BH3-mimetic GX15-070 and DNA damage-inducing CDDP induced cell death in the absence of both Bax/Bak and Apaf-1. GX15-070 induced autophagy-based cell death in all the cell lines analyzed. MEFS wt cells were protected from the cytotoxic effects of ABT737 and CDDP by chemical inhibition of the apoptosome through QM31, but not by using general caspase inhibitors. CONCLUSIONS: BH3-mimetic ABT737 not only requires Bax/Bak to exert its apoptosis-inducing effect, but also Apaf-1, while GX15-070 and CDDP induce different modalities of cell death in the absence of Bax/Bak or Apaf-1. Inclusion of specific Apaf-1 inhibitors in topical and well

The BH3 Mimetic Obatoclax Accumulates in Lysosomes and Causes Their Alkalinization.

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Stamelos, Vasileios A; Fisher, Natalie; Bamrah, Harnoor; Voisey, Carolyn; Price, Joshua C; Farrell, William E; Redman, Charles W; Richardson, Alan

2016-01-01

Obatoclax belongs to a class of compounds known as BH3 mimetics which function as antagonists of Bcl-2 family apoptosis regulators. It has undergone extensive preclinical and clinical evaluation as a cancer therapeutic. Despite this, it is clear that obatoclax has additional pharmacological effects that contribute to its cytotoxic activity. It has been claimed that obatoclax, either alone or in combination with other molecularly targeted therapeutics, induces an autophagic form of cell death. In addition, obatoclax has been shown to inhibit lysosomal function, but the mechanism of this has not been elucidated. We have evaluated the mechanism of action of obatoclax in eight ovarian cancer cell lines. Consistent with its function as a BH3 mimetic, obatoclax induced apoptosis in three cell lines. However, in the remaining cell lines another form of cell death was evident because caspase activation and PARP cleavage were not observed. Obatoclax also failed to show synergy with carboplatin and paclitaxel, chemotherapeutic agents which we have previously shown to be synergistic with authentic Bcl-2 family antagonists. Obatoclax induced a profound accumulation of LC-3 but knockdown of Atg-5 or beclin had only minor effects on the activity of obatoclax in cell growth assays suggesting that the inhibition of lysosomal function rather than stimulation of autophagy may play a more prominent role in these cells. To evaluate how obatoclax inhibits lysosomal function, confocal microscopy studies were conducted which demonstrated that obatoclax, which contains two basic pyrrole groups, accumulates in lysosomes. Studies using pH sensitive dyes demonstrated that obatoclax induced lysosomal alkalinization. Furthermore, obatoclax was synergistic in cell growth/survival assays with bafilomycin and chloroquine, two other drugs which cause lysosomal alkalinization. These studies explain, for the first time, how obatoclax inhibits lysosomal function and suggest that lysosomal

Human plasma lipid modulation in schistosomiasis mansoni depends on apolipoprotein E polymorphism.

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Caíque Silveira Martins da Fonseca

Full Text Available Schistosomiasis mansoni is a parasitic liver disease, which causes several metabolic disturbances. Here, we evaluate the influence of Apolipoprotein E (APOE gene polymorphism, a known modulator of lipid metabolism, on plasma lipid levels in patients with hepatosplenic schistosomiasis.Blood samples were used for APOE genotyping and to measure total cholesterol (TC, LDL-C, HDL-C and triglycerides. Schistosomiasis patients had reduced TC, LDL-C and triglycerides (25%, 38% and 32% lower, respectively; Pε3>ε4 was absent in patients (ε2 or ε4>ε3, and the increase in HDL-C of ε2 or ε4 patients compared to ε3 patients was not seen in the control groups.We confirm that human schistosomiasis causes dyslipidemia and report for the first time that certain changes in plasma lipid and lipoprotein levels depend on APOE gene polymorphism. Importantly, we also concluded that S. mansoni disrupts the expected regulation of plasma lipids by the different ApoE isoforms. This finding suggests ways to identify new metabolic pathways affected by schistosomiasis and also potential molecular targets to treat associated morbidities.

Endothelial dysfunction of resistance vessels in female apolipoprotein E-deficient mice

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Vasquez Elisardo C

2010-05-01

Full Text Available Abstract Background The effects of hypercholesterolemia on vasomotricity in apolipoprotein E-deficient (ApoE mice, a murine model of spontaneous atherosclerosis, are still unclear. The studies were mostly performed in conductance vessels from male mice fed a high-fat diet. In the present study, we evaluated the endothelial function of resistance vessels from normal C57BL/6 (C57 and hypercholesterolemic (ApoE female mice in both normal and ovariectomized conditions. Methods Twenty week-old C57 and ApoE mice underwent ovariectomy or sham surgery and were studied 30 days later. The vascular reactivities to norepinephrine (NE, 10-9 to 2 × 10-3 mol/L, acetylcholine (ACh and sodium nitroprusside (SNP (10-10 to 10-3 mol/L were evaluated in the isolated mesenteric arteriolar bed through dose-response curves. Results ACh-induced relaxation was significantly reduced (P 50 (-5.67 ± 0.18 vs. -6.23 ± 0.09 mol/L. Ovariectomy caused a significant impairment in ACh-induced relaxation in the C57 group (maximal response: 61 ± 4% but did not worsen the deficient state of relaxation in ApoE animals (maximal response: 39 ± 5%. SNP-induced vasorelaxation and NE-induced vasoconstriction were similar in ApoE and C57 female mice. Conclusion These data show an impairment of endothelial function in the resistance vessels of spontaneously atherosclerotic (ApoE-deficient female mice compared with normal (C57 female mice. The endothelial dysfunction in hypercholesterolemic animals was so marked that ovariectomy, which impaired endothelial function in C57 mice, did not cause additional vascular damage in ApoE-deficient mice.

Association of Apolipoprotein E Polymorphism with Ischemic Stroke Subtypes in Taiwan

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Chiou-Lian Lai

2007-10-01

Full Text Available The aim of this study was to clarify whether the apolipoprotein E gene (APOE is related to ischemic stroke subtypes in Taiwan's Chinese population. Using the classification of Cerebrovascular Diseases III, 143 patients with lacunar infarction, 114 patients with atherothrombotic infarction, and 112 healthy controls were enrolled. APOE genotype was determined using polymerase chain reaction. Regarding the distribution of APOE genotypes, the frequency of ϵ3/ϵ4 genotypes in lacunar patients was significantly different from that in control subjects, by logistic regression, using ϵ3/ϵ3 as a reference group. There was no significant difference between atherothrombotic patients and the control group in the distribution of APOE genotypes or alleles. The present finding suggests that there is a probable association between ϵ3/ϵ4 genotype and lacunar infarcts, but not atherothrombotic infarcts. This indicates that genetic factors may play a role, at least partially, in lacunar infarction in Taiwan's Chinese population.

Cigarette smoke exposure promotes arterial thrombosis and vessel remodeling after vascular injury in apolipoprotein E-deficient mice.

Science.gov (United States)

Schroeter, Marco R; Sawalich, Matthias; Humboldt, Tim; Leifheit, Maren; Meurrens, Kris; Berges, An; Xu, Haiyan; Lebrun, Stefan; Wallerath, Thomas; Konstantinides, Stavros; Schleef, Raymond; Schaefer, Katrin

2008-01-01

Cigarette smoking is a major risk factor for the development of cardiovascular disease. However, in terms of the vessel wall, the underlying pathomechanisms of cigarette smoking are incompletely understood, partly due to a lack of adequate in vivo models. Apolipoprotein E-deficient mice were exposed to filtered air (sham) or to cigarette mainstream smoke at a total particulate matter (TPM) concentration of 600 microg/l for 1, 2, 3, or 4 h, for 5 days/week. After exposure for 10 +/- 1 weeks, arterial thrombosis and neointima formation at the carotid artery were induced using 10% ferric chloride. Mice exposed to mainstream smoke exhibited shortened time to thrombotic occlusion (p < 0.01) and lower vascular patency rates (p < 0.001). Morphometric and immunohistochemical analysis of neointimal lesions demonstrated that mainstream smoke exposure increased the amount of alpha-actin-positive smooth muscle cells (p < 0.05) and dose-dependently increased the intima-to-media ratio (p < 0.05). Additional analysis of smooth muscle cells in vitro suggested that 10 microg TPM/ml increased cell proliferation without affecting viability or apoptosis, whereas higher concentrations (100 and 500 microg TPM/ml) appeared to be cytotoxic. Taken together, these findings suggest that cigarette smoking promotes arterial thrombosis and modulates the size and composition of neointimal lesions after arterial injury in apolipoprotein E-deficient mice. Copyright 2008 S. Karger AG, Basel.

Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer

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Schwarz Margaret A

2011-01-01

Full Text Available Abstract Background Pancreatic ductal adenocarcinoma (PDAC is highly resistant to conventional chemotherapy, in part due to the overexpression of inhibitors of apoptosis proteins (IAPs. Smac is an endogenous IAP-antagonist, which renders synthetic Smac mimetics attractive anticancer agents. We evaluated the benefits of combining a Smac mimetic, JP1201 (JP, with conventional chemotherapy agents used for PDAC management. Methods Cell viability assays and protein expression analysis were performed using WST-1 reagent and Western blotting, respectively. Apoptosis was detected by annexin V/propidium iodide staining. In vivo tumor growth and survival studies were performed in murine PDAC xenografts. Results JP and gemcitabine (Gem inhibited PDAC cell proliferation with additive effects in combination. The percentage of early apoptotic cells in controls, JP, Gem and JP + Gem was 17%, 26%, 26% and 38%, respectively. JP-induced apoptosis was accompanied by PARP-1 cleavage. Similar additive anti-proliferative effects were seen for combinations of JP with doxorubicin (Dox and docetaxel (DT. The JP + Gem combination caused a 30% decrease in tumor size in vivo compared to controls. Median animal survival was improved significantly in mice treated with JP + Gem (38 d compared to controls (22 d, JP (28 d or Gem (32 d (p = 0.01. Animal survival was also improved with JP + DT treatment (32 d compared to controls (16 d, JP (21 d or DT alone (27 d. Conclusions These results warrant further exploration of strategies that promote chemotherapy-induced apoptosis of tumors and highlight the potential of Smac mimetics in clinical PDAC therapy.

Human apolipoprotein e resequencing by proteomic analysis and its application to serotyping.

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Motoi Nishimura

Full Text Available BACKGROUND: Apolipoprotein E (ApoE typing is considered important because of the association between ApoE and Alzheimer's disease and familial dyslipidemia and is currently performed by genetic testing (APOE genotyping. ApoE levels in plasma and serum are clinically determined by immunoassay. METHODS: Combining an ApoE immunoassay reagent with proteomic analysis using an Orbitrap mass spectrometer, we attempted to resequence ApoE from trace amounts of serum for typing (serotyping. Most (24 of 33 ApoE mutant proteins registered to date with Online Mendelian Inheritance in Man, such as ApoE2 and ApoE4, involve lysine and arginine mutations. Digestion of mutant ApoE with trypsin will thus result in fragments that differ substantially from wild-type ApoE3 in terms of mass, making serotyping ideally suited to mass spectrometry analysis. RESULTS: The mean coverage of the amino acid sequence of full-length ApoE was 91.6% in the protein resequence. Residues 112 and 158 (which are mutated in ApoE2 and ApoE4 were covered in all samples, and the protein sequences were used for serotyping. Serotypes including all heterozygous combinations (ApoE2/E3, E2/E4, E3/E4 corresponded exactly to the APOE genotyping results in each of the subjects. CONCLUSION: Our novel ApoE serotyping method with protein resequencing requires no synthesis of stable isotope-labeled peptides or genome analysis. The method can use residual blood from samples collected for routine clinical tests, thus enabling retrospective studies with preserved body fluids. The test could be applied to samples from subjects whose DNA is unavailable. In future studies, we hope to demonstrate the capability of our method to detect rare ApoE mutations.

Aspartate and glutamate mimetic structures in biologically active compounds.

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Stefanic, Peter; Dolenc, Marija Sollner

2004-04-01

Glutamate and aspartate are frequently recognized as key structural elements for the biological activity of natural peptides and synthetic compounds. The acidic side-chain functionality of both the amino acids provides the basis for the ionic interaction and subsequent molecular recognition by specific receptor sites that results in the regulation of physiological or pathophysiological processes in the organism. In the development of new biologically active compounds that possess the ability to modulate these processes, compounds offering the same type of interactions are being designed. Thus, using a peptidomimetic design approach, glutamate and aspartate mimetics are incorporated into the structure of final biologically active compounds. This review covers different bioisosteric replacements of carboxylic acid alone, as well as mimetics of the whole amino acid structure. Amino acid analogs presented include those with different distances between anionic moieties, and analogs with additional functional groups that result in conformational restriction or alternative interaction sites. The article also provides an overview of different cyclic structures, including various cycloalkane, bicyclic and heterocyclic analogs, that lead to conformational restriction. Higher di- and tripeptide mimetics in which carboxylic acid functionality is incorporated into larger molecules are also reviewed. In addition to the mimetic structures presented, emphasis in this article is placed on their steric and electronic properties. These mimetics constitute a useful pool of fragments in the design of new biologically active compounds, particularly in the field of RGD mimetics and excitatory amino acid agonists and antagonists.

Structural and functional characterization of human apolipoprotein E 72-166 peptides in both aqueous and lipid environments

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Chou Chi-Yuan

2011-01-01

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.

Increase of arginase activity in old apolipoprotein-E deficient mice under Western diet associated with changes in neurovascular unit

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Badaut Jérôme

2012-06-01

Full Text Available Abstract Aging and atherosclerosis are well-recognized risk factors for cardiac and neurovascular diseases. The Apolipoprotein E deficient (ApoE−/− mouse on a high-fat diet is a classical model of atherosclerosis, characterized by the presence of atherosclerotic plaques in extracranial vessels but not in cerebral arteries. Increase in arginase activity was shown to participate in vascular dysfunction in the peripheral arteries of atherosclerotic mice by changing the level of nitric oxide (NO. NO plays a key role in the physiological functions of the neurovascular unit (NVU. However, the regulation of arginase expression and activity in the brain was never investigated in association with changes in the NVU, ApoE deficiency and high fat diet. Fourteen-month-old ApoE−/− mice on high-fat diet exhibited deposition of lipids in the NVU, impairment of blood–brain barrier properties, astrogliosis and an increase of aquaporin 4 staining. In association with these changes, brain arginase activity was significantly increased in the old ApoE−/− mice as compared to old wild type mice, with an increase in the level of arginase type I in the blood vessels. In conclusion, aging in this classical mouse model of atherosclerosis induces an increase in the level and activity of arginase I that may impair NO synthesis and contribute to changes in the NVU leading to blood–brain barrier leakage and inflammation.

Polymorphisms in apolipoprotein B and risk of ischemic stroke

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

2007-01-01

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....

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

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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.

Apolipoprotein E genotypes associated with Alzheimer disease and concomitant stroke.

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Fekih-Mrissa, Najiba; Klai, Sarra; Mrad, Meriem; Mansour, Malek; Zaouali, Jamel; Gritli, Nasreddine; Mrissa, Ridha

2014-04-01

The ɛ4 allele of the apolipoprotein E (APOE) gene is a well-characterized genetic risk factor for Alzheimer disease (AD). The association between stroke and a higher risk for AD has also been reported. Our study sought to determine the relationship between the APOE gene and AD and the comorbid risk of stroke. The subjects of this study consisted of 48 patients with AD and 48 members of a control group. All subjects were genotyped for APOE. The results clearly show a significant increased risk of AD in carriers of the APOE ε3/ε4 genotype (P = .003, odds ratio [OR] = 4.1) or ε4 allele (P = .001, OR = 4.2). The risk for stroke in AD patients was also increased for carriers of the APOE ε3/ε4 genotype (P = .02, OR = 9.0) and for carriers of the APOE ε4 allele (P = .004, OR = 5.5). The present study is the first to establish a relationship between APOE ε4 and concomitant AD and stroke in the Tunisian population. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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

2009-01-01

OBJECTIVES: High-salt diet likely elevates blood pressure (BP), thus increasing the risk of cardiovascular events. We hypothesized that a high-salt diet plays a critical role in subjects whose renin-angiotensin systems cannot adjust to variable salt intake, rendering them more susceptible...... 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...... used urinary isoprostane as a marker for oxidative stress. RESULTS: Although high-salt diet per se did not affect plaque extension, high salt combined with Ang II increased plaque area significantly in both the aorta and the innominate artery as compared with Ang II or salt alone (P

Enhanced synthesis and secretion of apolipoprotein E from sciatic nerves of streptozotocin-induced diabetic rats after injury

International Nuclear Information System (INIS)

Ishibashi, S.; Yamada, N.; Oka, Y.

1988-01-01

To elucidate the pathogenesis of diabetic neuropathy, synthesis and secretion of apolipoprotein E (apo E) from sciatic nerves after injury was studied in normal and streptozotocin-induced diabetic rats. Seven, 14, 28, 45 and 59 days after making crush injury on sciatic nerves with concomitant administration of streptozotocin (50 mg/kg body weight), the nerves were taken out and incubated with [ 35 S]methionine. The [ 35 S]labeled apo E was precipitated with specific antiserum. The amounts of apo E secreted into medium by nerves of diabetic rats were 7 times greater than those of non-diabetic rats 7 days after injury. This enhanced secretion of apo E was relatively selective for this protein, since the ratio of the immunoprecipitable apo E to the TCA preciptitable protein in the medium increased in diabetic rats. Intriguing possibility deduced from these results is that the secretion of apo E is involved in the development of diabetic neuropathy

Apolipoprotein E Gene Polymorphism and Its Association with Cardiovascular Heart Disease Risk Factors in Type 2 Diabetes Mellitus

OpenAIRE

Amani Ashari; Julia Omar; Arif Hashim; Shahrul Hamid

2016-01-01

Apolipoprotein E (APOE) gene polymorphism has influence on serum lipids which relates to cardiovascular risk. The purpose of this study was to determine the frequency distribution of APOE alleles among Malaysian Type 2 Diabetes Mellitus (DM) patients with and without coronary artery disease (CAD) and their association with serum lipid profiles. A total of 115 patients were recruited in which 78 patients had Type 2 DM without CAD and 37 patients had Type 2 DM with CAD. The APOE polymorphism wa...

In search of new structural states of exchangeable apolipoproteins

International Nuclear Information System (INIS)

Xicohtencatl-Cortes, J.; Castillo, R.; Mas-Oliva, J.

2004-01-01

Based upon state of the art biophysical experimentation, this article focuses on the different structural arrangements exchangeable apolipoproteins achieve when placed on Langmuir monolayers and subjected to changes in lateral pressure. We have studied the monolayers of apolipoproteins CI, CIII, AI, AII, and E that show as secondary structure a high percentage of amphipathic α-helix. This has been achieved employing techniques such as Brewster angle microscopy, synchrotron X-ray diffraction, and surface pressure measurements. In addition, the lateral order of protein arrays has been also studied by atomic force microscopy. These monolayers show that a phase transition from a two-dimensional disorder fluid to an ordered state is detected at relatively high lateral pressure, where unusual one-dimensional solid phases are discovered. While several helices that conform the apolipoprotein are confined to the interface, others are uniformly tilted toward the hydrophobic air or the phospholipid fatty acid chains. Our results suggest that a similar ordering might also occur when these apolipoproteins are attached to a lipoprotein particle such as a high density lipoprotein (HDL) particle. Therefore, changes from a nascent or discoidal HDL to a mature spherical HDL might in parallel involve structural changes as those described in our Langmuir interfaces. Current experimentation is being carried out in order to elucidate if the structural states already found are related to the efficiency of lipid transfer between lipoprotein particles or lipoproteins and the plasma membrane of cells, as well as receptor ligand recognition

Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease.

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Harrington, C R; Louwagie, J; Rossau, R; Vanmechelen, E; Perry, R H; Perry, E K; Xuereb, J H; Roth, M; Wischik, C M

1994-12-01

Alzheimer's disease (AD) is associated with an increased frequency of the apolipoprotein E type epsilon 4 allele. To address both the disease and the allele specificity of this association, we have examined the apolipoprotein E allele distribution in 255 elderly persons including those with autopsy-confirmed AD, senile dementia of the Lewy body type (SDLT), vascular dementia, Parkinson's disease (PD) or Huntington's disease and in nondemented controls either with or without coronary complications. The epsilon 4 allele frequency was increased in SDLT (0.365) and AD (0.328) as compared with controls (0.147), PD (0.098), or Huntington's chorea (0.171). Coronary disease and vascular dementia were associated with marginally higher epsilon 4 allele frequencies than in controls. In PD, amyloid beta-protein accumulated to a greater extent in those cases possessing an epsilon 4 allele than in those without. Those PD cases with dementia were not distinguished from either controls or PD cases without dementia, whether tested biochemically or by apolipoprotein E genotype. It is the comparison of the results in AD and SDLT that yielded the most significant findings. There was a 1.8-fold excess of amyloid beta-protein in AD as compared with controls, and the levels in SDLT were intermediate between those in AD and controls. In contrast, AD was discriminated from both controls and SDLT by the substantial accumulation of paired helical filament tau and phosphorylated tau (both increased more than 20-fold as compared with controls). SDLT was nevertheless characterized by an increased epsilon 4 allele frequency in the absence of significant tau pathology (at least 10-fold less than that in AD). These findings indicate that tau processing is more specifically associated with AD than is amyloid beta-protein accumulation and that presence of the epsilon 4 allele is not an etiological factor that accounts for tau pathology.

Apolipoprotein E Genotype and Sex Influence Glucose Tolerance in Older Adults: A Cross-Sectional Study

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Angela J. Hanson

2016-03-01

Full Text Available Background: Glucose intolerance and apolipoprotein ε4 allele (E4+ are risk factors for Alzheimer's disease (AD. Insulin sensitizers show promise for treating AD, but are less effective in E4+ individuals. Little is known about how the APOE genotype influences glucose metabolism. Methods: Cross-sectional analysis of 319 older adults who underwent oral glucose tolerance tests; a subset had insulin, amyloid beta (Aβ42, and Mini Mental Status Examination. Glucose and insulin patterns with respect to cognitive diagnosis, E4 status, and sex were examined with analysis of covariance and Pearson correlation. Results: People with cognitive impairment had higher fasting insulin levels. E4 status did not affect fasting glucose values, whereas men had higher fasting glucose levels than women. E4+ men had the lowest and E4+ women had the highest glucose levels, compared to E4- groups; insulin did not differ by sex or E4 group. E4 status and sex moderated correlations between metabolic measures and AD risk factors including age and Aβ. Conclusions: Insulin resistance was associated with cognitive impairment, and sex, E4 status, and glucose values are interrelated in older adults at risk of AD. Understanding glucose metabolism for different APOE and sex groups may help elucidate differences in therapeutic responses.

A novel peptide thrombopoietin mimetic designing and optimization using computational approach

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Vimal kishor Singh

2016-08-01

Full Text Available Thrombopoietin receptor (TPOR is a cytokine receptor protein; activation of cell surface TPOR by thrombopoietin (TPO triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets. TPO is a glycoprotein hormone which stimulates megakaryocytes formation and maturation to platelets in bone marrow. Ex vivo megakaryocytopoiesis is in highlight for its vast role in therapeutics and field of regenerative medicine. For therapeutic uses, various TPO alternatives have been used however they are associated with issues like recombinant TPO administration is associated with the generation of auto antibodies and its production is an expensive process. Moreover, reported thrombopoietin mimetic peptide (TMP has no sequence homology with TPO and low specificity to TPOR. Hence, in this study, a novel peptidic TPO mimetic is designed through computational studies by studying the binding sites of TPO and TMP to TPOR and analogs of known mimetics. Screening of combinatorial library was done through molecular docking using ClusPro and mimetic-9 was found to have better binding score of -938.8 kcal/mol with seven hydrogen bonds and a high number of hydrophobic interactions, than known mimetic TMP with docking score of -798.4 kcal/mol and TMP dimer with docking score of -811.9 kcal/mol for TPOR. Mimetic-9 interaction with TPOR was further assessed by the molecular dynamics simulation and their complex was found to be stable with an RMSD value of 0.091 Aº. Resulting mimetic-9 was found to have overall good physiochemical properties with positive grand average hydropathy (GRAVY score and high instability index score and it was found to be localized in the extracellular region. The designed mimetic-9 might prove to be a useful lead molecule for mimicking the role of TPO and to help for platelet production in vitro with higher efficiency.

Apolipoprotein E Genotype and educational attainment predict the rate of cognitive decline in normal aging? A 12-year follow-up of the Maastricht Aging Study

NARCIS (Netherlands)

van Gerven, P.W.; van Boxtel, M.P.J.; Bekers, O.; Ausems, E.E.B.; Jolles, J.

2012-01-01

Objective: We investigated suspected longitudinal interaction effects of apolipoprotein E (APOE) genotype and educational attainment on cognitive decline in normal aging. Method: Our sample consisted of 571 healthy, nondemented adults aged between 49 and 82 years. Linear mixed-models analyses were

Reduced apolipoprotein glycosylation in patients with the metabolic syndrome.

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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.

Apolipoprotein A-IV inhibits AgRP/NPY neurons and activates POMC neurons in the arcuate nucleus

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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...

Cooperation for Better Inhibiting.

Science.gov (United States)

Novoa, Eva Maria; Ribas de Pouplana, Lluís

2015-06-18

Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

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Montine Thomas J

2006-04-01

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.

On (in)stabilities of perturbations in mimetic models with higher derivatives

Energy Technology Data Exchange (ETDEWEB)

Zheng, Yunlong; Shen, Liuyuan [Department of Physics, Nanjing University, Nanjing 210093 (China); Mou, Yicen; Li, Mingzhe, E-mail: zylakx@163.com, E-mail: sly12271103@163.com, E-mail: moinch@mail.ustc.edu.cn, E-mail: limz@ustc.edu.cn [Interdisciplinary Center for Theoretical Study, University of Science and Technology of China, Hefei, Anhui 230026 (China)

2017-08-01

Usually when applying the mimetic model to the early universe, higher derivative terms are needed to promote the mimetic field to be dynamical. However such models suffer from the ghost and/or the gradient instabilities and simple extensions cannot cure this pathology. We point out in this paper that it is possible to overcome this difficulty by considering the direct couplings of the higher derivatives of the mimetic field to the curvature of the spacetime.

Bio-Mimetic Sensors Based on Molecularly Imprinted Membranes

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Catia Algieri

2014-07-01

Full Text Available An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. By means of this technology, selective molecular recognition sites are introduced in a polymer, thus conferring it bio-mimetic properties. The potential applications of these systems include affinity separations, medical diagnostics, drug delivery, catalysis, etc. Recently, bio-sensing systems using molecularly imprinted membranes, a special form of imprinted polymers, have received the attention of scientists in various fields. In these systems imprinted membranes are used as bio-mimetic recognition elements which are integrated with a transducer component. The direct and rapid determination of an interaction between the recognition element and the target analyte (template was an encouraging factor for the development of such systems as alternatives to traditional bio-assay methods. Due to their high stability, sensitivity and specificity, bio-mimetic sensors-based membranes are used for environmental, food, and clinical uses. This review deals with the development of molecularly imprinted polymers and their different preparation methods. Referring to the last decades, the application of these membranes as bio-mimetic sensor devices will be also reported.

Bio-Mimetic Sensors Based on Molecularly Imprinted Membranes

Science.gov (United States)

Algieri, Catia; Drioli, Enrico; Guzzo, Laura; Donato, Laura

2014-01-01

An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. By means of this technology, selective molecular recognition sites are introduced in a polymer, thus conferring it bio-mimetic properties. The potential applications of these systems include affinity separations, medical diagnostics, drug delivery, catalysis, etc. Recently, bio-sensing systems using molecularly imprinted membranes, a special form of imprinted polymers, have received the attention of scientists in various fields. In these systems imprinted membranes are used as bio-mimetic recognition elements which are integrated with a transducer component. The direct and rapid determination of an interaction between the recognition element and the target analyte (template) was an encouraging factor for the development of such systems as alternatives to traditional bio-assay methods. Due to their high stability, sensitivity and specificity, bio-mimetic sensors-based membranes are used for environmental, food, and clinical uses. This review deals with the development of molecularly imprinted polymers and their different preparation methods. Referring to the last decades, the application of these membranes as bio-mimetic sensor devices will be also reported. PMID:25196110

Population genetics of apolipoprotein A-4, E, and H polymorphisms in Yanomami Indians of northwestern Brazil: associations with lipids, lipoproteins, and carbohydrate metabolism.

Science.gov (United States)

Crews, D E; Kamboh, M I; Mancilha-Carvalho, J J; Kottke, B

1993-04-01

Using isoelectric focusing and immunoblotting techniques, we screened 96 serum samples from Yanomami Indians of northwestern Brazil to determine structural variation at three apolipoprotein loci: A4, E, and H. The APO-H locus, which is commonly polymorphic in white and black samples, was found to be monomorphic. At the APO-E locus only two alleles, APOE*3 and APOE*4, rather than the three-allele polymorphism commonly seen in Caucasians, was observed. At the APO-A4 locus no example of the APOA4*2 allele, found in Caucasians, was detected. However, the frequency of the less common APOA4*4 allele was above what has been observed in any other population. We investigated the impact of genetic variation at both polymorphic loci on quantitative differences in lipids, apolipoproteins, serum glucose, glycated hemoglobin, and uric acid. Contrary to the cholesterol-elevating effect of APOE*4 reported elsewhere, in both univariate analyses and after adjustments for age, sex, weight, and height, APOE*4 was associated with about a 4% lower mean serum cholesterol. Only after adjustment was this association statistically significant. The APOE*4 allele was significantly associated with unadjusted APO-A1 and APO-E levels but not with any other dependent variable; associations with adjusted APO-A1, APO-C2, and uric acid also approached standard levels of statistical significance (p < or = 0.05). In univariate analyses the APOA4*4 allele was significantly associated with APO-B, serum glucose, percent glycated hemoglobin, and uric acid, but no significant associations were observed after dependent variables were adjusted for age, sex, weight, and height. These results support the notion that apolipoprotein distributions and their associations with lipid and carbohydrate metabolism show ethnic variability.

The apolipoprotein m-sphingosine-1-phosphate axis

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

2013-01-01

Apolipoprotein M (apoM) is a plasma apolipoprotein that mainly associates with high-density lipoproteins. Hence, most studies on apoM so far have investigated its effect on and association with lipid metabolism and atherosclerosis. The insight into apoM biology recently took a major turn. Apo...

Affinity of serum apolipoproteins for lipid monolayers

International Nuclear Information System (INIS)

Ibdah, J.A.

1987-01-01

The effects of lipid composition and packing as well as the structure of the protein on the affinities of apolipoproteins for lipid monolayers have been investigated. The adsorption of 14 C-reductively methylated human apolipoproteins A-I and A-II at saturating subphase concentrations to monolayers prepared with synthetic lipids or lipoprotein surface lipids spread at various initial surface pressures has been studied. The adsorption of apolipoproteins is monitored by following the surface radioactivity using a gas flow counter and Wilhelmy plate, respectively. The physical states of the lipid monolayers are evaluated by measurement of the surface pressure-molecular area isotherms using a Langmuir-Adam surface balance. The probable helical regions in various apolipoproteins have been predicted using a secondary structure analysis computer program. The mean residue hydrophobicity and mean residue hydrophobic moment for the predicted helical segments have been calculated. The surface properties of synthetic peptides which are amphipathic helix analogs have been investigated at the air-water and lipid-water interfaces

Effects of apolipoprotein E genotype on cortical neuropathology in senile dementia of the Lewy body and Alzheimer's disease.

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Benjamin, R; Leake, A; Ince, P G; Perry, R H; McKeith, I G; Edwardson, J A; Morris, C M

1995-12-01

Apolipoprotein E (APO E) genotypes were determined in a UK population of neuropathologically confirmed control cases, and in cases of Lewy body dementia (SDLT) and late onset Alzheimer's disease (AD). APO E epsilon 4 allele frequency was significantly elevated in both SDLT and AD groups with a concomitant reduction in the APO E epsilon 3 allele frequency. The epsilon 2 allele frequency in the AD group was only 25% of the control population, though because of the relatively small sample size this reduction was not significant; the epsilon 2 allele frequency in the SDLT group was normal. No significant association was found between senile plaque density and neurofibrillary tangle density in the neocortex and APO E allele dose in either SDLT or AD. Although the possession of APO E epsilon 4 is associated with an increased risk of developing SDLT and AD, actual APO E genotype does not appear to affect the burden of pathology.

Smac Mimetic Bypasses Apoptosis Resistance in FADD- or Caspase-8-Deficient Cells by Priming for Tumor Necrosis Factor α-Induced Necroptosis

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Bram Laukens

2011-10-01

Full Text Available Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.

Quantitation of apolipoprotein epsilon gene expression by competitive polymerase chain reaction in a patient with familial apolipoprotein E deficiency.

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Dobmeyer, J M; Rexin, M; Dobmeyer, T S; Klein, S A; Rossol, R; Feussner, G

1998-06-22

A simple method of obtaining semiquantitative and reliable data on apolipoprotein (apo) sigma gene expression is described. We detected apo sigma specific sequences by reverse transcription (rT)-PCR. For quantitative measurement, an apo sigma DNA standard was produced allowing the development of a competitive PCR-method. The efficiency of RNA extraction and cDNA synthesis was controlled by quantitation of a housekeeping gene (glyceraldehyde-3-phosphatedehydrogenase, G3PDH) in separate reactions. To imitate a defined induction of apo sigma gene expression, serial twofold dilutions of total RNA were reversely transcribed and the respective cDNAs used to perform a competitive apo sigma and G3PDH PCR. The change in apo sigma cDNA and G3PDH cDNA was 1.7-2.3-fold with an expected value of 2.0-fold. Standard deviations in three independently performed experiments were within a range of < 15% of the mean, indicating low intra-assay variation and high reproducibility. To illustrate this method, apo sigma gene expression was measured in a patient with complete lack of functional active apo E in comparison to healthy controls. The method presented here might be valuable in assessment of apo sigma gene expression in human disease.

Increased sensitivity of apolipoprotein E knockout mice to copper-induced oxidative injury to the liver.

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

2015-04-10

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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

DEFF Research Database (Denmark)

Bentzen, J.; Poulsen, P.; Vaag, A.

2003-01-01

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

Apolipoprotein E Allelic Frequency Altered in Women with Early-onset Breast Cancer

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Tirtsa Porrata-Doria

2010-01-01

Full Text Available Among women, the most prevalent type of cancer is breast cancer, affecting 1 out of every 8 women in the United States; in Puerto Rico, 70 out of every 100,000 will develop some type of breast cancer. Therefore, a better understanding of the potential risk factors for breast cancer could lead to the development of early detection tools. A gene that has been proposed as a risk factor in several populations around the world is Apolipoprotein E (apoE. ApoE functions as a mechanism of transport for lipoproteins and cholesterol throughout the body, with 3 main isoforms present in humans (apoE2, apoE3, and apoE4. Whether or not apoE4 is a risk factor for breast cancer remains controversial. Previous studies have either included test subjects of all ages (20–80 or have focused on late-onset (after age 50 breast cancer; none has concentrated specifically on early-onset (aged 50 and younger breast cancer. The objectives of this study was to examine (in a Puerto Rican population the differences in the relative frequency of occurrence of apoE4 in non-breast cancer versus breast cancer patients and to examine, as well, the potential differences of same in early- versus late-onset patients. We found an increased frequency of apoE4 (odds ratio 2.15 only in early-onset breast cancer survivors, which is similar to the findings of those studies that combined or adjusted for age as well as for an association between apoE4 and decreased tumor size. ApoE is also a potential risk factor for long-term cognitive effects after chemotherapy and affects response to hormone replacement. Our data supports the theory that knowing the apoE genotype of women who are at risk of developing breast cancer may be beneficial, as such knowledge would aid in the prediction of tumor size and the development of treatment regimens.

Temperature-sensitive elastin-mimetic dendrimers: Effect of peptide length and dendrimer generation to temperature sensitivity.

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Kojima, Chie; Irie, Kotaro; Tada, Tomoko; Tanaka, Naoki

2014-06-01

Dendrimers are synthetic macromolecules with unique structure, which are a potential scaffold for peptides. Elastin is one of the main components of extracellular matrix and a temperature-sensitive biomacromolecule. Previously, Val-Pro-Gly-Val-Gly peptides have been conjugated to a dendrimer for designing an elastin-mimetic dendrimer. In this study, various elastin-mimetic dendrimers using different length peptides and different dendrimer generations were synthesized to control the temperature dependency. The elastin-mimetic dendrimers formed β-turn structure by heating, which was similar to the elastin-like peptides. The elastin-mimetic dendrimers exhibited an inverse phase transition, largely depending on the peptide length and slightly depending on the dendrimer generation. The elastin-mimetic dendrimers formed aggregates after the phase transition. The endothermal peak was observed in elastin-mimetic dendrimers with long peptides, but not with short ones. The peptide length and the dendrimer generation are important factors to tune the temperature dependency on the elastin-mimetic dendrimer. Copyright © 2013 Wiley Periodicals, Inc.

Glycosaminoglycan-Mimetic Signals Direct the Osteo/Chondrogenic Differentiation of Mesenchymal Stem Cells in a Three-Dimensional Peptide Nanofiber Extracellular Matrix Mimetic Environment.

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Arslan, Elif; Guler, Mustafa O; Tekinay, Ayse B

2016-04-11

Recent efforts in bioactive scaffold development focus strongly on the elucidation of complex cellular responses through the use of synthetic systems. Designing synthetic extracellular matrix (ECM) materials must be based on understanding of cellular behaviors upon interaction with natural and artificial scaffolds. Hence, due to their ability to mimic both the biochemical and mechanical properties of the native tissue environment, supramolecular assemblies of bioactive peptide nanostructures are especially promising for development of bioactive ECM-mimetic scaffolds. In this study, we used glycosaminoglycan (GAG) mimetic peptide nanofiber gel as a three-dimensional (3D) platform to investigate how cell lineage commitment is altered by external factors. We observed that amount of fetal bovine serum (FBS) presented in the cell media had synergistic effects on the ability of GAG-mimetic nanofiber gel to mediate the differentiation of mesenchymal stem cells into osteogenic and chondrogenic lineages. In particular, lower FBS concentration in the culture medium was observed to enhance osteogenic differentiation while higher amount FBS promotes chondrogenic differentiation in tandem with the effects of the GAG-mimetic 3D peptide nanofiber network, even in the absence of externally administered growth factors. We therefore demonstrate that mesenchymal stem cell differentiation can be specifically controlled by the combined influence of growth medium components and a 3D peptide nanofiber environment.

Mimetic Gravity: A Review of Recent Developments and Applications to Cosmology and Astrophysics

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Lorenzo Sebastiani

2017-01-01

Full Text Available Mimetic gravity is a Weyl-symmetric extension of General Relativity, related to the latter by a singular disformal transformation, wherein the appearance of a dust-like perfect fluid can mimic cold dark matter at a cosmological level. Within this framework, it is possible to provide a unified geometrical explanation for dark matter, the late-time acceleration, and inflation, making it a very attractive theory. In this review, we summarize the main aspects of mimetic gravity, as well as extensions of the minimal formulation of the model. We devote particular focus to the reconstruction technique, which allows the realization of any desired expansionary history of the universe by an accurate choice of potential or other functions defined within the theory (as in the case of mimetic f(R gravity. We briefly discuss cosmological perturbation theory within mimetic gravity. As a case study within which we apply the concepts previously discussed, we study a mimetic Hořava-like theory, of which we explore solutions and cosmological perturbations in detail. Finally, we conclude the review by discussing static spherically symmetric solutions within mimetic gravity and apply our findings to the problem of galactic rotation curves. Our review provides an introduction to mimetic gravity, as well as a concise but self-contained summary of recent findings, progress, open questions, and outlooks on future research directions.

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

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Elsøe, Sara; Ahnström, Josefin; Christoffersen, Christina

2012-01-01

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 lip...... 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....

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

Science.gov (United States)

Caterer, Nigel R; Graversen, Jonas H; Jacobsen, Christian; Moestrup, Søren K; Sigurskjold, Bent W; Etzerodt, Michael; Thøgersen, Hans C

2002-11-01

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 of lipoprotein B100 and the plasminogen kringle 4 binding plasma protein tetranectin. In this study recombinant KIV(2), KIV(7) and KIV(10) derived from apolipoprotein(a) were produced in E. coli and the binding to tetranectin and low density lipoprotein was examined. Only KIV(10) bound to tetranectin and binding 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).

Major lipids, apolipoproteins, and risk of vascular disease

DEFF Research Database (Denmark)

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

2009-01-01

CONTEXT: Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. OBJECTIVE: To assess major lipids and apolipoproteins in vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Individual records were supplied on 302,430 people without...

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

Science.gov (United States)

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and

Swapping the N- and C-terminal domains of human apolipoprotein E3 and AI reveals insights into their structure/activity relationship.

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Mark T Lek

Full Text Available Apolipoprotein (apo E3 and apoAI are exchangeable apolipoproteins that play a dominant role in regulating plasma lipoprotein metabolism. ApoE3 (299 residues is composed of an N-terminal (NT domain bearing a 4-helix bundle and a C-terminal (CT domain bearing a series of amphipathic α-helices. ApoAI (243 residues also comprises a highly helical NT domain and a less structured CT tail. The objective of this study was to understand their structural and functional role by generating domain swapped chimeras: apoE3-NT/apoAI-CT and apoAI-NT/apoE-CT. The bacterially overexpressed chimeras were purified by affinity chromatography and their identity confirmed by immunoblotting and mass spectrometry. Their α-helical content was comparable to that of the parent proteins. ApoE3-NT/apoAI-CT retained the denaturation profile of apoE3 NT domain, with apoAI CT tail eliciting a relatively unstructured state; its lipid binding ability improved dramatically compared to apoE3 indicative of a significant role of apoAI CT tail in lipid binding interaction. The LDL receptor interaction and ability to promote ABCA1-mediated cholesterol efflux of apoE3-NT/apoAI-CT was comparable to that of apoE3. In contrast, apoAI-NT/apoE-CT elicited an unfolding pattern and lipid binding ability that were similar to that of apoAI. As expected, DMPC/apoAI-NT/apoE-CT discoidal particles did not elicit LDLr binding ability, and promoted SR-B1 mediated cellular uptake of lipids to a limited extent. However, apoAI-NT/apoE-CT displayed an enhanced ability to promote cholesterol efflux compared to apoAI, indicative of a significant role for apoE CT domain in mediating this function. Together, these results indicate that the functional attributes of apoAI and apoE3 can be conferred on each other and that NT-CT domain interactions significantly modulate their structure and function.

Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis.

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Yu, Xiaowen; Yang, Yu-Ping; Dikici, Emre; Deo, Sapna K; Daunert, Sylvia

2017-06-12

The emergence of novel binding proteins or antibody mimetics capable of binding to ligand analytes in a manner analogous to that of the antigen-antibody interaction has spurred increased interest in the biotechnology and bioanalytical communities. The goal is to produce antibody mimetics designed to outperform antibodies with regard to binding affinities, cellular and tumor penetration, large-scale production, and temperature and pH stability. The generation of antibody mimetics with tailored characteristics involves the identification of a naturally occurring protein scaffold as a template that binds to a desired ligand. This scaffold is then engineered to create a superior binder by first creating a library that is then subjected to a series of selection steps. Antibody mimetics have been successfully used in the development of binding assays for the detection of analytes in biological samples, as well as in separation methods, cancer therapy, targeted drug delivery, and in vivo imaging. This review describes recent advances in the field of antibody mimetics and their applications in bioanalytical chemistry, specifically in diagnostics and other analytical methods.

Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of 56Fe Irradiation on the Brain

International Nuclear Information System (INIS)

Haley, Gwendolen E.; Villasana, Laura; Dayger, Catherine; Davis, Matthew J.; Raber, Jacob

2012-01-01

Purpose: In humans, apolipoprotein E (apoE) is encoded by three major alleles (ε2, ε3, and ε4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of 56 Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk. Methods and Materials: We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after 56 Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis. Results: In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice. Conclusions: The short-term effects of 56 Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.

Plasma lipid oxidation predicts atherosclerotic status better than cholesterol in diabetic apolipoprotein E deficient mice

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Petersen, Karen Ekkelund; Lykkesfeldt, Jens; Raun, Kirsten

2017-01-01

Increased levels of oxidative stress have been suggested to play a detrimental role in the development of diabetes-related vascular complications. Here, we investigated whether the concentration of malondialdehyde, a marker of lipid oxidation correlated to the degree of aortic plaque lesions...... in a proatherogenic diabetic mouse model. Three groups of apolipoprotein E knockout mice were studied for 20 weeks, a control, a streptozotocin-induced diabetic, and a diabetic enalapril-treated group. Enalapril was hypothesized to lower oxidative stress level and thus the plaque burden. Both diabetic groups were...... significantly different from the control group as they had higher blood glucose, HbA1c, total cholesterol, low-density lipoprotein, very low-density lipoprotein, together with a lower high-density lipoprotein concentration and body weight. Animals in the diabetic group had significantly higher plaque area...

Association of apolipoprotein e gene polymorphisms with blood lipids and their interaction with dietary factors

DEFF Research Database (Denmark)

Shatwan, Israa M.; Winther, Kristian Hillert; Ellahi, Basma

2018-01-01

of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. Methods: The population studied for this investigation included 660 individuals from...... the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ......Background: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association...

Copper Complexes of Nicotinic-Aromatic Carboxylic Acids as Superoxide Dismutase Mimetics

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Virapong Prachayasittikul

2008-12-01

Full Text Available Nicotinic acid (also known as vitamin B3 is a dietary element essential for physiological and antihyperlipidemic functions. This study reports the synthesis of novel mixed ligand complexes of copper with nicotinic and other select carboxylic acids (phthalic, salicylic and anthranilic acids. The tested copper complexes exhibited superoxide dismutase (SOD mimetic activity and antimicrobial activity against Bacillus subtilis ATCC 6633, with a minimum inhibition concentration of 256 μg/mL. Copper complex of nicotinic-phthalic acids (CuNA/Ph was the most potent with a SOD mimetic activity of IC50 34.42 μM. The SOD activities were observed to correlate well with the theoretical parameters as calculated using density functional theory (DFT at the B3LYP/LANL2DZ level of theory. Interestingly, the SOD activity of the copper complex CuNA/Ph was positively correlated with the electron affinity (EA value. The two quantum chemical parameters, highest occupied molecular orbital (HOMO and lowest unoccupied molecular orbital (LUMO, were shown to be appropriate for understanding the mechanism of the metal complexes as their calculated energies show good correlation with the SOD activity. Moreover, copper complex with the highest SOD activity were shown to possess the lowest HOMO energy. These findings demonstrate a great potential for the development of value-added metallovitamin-based therapeutics.

Apolipoprotein E Genotype in Very Preterm Neonates with Intrauterine Growth Restriction: An Analysis of the German Neonatal Network Cohort.

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Norda, Stephen; Rausch, Tanja K; Orlikowsky, Thorsten; Hütten, Matthias; Schulz, Sören; Göpel, Wolfgang; Pecks, Ulrich

2017-01-01

Aim. Cord blood of intrauterine growth restricted (IUGR) neonates displays lipid changes towards atherosclerotic profiles. Apolipoprotein E (ApoE) and its isoforms (e2, e3, and e4) are involved in the regulation of lipid metabolism. Specifically, ApoE e4 has been associated with atherosclerotic diseases, while e2 has a favorable effect. We therefore hypothesized that ApoE e4 haplotype is frequently observed in IUGR neonates and contributes to impaired fetal growth and the association of IUGR with cardiovascular and metabolic diseases later in life. Methods. A cohort of 4885 preterm infants (≥22+0 and 10th birth weight percentile. Analysis of the single nucleotides rs429358 and rs7412, identifying the ApoE genotype, was carried out using TaqMan® SNP genotyping assays. The proportional odds model was used to assess data. Results. No association was found between genotype and birth weight percentiles in each of the subgroups. Conclusion. ApoE genotype and low birth weight depict two distinct risk factors for cardiovascular disease without being directly associated.

Apolipoprotein E Genotype in Very Preterm Neonates with Intrauterine Growth Restriction: An Analysis of the German Neonatal Network Cohort

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Stephen Norda

2017-01-01

Full Text Available Aim. Cord blood of intrauterine growth restricted (IUGR neonates displays lipid changes towards atherosclerotic profiles. Apolipoprotein E (ApoE and its isoforms (e2, e3, and e4 are involved in the regulation of lipid metabolism. Specifically, ApoE e4 has been associated with atherosclerotic diseases, while e2 has a favorable effect. We therefore hypothesized that ApoE e4 haplotype is frequently observed in IUGR neonates and contributes to impaired fetal growth and the association of IUGR with cardiovascular and metabolic diseases later in life. Methods. A cohort of 4885 preterm infants (≥22+0 and 10th birth weight percentile. Analysis of the single nucleotides rs429358 and rs7412, identifying the ApoE genotype, was carried out using TaqMan® SNP genotyping assays. The proportional odds model was used to assess data. Results. No association was found between genotype and birth weight percentiles in each of the subgroups. Conclusion. ApoE genotype and low birth weight depict two distinct risk factors for cardiovascular disease without being directly associated.

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside.

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Vela, Laura; Marzo, Isabel

2015-08-01

Bcl-2 proteins are key determinants in the life-death balance. In recent years, proteins in this family have been identified as drug targets in the design of new anti-tumor therapies. Advances in the knowledge of the mechanism of action of anti-apoptotic and pro-apoptotic members of the Bcl-2 family have enabled the development of the so-called 'BH3 mimetics'. These compounds act by inhibiting anti-apoptotic proteins of the family, imitating the function of the BH3-only subset of pro-apoptotic members. Combinations of BH3-mimetics with anti-tumor drugs are being evaluated in both preclinical models and clinical trials. Recent advances in these approaches will be reviewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Elaborate Mimetic Vocal Displays by Female Superb Lyrebirds

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Anastasia H Dalziell

2016-04-01

Full Text Available Some of the most striking vocalizations in birds are made by males that incorporate vocal mimicry in their sexual displays. Mimetic vocalization in females is largely undescribed, but it is unclear whether this is because of a lack of selection for vocal mimicry in females, or whether the phenomenon has simply been overlooked. These issues are thrown into sharp relief in the superb lyrebird, Menura novaehollandiae, a basal oscine passerine with a lek-like mating system and female uniparental care. The spectacular mimetic song display produced by courting male lyrebirds is a textbook example of a sexually selected trait, but the vocalizations of female lyrebirds are largely unknown. Here, we provide the first analysis of the structure and context of the vocalizations of female lyrebirds. Female lyrebirds were completely silent during courtship; however, females regularly produced sophisticated vocal displays incorporating both lyrebird-specific vocalizations and imitations of sounds within their environment. The structure of female vocalizations varied significantly with context. While foraging, females mostly produced a complex lyrebird-specific song, whereas they gave lyrebird-specific alarm calls most often during nest defense. Within their vocal displays females also included a variety of mimetic vocalizations, including imitations of the calls of dangerous predators, and of alarm calls and song of harmless heterospecifics. Females gave more mimetic vocalizations during nest defense than while foraging, and the types of sounds they imitated varied between these contexts, suggesting that mimetic vocalizations have more than one function. These results are inconsistent with previous portrayals of vocalizations by female lyrebirds as rare, functionless by-products of sexual selection on males. Instead, our results support the hypotheses that complex female vocalizations play a role in nest defense and mediate female-female competition for

Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes

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Sauerbeck Laura

2007-07-01

Full Text Available Abstract Background Apolipoprotein E (APOE and elastin (ELN are plausible candidate genes involved in the pathogenesis of stroke. We tested for association of variants in APOE and ELN with subarachnoid hemorrhage (SAH in a population-based study. We genotyped 12 single nucleotide polymorphisms (SNPs on APOE and 10 SNPs on ELN in a sample of 309 Caucasian individuals, of whom 107 are SAH cases and 202 are age-, race-, and gender-matched controls from the Greater Cincinnati/Northern Kentucky region. Associations were tested at genotype, allele, and haplotype levels. A genomic control analysis was performed to check for spurious associations resulting from population substructure. Results At the APOE locus, no individual SNP was associated with SAH after correction for multiple comparisons. Haplotype analysis revealed significant association of the major haplotype (Hap1 in APOE with SAH (p = 0.001. The association stemmed from both the 5' promoter and the 3' region of the APOE gene. APOE ε2 and ε 4 were not significantly associated with SAH. No association was observed for ELN at genotype, allele, or haplotype level and our study failed to confirm previous reports of ELN association with aneurysmal SAH. Conclusion This study suggests a role of the APOE gene in the etiology of aneurysmal SAH.

Longitudinal Trajectories of Cholesterol from Midlife through Late Life according to Apolipoprotein E Allele Status

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Brian Downer

2014-10-01

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.

Reissner–Nordström Anti-de Sitter Black Holes in Mimetic F(R Gravity

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V. K. Oikonomou

2016-05-01

Full Text Available In this paper, we study under which conditions the Reissner–Nordström anti-de Sitter black hole can be a solution of the vacuum mimetic F ( R gravity with Lagrange multiplier and mimetic scalar potential. As the author demonstrates, the resulting picture in the mimetic F ( R gravity case is a trivial extension of the standard F ( R approach, and in effect, the metric perturbations in the mimetic F ( R gravity case, for the Reissner–Nordström anti-de Sitter black hole metric, at the first order of the perturbed variables are the same at the leading order.

Apolipoprotein E4 causes early olfactory network abnormalities and short-term olfactory memory impairments.

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Peng, Katherine Y; Mathews, Paul M; Levy, Efrat; Wilson, Donald A

2017-02-20

While apolipoprotein (Apo) E4 is linked to increased incidence of Alzheimer's disease (AD), there is growing evidence that it plays a role in functional brain irregularities that are independent of AD pathology. However, ApoE4-driven functional differences within olfactory processing regions have yet to be examined. Utilizing knock-in mice humanized to ApoE4 versus the more common ApoE3, we examined a simple olfactory perceptual memory that relies on the transfer of information from the olfactory bulb (OB) to the piriform cortex (PCX), the primary cortical region involved in higher order olfaction. In addition, we have recorded in vivo resting and odor-evoked local field potentials (LPF) from both brain regions and measured corresponding odor response magnitudes in anesthetized young (6-month-old) and middle-aged (12-month-old) ApoE mice. Young ApoE4 compared to ApoE3 mice exhibited a behavioral olfactory deficit coinciding with hyperactive odor-evoked response magnitudes within the OB that were not observed in older ApoE4 mice. Meanwhile, middle-aged ApoE4 compared to ApoE3 mice exhibited heightened response magnitudes in the PCX without a corresponding olfactory deficit, suggesting a shift with aging in ApoE4-driven effects from OB to PCX. Interestingly, the increased ApoE4-specific response in the PCX at middle-age was primarily due to a dampening of baseline spontaneous activity rather than an increase in evoked response power. Our findings indicate that early ApoE4-driven olfactory memory impairments and OB network abnormalities may be a precursor to later network dysfunction in the PCX, a region that not only is targeted early in AD, but may be selectively vulnerable to ApoE4 genotype. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

The association between the apolipoprotein B/A-I ratio and coronary calcification may differ depending on kidney function in a healthy population.

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Seok-Hyung Kim

Full Text Available The apolipoprotein B/A-1 ratio has been reported to be one of the strongest risk predictors of cardiovascular events. However, its prognostic value for cardiovascular disease is still uncertain, especially in patients with chronic kidney disease. This study aimed to investigate whether the association between the apolipoprotein B/A-I ratio and coronary artery calcification differed according to kidney function in a healthy population.Of the data from 7,780 participants from the medical records database in Gangnam Severance Hospital from 2005 through 2016, a cross-sectional analysis included participants with an estimated glomerular filtration rate (eGFR ≥ 60 mL/min/1.73 m2 determined based on the Chronic Kidney Disease -Epidemiology Collaboration equation (n  =  1,800. Mild renal insufficiency was defined as an eGFR of 60-90 mL/min/1.73 m2. Coronary artery calcification measured with computed tomography was defined as an above-zero score. Logistic regression analyses were used to determine the association between coronary calcification and the apolipoprotein B/A-I ratio according to eGFR by adjusting for the influence of confounders.The mean apolipoprotein B/A-I level was significantly higher in the participants with coronary artery calcification than in the participants without coronary artery calcification. The apolipoprotein B/A-I ratio was significantly different according to coronary artery calcification in the participants with normal kidney function, but in the participants with mild renal insufficiency, it was not different. After adjusting for age, male sex, systolic blood pressure, body mass index, current smoking status, and fasting plasma glucose, the apolipoprotein B/A-I ratio was significantly associated with an increased risk of coronary artery calcification in participants with normal kidney function (odds ratio = 2.411, p = 0.011, while in the participants with mild renal insufficiency, the apolipoprotein B/A-I ratio was

Age-Related Association between Apolipoprotein E ε4 and Cognitive Function in Japanese Patients with Alzheimer's Disease

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Tomoyuki Nagata

2013-03-01

Full Text Available Aims: In the present study, we investigated whether apolipoprotein E (APOE polymorphisms influenced the cognitive function of Japanese patients with Alzheimer's disease (AD at certain ages. Methods: Among 200 outpatients with dementia and amnestic mild cognitive impairment, 133 Japanese patients with AD were recruited and divided into two genotypic groups: APOE ε4 carriers and noncarriers. Then, we compared several neuropsychological test scores between the two genotypic groups for two different generations: 70s (70-79 years and 80s (80-89 years. Results: The total Mini-Mental State Examination score (p Conclusion: The present results suggest that APOE may significantly influence comparatively simple memory processing in certain generations of Japanese patients with AD.

Elementary dispersion analysis of some mimetic discretizations on triangular C-grids

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Korn, P., E-mail: peter.korn@mpimet.mpg.de [Max Planck Institute for Meteorology, Hamburg (Germany); Danilov, S. [Alfred Wegener Institute for Polar and Marine Research, Bremerhaven (Germany); A.M. Obukhov Institute of Atmospheric Physics, Moscow (Russian Federation)

2017-02-01

Spurious modes supported by triangular C-grids limit their application for modeling large-scale atmospheric and oceanic flows. Their behavior can be modified within a mimetic approach that generalizes the scalar product underlying the triangular C-grid discretization. The mimetic approach provides a discrete continuity equation which operates on an averaged combination of normal edge velocities instead of normal edge velocities proper. An elementary analysis of the wave dispersion of the new discretization for Poincaré, Rossby and Kelvin waves shows that, although spurious Poincaré modes are preserved, their frequency tends to zero in the limit of small wavenumbers, which removes the divergence noise in this limit. However, the frequencies of spurious and physical modes become close on shorter scales indicating that spurious modes can be excited unless high-frequency short-scale motions are effectively filtered in numerical codes. We argue that filtering by viscous dissipation is more efficient in the mimetic approach than in the standard C-grid discretization. Lumping of mass matrices appearing with the velocity time derivative in the mimetic discretization only slightly reduces the accuracy of the wave dispersion and can be used in practice. Thus, the mimetic approach cures some difficulties of the traditional triangular C-grid discretization but may still need appropriately tuned viscosity to filter small scales and high frequencies in solutions of full primitive equations when these are excited by nonlinear dynamics.

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

NARCIS (Netherlands)

Dijk, K.W. van; Vlijmen, B.J.M. van; Hof, H.B. van 't; Zee, A. van der; Santamarina-Fojo, S.; Berkel, T.J.C. van; Havekes, L.M.; Hofker, M.H.

1999-01-01

To investigate the quantitative requirement for apolipoprotein (apo) E in the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes

Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice

DEFF Research Database (Denmark)

Madsen, Marie; Hansen, Peter Riis; Nielsen, Lars Bo

2016-01-01

BACKGROUND: Risk of cardiovascular disease is increased in patients with psoriasis, but molecular mechanisms linking the two conditions have not been clearly established. Lack of appropriate animal models has hampered generation of new knowledge in this area of research and we therefore sought...... to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation. METHODS: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice. RESULTS: TPA led to localized...

Acrolein Modification Impairs Key Functional Features of Rat Apolipoprotein E: Identification of Modified Sites by Mass Spectrometry

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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

2014-01-01

Apolipoprotein E (apoE), an anti-atherogenic apolipoprotein, plays a significant role in the metabolism of lipoproteins. It lowers plasma lipid levels by acting as a ligand for 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 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 ten-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 lipid-free fraction compared to 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 Nε-(3-methylpyridinium)lysine (MP-lysine) at K64, K67 and K254 (+76), and Nε-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) derivative at position K68 (+94), as determined by Matrix-Assisted Laser

A review of underwater bio-mimetic propulsion: cruise and fast-start

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Chao, Li-Ming; Cao, Yong-Hui; Pan, Guang

2017-08-01

This paper reviews recent developments in the understanding of underwater bio-mimetic propulsion. Two impressive models of underwater propulsion are considered: cruise and fast-start. First, we introduce the progression of bio-mimetic propulsion, especially underwater propulsion, where some primary conceptions are touched upon. Second, the understanding of flapping foils, considered as one of the most efficient cruise styles of aquatic animals, is introduced, where the effect of kinematics and the shape and flexibility of foils on generating thrust are elucidated respectively. Fast-start propulsion is always exhibited when predator behaviour occurs, and we provide an explicit introduction of corresponding zoological experiments and numerical simulations. We also provide some predictions about underwater bio-mimetic propulsion.

A review of underwater bio-mimetic propulsion: cruise and fast-start

Energy Technology Data Exchange (ETDEWEB)

Chao, Li-Ming; Cao, Yong-Hui; Pan, Guang, E-mail: PanGuang_010@163.com [School of Marine Science and Technology, Northwestern Polytechnical University, Xian 710072 (China)

2017-08-15

This paper reviews recent developments in the understanding of underwater bio-mimetic propulsion. Two impressive models of underwater propulsion are considered: cruise and fast-start. First, we introduce the progression of bio-mimetic propulsion, especially underwater propulsion, where some primary conceptions are touched upon. Second, the understanding of flapping foils, considered as one of the most efficient cruise styles of aquatic animals, is introduced, where the effect of kinematics and the shape and flexibility of foils on generating thrust are elucidated respectively. Fast-start propulsion is always exhibited when predator behaviour occurs, and we provide an explicit introduction of corresponding zoological experiments and numerical simulations. We also provide some predictions about underwater bio-mimetic propulsion. (review)

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

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Masoumeh Sadeghi

2011-01-01

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

Reproductive isolation related to mimetic divergence in the poison frog Ranitomeya imitator

DEFF Research Database (Denmark)

Twomey, Evan; Vestergaard, Jacob Schack; Summers, Kyle

2014-01-01

study the Peruvian poison frog Ranitomeya imitator, a species that has undergone a mimetic radiation into four distinct morphs. Using a combination of colour–pattern analysis, landscape genetics and mate-choice experiments, we show that a mimetic shift in R. imitator is associated with a narrow...

Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters.

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Briand, François; Thieblemont, Quentin; Muzotte, Elodie; Sulpice, Thierry

2013-01-01

This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters. In vivo reverse cholesterol transport was measured after an intravenous injection of (3)H-cholesteryl-oleate-labeled/oxidized low density lipoprotein particles ((3)H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further (3)H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E-rich HDL levels and significantly increased (3)H-tracer appearance in HDL by 30% over 72 hours after (3)H-oxLDL injection. However, TOR did not change (3)H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After (3)H-oxLDL injection, TOR+berberine significantly increased (3)H-tracer appearance in fecal cholesterol by 109%. Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process.

A mucosa-mimetic material for the mucoadhesion testing of thermogelling semi-solids.

Science.gov (United States)

da Silva, Jéssica Bassi; Khutoryanskiy, Vitaliy V; Bruschi, Marcos L; Cook, Michael T

2017-08-07

Mucosa-mimetic materials are synthetic substrates which aim to replace animal tissue in mucoadhesion experiments. One potential mucosa-mimetic material is a hydrogel comprised of N-acryloyl-d-glucosamine and 2-hydroxyethylmethacrylate, which has been investigated as a surrogate for animal mucosae in the mucoadhesion testing of tablets and solution formulations. This study aims to investigate the efficacy of this mucosa-mimetic material in the testing of thermogelling semi-solid formulations, which transition from solution to gel upon warming. Two methods for assessing mucoadhesion have been used; tensile testing and a flow-through system, which allow for investigation under dramatically different conditions. It was found that the mucosa-mimetic material was a good surrogate for buccal mucosa using both testing methods. This material may be used to replace animal tissue in these experiments, potentially reducing the number of laboratory animals used in studies of this type. Copyright © 2017 Elsevier B.V. All rights reserved.

René Girard and the Mimetic Nature of Eating Disorders.

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Strand, Mattias

2018-03-07

French historian and literary critic René Girard (1923-2015), most widely known for the concepts of mimetic desire and scapegoating, also engaged in the discussion of the surge of eating disorders in his 1996 essay Eating Disorders and Mimetic Desire. This article explores Girard's ideas on the mimetic nature and origin of eating disorders from a clinical psychiatric perspective and contextualizes them within the field of eating disorders research as well as in relation to broader psychological, sociological and anthropological models of social comparison and non-consumption. Three main themes in Girard's thinking on the topic of eating disorders are identified and explored: the 'end of prohibitions' as a driving force in the emergence of eating disorders, eating disorders as a phenomenon specific to modernity, and the significance of 'conspicuous non-consumption' in the emergence of eating disorders.

Modular protein switches derived from antibody mimetic proteins.

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Nicholes, N; Date, A; Beaujean, P; Hauk, P; Kanwar, M; Ostermeier, M

2016-02-01

Protein switches have potential applications as biosensors and selective protein therapeutics. Protein switches built by fusion of proteins with the prerequisite input and output functions are currently developed using an ad hoc process. A modular switch platform in which existing switches could be readily adapted to respond to any ligand would be advantageous. We investigated the feasibility of a modular protein switch platform based on fusions of the enzyme TEM-1 β-lactamase (BLA) with two different antibody mimetic proteins: designed ankyrin repeat proteins (DARPins) and monobodies. We created libraries of random insertions of the gene encoding BLA into genes encoding a DARPin or a monobody designed to bind maltose-binding protein (MBP). From these libraries, we used a genetic selection system for β-lactamase activity to identify genes that conferred MBP-dependent ampicillin resistance to Escherichia coli. Some of these selected genes encoded switch proteins whose enzymatic activity increased up to 14-fold in the presence of MBP. We next introduced mutations into the antibody mimetic domain of these switches that were known to cause binding to different ligands. To different degrees, introduction of the mutations resulted in switches with the desired specificity, illustrating the potential modularity of these platforms. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice.

Science.gov (United States)

Li, Melissa W; Mian, Muhammad Oneeb Rehman; Barhoumi, Tlili; Rehman, Asia; Mann, Koren; Paradis, Pierre; Schiffrin, Ernesto L

2013-10-01

Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E(-/-) (Apoe(-/-)) mice. ET-1-induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development. Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe(-/-) mice, and eET-1/Apoe(-/-) mice were fed high-fat diet for 8 weeks. eET-1/Apoe(-/-) had a 45% reduction in plasma high-density lipoprotein (P<0.05) and presented ≥ 2-fold more aortic atherosclerotic lesions compared with Apoe(-/-) (P<0.01). AAAs were detected only in eET-1/Apoe(-/-) (8/21; P<0.05). Reactive oxygen species production was increased ≥ 2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). Monocyte/macrophage infiltration was enhanced ≥ 2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). CD4(+) T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/Apoe(-/-) (P<0.05). The percentage of spleen proinflammatory Ly-6C(hi) monocytes was enhanced 26% by ET-1 overexpression in Apoe(-/-) (P<0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/Apoe(-/-) (P<0.05) compared with Apoe(-/-). ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions.

Oestrogene mimetic isoflavones’ pharmacokinetics and pharmacodynamics

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Anca Dragomirescu,

2008-12-01

Full Text Available Genisteine is the most abundant and the most studied estrogen-mimetic izoflavone. It's chemical formula is 4',5,7 – trihidroxyisoflavone. It has also estrogen-modulated properties by its binding ability to the beta type estrogen receptor. Genisteine presents the following farmacodinamic effects: antiaterogen effect, prevention of estrogen-dependent cancers, especially breast cancer, prevention of skin aging body, osteoprogen effect, prevention of osteoporosis at the menopauses women. Despite all these real benefits, there are also many adverse effects, registered both in humans and animals. Thus, the sheep feeding with some Fabaceae species, containing estrogen-mimetic isoflavones were stopped their reproductive function(isoflavones acted as an oral contraceptive. In humans, phytoestroges influence is still under evaluation, being suspected effects such as cerebral involution - via abusive apoptosis - or disturbance in hormonal status, in male children. All these are added to already known allergies, caused by soy proteins.

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

2008-01-01

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...... (mainly high density lipoprotein). Uniquely, however, apoM is secreted to plasma without cleavage of its hydrophobic NH(2)-terminal signal peptide. To test whether the signal peptide serves as a lipoprotein anchor for apoM in plasma, we generated mice expressing a mutated apoM(Q22A) cDNA in the liver (apoM......(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...

The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Protects against Dyslipidemia-Related Kidney Injury in Apolipoprotein E Knockout Mice

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Jingjing Li

2014-06-01

Full Text Available The goal of this study was to investigate the possible protective effects of sitagliptin against dyslipidemia-related kidney injury in apolipoprotein E knockout (apoE−/− mice. Eight-week-old male apoE−/− mice were randomized to receive either a high fat diet (HFD, apoE−/− group or HFD mixed with sitagliptin (sita + apoE−/− group for 16 weeks. A control group of age- and gender-matched C57BL/6J mice were fed a HFD. The apoE−/− group exhibited increases in body weight and serum lipid levels in addition to high-density lipoprotein, and increases in 24-h urinary 8-hydroxy-2-deoxyguanosine and albuminuria excretion. Decreased insulin sensitivity was also observed in the apoE−/− group. These mice additionally contained enlargements of the glomerular mesangial matrix area, lipid deposition area, and renal interstitium collagen area. The apoE−/− group also demonstrated down-regulation of phosphorylated AMP-activated protein kinase (AMPK, increases in renal mRNA expression of transforming growth factor-beta 1 (TGF-β1 and fibronectin (FN, and increased protein expression of Akt, TGF-β1, FN and p38/ERK mitogen-activated protein kinase (MAPK. Sitagliptin treatment successfully ameliorated all the deleterious effects of dyslipidemia tested. To our knowledge, this is the first time that sitagliptin has been shown to reverse the renal dysfunction and structural damage induced by dyslipidemia in apoE−/− mice. Our results suggest that the renoprotective mechanism of sitagliptin may be due to a reduction in Akt levels, a restoration of AMPK activity, and inhibition of TGF-β1, FN, and p38/ERK MAPK signaling pathways.

Scavenger Receptor B1 is a Potential Biomarker of Human Nasopharyngeal Carcinoma and Its Growth is Inhibited by HDL-mimetic Nanoparticles

Science.gov (United States)

Zheng, Ying; Liu, Yanyan; Jin, Honglin; Pan, Shaotao; Qian, Yuan; Huang, Chuan; Zeng, Yixin; Luo, Qingming; Zeng, Musheng; Zhang, Zhihong

2013-01-01

Nasopharyngeal carcinoma (NPC) is a very regional malignant head and neck cancer that has attracted widespread attention for its unique etiology, epidemiology and therapeutic options. To achieve high cure rates in NPC patients, theranostic approaches are actively being pursued and improved efforts remain desirable in identifying novel biomarkers and establishing effective therapeutic approaches with low long-term toxicities. Here, we discovered that the scavenger receptor class B type I (SR-B1) was overexpressed in all investigated NPC cell lines and 75% of NPC biopsies, demonstrating that SR-B1 is a potential biomarker of NPC. Additional functional analysis showed that SR-B1 has great effect on cell motility while showing no significant impact on cell proliferation. As high-density lipoproteins (HDL) exhibit strong binding affinities to SR-B1 and HDL mimetic peptides are reportedly capable of inhibiting tumor growth, we further examined the SR-B1 targeting ability of a highly biocompatible HDL-mimicking peptide-phospholipid scaffold (HPPS) nanocarrier and investigated its therapeutic effect on NPC. Results show that NPC cells with higher SR-B1 expression have superior ability in taking up the core constituents of HPPS. Moreover, HPPS inhibited the motility and colony formation of 5-8F cells, and significantly suppressed the NPC cell growth in nude mice without inducing tumor cell necrosis or apoptosis. These results indicate that HPPS is not only a NPC-targeting nanocarrier but also an effective anti-NPC drug. Together, the identification of SR-B1 as a potential biomarker and the use of HPPS as an effective anti-NPC agent may shed new light on the diagnosis and therapeutics of NPC. PMID:23843895

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

2010-01-01

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....

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

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de-Andrade F.M.

2000-01-01

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.

Modeling seismic wave propagation using staggered-grid mimetic finite differences

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Freysimar Solano-Feo

2017-04-01

Full Text Available Mimetic finite difference (MFD approximations of continuous gradient and divergence operators satisfy a discrete version of the Gauss-Divergence theorem on staggered grids. On the mimetic approximation of this integral conservation principle, an unique boundary flux operator is introduced that also intervenes on the discretization of a given boundary value problem (BVP. In this work, we present a second-order MFD scheme for seismic wave propagation on staggered grids that discretized free surface and absorbing boundary conditions (ABC with same accuracy order. This scheme is time explicit after coupling a central three-level finite difference (FD stencil for numerical integration. Here, we briefly discuss the convergence properties of this scheme and show its higher accuracy on a challenging test when compared to a traditional FD method. Preliminary applications to 2-D seismic scenarios are also presented and show the potential of the mimetic finite difference method.

Apolipoprotein E gene polymorphism and its effect on anthropometric measures in normoglycemic subjects and type 2 diabetes

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Tabatabaei-Malazy Ozra

2012-10-01

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.

Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms

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Mayo Kevin

2007-04-01

Full Text Available Abstract Background Animal studies suggest that brain apolipoprotein E (apoE levels influence amyloid-β (Aβ deposition and thus risk for Alzheimer's disease (AD. We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1 in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD. We then genotyped the subjects for ten previously identified ABCA1 single nucleotide polymorphisms (SNPs. Results In all subjects, the mean CSF apoE level was 9.09 μg/ml with a standard deviation of 2.70 μg/ml. Levels of apoE in CSF samples taken from the same individual two weeks apart were strongly correlated (r2 = 0.93, p APOE genotype, gender or race. Average apoE levels increased with age by ~0.5 μg/ml per 10 years (r2 = 0.05, p = 0.003. We found no significant associations between CSF apoE levels and the ten ABCA1 SNPs we genotyped. Moreover, in a separate sample of 1225 AD cases and 1431 controls, we found no association between the ABCA1 SNP rs2230806 and AD as has been previously reported. Conclusion We found that CSF apoE levels vary widely between individuals, but are stable within individuals over a two-week interval. AD status, APOE genotype, gender and race do not affect CSF apoE levels, but average CSF apoE levels increase with age. Given the lack of association between CSF apoE levels and genotypes for the ABCA1 SNPs we examined, either these SNPs do not affect ABCA1 function or if they do, they do not have strong effects in the CNS. Finally, we find no evidence for an association between the ABCA1 SNP rs2230806 and AD in a large sample set.

Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of {sup 56}Fe Irradiation on the Brain

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Haley, Gwendolen E. [Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR (United States); Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR (United States); Villasana, Laura; Dayger, Catherine; Davis, Matthew J. [Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR (United States); Raber, Jacob, E-mail: raberj@ohsu.edu [Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR (United States); Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR (United States); Department of Neurology, Oregon Health and Science University, Portland, OR (United States)

2012-11-01

Purpose: In humans, apolipoprotein E (apoE) is encoded by three major alleles ({epsilon}2, {epsilon}3, and {epsilon}4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of {sup 56}Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk. Methods and Materials: We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after {sup 56}Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis. Results: In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice. Conclusions: The short-term effects of {sup 56}Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.

Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation

Science.gov (United States)

Higuchi, Yoshinori; Nelson, Gregory A.; Vazquez, Marcelo; Laskowitz, Daniel T.; Slater, James M.; Pearlstein, Robert D.

2002-01-01

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. METHODS: 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. CONCLUSIONS: 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 CNS. ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process.

Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation

International Nuclear Information System (INIS)

Higuchi, Yoshinori; Nelson, G.A.; Slater, J.M.; Pearlstein, R.D.; Laskowitz, D.T.

2002-01-01

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)

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

2002-12-01

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)

Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

International Nuclear Information System (INIS)

Hirano, Shin'ichi; Nishi, Sakine; Kobayashi, Tsutomu

2017-01-01

We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which is free from ghost and gradient instabilities. As a side remark, we also show that mimetic F (R) theory is plagued with the Ostrogradsky instability.

Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

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Hirano, Shin' ichi; Nishi, Sakine; Kobayashi, Tsutomu, E-mail: s.hirano@rikkyo.ac.jp, E-mail: sakine@rikkyo.ac.jp, E-mail: tsutomu@rikkyo.ac.jp [Department of Physics, Rikkyo University, Toshima, Tokyo 171-8501 (Japan)

2017-07-01

We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which is free from ghost and gradient instabilities. As a side remark, we also show that mimetic F (R) theory is plagued with the Ostrogradsky instability.

Adverse Effects of the Apolipoprotein E ε4 Allele on Episodic Memory, Task Switching and Gray Matter Volume in Healthy Young Adults

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Jianfei Nao

2017-06-01

Full Text Available Many studies have shown that healthy elderly subjects and patients with Alzheimer’s disease (AD who carry the apolipoprotein E (ApoE ε4 allele have worse cognitive function and more severe brain atrophy than non-carriers. However, it remains unclear whether this ApoE polymorphism leads to changes of cognition and brain morphology in healthy young adults. In this study, we used an established model to measure verbal episodic memory and core executive function (EF components (response inhibition, working memory and task switching in 32 ApoE ε4 carriers and 40 non-carriers between 20 years and 40 years of age. To do this, we carried out an adapted auditory verbal learning test and three computerized EF tasks. High-resolution head magnetic resonance scans were performed in all participants and voxel-based morphometry (VBM was used for image processing and analysis. Multivariate analysis of variance (ANOVA performed on memory measures showed that the overall verbal episodic memory of ApoE ε4 carriers was significantly worse than non-carriers (Wilk’s λ = 4.884, P = 0.004. No significant differences were detected in overall EF between the two groups. Post hoc analyses revealed group differences in terms of immediate recall, recognition and task switching, which favored non-carriers. VBM analysis showed gray matter (GM bilateral reductions in the medial and dorsolateral frontal, parietal and left temporal cortices in the carrier group relative to the non-carrier group, which were most significant in the bilateral anterior and middle cingulate gyri. However, these changes in GM volume were not directly associated with changes in cognitive function. Our data show that the ApoE ε4 allele is associated with poorer performance in verbal episodic memory and task switching, and a reduction in GM volume in healthy young adults, suggesting that the effects of ApoE ε4 upon cognition and brain morphology exist long before the possible occurrence of AD.

Rapid radioimmunoassay of human apolipoproteins C-II and C-III

Energy Technology Data Exchange (ETDEWEB)

Gustafson, S; Oestlund-Lindqvist, A M; Vessby, B [Uppsala Univ. (Sweden)

1984-06-01

Apolipoprotein (apo) C-II is an activator of lipoprotein lipase, while apo C-III has the ability to inhibit apo C-II activated lipolysis. In order to study further the relationship between lipoprotein lipase mediated hydrolysis and the serum concentrations of apo C-II and apo C-III radioimmunoassays for these apolipoproteins have been developed. Formalin-treated Staphylococcus aureus Cowan I was used for immunoprecipitation and were shown to give rapid uptake of immune complexes that could easily be harvested by centrifugation. The assays were shown to be sensitive (10 ..mu..g/1), specific, precise (inter- and intra-assay coefficients of variation below 10%), rapid (completed in less than 6 h) and simple to perform. Delipidation of serum and lipoproteins had no effect on the results, indicating that the immunologically active sites of apo C-II and apo C-III are exposed to the aqueous environment under assay conditions. Serum apo C-II and apo C-III levels of normolipidaemic subjects were approximately 25 mg/1 and 110 mg/1, respectively. Highly significant positive correlations were found between VLDL apo C-II and VLDL apo C-III, respectively, and VLDL triglycerides, VLDL cholesterol and total serum TG. There was also a highly significant correlation between the HDL cholesterol concentration and the HDL apo C-III concentration.

Effect of lipid composition and packing on the adsorption of apolipoproteins to lipid monolayers

International Nuclear Information System (INIS)

Ibdah, J.A.; Lund-Katz, S.; Phillips, M.C.

1987-01-01

The monolayer system has been used to study the effects of lipoprotein surface lipid composition and packing on the affinities of apolipoproteins for the surfaces of lipoprotein particles. The adsorption of apolipoproteins injected beneath lipid monolayers prepared with pure lipids or lipoprotein surface lipids is evaluated by monitoring the surface pressure of the film and the surface concentration (Gamma) of 14 C-labelled apolipoprotein. At a given initial film pressure (π/sub i/) there is a higher adsorption of human apo A-I to unsaturated phosphatidylcholine (PC) monolayers compared to saturated PC monolayers (e.g., at π/sub i/ = 10 mN/m, Gamma = 0.35 and 0.06 mg/m 2 for egg PC and distearoyl PC, respectively, with 3 x 10 -4 mg/ml apo A-I in the subphase). In addition, adsorption of apo A-I is less to an egg sphingomyelin monolayer than to an egg PC monolayer. The adsorption of apo A-I to PC monolayers is decreased by addition of cholesterol. Generally, apo A-I adsorption diminishes as the lipid molecular area decreases. Apo A-I adsorbs more to monolayers prepared with HDL 3 surface lipids than with LDL surface lipids. These studies suggest that lipoprotein surface lipid composition and packing are crucial factors influencing the transfer and exchange of apolipoproteins among various lipoprotein classes during metabolism of lipoprotein particles

Late-time cosmological approach in mimetic f(R, T) gravity

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Baffou, E.H. [Institut de Mathematiques et de Sciences Physiques (IMSP), Porto-Novo (Benin); Houndjo, M.J.S. [Institut de Mathematiques et de Sciences Physiques (IMSP), Porto-Novo (Benin); Faculte des Sciences et Techniques de Natitingou, Natitingou (Benin); Hamani-Daouda, M. [Universite de Niamey, Departement de Physique, Niamey (Niger); Alvarenga, F.G. [Universidade Federal do Espirito Santo, Departamento de Engenharia e Ciencias Naturais, CEUNES, Sao Mateus, ES (Brazil)

2017-10-15

In this paper, we investigate the late-time cosmic acceleration in mimetic f(R, T) gravity with the Lagrange multiplier and potential in a Universe containing, besides radiation and dark energy, a self-interacting (collisional) matter. We obtain through the modified Friedmann equations the main equation that can describe the cosmological evolution. Then, with several models from Q(z) and the well-known particular model f(R, T), we perform an analysis of the late-time evolution. We examine the behavior of the Hubble parameter, the dark energy equation of state and the total effective equation of state and in each case we compare the resulting picture with the non-collisional matter (assumed as dust) and also with the collisional matter in mimetic f(R, T) gravity. The results obtained are in good agreement with the observational data and show that in the presence of the collisional matter the dark energy oscillations in mimetic f(R, T) gravity can be damped. (orig.)

7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

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Yang Tan

2016-11-01

Full Text Available 7,8-Dihydroxyflavone (7,8-DHF, a tyrosine kinase B (TrkB agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. 5-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5mg/kg or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterwards, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP as well as AEP-derived truncated tauN368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt/glycogen synthase kinase-3β (GSK-3β pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope. These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tauN368.

Synergistic effects of high fat feeding and apolipoprotein E deletion on enterocytic amyloid-beta abundance

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Dhaliwal Satvinder S

2008-04-01

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.

The reconstruction of f(ϕ)R and mimetic gravity from viable slow-roll inflation

Science.gov (United States)

Odintsov, S. D.; Oikonomou, V. K.

2018-04-01

In this work, we extend the bottom-up reconstruction framework of F (R) gravity to other modified gravities, and in particular for f (ϕ) R and mimetic F (R) gravities. We investigate which are the important conditions in order for the method to work, and we study several viable cosmological evolutions, focusing on the inflationary era. Particularly, for the f (ϕ) R theory case, we specify the functional form of the Hubble rate and of the scalar-to-tensor ratio as a function of the e-foldings number and accordingly, the rest of the physical quantities and also the slow-roll and the corresponding observational indices can be calculated. The same method is applied in the mimetic F (R) gravity case, and in both cases we thoroughly analyze the resulting free parameter space, in order to show that the viability of the models presented is guaranteed and secondly that there is a wide range of values of the free parameters for which the viability of the models occurs. In addition, the reconstruction method is also studied in the context of mimetic F (R) = R gravity. As we demonstrate, the resulting theory is viable, and also in this case, only the scalar-to-tensor ratio needs to be specified, since the rest follow from this condition. Finally, we discuss in brief how the reconstruction method could function for other modified gravities.

Apolipoprotein B, the villain in the drama?

Science.gov (United States)

Yu, Qi; Zhang, Yaping; Xu, Cang-Bao

2015-02-05

Low-density lipoprotein (LDL) is the major atherogenic lipoprotein and the primary target of lipid-lowering therapy for treating ischemic cardiovascular disease. Apolipoprotein B (apoB), an important structural component of LDL, plays a key role in cholesterol transport and removal in vascular wall. On the other hand, under pathological process, apoB interacts with the arterial wall to initiate the cascade of events that leads to atherosclerosis. However, interactions between apoB and vascular wall remain to be determined. Here, we address a pathological role of apoB per se and whole LDL particle in dysfunction of vascular endothelium and smooth muscle cells i.e. decreased endothelium-dependent vasodilation and increased receptor-mediated vasoconstriction. We intend to discuss: i) how apoB is responsible for the deleterious effects of LDL in the development of ischemic cardiovascular disease; ii) why vaccine based on peptides derived from apoB-100 is a promising therapy for treating ischemic cardiovascular disease, and iii) direct inhibition of apoB production should be a better therapeutic option than simple LDL-cholesterol lowering therapy in the patients with severe hypercholesterolemia at high cardiovascular risk with statin intolerance. In conclusion, apoB, but not cholesterol, plays a major role in LDL-induced dysfunction of endothelium, suggesting that direct apoB-targeting agents might be a promising therapy for the treatment of ischemic cardiovascular disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737.

Science.gov (United States)

Mani, Jens; Antonietti, Patrick; Rakel, Stefanie; Blaheta, Roman; Bartsch, Georg; Haferkamp, Axel; Kögel, Donat

2016-02-01

BAG3 is overexpressed in several malignancies and mediates a non-canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (-)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer.

Vitamin B-12, apolipoprotein E genotype, and cognitive performance in community-living older adults: evidence of a gene-micronutrient interaction.

Science.gov (United States)

Feng, Lei; Li, Jialiang; Yap, Keng-Bee; Kua, Ee-Heok; Ng, Tze-Pin

2009-04-01

The relation between vitamin B-12 and cognitive function in older adults is unclear. Limited evidence suggests that the relation is modulated by apolipoprotein E epsilon4. Hence, it is important to further examine this gene-nutrient interaction. The aim was to investigate the role of apolipoprotein E (APOE) epsilon4 as a genetic predisposing factor modulating the effect of vitamin B-12 on cognitive function. A battery of neuropsychological tests, including the Mini-Mental State Examination (MMSE) for global cognition, was administered at the baseline assessment to 539 Chinese adults aged > or =55 y. The MMSE was repeated at a median 18 mo (n = 376) and a median of 38 mo (n = 247) after baseline. The interaction of vitamin B-12 and APOE epsilon4 on cognitive function was examined in a linear mixed-effects model for MMSE and in a multiple linear regression model for neuropsychological test scores. APOE epsilon4 was associated with a lower MMSE score. Vitamin B-12 (natural log transformed) was positively related to MMSE score, and this association was much stronger in APOE epsilon4 carriers than in APOE epsilon4 noncarriers (P for interaction = 0.016). Significant interactions between natural log-transformed vitamin B-12 and APOE epsilon4 were also found for the Digit Span Backward Longest Sequence (P for interaction = 0.013) and Rey Auditory Verbal Learning Test immediate recall (P for interaction = 0.005). Better performance in these 2 tests was associated with vitamin B-12 in APOE epsilon4 carriers but not in APOE epsilon4 noncarriers. The association between vitamin B-12 and cognitive function was moderated by APOE epsilon4 status.

Relevance of apolipoprotein E4 for the lipid profile of Brazilian patients with coronary artery disease

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D.R.S. Souza

2007-02-01

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.

Deficiency of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 accelerates atherogenesis in apolipoprotein E-deficient mice

International Nuclear Information System (INIS)

Akyuerek, Levent M.; Boehm, Manfred; Olive, Michelle; Zhou, Alex-Xianghua; San, Hong; Nabel, Elizabeth G.

2010-01-01

Cyclin-dependent kinase inhibitors, p21 Cip1 and p27 Kip1 , are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21 Cip1 or p27 Kip1 in apolipoprotein E (apoE)-deficiency may increase atherosclerotic plaque formation. Compared to apoE -/- aortae, both apoE -/- /p21 -/- and apoE -/- /p27 -/- aortae exhibited significantly more atherosclerotic plaque following a high-cholesterol regimen. This increase was particularly observed in the abdominal aortic regions. Deficiency of p27 Kip1 accelerated plaque formation significantly more than p21 -/- in apoE -/- mice. This increased plaque formation was in parallel with increased intima/media area ratios. Deficiency of p21 Cip1 and p27 Kip1 accelerates atherogenesis in apoE -/- mice. These findings have significant implications for our understanding of the molecular basis of atherosclerosis associated with excessive proliferation of vascular cells.

Data on plasma levels of apolipoprotein E, correlations with lipids and lipoproteins stratified by APOE genotype, and risk of ischemic heart disease

DEFF Research Database (Denmark)

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

2016-01-01

Data on correlations of plasma apoE with levels of lipids and lipoproteins stratified by APOE genotypes as well as data exploring the association between plasma levels of apoE and risk of ischemic heart disease (IHD) are wanted. The present data on 91,695 individuals from the general population...... provides correlations between plasma levels of apoE and lipids and lipoproteins for the three APOE genotypes ε33, ε44 and ε22, representing each of the three apoE isoforms. Further, data on extreme groups of plasma apoE (highest 5%) versus lower levels of apoE at enrollment explores risk of IHD...... and myocardial infarction (MI) and is given as hazard ratios. In addition, IHD and MI as a function of apoE/high-density lipoprotein (HDL) cholesterol ratio, as well as data on lipids, lipoproteins and apolipoproteins are given as hazard ratios. Data is stratified by gender and presented for the Copenhagen...

Prey from the eyes of predators: Color discriminability of aposematic and mimetic butterflies from an avian visual perspective.

Science.gov (United States)

Su, Shiyu; Lim, Matthew; Kunte, Krushnamegh

2015-11-01

Predation exerts strong selection on mimetic butterfly wing color patterns, which also serve other functions such as sexual selection. Therefore, specific selection pressures may affect the sexes and signal components differentially. We tested three predictions about the evolution of mimetic resemblance by comparing wing coloration of aposematic butterflies and their Batesian mimics: (a) females gain greater mimetic advantage than males and therefore are better mimics, (b) due to intersexual genetic correlations, sexually monomorphic mimics are better mimics than female-limited mimics, and (c) mimetic resemblance is better on the dorsal wing surface that is visible to predators in flight. Using a physiological model of avian color vision, we quantified mimetic resemblance from predators' perspective, which showed that female butterflies were better mimics than males. Mimetic resemblance in female-limited mimics was comparable to that in sexually monomorphic mimics, suggesting that intersexual genetic correlations did not constrain adaptive response to selection for female-limited mimicry. Mimetic resemblance on the ventral wing surface was better than that on the dorsal wing surface, implying stronger natural and sexual selection on ventral and dorsal surfaces, respectively. These results suggest that mimetic resemblance in butterfly mimicry rings has evolved under various selective pressures acting in a sex- and wing surface-specific manner. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Associations between apolipoprotein E genotypes and serum levels of glucose, cholesterol, and triglycerides in a cognitively normal aging Han Chinese population.

Science.gov (United States)

Tao, Qing-Qing; Chen, Yan; Liu, Zhi-Jun; Sun, Yi-Min; Yang, Ping; Lu, Shen-Ji; Xu, Miao; Dong, Qin-Yun; Yang, Jia-Jun; Wu, Zhi-Ying

2014-01-01

To determine the associations between apolipoprotein E (APOE) genotypes and serum levels of glucose, total cholesterol, and triglycerides in a cognitively normal aging Han Chinese population. There were 1,003 cognitively normal aging subjects included in this study. APOE genotypes were analyzed and biochemical parameters were tested. All the subjects were divided into three groups according to APOE genotypes: (1) E2/2 or E2/3 (APOE E2); (2) E3/3 (APOE E3); and (3) E2/4, E3/4, or E4/4 (APOE E4). Correlations of serum levels of glucose, total cholesterol, and triglycerides with APOE genotypes were assessed. E2, E3, and E4 allele frequencies were found to be 6.2%, 82.1%, and 11.7%, respectively. Serum levels of total cholesterol were higher in the APOE E4 group (Ptriglycerides (adjusted odds ratio 1.042, 95% confidence interval 0.759-1.429, P=0.800). A higher serum level of total cholesterol was significantly correlated with APOE E4 status in a cognitively normal, nondiabetic aging population. However, there was no correlation between APOE genotypes and serum levels of glucose or total triglycerides.

Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.

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Speir, Mary; Lawlor, Kate E; Glaser, Stefan P; Abraham, Gilu; Chow, Seong; Vogrin, Adam; Schulze, Keith E; Schuelein, Ralf; O'Reilly, Lorraine A; Mason, Kylie; Hartland, Elizabeth L; Lithgow, Trevor; Strasser, Andreas; Lessene, Guillaume; Huang, David C S; Vince, James E; Naderer, Thomas

2016-02-24

Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.

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

2010-01-01

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...

Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

Science.gov (United States)

Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C

2014-02-01

The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. Copyright © 2014. Published by Elsevier Inc.

Serum concentrations of cholesterol, apolipoprotein A-I and apolipoprotein B in a total of 1694 meat-eaters, fish-eaters, vegetarians and vegans.

Science.gov (United States)

Bradbury, K E; Crowe, F L; Appleby, P N; Schmidt, J A; Travis, R C; Key, T J

2014-02-01

The objective of this study was to describe serum lipid concentrations, including apolipoproteins A-I and B, in different diet groups. A cross-sectional analysis of a sample of 424 meat-eaters, 425 fish-eaters, 423 vegetarians and 422 vegans, matched on sex and age, from the European Prospective Investigation into Cancer and Nutrition-Oxford cohort. Serum concentrations of total, and high-density lipoprotein (HDL) cholesterol, as well as apolipoproteins A-I and B were measured, and serum non-HDL cholesterol was calculated. Vegans had the lowest body mass index (BMI) and the highest and lowest intakes of polyunsaturated and saturated fat, respectively. After adjustment for age, alcohol and physical activity, compared with meat-eaters, fish-eaters and vegetarians, serum concentrations of total and non-HDL cholesterol and apolipoprotein B were significantly lower in vegans. Serum apolipoprotein A-I concentrations did not differ between the diet groups. In males, the mean serum total cholesterol concentration was 0.87 mmol/l lower in vegans than in meat-eaters; after further adjustment for BMI this difference was 0.76 mmol/l. In females, the difference in total cholesterol between these two groups was 0.6 mmol/l, and after further adjustment for BMI was 0.55 mmol/l. [corrected]. In this study, which included a large number of vegans, serum total cholesterol and apolipoprotein B concentrations were lower in vegans compared with meat-eaters, fish-eaters and vegetarians. A small proportion of the observed differences in serum lipid concentrations was explained by differences in BMI, but a large proportion is most likely due to diet.

Molecular Design, Structures, and Activity of Antimicrobial Peptide-Mimetic Polymers

Science.gov (United States)

Takahashi, Haruko; Palermo, Edmund F.; Yasuhara, Kazuma; Caputo, Gregory A.

2014-01-01

There is an urgent need for new antibiotics which are effective against drug-resistant bacteria without contributing to resistance development. We have designed and developed antimicrobial copolymers with cationic amphiphilic structures based on the mimicry of naturally occurring antimicrobial peptides. These copolymers exhibit potent antimicrobial activity against a broad spectrum of bacteria including methicillin-resistant Staphylococcus aureus with no adverse hemolytic activity. Notably, these polymers also did not result in any measurable resistance development in E. coli. The peptide-mimetic design principle offers significant flexibility and diversity in the creation of new antimicrobial materials and their potential biomedical applications. PMID:23832766

Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity

Science.gov (United States)

Hua, J; Scott, R.W.; Diamond, G

2011-01-01

Whereas periodontal disease is ultimately of bacterial etiology, from multispecies biofilms of gram-negative anaerobic microorganisms, much of the deleterious effects are caused by the resultant epithelial inflammatory response. Hence, development of a treatment that combines anti-biofilm antibiotic activity with anti-inflammatory activity would be of great utility. Antimicrobial peptides (AMPs) such as defensins are naturally occurring peptides that exhibit broad-spectrum activity as well as a variety of immunomodulatory activities. Furthermore, bacteria do not readily develop resistance to these agents. However, clinical studies have suggested that they do not represent optimal candidates for exogenous therapeutic agents. Small-molecule mimetics of these AMPs exhibit similar activities to the parent peptides, in addition to having low toxicity, high stability and low cost. To determine whether AMP mimetics have the potential for treatment of periodontal disease, we examined the activity of one mimetic, mPE, against biofilm cultures of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Metabolic assays as well as culture and biomass measurement assays demonstrated that mPE exhibits potent activity against biofilm cultures of both species. Furthermore, as little as 2 µg ml−1 mPE was sufficient to inhibit interleukin-1β-induced secretion of interleukin-8 in both gingival epithelial cells and THP-1 cells. This anti-inflammatory activity is associated with a reduction in activation of nuclear factor-κB, suggesting that mPE can act both as an anti-biofilm agent in an anaerobic environment and as an anti-inflammatory agent in infected tissues. PMID:21040516

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

2004-02-15

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.

Static spherically symmetric solutions in mimetic gravity: rotation curves and wormholes

International Nuclear Information System (INIS)

Myrzakulov, Ratbay; Sebastiani, Lorenzo; Vagnozzi, Sunny; Zerbini, Sergio

2016-01-01

In this work, we analyse static spherically symmetric solutions in the framework of mimetic gravity, an extension of general relativity where the conformal degree of freedom of gravity is isolated in a covariant fashion. Here we extend previous works by considering, in addition, a potential for the mimetic field. An appropriate choice of such a potential allows for the reconstruction of a number of interesting cosmological and astrophysical scenarios. We explicitly show how to reconstruct such a potential for a general static spherically symmetric space-time. A number of applications and scenarios are then explored, among which are traversable wormholes. Finally, we analytically reconstruct potentials, which leads to solutions to the equations of motion featuring polynomial corrections to the Schwarzschild space-time. Accurate choices for such corrections could provide an explanation for the inferred flat rotation curves of spiral galaxies within the mimetic gravity framework, without the need for particle dark matter. (paper)

The reconstruction of f(ϕR and mimetic gravity from viable slow-roll inflation

Directory of Open Access Journals (Sweden)

S.D. Odintsov

2018-04-01

Full Text Available In this work, we extend the bottom-up reconstruction framework of F(R gravity to other modified gravities, and in particular for f(ϕR and mimetic F(R gravities. We investigate which are the important conditions in order for the method to work, and we study several viable cosmological evolutions, focusing on the inflationary era. Particularly, for the f(ϕR theory case, we specify the functional form of the Hubble rate and of the scalar-to-tensor ratio as a function of the e-foldings number and accordingly, the rest of the physical quantities and also the slow-roll and the corresponding observational indices can be calculated. The same method is applied in the mimetic F(R gravity case, and in both cases we thoroughly analyze the resulting free parameter space, in order to show that the viability of the models presented is guaranteed and secondly that there is a wide range of values of the free parameters for which the viability of the models occurs. In addition, the reconstruction method is also studied in the context of mimetic F(R=R gravity. As we demonstrate, the resulting theory is viable, and also in this case, only the scalar-to-tensor ratio needs to be specified, since the rest follow from this condition. Finally, we discuss in brief how the reconstruction method could function for other modified gravities.

Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke : Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals

NARCIS (Netherlands)

Khan, Tauseef A.; Shah, Tina; Prieto, David; Zhang, Weili; Price, Jackie; Fowkes, Gerald R.; Cooper, Jackie; Talmud, Philippa J.; Humphries, Steve E.; Sundstrom, Johan; Hubacek, Jaroslav A.; Ebrahim, Shah; Lawlor, Debbie A.; Ben-Shlomo, Yoav; Abdollahi, Mohammad R.; Slooter, Arjen J. C.; Szolnoki, Zoltan; Sandhu, Manjinder; Wareham, Nicholas; Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne; Fillenbaum, Gerda; Heijmans, Bastiaan T.; Katsuya, Tomohiro; Gromadzka, Grazyna; Singleton, Andrew; Ferrucci, Luigi; Hardy, John; Worrall, Bradford; Rich, Stephen S.; Matarin, Mar; Whittaker, John; Gaunt, Tom R.; Whincup, Peter; Morris, Richard; Deanfield, John; Donald, Ann; Smith, George Davey; Kivimaki, Mika; Kumari, Meena; Smeeth, Liam; Khaw, Kay-Tee; Nalls, Michael; Meschia, James; Sun, Kai; Hui, Rutai; Day, Ian; Hingorani, Aroon D.; Casas, Juan P.

Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 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

Effect of fatty acids on the synthesis and secretion of apolipoprotein B by rat hepatocytes

International Nuclear Information System (INIS)

Suresh Kumar, N.; Abraham, Rita; Suresh Kumar, G.; Sudhakaran, P.R.; Kurup, P.A.

1992-01-01

The modulation of apolipoprotein B synthesis and secretion by fatty acids in rat hepatocytes was studied. Maximum apolipoprotein B production was obtained in the case of oleic acid followed by linoleic, stearic and palmitic/linolenic acid when compared to control which was not supplemented with any fatty acids. Oleic acid was found to exert a concentration dependent increase in the secretion of [ 3 H] apolipoprotein B into the medium while that associated with the cell layer was not affected. Pulse chase experiments in the presence of oleic acid showed that it caused an increase in the secretion of apolipoprotein B into the medium. 14 C-acetate incorporation into cholesterol and cholesteryl ester associated with the cell layer and secreted very low density lipoproteins also showed an increase in the presence of oleic acid indicating an increase in cholesterogenesis. The effect of oleic acid on [ 3 H] apolipoprotein B and very low density lipoprotein secretion appeared to be mediated through cholesterol as (i)ketoconazole, an inhibitor of cholesterol synthesis caused significant reduction in the stimulatory effect of oleic acid on apolipoprotein secretion and (ii) mevinolin, another inhibitor of cholesterol synthesis also reversed the stimulatory effect of oleic acid on apolipoprotein B secretion. These results indicated that oleic acid may influence apolipoprotein B synthesis and secretion in hepatocytes probably by affecting cholesterol/cholesteryl ester formation which may be a critical component in the secretion of apolipoprotein B as lipoproteins. (author). 21 refs., 4 figs., 2 tabs

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: thomas.grewal@sydney.edu.au [Faculty of Pharmacy A15, The University of Sydney, Sydney, NSW 2006 (Australia); Heeren, Joerg, E-mail: heeren@uke.de [Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg (Germany)

2015-09-10

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. �

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

2002-01-01

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.

Apolipoprotein M promotes mobilization of cellular cholesterol in vivo

DEFF Research Database (Denmark)

Elsøe, Sara; Christoffersen, Christina; Luchoomun, Jayraz

2013-01-01

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

Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with hyperthyroidism

DEFF Research Database (Denmark)

Klausen, I C; Hegedüs, L; Hansen, P S

1995-01-01

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apoB) is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are ...

Apolipoprotein E (APOE) ε4 and episodic memory decline in Alzheimer's disease: A review.

Science.gov (United States)

El Haj, Mohamad; Antoine, Pascal; Amouyel, Philippe; Lambert, Jean-Charles; Pasquier, Florence; Kapogiannis, Dimitrios

2016-05-01

A growing body of research has examined the relationship between episodic memory decline, the cognitive hallmark of Alzheimer's disease (AD), and the presence of Apolipoprotein E ε4 (APOE ε4) allele, a major genetic risk factor for the disease. Our review attempts to summarize and critically evaluate this literature. We performed a systematic search for studies assessing episodic memory in AD patients who were genotyped for APOE ε4 and identified fourteen papers. Although most of these papers reported significant relationships between APOE ε4 and episodic memory decline in AD, some papers did not confirm this relationship. Our review links this controversy to the conflicting literature about the effects of APOE ε4 on general cognitive functioning in AD. We identify several shortcoming and limitations of the research on the relationship between APOE ε4 and episodic memory in AD, such as small sample sizes, non-representative populations, lack of comparison of early-onset vs. late-onset disease, and lack of comparison among different genotypes that include APOE ε4 (i.e., zero, one, or two ε4 alleles). Another major shortcoming of the reviewed literature was the lack of comprehensive evaluation of episodic memory decline, since episodic memory was solely evaluated with regard to encoding and retrieval, omitting evaluation of core episodic features that decline in AD, such as context recall (e.g., how, where, and when an episodic event has occurred) and subjective experience of remembering (e.g., reliving, emotion and feeling during episodic recollection). Future research taking these limitations into consideration could illuminate the nature of the relationship between APOE ε4 and episodic memory decline in AD. Copyright © 2016 Elsevier B.V. All rights reserved.

Taurine reduces the secretion of apolipoprotein B100 and lipids in HepG2 cells

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Nagao Koji

2008-10-01

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.

Targeting nanodisks via a single chain variable antibody - Apolipoprotein chimera

International Nuclear Information System (INIS)

Iovannisci, David M.; Beckstead, Jennifer A.; Ryan, Robert O.

2009-01-01

Nanodisks (ND) are nanometer scale complexes of phospholipid and apolipoprotein that have been shown to function as drug delivery vehicles. ND harboring significant quantities of the antifungal agent, amphotericin B, or the bioactive isoprenoid, all trans retinoic acid, have been generated and characterized. As currently formulated, ND possess limited targeting capability. In this study, we constructed a single chain variable antibody (scFv).apolipoprotein chimera and assessed the ability of this fusion protein to form ND and recognize the antigen to which the scFv is directed. Data obtained revealed that α-vimentin scFv.apolipoprotein A-I is functional in ND formation and antigen recognition, opening the door to the use of such chimeras in targeting drug-enriched ND to specific tissues.

From Dalek half balls to Daft Punk helmets: Mimetic fandom and the crafting of replicas

Directory of Open Access Journals (Sweden)

Matt Hills

2014-06-01

Full Text Available Mimetic fandom is a surprisingly understudied mode of (culturally masculinized fan activity in which fans research and craft replica props. Mimetic fandom can be considered as (inauthentic and (immaterial, combining noncommercial status with grassroots marketing or brand reinforcement as well as fusing an emphasis on material artifacts with Web 2.0 collective intelligence. Simply analyzing mimetic fandom as part of fannish material culture fails to adequately assess the nonmaterial aspects of this collaborative creativity. Two fan cultures are taken as case studies: Dalek building groups and Daft Punk helmet constructors. These diverse cases indicate that mimetic fandom has a presence and significance that moves across media fandoms and is not restricted to the science fiction, fantasy, and horror followings with which it is most often associated. Mimetic fandom may be theorized as an oscillatory activity that confuses binaries and constructions of (academic/fan authenticity. This fan practice desires and pursues a kind of ontological bridging or unity—from text to reality—that is either absent or less dominant in many other fan activities such as cosplay, screen-used prop collecting, and geographical pilgrimage. Fan studies may benefit from reassessing the place of mimesis, especially in order to theorize fan practices that are less clearly transformative in character.

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

International Nuclear Information System (INIS)

Steinmetz, Martin; Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain; Mallat, Ziad

2015-01-01

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 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

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: martin.steinmetz@ukb.uni-bonn.de [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)

2015-08-14

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

Requirement of phosphorylatable endothelial nitric oxide synthase at Ser-1177 for vasoinhibin-mediated inhibition of endothelial cell migration and proliferation in vitro.

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García, Celina; Nuñez-Anita, Rosa Elvira; Thebault, Stéphanie; Arredondo Zamarripa, David; Jeziorsky, Michael C; Martínez de la Escalera, Gonzalo; Clapp, Carmen

2014-03-01

Endothelial nitric oxide synthase (eNOS)-derived nitric oxide is a major vasorelaxing factor and a mediator of vasopermeability and angiogenesis. Vasoinhibins, a family of antiangiogenic prolactin fragments that include 16 K prolactin, block most eNOS-mediated vascular effects. Vasoinhibins activate protein phosphatase 2A, causing eNOS inactivation through dephosphorylation of eNOS at serine residue 1179 in bovine endothelial cells and thereby blocking vascular permeability. In this study, we examined whether human eNOS phosphorylation at S1177 (analogous to bovine S1179) influences other actions of vasoinhibins. Bovine umbilical vein endothelial cells were stably transfected with human wild-type eNOS (WT) or with phospho-mimetic (S1177D) or non-phosphorylatable (S1177A) eNOS mutants. Vasoinhibins inhibited the increases in eNOS activity, migration, and proliferation following the overexpression of WT eNOS but did not affect these responses in cells expressing S1177D and S1177A eNOS mutants. We conclude that eNOS inhibition by dephosphorylation of S1177 is fundamental for the inhibition of endothelial cell migration and proliferation by vasoinhibins.

Postmenopausal hypertension, abdominal obesity, apolipoprotein and insulin resistance.

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Ben Ali, Samir; Belfki-Benali, Hanen; Ahmed, Decy Ben; Haddad, Najet; Jmal, Awatef; Abdennebi, Monia; Romdhane, Habiba Ben

This study aimed to evaluate the association of abdominal obesity, apolipoprotein and insulin resistance (IR) with the risk of hypertension in postmenopausal women. We analyzed a total of 242 women aged between 35 and 70 years. Blood pressure (BP), anthropometric indices, lipid profile, fasting glucose, insulin, C-reactive protein (CRP) and apolipoprotein concentrations were measured. Homeostasis model assessment (HOMA) was used to assess IR. Hypertension was defined as a systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg or current treatment with antihypertensive drugs. Women with hypertension showed significantly higher mean values of age, SBP and DBP, waist circumference (WC), fasting plasma glucose (FPG), insulin, HOMAIR and the apolipoprotein B (apoB). When analyses were done according to the menopausal status, higher prevalence of hypertension was observed in postmenopausal women (72.8% vs. 26.0%, p menopause (p = 0.008) were significantly associated with higher risk for hypertension. These results suggest that changes in WC, apoB and IR accompanying menopause lead to a greater prevalence of hypertension in postmenopausal women.

Pharmacological inhibition of dynamin II reduces constitutive protein secretion from primary human macrophages.

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Maaike Kockx

Full Text Available Dynamins are fission proteins that mediate endocytic and exocytic membrane events and are pharmacological therapeutic targets. These studies investigate whether dynamin II regulates constitutive protein secretion and show for the first time that pharmacological inhibition of dynamin decreases secretion of apolipoprotein E (apoE and several other proteins constitutively secreted from primary human macrophages. Inhibitors that target recruitment of dynamin to membranes (MiTMABs or directly target the GTPase domain (Dyngo or Dynole series, dose- and time- dependently reduced the secretion of apoE. SiRNA oligo's targeting all isoforms of dynamin II confirmed the involvement of dynamin II in apoE secretion. Inhibition of secretion was not mediated via effects on mRNA or protein synthesis. 2D-gel electrophoresis showed that inhibition occurred after apoE was processed and glycosylated in the Golgi and live cell imaging showed that inhibited secretion was associated with reduced post-Golgi movement of apoE-GFP-containing vesicles. The effect was not restricted to macrophages, and was not mediated by the effects of the inhibitors on microtubules. Inhibition of dynamin also altered the constitutive secretion of other proteins, decreasing the secretion of fibronectin, matrix metalloproteinase 9, Chitinase-3-like protein 1 and lysozyme but unexpectedly increasing the secretion of the inflammatory mediator cyclophilin A. We conclude that pharmacological inhibitors of dynamin II modulate the constitutive secretion of macrophage apoE as a class effect, and that their capacity to modulate protein secretion may affect a range of biological processes.

Interactions of Bio-Inspired Membranes with Peptides and Peptide-Mimetic Nanoparticles

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Michael Sebastiano

2015-08-01

Full Text Available Via Dissipative Particle Dynamics (DPD and implicit solvent coarse-grained (CG Molecular Dynamics (MD we examine the interaction of an amphiphilic cell-penetrating peptide PMLKE and its synthetic counterpart with a bio-inspired membrane. We use the DPD technique to investigate the interaction of peptide-mimetic nanoparticles, or nanopins, with a three-component membrane. The CG MD approach is used to investigate the interaction of a cell-penetrating peptide PMLKE with single-component membrane. We observe the spontaneous binding and subsequent insertion of peptide and nanopin in the membrane by using CG MD and DPD approaches, respectively. In addition, we find that the insertion of peptide and nanopins is mainly driven by the favorable enthalpic interactions between the hydrophobic components of the peptide, or nanopin, and the membrane. Our study provides insights into the mechanism underlying the interactions of amphiphilic peptide and peptide-mimetic nanoparticles with a membrane. The result of this study can be used to guide the functional integration of peptide and peptide-mimetic nanoparticles with a cell membrane.

The pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease.

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Han, Xianlin

2010-06-01

Alzheimer's disease (AD) is the most common cause of dementia in the aging population. Prior work has shown that the epsilon4 allele of apolipoprotein E (apoE4) is a major risk factor for "sporadic" AD, which accounts for >99% of AD cases without a defined underlying mechanism. Recently, we have demonstrated that sulfatides are substantially and specifically depleted at the very early stage of AD. To identify the mechanism(s) of sulfatide loss concurrent with AD onset, we have found that: (1) sulfatides are specifically associated with apoE-associated particles in cerebrospinal fluid (CSF); (2) apoE modulates cellular sulfatide levels; and (3) the modulation of sulfatide content is apoE isoform dependent. These findings not only lead to identification of the potential mechanisms underlying sulfatide depletion at the earliest stages of AD but also serve as mechanistic links to explain the genetic association of apoE4 with AD. Moreover, our recent studies further demonstrated that (1) apoE mediates sulfatide depletion in amyloid-beta precursor protein transgenic mice; (2) sulfatides enhance amyloid beta (Abeta) peptides binding to apoE-associated particles; (3) Abeta42 content notably correlates with sulfatide content in CSF; (4) sulfatides markedly enhance the uptake of Abeta peptides; and (5) abnormal sulfatide-facilitated Abeta uptake results in the accumulation of Abeta in lysosomes. Collectively, our studies clearly provide a link between apoE, Abeta, and sulfatides in AD and establish a foundation for the development of effective therapeutic interventions for AD.

B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins.

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Renault, Thibaud T; Elkholi, Rana; Bharti, Archana; Chipuk, Jerry E

2014-09-19

The B cell lymphoma-2 (BCL-2) family is the key mediator of cellular sensitivity to apoptosis during pharmacological interventions for numerous human pathologies, including cancer. There is tremendous interest to understand how the proapoptotic BCL-2 effector members (e.g. BCL-2-associated X protein, BAX) cooperate with the BCL-2 homology domain only (BH3-only) subclass (e.g. BCL-2 interacting mediator of death, BIM; BCL-2 interacting-domain death agonist, BID) to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis and whether these mechanisms may be pharmacologically exploited to enhance the killing of cancer cells. Indeed, small molecule inhibitors of the anti-apoptotic BCL-2 family members have been designed rationally. However, the success of these "BH3 mimetics" in the clinic has been limited, likely due to an incomplete understanding of how these drugs function in the presence of multiple BCL-2 family members. To increase our mechanistic understanding of how BH3 mimetics cooperate with multiple BCL-2 family members in vitro, we directly compared the activity of several BH3-mimetic compounds (i.e. ABT-263, ABT-737, GX15-070, HA14.1, TW-37) in biochemically defined large unilamellar vesicle model systems that faithfully recapitulate BAX-dependent mitochondrial outer membrane permeabilization. Our investigations revealed that the presence of BAX, BID, and BIM differentially regulated the ability of BH3 mimetics to derepress proapoptotic molecules from anti-apoptotic proteins. Using mitochondria loaded with fluorescent BH3 peptides and cells treated with inducers of cell death, these differences were supported. Together, these data suggest that although the presence of anti-apoptotic BCL-2 proteins primarily dictates cellular sensitivity to BH3 mimetics, additional specificity is conferred by proapoptotic BCL-2 proteins. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Host-derived apolipoproteins play comparable roles with viral secretory proteins Erns and NS1 in the infectious particle formation of Flaviviridae.

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Takasuke Fukuhara

2017-06-01

Full Text Available Amphipathic α-helices of exchangeable apolipoproteins have shown to play crucial roles in the formation of infectious hepatitis C virus (HCV particles through the interaction with viral particles. Among the Flaviviridae members, pestivirus and flavivirus possess a viral structural protein Erns or a non-structural protein 1 (NS1 as secretory glycoproteins, respectively, while Hepacivirus including HCV has no secretory glycoprotein. In case of pestivirus replication, the C-terminal long amphipathic α-helices of Erns are important for anchoring to viral membrane. Here we show that host-derived apolipoproteins play functional roles similar to those of virally encoded Erns and NS1 in the formation of infectious particles. We examined whether Erns and NS1 could compensate for the role of apolipoproteins in particle formation of HCV in apolipoprotein B (ApoB and ApoE double-knockout Huh7 (BE-KO, and non-hepatic 293T cells. We found that exogenous expression of either Erns or NS1 rescued infectious particle formation of HCV in the BE-KO and 293T cells. In addition, expression of apolipoproteins or NS1 partially rescued the production of infectious pestivirus particles in cells upon electroporation with an Erns-deleted non-infectious RNA. As with exchangeable apolipoproteins, the C-terminal amphipathic α-helices of Erns play the functional roles in the formation of infectious HCV or pestivirus particles. These results strongly suggest that the host- and virus-derived secretory glycoproteins have overlapping roles in the viral life cycle of Flaviviridae, especially in the maturation of infectious particles, while Erns and NS1 also participate in replication complex formation and viral entry, respectively. Considering the abundant hepatic expression and liver-specific propagation of these apolipoproteins, HCV might have evolved to utilize them in the formation of infectious particles through deletion of a secretory viral glycoprotein gene.

Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling.

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Liu, Yaquan; Tian, Fang; Zhi, Dejuan; Wang, Haiqing; Zhao, Chunyan; Li, Hongyu

2017-02-01

Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7' positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative Allometric Growth of the Mimetic Ephippid Reef Fishes Chaetodipterus faber and Platax orbicularis.

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Breno Barros

Full Text Available Mimesis is a relatively widespread phenomenon among reef fish, but the ontogenetic processes relevant for mimetic associations in fish are still poorly understood. In the present study, the allometric growth of two allopatric leaf-mimetic species of ephippid fishes, Chaetodipterus faber from the Atlantic and Platax orbicularis from the Indo-Pacific, was analyzed using ten morphological variables. The development of fins was considered owing to the importance of these structures for mimetic behaviors during early life stages. Despite the anatomical and behavioral similarities in both juvenile and adult stages, C. faber and P. orbicularis showed distinct patterns of growth. The overall shape of C. faber transforms from a rounded-shape in mimetic juveniles to a lengthened profile in adults, while in P. orbicularis, juveniles present an oblong profile including dorsal and anal fins, with relative fin size diminishing while the overall profile grows rounder in adults. Although the two species are closely-related, the present results suggest that growth patterns in C. faber and P. orbicularis are different, and are probably independent events in ephippids that have resulted from similar selective processes.

Effects of apolipoproteins on the kinetics of cholesterol exchange

International Nuclear Information System (INIS)

Letizia, J.Y.; Phillips, M.C.

1991-01-01

The effects of apolipoproteins on the kinetics of cholesterol exchange have been investigated by monitoring the transfer of [ 14 C]cholesterol from donor phospholipid/cholesterol complexes containing human apolipoproteins A, B, or C. Negatively charged discoidal and vesicular particles containing purified apolipoproteins complexed with lipid and a trace of [ 14 C]cholesterol were incubated with a 10-fold excess of neutral, acceptor, small unilamellar vesicles. The donor and acceptor particles were separated by chromatogrphy of DEAE-Sepharose, and the rate of movement of labeled cholesterol was analyzed as a first-order exchange process. The kinetics of exchange of cholesterol from both vesicular and discoidal complexes that contain apoproteins are consistent with an aqueous diffusion mechanism, as has been established previously for PC/cholesterol SUV. Apolipoproteins A-I, A-II, reduced and carboxymethylated A-11, and B-100 present in SUV at the same lipid/protein (w/w) ratio all enhance the rate of cholesterol exchange to about the same degree. Cholesterol molecules exchange more rapidly from discoidal complexes. Generally, as the diameter of apoprotein/phospholipid/cholesterol discs decreases, t 1/2 for cholesterol exchange decreases. Since small bilayer discs have a relatively high ratio of boundary to face surface area, cholesterol molecules desorb more rapidly than from larger discs. The modulation of lipid packing by the apoprotein molecules present at the surface of lipoprotein particles affects the rate of cholesterol exchange from such particles

Apical secretion of apolipoproteins from enterocytes

DEFF Research Database (Denmark)

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

1993-01-01

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...... in the soluble fraction, suggesting a basolateral secretion into the intercellular space, and both this accumulation and the release to the medium was prevented by culture at 20 degrees C. The specific radioactivity of apo A-1 and apo B-48 released to the medium was significantly higher than...... 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...

Targeting apoptotic machinery as approach for anticancer therapy: Smac mimetics as anticancer agents

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Nevine M.Y. Elsayed

2015-06-01

Full Text Available Apoptosis is a chief regulator of cellular homeostasis. Impairment of apoptotic machinery is a main characteristic of several diseases such as cancer, where the evasion of apoptosis is a cardinal hallmark of cancer. Apoptosis is regulated by contribution of pro- and anti- apoptotic proteins, where caspases are the main executioners of the apoptotic machinery. IAP (inhibitors of apoptosis proteins is a family of endogenous inhibitors of apoptosis, which perform their function through interference with the function of caspases. Smac (second mitochondria-derived activator of caspases is endogenous inhibitor of IAPs, thus it is one of the major proapoptotic endogenous proteins. Thus, the development of Smac mimetics has evolved as an approach for anticancer therapy. Several Smac mimetic agents have been introduced to clinical trial such as birinapanet 12. Herein, the history of development of Smac mimetics along with the recent development in this field is briefly discussed.

Genetic influence of apolipoprotein E4 genotype on hippocampal morphometry: An N = 725 surface-based Alzheimer's disease neuroimaging initiative study.

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Shi, Jie; Leporé, Natasha; Gutman, Boris A; Thompson, Paul M; Baxter, Leslie C; Caselli, Richard J; Wang, Yalin

2014-08-01

The apolipoprotein E (APOE) e4 allele is the most prevalent genetic risk factor for Alzheimer's disease (AD). Hippocampal volumes are generally smaller in AD patients carrying the e4 allele compared to e4 noncarriers. Here we examined the effect of APOE e4 on hippocampal morphometry in a large imaging database-the Alzheimer's Disease Neuroimaging Initiative (ADNI). We automatically segmented and constructed hippocampal surfaces from the baseline MR images of 725 subjects with known APOE genotype information including 167 with AD, 354 with mild cognitive impairment (MCI), and 204 normal controls. High-order correspondences between hippocampal surfaces were enforced across subjects with a novel inverse consistent surface fluid registration method. Multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance were computed for surface deformation analysis. Using Hotelling's T(2) test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the nondemented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes. Our findings are consistent with previous studies that showed e4 carriers exhibit accelerated hippocampal atrophy; we extend these findings to a novel measure of hippocampal morphometry. Hippocampal morphometry has significant potential as an imaging biomarker of early stage AD. Copyright © 2014 Wiley Periodicals, Inc.

A fast and cost-effective method for apolipoprotein E isotyping as an alternative to APOE genotyping for patient screening and stratification.

Science.gov (United States)

Calero, Olga; García-Albert, Luis; Rodríguez-Martín, Andrés; Veiga, Sergio; Calero, Miguel

2018-04-13

Apolipoprotein E (apoE) is a 34 kDa glycoprotein involved in lipid metabolism. The human APOE gene encodes for three different apoE protein isoforms: E2, E3 and E4. The interest in apoE isoforms is high for epidemiological research, patient stratification and identification of those at increased risk for clinical trials and prevention. The isoform apoE4 is associated with increased risk for coronary heart and Alzheimer's diseases. This paper describes a method for specifically detecting the apoE4 isoform from biological fluids by taking advantage of the capacity of apoE to bind "specifically" to polystyrene surfaces as capture and a specific anti-apoE4 monoclonal antibody as reporter. Our results indicate that the apoE-polystyrene binding interaction is highly stable, resistant to detergents and acid and basic washes. The methodology here described is accurate, easily implementable, fast and cost-effective. Although at present, our technique is unable to discriminate homozygous APOE ε4/ε4 from APOE ε3/ε4 and ε2/ε4 heterozygous, it opens new avenues for the development of inexpensive, yet effective, tests for the detection of apoE4 for patients' stratification. Preliminary results indicated that this methodology is also adaptable into turbidimetric platforms, which make it a good candidate for clinical implementation through its translation to the clinical analysis routine.

Salicylamide and salicylglycine oxidovanadium complexes with insulin-mimetic properties.

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Nilsson, Jessica; Shteinman, Albert A; Degerman, Eva; Enyedy, Eva A; Kiss, Tamás; Behrens, Ulrich; Rehder, Dieter; Nordlander, Ebbe

2011-12-01

Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the oxidovanadium(V) oxido-bridged dimer [{(papy)(VO)}(2) μ-O)] (1). Similarly, reaction of N-(2-hydroxybenzyl) glycine (H(2)glysal) with VOSO(4) gives [(glysal)VO(H(2)O)] (2) and reaction of salicylamide (Hsalam) with VOSO(4) in methanol gives [(salam)(2)VO] (3). The crystal structure of the oxido-bridged complex 1 is reported. The insulin-mimetic activity of all three complexes was evaluated with respect to their ability to phosphorylate protein kinase B (PKB). The speciations of complexes 1 and 2 were studied over the pH range 2-10. Complex 1 shows greater stability over the whole pH range but only 2 and 3 exhibit an insulin-mimetic effect. Copyright © 2011 Elsevier Inc. All rights reserved.

Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

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C.V. Araújo

2015-06-01

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.

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)

2015-04-28

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

Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

International Nuclear Information System (INIS)

Araújo, C.V.; Lazzarotto, C.R.; Aquino, C.C.; Figueiredo, I.L.; Costa, T.B.; Oliveira Alves, L.A. de; Ribeiro, R.A.; Bertolini, L.R.; Lima, A.A.M.; Brito, G.A.C.; Oriá, R.B.

2015-01-01

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

Sildenafil restores endothelial function in the apolipoprotein E knockout mouse

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Balarini Camille M

2013-01-01

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

Metabolic benefits of inhibiting cAMP-PDEs with resveratrol.

Science.gov (United States)

Chung, Jay H

2012-10-01

Calorie restriction (CR) extends lifespan in species ranging from yeast to mammals. There is evidence that CR also protects against aging-related diseases in non-human primates. This has led to an intense interest in the development of CR-mimetics to harness the beneficial effects of CR to treat aging-related diseases. One CR-mimetic that has received a great deal of attention is resveratrol. Resveratrol extends the lifespan of obese mice and protects against obesity-related diseases such as type 2 diabetes. The specific mechanism of resveratrol action has been difficult to elucidate because resveratrol has a promiscuous target profile. A recent finding indicates that the metabolic effects of resveratrol may result from competitive inhibition of cAMP-degrading phosphodiesterases (PDEs), which increases cAMP levels. The cAMP-dependent pathways activate AMP-activated protein kinase (AMPK), which is essential for the metabolic effects of resveratrol. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including protection against diet-induced obesity and an increase in mitochondrial function, physical stamina and glucose tolerance in mice. This discovery suggests that PDE inhibitors may be useful for treating metabolic diseases associated with aging.

Enhanced capillary electrophoretic screening of Alzheimer based on direct apolipoprotein E genotyping and one-step multiplex PCR.

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Woo, Nain; Kim, Su-Kang; Sun, Yucheng; Kang, Seong Ho

2018-01-01

Human apolipoprotein E (ApoE) is associated with high cholesterol levels, coronary artery disease, and especially Alzheimer's disease. In this study, we developed an ApoE genotyping and one-step multiplex polymerase chain reaction (PCR) based-capillary electrophoresis (CE) method for the enhanced diagnosis of Alzheimer's. The primer mixture of ApoE genes enabled the performance of direct one-step multiplex PCR from whole blood without DNA purification. The combination of direct ApoE genotyping and one-step multiplex PCR minimized the risk of DNA loss or contamination due to the process of DNA purification. All amplified PCR products with different DNA lengths (112-, 253-, 308-, 444-, and 514-bp DNA) of the ApoE genes were analyzed within 2min by an extended voltage programming (VP)-based CE under the optimal conditions. The extended VP-based CE method was at least 120-180 times faster than conventional slab gel electrophoresis methods In particular, all amplified DNA fragments were detected in less than 10 PCR cycles using a laser-induced fluorescence detector. The detection limits of the ApoE genes were 6.4-62.0pM, which were approximately 100-100,000 times more sensitive than previous Alzheimer's diagnosis methods In addition, the combined one-step multiplex PCR and extended VP-based CE method was also successfully applied to the analysis of ApoE genotypes in Alzheimer's patients and normal samples and confirmed the distribution probability of allele frequencies. This combination of direct one-step multiplex PCR and an extended VP-based CE method should increase the diagnostic reliability of Alzheimer's with high sensitivity and short analysis time even with direct use of whole blood. Copyright © 2017 Elsevier B.V. All rights reserved.

Influences of a-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet

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Peluzio M.C.G.

2001-01-01

Full Text Available Although the role of oxidized lipoproteins is well known in atherogenesis, the role of vitamin E supplementation is still controversial. There is also little information about cholesterol metabolism (hepatic concentration and fecal excretion in the new models of atherosclerosis. In the present study, we evaluated the effect of moderate vitamin E supplementation on cholesterol metabolism and atherogenesis in apolipoprotein E (apo E-deficient mice. Apo E-deficient mice were fed an atherogenic diet containing 40 or 400 mg/kg of alpha-tocopherol acetate for 6 weeks. Total cholesterol in serum and liver and 3-OH-alpha-sterols in feces, and fecal excretion of bile acids were determined and histological analyses of aortic lesion were performed. A vitamin E-rich diet did not affect body weight, food intake or serum cholesterol. Serum and hepatic concentrations of cholesterol as well as sterol concentration in feces were similar in both groups. However, when compared to controls, the alpha-tocopherol-treated mice showed a reduction of about 60% in the atherosclerotic lesions when both the sum of lesion areas and the average of the largest lesion area were considered. These results demonstrate that supplementation of moderate doses of alpha-tocopherol was able to slow atherogenesis in apo E-deficient mice and to reduce atherogenic lipoproteins without modifying the hepatic pool or fecal excretion of cholesterol and bile acids.

Apolipoprotein CIII Reduces Proinflammatory Cytokine-Induced Apoptosis in Rat Pancreatic Islets via the Akt Prosurvival Pathway

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Størling, Joachim; Juntti-Berggren, Lisa; Olivecrona, Gunilla

2011-01-01

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...... 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...

Apolipoprotein J (clusterin) and Alzheimer's disease.

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Calero, M; Rostagno, A; Matsubara, E; Zlokovic, B; Frangione, B; Ghiso, J

2000-08-15

Apolipoprotein J (clusterin) is a ubiquitous multifunctional glycoprotein capable of interacting with a broad spectrum of molecules. In pathological conditions, it is an amyloid associated protein, co-localizing with fibrillar deposits in systemic and localized amyloid disorders. In Alzheimer's disease, the most frequent form of amyloidosis in humans and the major cause of dementia in the elderly, apoJ is present in amyloid plaques and cerebrovascular deposits but is rarely seen in NFT-containing neurons. ApoJ expression is up-regulated in a wide variety of insults and may represent a defense response against local damage to neurons. Four different mechanisms of action could be postulated to explain the role of apoJ as a neuroprotectant during cellular stress: (1) function as an anti-apoptotic signal, (2) protection against oxidative stress, (3) inhibition of the membrane attack complex of complement proteins locally activated as a result of inflammation, and (4) binding to hydrophobic regions of partially unfolded, stressed proteins, and therefore avoiding aggregation in a chaperone-like manner. This review focuses on the association of apoJ in biological fluids with Alzheimer's soluble Abeta. This interaction prevents Abeta aggregation and fibrillization and modulates its blood-brain barrier transport at the cerebrovascular endothelium. Copyright 2000 Wiley-Liss, Inc.

Proteomic Profile of Unstable Atheroma Plaque: Increased Neutrophil Defensin 1, Clusterin, and Apolipoprotein E Levels in Carotid Secretome.

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Aragonès, Gemma; Auguet, Teresa; Guiu-Jurado, Esther; Berlanga, Alba; Curriu, Marta; Martinez, Salomé; Alibalic, Ajla; Aguilar, Carmen; Hernández, Esteban; Camara, María-Luisa; Canela, Núria; Herrero, Pol; Ruyra, Xavier; Martín-Paredero, Vicente; Richart, Cristóbal

2016-03-04

Because of the clinical significance of carotid atherosclerosis, the search for novel biomarkers has become a priority. The aim of the present study was to compare the protein secretion profile of the carotid atherosclerotic plaque (CAP, n = 12) and nonatherosclerotic mammary artery (MA, n = 10) secretomes. We used a nontargeted proteomic approach that incorporated tandem immunoaffinity depletion, iTRAQ labeling, and nanoflow liquid chromatography coupled to high-resolution mass spectrometry. In total, 162 proteins were quantified, of which 25 showed statistically significant differences in secretome levels between carotid atherosclerotic plaque and nondiseased mammary artery. We found increased levels of neutrophil defensin 1, apolipoprotein E, clusterin, and zinc-alpha-2-glycoprotein in CAP secretomes. Results were validated by ELISA assays. Also, differentially secreted proteins are involved in pathways such as focal adhesion and leukocyte transendothelial migration. In conclusion, this study provides a subset of identified proteins that are differently expressed in secretomes of clinical significance.

A case–control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression

International Nuclear Information System (INIS)

De Feo, Emma; Boccia, Stefania; Simone, Benedetto; Persiani, Roberto; Cananzi, Ferdinando; Biondi, Alberto; Arzani, Dario; Amore, Rosarita; D’Ugo, Domenico; Ricciardi, Gualtiero

2012-01-01

Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far. One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model. Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium. Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings

Isolation and characterization of human apolipoprotein M-containing lipoproteins

DEFF Research Database (Denmark)

Christoffersen, Christina; Nielsen, Lars Bo; Axler, Olof

2006-01-01

Apolipoprotein M (apoM) is a novel apolipoprotein with unknown function. In this study, we established a method for isolating apoM-containing lipoproteins and studied their composition and the effect of apoM on HDL function. ApoM-containing lipoproteins were isolated from human plasma...... with immunoaffinity chromatography and compared with lipoproteins lacking apoM. The apoM-containing lipoproteins were predominantly of HDL size; approximately 5% of the total HDL population contained apoM. Mass spectrometry showed that the apoM-containing lipoproteins also contained apoJ, apoA-I, apoA-II, apoC-I, apo...

Synthesis of new enantiopure poly(hydroxyaminooxepanes as building blocks for multivalent carbohydrate mimetics

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Léa Bouché

2014-01-01

Full Text Available New compounds with carbohydrate-similar structure (carbohydrate mimetics are presented in this article. Starting from enantiopure nitrones and lithiated TMSE-allene we prepared three 1,2-oxazine derivatives which underwent a highly stereoselective Lewis acid-induced rearrangement to give bicyclic products in good yield. Subsequent reductive transformations delivered a library of new poly(hydroxyaminooxepane derivatives. The crucial final palladium-catalyzed hydrogenolysis of the 1,2-oxazine moiety was optimized resulting in a reasonably efficient approach to a series of new seven-membered carbohydrate mimetics.

Apolipoprotein E4 Allele and Gait Performance in Mild Cognitive Impairment: Results From the Gait and Brain Study.

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Sakurai, Ryota; Montero-Odasso, Manuel

2017-11-09

The apolipoprotein E polymorphism ε4 allele (ApoE4) and gait impairment are both known risk factors for developing cognitive decline and dementia. However, it is unclear the interrelationship between these factors, particularly among older adults with mild cognitive impairment (MCI) who are considered as prodromal for Alzheimer's disease. This study aimed to determine whether ApoE4 carrier individuals with MCI may experience greater impairment in gait performance. Fifty-six older adults with MCI from the "Gait and Brain Study" who were identified as either ApoE4 carriers (n = 20) or non-ApoE4 carriers (n = 36) with 1 year of follow-up were included. Gait variability, the main outcome variable, was assessed as stride time variability with an electronic walkway. Additional gait variables and cognitive performance (mini-mental state examination [MMSE] and Montreal Cognitive Assessment [MoCA]) were also recorded. Covariates included age, sex, education level, body mass index, and number of comorbidities. Baseline characteristics were similar for both groups. Repeated measures analysis of covariance showed that gait stride time and stride length variabilities significantly increased in ApoE4 carriers but was maintained in the non-ApoE4 carriers. Similarly, ApoE4 carriers showed greater decrease in MMSE score at follow-up. In this sample of older adults with MCI, the presence of at least one copy of ApoE4 was associated with the development of both increased gait variability and cognitive decline during 1 year of follow-up. ApoE4 genotype might be considered as a potential mediator of decline in mobility function in MCI; future studies with larger samples are needed to confirm our preliminary findings. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

cDNA sequences of two apolipoproteins from lamprey

International Nuclear Information System (INIS)

Pontes, M.; Xu, X.; Graham, D.; Riley, M.; Doolittle, R.F.

1987-01-01

The messages for two small but abundant apolipoproteins found in lamprey blood plasma were cloned with the aid of oligonucleotide probes based on amino-terminal sequences. In both cases, numerous clones were identified in a lamprey liver cDNA library, consistent with the great abundance of these proteins in lamprey blood. One of the cDNAs (LAL1) has a coding region of 105 amino acids that corresponds to a 21-residue signal peptide, a putative 8-residue propeptide, and the 76-residue mature protein found in blood. The other cDNA (LAL2) codes for a total of 191 residues, the first 23 of which constitute a signal peptide. The two proteins, which occur in the high-density lipoprotein fraction of ultracentrifuged plasma, have amino acid compositions similar to those of apolipoproteins found in mammalian blood; computer analysis indicates that the sequences are largely helix-permissive. When the sequences were searched against an amino acid sequence data base, rat apolipoprotein IV was the best matching candidate in both cases. Although a reasonable alignment can be made with that sequence and LAL1, definitive assignment of the two lamprey proteins to typical mammalian classes cannot be made at this point

Apolipoprotein E polymorphism in India

DEFF Research Database (Denmark)

Singh, P; Singh, M; Gerdes, Lars Ulrik

2001-01-01

to be the highest (0.913) in Ramgarhia in comparison to forty-one populations of the world. A decreasing cline from south to north was evident for *E2 and *E4 allele frequencies (y = -0.002x + 0.141, r = 0.78 and y = -0.004x + 0.229, r = 0.83, respectively, and an increasing cline for the *E3 allele towards north......, India. Three alleles APOE*E2, APOE*E3 and APOE*E4 were observed in Ramgarhia and Ramdasia with the frequencies of 0.031, 0.913, 0.056 and 0.043, 0.886 and 0.071, respectively. Higher heterozygosity (20.8%) in Ramdasia reflects greater variation at the APOE locus. The APOE*E3 allele is found...

Interaction of GABA-mimetics with the taurine transporter (TauT, Slc6a6) in hyperosmotic treated Caco-2, LLC-PK1 and rat renal SKPT cells.

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Rasmussen, Rune Nørgaard; Lagunas, Candela; Plum, Jakob; Holm, René; Nielsen, Carsten Uhd

2016-01-20

The aim of the present study was to investigate if basic GABA-mimetics interact with the taurine transporter (TauT, Slc6a6), and to find a suitable cell based model that is robust towards extracellular changes in osmolality during uptake studies. Taurine uptake was measured in human Caco-2 cells, porcine LLC-PK1 cells, and rat SKPT cells using radiolabelled taurine. Hyperosmotic conditions were obtained by incubation with raffinose (final osmolality of 500mOsm) for 24h prior to the uptake experiments. Expression of the taurine transporter, TauT, was investigated at the mRNA level by real-time PCR. Uptake of the GABA-mimetics gaboxadol and vigabatrin was investigated in SKPT cells, and quantified by liquid scintillation or HPLC-MS/MS analysis, respectively. The uptake rate of [(3)H]-taurine was Na(+) and Cl(-) and concentration dependent with taurine with an apparent Vmax of 6.3±1.6pmolcm(-2)min(-1) and a Km of 24.9±15.0μM. β-alanine, nipecotic acid, gaboxadol, GABA, vigabatrin, δ-ALA and guvacine inhibited the taurine uptake rate in a concentration dependent manner. The order of affinity for TauT was β-alanine>GABA>nipecotic acid>guvacine>δ-ALA>vigabatrin>gaboxadol with IC50-values of 0.04, 1.07, 2.02, 4.19, 4.94, 31.4 and 39.9mM, respectively. In conclusion, GABA mimetics inhibited taurine uptake in hyperosmotic rat renal SKPT cells. SKPT cells, which seem to be a useful model for investigating taurine transport in the short-term presence of high concentrations of osmolytes. Furthermore, analogues of β-alanine appear to have higher affinities for TauT than GABA-analogues. Copyright © 2015 Elsevier B.V. All rights reserved.

Improved surface bioactivity of stainless steel substrates using osteocalcin mimetic peptide

International Nuclear Information System (INIS)

Hosseini, Samaneh; Naderi-Manesh, Hossein; Vali, Hojatollah; Faghihi, Shahab

2014-01-01

Although stainless steel has a good biocompatibility for most clinical cases, the higher tissue response (bone bonding property) is required in orthopedic field. In this study, to improve bone-bonding ability of stainless steel substrates, a specific sequence of osteocalcin mimetic peptide is used as bioactive coating material to biochemically modify the surface of metallic samples. This sequence consists of thirteen amino acids present in the first helix of osteocalcin is synthesized in amidic form and physically adsorbed on the surface of 316LS (316 low carbon surgical grade) stainless steel substrates. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) are used to characterize the surface of peptide coated and uncoated substrates. The bioactivity and bone bonding ability of coated and uncoated substrates are assessed by level of hydroxyapatite formation, using transmission electron microscopy (TEM), energy-dispersive x-ray (EDS), and scanning electron microscopy (SEM). The pre-osteoblast cell attachment and proliferation are also evaluated by MTT assay. The results show that the surface of coated sample is homogenously covered by the peptide and display a rougher surface relative to uncoated sample. TEM images reveal the formation of plate-like hydroxyapatite crystals in the presence of the peptide and an amorphous calcium phosphate phase without the peptide. Pre-osteoblast cells proliferation is significantly higher on the surface of peptide coated substrate, while cell attachment remains unaffected by the peptide coatings. Pre-osteoblast cells also demonstrate a higher degree of spreading on the surface of coated sample. It is believed that osteocalcin mimetic peptide improve surface bioactivity and promote hydroxyapatite crystal formation may lead to increased mineralization and bone formation on the surface of metallic biomedical devices. - Graphical abstract: A peptide sequence located in the first helix of OC is selected based on its

Improved surface bioactivity of stainless steel substrates using osteocalcin mimetic peptide

Energy Technology Data Exchange (ETDEWEB)

Hosseini, Samaneh [Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Tissue Engineering and Biomaterials Division, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161 (Iran, Islamic Republic of); Naderi-Manesh, Hossein, E-mail: naderman@modares.ac.ir [Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Vali, Hojatollah [Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montréal, QC H3A 0C7 (Canada); Faghihi, Shahab, E-mail: sfaghihi@nigeb.ac.ir [Tissue Engineering and Biomaterials Division, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161 (Iran, Islamic Republic of)

2014-02-14

Although stainless steel has a good biocompatibility for most clinical cases, the higher tissue response (bone bonding property) is required in orthopedic field. In this study, to improve bone-bonding ability of stainless steel substrates, a specific sequence of osteocalcin mimetic peptide is used as bioactive coating material to biochemically modify the surface of metallic samples. This sequence consists of thirteen amino acids present in the first helix of osteocalcin is synthesized in amidic form and physically adsorbed on the surface of 316LS (316 low carbon surgical grade) stainless steel substrates. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) are used to characterize the surface of peptide coated and uncoated substrates. The bioactivity and bone bonding ability of coated and uncoated substrates are assessed by level of hydroxyapatite formation, using transmission electron microscopy (TEM), energy-dispersive x-ray (EDS), and scanning electron microscopy (SEM). The pre-osteoblast cell attachment and proliferation are also evaluated by MTT assay. The results show that the surface of coated sample is homogenously covered by the peptide and display a rougher surface relative to uncoated sample. TEM images reveal the formation of plate-like hydroxyapatite crystals in the presence of the peptide and an amorphous calcium phosphate phase without the peptide. Pre-osteoblast cells proliferation is significantly higher on the surface of peptide coated substrate, while cell attachment remains unaffected by the peptide coatings. Pre-osteoblast cells also demonstrate a higher degree of spreading on the surface of coated sample. It is believed that osteocalcin mimetic peptide improve surface bioactivity and promote hydroxyapatite crystal formation may lead to increased mineralization and bone formation on the surface of metallic biomedical devices. - Graphical abstract: A peptide sequence located in the first helix of OC is selected based on its

Social variables exert selective pressures in the evolution and form of primate mimetic musculature.

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Burrows, Anne M; Li, Ly; Waller, Bridget M; Micheletta, Jerome

2016-04-01

Mammals use their faces in social interactions more so than any other vertebrates. Primates are an extreme among most mammals in their complex, direct, lifelong social interactions and their frequent use of facial displays is a means of proximate visual communication with conspecifics. The available repertoire of facial displays is primarily controlled by mimetic musculature, the muscles that move the face. The form of these muscles is, in turn, limited by and influenced by phylogenetic inertia but here we use examples, both morphological and physiological, to illustrate the influence that social variables may exert on the evolution and form of mimetic musculature among primates. Ecomorphology is concerned with the adaptive responses of morphology to various ecological variables such as diet, foliage density, predation pressures, and time of day activity. We present evidence that social variables also exert selective pressures on morphology, specifically using mimetic muscles among primates as an example. Social variables include group size, dominance 'style', and mating systems. We present two case studies to illustrate the potential influence of social behavior on adaptive morphology of mimetic musculature in primates: (1) gross morphology of the mimetic muscles around the external ear in closely related species of macaque (Macaca mulatta and Macaca nigra) characterized by varying dominance styles and (2) comparative physiology of the orbicularis oris muscle among select ape species. This muscle is used in both facial displays/expressions and in vocalizations/human speech. We present qualitative observations of myosin fiber-type distribution in this muscle of siamang (Symphalangus syndactylus), chimpanzee (Pan troglodytes), and human to demonstrate the potential influence of visual and auditory communication on muscle physiology. In sum, ecomorphologists should be aware of social selective pressures as well as ecological ones, and that observed morphology might

Differential effect of walnut oil and safflower oil on the serum cholesterol level and lesion area in the aortic root of apolipoprotein E-deficient mice.

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Iwamoto, Masako; Kono, Misaki; Kawamoto, Daisuke; Tomoyori, Hiroko; Sato, Masao; Imaizumi, Katsumi

2002-01-01

Walnut oil (WO) is a good source of alpha-linolenic acid. We compared the effects of WO and high-linoleic safflower oil (HLSO) on the serum lipid level and atherosclerosis development in male and female apolipoprotein (apo) E-deficient mice. The WO diet resulted in a higher level of serum cholesterol than with HLSO. Female mice fed on the WO diet had a greater lesion area in the aortic root than did those on the HLSO diet. There was no diet-dependent difference in the level of cholesterol and its oxidation products in the abdominal and thoracic aorta. These results suggest that the unpleasant effects of the WO diet on apo E-deficient mice may be attributable to alpha-linolenic acid.

JSI-124 inhibits IgE production in an IgE B cell line

International Nuclear Information System (INIS)

Cui, Lulu; Bi, Jiacheng; Yan, Dehong; Ye, Xiufeng; Zheng, Mingxing; Yu, Guang; Wan, Xiaochun

2017-01-01

IgE is a key effector molecule in atopic diseases; however, the regulation mechanisms of IgE production in IgE B cells remain poorly understood. In the present study, we demonstrate that JSI-124 (cucurbitacin I), a selective STAT3 inhibitor, selectively inhibits production of IgE by a human IgE B cell line, CRL-8033 cells, while does not affect the IgG production by IgG B cell lines. In the aspect of molecular mechanism, we found that Igλ, but not Ighe, gene expression was suppressed by JSI-124. The above effects of JSI-124 were not mediated by affecting cellular proliferation or apoptosis. Furthermore, multiple B cell differentiation-related genes expression was not significantly affected by JSI-124. Taken together, we demonstrate a potential strategy of therapeutically suppressing IgE production without affecting IgG production in atopic patients. - Highlights: • JSI-124 inhibits IgE production in an IgE B cell line, CRL-8033 cells. • JSI-124 does not affect IgG production by IgG B cell lines. • JSI-124 inhibits IgE production mainly by suppressing transcription of Igλ.

HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

Science.gov (United States)

Sanchez-Gaytan, Brenda L; Fay, Francois; Lobatto, Mark E; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E M; van Rijs, Sarian M; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J; Langer, Robert; Fayad, Zahi A; Mulder, Willem J M

2015-03-18

High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers.

Albumin nanoparticles targeted with Apo E enter the CNS by transcytosis and are delivered to neurones.

Science.gov (United States)

Zensi, Anja; Begley, David; Pontikis, Charles; Legros, Celine; Mihoreanu, Larisa; Wagner, Sylvia; Büchel, Claudia; von Briesen, Hagen; Kreuter, Jörg

2009-07-01

The blood-brain barrier (BBB) represents a considerable obstacle to brain entry of the majority of drugs and thus severely restricts the therapy of many serious CNS diseases including brain tumours, brain HIV, Alzheimer and other neurodegenerative diseases. The use of nanoparticles coated with polysorbate 80 or with attached apolipoprotein E has enabled the delivery of drugs across the BBB. However, the mechanism of this enhanced transport is still not fully understood. In this present study, human serum albumin nanoparticles, with covalently bound apolipoprotein E (Apo E) as a targetor as well as without apolipoprotein E, were manufactured and injected intravenously into SV 129 mice. The animals were sacrificed after 15 and 30 min, and their brains were examined by transmission electron microscopy. Only the nanoparticles with covalently bound apolipoprotein E were detected in brain capillary endothelial cells and neurones, whereas no uptake into the brain was detectable with nanoparticles without apolipoprotein E. We have also demonstrated uptake of the albumin/ApoE nanoparticles into mouse endothelial (b.End3) cells in vitro and their intracellular localisation. These findings indicate that nanoparticles with covalently bound apolipoprotein E are taken up into the cerebral endothelium by an endocytic mechanism followed by transcytosis into brain parenchyma.

Phylogeny and evolution of Müllerian mimicry in aposematic Dilophotes: evidence for advergence and size-constraints in evolution of mimetic sexual dimorphism.

Science.gov (United States)

Motyka, Michal; Kampova, Lucie; Bocak, Ladislav

2018-02-27

Multiple patterns and intraspecific polymorphism should not persist in mutualistic Müllerian systems due to purifying and frequency-dependent selection, but they are commonly identified in nature. We analysed molecular phylogeny and reconstructed dispersal history of 58 species of Dilophotes (Coleoptera: Lycidae) in Asia. Dilophotes colonized the Great Sundas and Malay Peninsula where they joined extensive mimetic communities of net-winged beetles. We identified the brightly bi-coloured males and females which adverged on five occasions to different autochthonous models. This is the first described case of Müllerian sexual dimorphism based on sex-specific body size. We propose that the constraint, i.e. the conservative sexual size dimorphism, forced the unprofitable prey to such complex adaptation in a multi-pattern environment. Although mimetic sexual dimorphism has frequently evolved in Dilophotes, a single pattern has been maintained by both sexes in multiple closely related, sympatrically occurring species. Some patterns may be suboptimal because they are rare, crudely resemble co-mimics, or are newly evolved, but they persist in Müllerian communities for a long time. We assume that failure to closely resemble the most common model can increase the diversity of large Müllerian communities and produce mimetic dimorphism.

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))

1993-05-01

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

Spectral mimetic least-squares method for div-curl systems

NARCIS (Netherlands)

Gerritsma, Marc; Palha, Artur; Lirkov, I.; Margenov, S.

2018-01-01

In this paper the spectral mimetic least-squares method is applied to a two-dimensional div-curl system. A test problem is solved on orthogonal and curvilinear meshes and both h- and p-convergence results are presented. The resulting solutions will be pointwise divergence-free for these test

Interaction of GABA-mimetics with the taurine transporter (TauT, Slc6a6) in hyperosmotic treated caco-2, LLC-PK1 and rat renal SKPT cells

DEFF Research Database (Denmark)

Rasmussen, Rune Nørgaard; Lagunas, Candela; Plum, Jakob Munk

2016-01-01

The aim of the present study was to investigate if basic GABA-mimetics interact with the taurine transporter (TauT, Slc6a6), and to find a suitable cell based model that is robust towards extracellular changes in osmolality during uptake studies. Taurine uptake was measured in human Caco-2 cells....... Uptake of the GABA-mimetics gaboxadol and vigabatrin was investigated in SKPT cells, and quantified by liquid scintillation or HPLC-MS/MS analysis, respectively. The uptake rate of [(3)H]-taurine was Na(+) and Cl(-) and concentration dependent with taurine with an apparent Vmax of 6.3±1.6pmolcm(-2)min(-1......) and a Km of 24.9±15.0μM. β-alanine, nipecotic acid, gaboxadol, GABA, vigabatrin, δ-ALA and guvacine inhibited the taurine uptake rate in a concentration dependent manner. The order of affinity for TauT was β-alanine>GABA>nipecotic acid>guvacine>δ-ALA>vigabatrin>gaboxadol with IC50-values of 0.04, 1.07, 2...

N-3 PUFAs protect against aortic inflammation and oxidative stress in angiotensin II-infused apolipoprotein E-/- mice.

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Kathryn M Wales

Full Text Available Abdominal aortic aneurysm is associated with infiltration of inflammatory cells into the aortic wall. The inflammatory response is also evident in animal models, such as apolipoprotein E-deficient (ApoE-/- mice that have been infused with angiotensin II, prior to development of aortic aneurysm. Since omega-3 polyunsaturated fatty acids (n-3 PUFAs and their metabolites have anti-inflammatory and pro-resolving activity, we hypothesised that dietary supplementation with n-3 PUFAs would protect against inflammatory processes in this mouse model. Twenty C57 and 20 ApoE-/- 3-4 week old male mice were supplemented with a low (0.14%, n = 10/group or high (0.70%, n = 10/group n-3 PUFA diet for 8 weeks before 2-day infusion with 0.9% saline or angiotensin II (1000 ng/kg/min. Four ApoE-/- mice on the low n-3 PUFA diet and none of the ApoE-/- mice on the high n-3 PUFA diet showed morphological evidence of abdominal aortic dissection. The plasma concentration of the n-3 PUFA metabolite, resolvin D1 was higher in angiotensin II-infused ApoE-/- mice fed the high, compared to the low n-3 PUFA diet. The number of neutrophils and macrophages infiltrating the abdominal aorta was elevated in ApoE-/- mice on the low n-3 PUFA diet, and this was significantly attenuated in mice that were fed the high n-3 PUFA diet. Most neutrophils and macrophages were associated with dissected aortas. Immunoreactivity of the catalytic subunit of nicotinamide-adenine dinucleotide phosphate (NADPH oxidase, Nox2, and superoxide were elevated in ApoE-/- mice that were fed the low n-3 PUFA diet, and this was also significantly attenuated in mice that were fed the high n-3 PUFA diet. Together, the findings indicate that supplementation of ApoE-/- mice with a diet high in n-3 PUFA content protected the mice against pro-inflammatory and oxidative stress responses following short-term infusion with angiotensin II.

Association between apolipoprotein E genotype, serum lipids, and colorectal cancer in Brazilian individuals.

Science.gov (United States)

Souza, D R S; Nakazone, M A; Pinhel, M A S; Alvares, R M; Monaco, A C; Pinheiro, A; Barros, C F D C; Cury, P M; Cunrath, G S; Netinho, J G

2009-05-01

We evaluated genetic variants of apolipoprotein E (APOE HhaI) and their association with serum lipids in colorectal cancer (CRC), together with eating habits and personal history. Eight-seven adults with CRC and 73 controls were studied. APOE*2 (rs7412) and APOE*4 (rs429358) were identified by polymerase chain reaction-restriction fragment length polymorphism. APOE gene polymorphisms were similar in both groups, but the epsilon4/epsilon4 genotype (6%) was present only in controls. The patients had reduced levels (mean +/- SD) of total cholesterol and low-density lipoprotein cholesterol fraction (180.4 +/- 49.5 and 116.1 +/- 43.1 mg/dL, respectively) compared to controls (204.2 +/- 55.6, P = 0.135 and 134.7 +/- 50.8 mg/dL; P = 0.330, respectively) indicating that they were not statistically significant after the Bonferroni correction. The APOE*4 allele was associated with lower levels of total cholesterol, low- and high-density lipoprotein cholesterol fraction and increased levels of very low-density lipoprotein cholesterol fraction and triglycerides only among patients (P = 0.014). There was a positive correlation between the altered lipid profile and increased body mass indexes in both groups (P hypertension and overweight was observed in controls (P < 0.002). In conclusion, the presence of the epsilon4/epsilon4 genotype only in controls may be due to a protective effect against CRC. Lower lipid profile values among patients, even those on lipid-rich diets associated with the APOE*4 allele, suggest alterations in the lipid synthesis and metabolism pathways in CRC.

M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

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He Zhou

Full Text Available Heparan sulfate proteoglycans (HSPGs play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis.

Science.gov (United States)

Bisoendial, Radjesh; Tabet, Fatiha; Tak, Paul P; Petrides, Francine; Cuesta Torres, Luisa F; Hou, Liming; Cook, Adam; Barter, Philip J; Weninger, Wolfgang; Rye, Kerry-Anne

2015-11-01

Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature. © 2015 American Heart Association, Inc.

Selective labelling of apolipoproteins A-I and C-I at methionine residues by (TH) methyl exchange

Energy Technology Data Exchange (ETDEWEB)

Hancock, W.S.; Harding, D.R.K.; Barling, P.M.; Sparrow, J.T.

1985-01-01

Apolipoproteins C-I and A-I were radioactively labelled with tritium by (TH)-methyl exchange. The methionine residues were first methylated with (TH)-methyl iodide at pH4 and the reaction products were purified by gel filtration and cation exchange chromatography. The products were then demethylated with 2-mercaptoethanol (6 M) at pH 8.6 to regenerate the apolipoproteins in an unmodified but tritiated form. The specific radioactivity for apolipoprotein C-I and A-I was 3.5 x 10W and 1.5 x 10X dpm/pmol respectively. The properties of (TH)-apolipoprotein C-I were examined by reversed phase HPLC and by incorporation into very low density lipoproteins (VLDL).

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

2008-01-01

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

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

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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.

[Prevalence of Variants in the Apolipoprotein E (APOE) Gene in a General Population of Adults from an Urban Area of Medellin (Antioquia)].

Science.gov (United States)

Arango Viana, Juan Carlos; Valencia, Ana Victoria; Páez, Ana Lucía; Montoya Gómez, Nilton; Palacio, Carlos; Arbeláez, María Patricia; Bedoya Berrío, Gabriel; García Valencia, Jenny

2014-01-01

To determine the allelic and genotype frequencies of apolipoproteine E (APOE) gene in a representative sample of the adult population of Medellin in 2010. A representative sample of the adult population of Medellin, was obtained by means of a multi-stage, stratified, conglomerate based sampling method. APOE genotyping was carried out on each of the participants. The sampling design was taken into consideration for the frequencies and association analysis. The frequencies of the APOE alleles E2, E3 and E4 were 3.9, 92.0 and 4.1%, respectively. The frequencies of the different APOE genotypes were as follows: 2/2, 0.2%; 2/3, 6.8%; 2/4, 0.6%; 3/3, 85.0%; 3/4, 7.2%, and 4/4, 0.3%. The allelic and genotype frequencies of APOE in an adult population of Medellin did not differ substantially from other series reported in South America. These data are important to determine the real impact of APOE on the population risk of several psychiatric diseases. Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Loss of PDZK1 causes coronary artery occlusion and myocardial infarction in Paigen diet-fed apolipoprotein E deficient mice.

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Ayce Yesilaltay

2009-12-01

Full Text Available PDZK1 is a four PDZ-domain containing protein that binds to the carboxy terminus of the HDL receptor, scavenger receptor class B type I (SR-BI, and regulates its expression, localization and function in a tissue-specific manner. PDZK1 knockout (KO mice are characterized by a marked reduction of SR-BI protein expression ( approximately 95% in the liver (lesser or no reduction in other organs with a concomitant 1.7 fold increase in plasma cholesterol. PDZK1 has been shown to be atheroprotective using the high fat/high cholesterol ('Western' diet-fed murine apolipoprotein E (apoE KO model of atherosclerosis, presumably because of its role in promoting reverse cholesterol transport via SR-BI.Here, we have examined the effects of PDZK1 deficiency in apoE KO mice fed with the atherogenic 'Paigen' diet for three months. Relative to apoE KO, PDZK1/apoE double KO (dKO mice showed increased plasma lipids (33% increase in total cholesterol; 49 % increase in unesterified cholesterol; and 36% increase in phospholipids and a 26% increase in aortic root lesions. Compared to apoE KO, dKO mice exhibited substantial occlusive coronary artery disease: 375% increase in severe occlusions. Myocardial infarctions, not observed in apoE KO mice (although occasional minimal fibrosis was noted, were seen in 7 of 8 dKO mice, resulting in 12 times greater area of fibrosis in dKO cardiac muscle.These results show that Paigen-diet fed PDZK1/apoE dKO mice represent a new animal model useful for studying coronary heart disease and suggest that PDZK1 may represent a valuable target for therapeutic intervention.

Clinical relevance of apolipoprotein E genotyping based on a family history of Alzheimer's disease.

Science.gov (United States)

Luckhoff, Hilmar K; Brand, Theresa; van Velden, Dawid P; Kidd, Martin; Fisher, Leslie R; van Rensburg, Susan J; Kotze, Maritha J

2015-01-01

Having a family history of Alzheimer' s disease (AD) may potentiate cumulative risk associated with phenotypic expression of the ε-4 allele of the apolipoprotein E (APOE) gene. In this study, we compared the genotype distribution and allele frequencies of APOE ε-2 (rs7412) and ε -4 (rs429358) in 537 South African individuals participating in a chronic disease screening program, in order to establish whether AD family history modulates the expression of their dyslipidemic effects. Significant differences in the genotype distribution for APOE ε-2 (p=0.034) as well as APOE ε-4 (p=0.038) were found between study participants with (n=67) and without (n=470) a family history of AD. LDL cholesterol levels were inversely associated with physical activity in the study group with a positive family history of AD (pfamilial hypercholesterolemia, clinical inquiry regarding family history was identified as an important determinant of eligibility for APOE genotyping performed in the context of chronic disease risk management. To our knowledge, this is the first study to demonstrate the modulating influence of AD family history on expression of a dyslipidemic phenotype associated with the APOE ε-4 allele. Our findings provide the scientific rationale supporting a novel clinical application for APOE genotyping as a means of identifying a genetic subgroup of dyslipidemic patients set to derive the greatest benefit from early lifestyle-based interventions aimed at decreasing cumulative risk for cardiovascular disease and prevention of AD later in life.

The X-X-/E+E+ genotype of the XbaI/EcoRI polymorphisms of the apolipoprotein B gene as a marker of coronary artery disease in a Brazilian sample

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M. Scartezini

2003-03-01

Full Text Available Studies that consider polymorphisms within the apolipoprotein B (apo B gene as risk factors for coronary artery disease (CAD have reported conflicting results. The aim of the present study was to search for associations between two DNA RFLPs (XbaI and EcoRI of the apo B gene and CAD diagnosed by angiography. In the present study we compared 116 Brazilian patients (92 men with CAD (CAD+ to 78 control patients (26 men without ischemia or arterial damage (CAD-. The allele frequencies at the XbaI (X and EcoRI (E sites did not differ between groups. The genotype distributions of CAD+ and CAD- patients were different (chi²(1 = 6.27, P = 0.012 when assigned to two classes (X-X-/E+E+ and the remaining XbaI/EcoRI genotypes. Multivariate logistic regression analysis showed that individuals with the X-X-/E+E+ genotype presented a 6.1 higher chance of developing CAD than individuals with the other XbaI/EcoRI genotypes, independently of the other risk factors considered (sex, tobacco consumption, total cholesterol, hypertension, and triglycerides. We conclude that the X-X-/E+E genotype may be in linkage disequilibrium with an unknown variation in the apo B gene or with a variation in another gene that affects the risk of CAD.

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

2014-01-01

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.

Secretion of apolipoproteins A-I and B by HepG2 cells: regulation by substrates and metabolic inhibitors.

Science.gov (United States)

Kempen, H J; Imbach, A P; Giller, T; Neumann, W J; Hennes, U; Nakada, N

1995-08-01

It was the aim of this study to i) compare the effects of glucose and other hexoses with that of oleate on secretion of apolipoproteins (apos) A-I and B by HepG2 cells, and ii) document the effect of various metabolic inhibitors on the secretion of these apos in the absence or presence of extra glucose/oleate. i) The addition of 10 mM glucose increased secretion of apoA-I and apoB, as measured by enzyme immunoassay, by about 60% when cells were incubated for 48 h in DMEM + 10% fetal calf serum. The addition of extra glucose also increased the mRNA levels for these apos. Increased radioactivity was also found in these apolipoproteins by immunoprecipitation after metabolic labeling with [35S]methionine for 48 h. However, in a pulse-chase experiment (15 min labeling, 2 h chase), glucose was found to increase apoA-I synthesis but not apoB synthesis. More labeled apoB appeared in the medium during the chase because glucose inhibited its intracellular degradation. The effect of glucose on secretion of these apos could be mimicked by fructose and mannose but not by 6-deoxyglucose, showing that the hexoses must enter the cells and be phosphorylated. In contrast, the addition of 0.5 mM oleate had a weak inhibitory effect on secretion of apoA-I whereas it increased the secretion of apoB by more than twofold. The combination of 10 mM glucose and 0.5 mM oleate had no greater effect than glucose alone on apoA-I secretion but increased apoB secretion by fourfold. ii) Inhibiting glycolysis (by glucosamine) lowered secretion of both apoA-I and apoB, while inhibiting lipogenesis (using 8-Br-cyclic AMP or 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA)) did not affect apoA-I secretion but clearly decreased that of apoB. However, the inhibitory effect of TOFA on apoB secretion was much smaller in the presence of 0.5 mM oleate instead of extra glucose. Actinomycin-D and cycloheximide strongly suppressed the stimulatory effect of glucose on secretion of both apolipoproteins

Effects of apolipoprotein M in uremic atherosclerosis

DEFF Research Database (Denmark)

Bosteen, Markus Høybye; Madsen Svarrer, Eva Martha; Bisgaard, Line Stattau

2017-01-01

BACKGROUND AND AIMS: Chronic kidney disease is characterized by uremia and causes premature death, partly due to accelerated atherosclerosis. Apolipoprotein (apo) M is a plasma carrier protein for the lipid sphingosine-1-phosphate (S1P). The Apom-S1P complex associates with HDL, and may contribute...

Association between amylin and amyloid-β peptides in plasma in the context of apolipoprotein E4 allele.

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Wei Qiao Qiu

Full Text Available Amylin, a pancreatic peptide that readily crosses the blood brain barrier (BBB, and amyloid-beta peptide (Aβ, the main component of amyloid plaques and a major component of Alzheimer's disease (AD pathology in the brain, share several features. These include having similar β-sheet secondary structures, binding to the same receptor, and being degraded by the same protease. Thus, amylin may be associated with Aβ, but the nature of their relationship remains unclear. In this study, we used human samples to study the relationship between plasma amylin and Aβ in the context of the apolipoprotein E alleles (ApoE. We found that concentrations of Aβ1-42 (P<0.0001 and Aβ1-40 (P<0.0001 increased with each quartile increase of amylin. Using multivariate regression analysis, the study sample showed that plasma amylin was associated with Aβ1-42 (β = +0.149, SE = 0.025, P<0.0001 and Aβ1-40 (β = +0.034, SE = 0.016, P = 0.04 as an outcome after adjusting for age, gender, ethnicity, ApoE4, BMI, diabetes, stroke, kidney function and lipid profile. This positive association between amylin and Aβ1-42 in plasma was found regardless of the ApoE genotype. In contrast, the relationship between amylin and Aβ1-40 in plasma seen in ApoE4 non-carriers disappeared in the presence of ApoE4. Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p. injection of synthetic amylin enhances the removal of Aβ from the brain into blood, thus resulting in increased blood levels of both amylin and Aβ. The positive association between amylin and Aβ, especially Aβ1-42, in human blood samples is probably relevant to the findings in the AD mouse models. The presence of ApoE4 may attenuate amylin's capacity to remove Aβ, especially Aβ1-40, from the AD brain.

Learning from biology: synthetic lipoproteins for drug delivery.

Science.gov (United States)

Huang, Huang; Cruz, William; Chen, Juan; Zheng, Gang

2015-01-01

Synthetic lipoproteins represent a relevant tool for targeted delivery of biological/chemical agents (chemotherapeutics, siRNAs, photosensitizers, and imaging contrast agents) into various cell types. These nanoparticles offer a number of advantages for drugs delivery over their native counterparts while retaining their natural characteristics and biological functions. Their ultra-small size (lipoprotein receptors, i.e., low-density lipoprotein receptor (LDLR) and Scavenger receptor class B member 1 (SRB1) that are found in a number of pathological conditions (e.g., cancer, atherosclerosis), make them superior delivery strategies when compared with other nanoparticle systems. We review the various approaches that have been developed for the generation of synthetic lipoproteins and their respective applications in vitro and in vivo. More specifically, we summarize the approaches employed to address the limitation on use of reconstituted lipoproteins by means of natural or recombinant apolipoproteins, as well as apolipoprotein mimetic molecules. Finally, we provide an overview of the advantages and disadvantages of these approaches and discuss future perspectives for clinical translation of these nanoparticles. © 2014 Wiley Periodicals, Inc.

Role of phosphate on stability and catalase mimetic activity of cerium oxide nanoparticles.

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Singh, Ragini; Singh, Sanjay

2015-08-01

Cerium oxide nanoparticles (CeNPs) have been recently shown to scavenge reactive oxygen and nitrogen species (ROS and RNS) in different experimental model systems. CeNPs (3+) and CeNPs (4+) have been shown to exhibit superoxide dismutase (SOD) and catalase mimetic activity, respectively. Due to their nanoscale dimension, CeNPs are expected to interact with the components of biologically relevant buffers and medium, which could alter their catalytic properties. We have demonstrated earlier that CeNPs (3+) interact with phosphate and lose the SOD activity. However, very little is known about the interaction of CeNPs (4+) with the phosphate and other anions, predominantly present in biological buffers and their effects on the catalase mimetic-activity of these nanoparticles. In this study, we report that catalase mimetic-activity of CeNPs (4+) is resistant to the phosphate anions, pH changes and composition of cell culture media. Given the abundance of phosphate anions in the biological system, it is likely that internalized CeNPs would be influenced by cytoplasmic and nucleoplasmic concentration of phosphate. Copyright © 2015 Elsevier B.V. All rights reserved.

The mimetic repertoire of the spotted bowerbird Ptilonorhynchus maculatus

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Kelley, Laura A.; Healy, Susan D.

2011-06-01

Although vocal mimicry in songbirds is well documented, little is known about the function of such mimicry. One possibility is that the mimic produces the vocalisations of predatory or aggressive species to deter potential predators or competitors. Alternatively, these sounds may be learned in error as a result of their acoustic properties such as structural simplicity. We determined the mimetic repertoires of a population of male spotted bowerbirds Ptilonorhynchus maculatus, a species that mimics predatory and aggressive species. Although male mimetic repertoires contained an overabundance of vocalisations produced by species that were generally aggressive, there was also a marked prevalence of mimicry of sounds that are associated with alarm such as predator calls, alarm calls and mobbing calls, irrespective of whether the species being mimicked was aggressive or not. We propose that it may be the alarming context in which these sounds are first heard that may lead both to their acquisition and to their later reproduction. We suggest that enhanced learning capability during acute stress may explain vocal mimicry in many species that mimic sounds associated with alarm.

Apolipoprotein E epsilon 4 allele and outcomes of traumatic spinal cord injury in a Chinese Han population.

Science.gov (United States)

Sun, Chongyi; Ji, Guangrong; Liu, Qingpeng; Yao, Meng

2011-10-01

The association between apolipoprotein E (APOE) epsilon 4 (ε4) allele and outcomes of traumatic spinal cord injury (SCI) is still controversial and ambiguous. The objective of this study was to test the hypothesis that APOE polymorphisms are associated with outcomes after SCI in Chinese Han patients. APOE polymorphisms were determined in 100 patients with cervical SCI (C3-C8). The genotype frequency of this polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Patients with an APOE ε4 allele had significantly less motor recovery during rehabilitation than did patients without an APOE ε4 allele (mean 3.7 vs. 6.1; P = 0.04) and a longer rehabilitation length of stay (LOS) (mean 117.4 vs. 94.5; P = 0.02), but better sensory-pinprick recovery (mean 6.1 vs. 4.0; P = 0.03). There were no significant differences by APOE ε4 allele status in sensory-light touch recovery or acute LOS. This study suggests that the APOE ε4 allele is associated with outcomes after SCI and longer rehabilitation LOS in Chinese Han patients.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

Science.gov (United States)

Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

2014-01-01

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

Association between apolipoprotein E genotype, serum lipids, and colorectal cancer in Brazilian individuals

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D.R.S. Souza

2009-05-01

Full Text Available We evaluated genetic variants of apolipoprotein E (APOE HhaI and their association with serum lipids in colorectal cancer (CRC, together with eating habits and personal history. Eight-seven adults with CRC and 73 controls were studied. APOE*2 (rs7412 and APOE*4 (rs429358 were identified by polymerase chain reaction-restriction fragment length polymorphism. APOE gene polymorphisms were similar in both groups, but the ε4/ε4 genotype (6% was present only in controls. The patients had reduced levels (mean ± SD of total cholesterol and low-density lipoprotein cholesterol fraction (180.4 ± 49.5 and 116.1 ± 43.1 mg/dL, respectively compared to controls (204.2 ± 55.6, P = 0.135 and 134.7 ± 50.8 mg/dL; P = 0.330, respectively indicating that they were not statistically significant after the Bonferroni correction. The APOE*4 allele was associated with lower levels of total cholesterol, low- and high-density lipoprotein cholesterol fraction and increased levels of very low-density lipoprotein cholesterol fraction and triglycerides only among patients (P = 0.014. There was a positive correlation between the altered lipid profile and increased body mass indexes in both groups (P < 0.010. Moreover, a higher rate of hypertension and overweight was observed in controls (P < 0.002. In conclusion, the presence of the ε4/ε4 genotype only in controls may be due to a protective effect against CRC. Lower lipid profile values among patients, even those on lipid-rich diets associated with the APOE*4 allele, suggest alterations in the lipid synthesis and metabolism pathways in CRC.

Apolipoprotein E mRNA expression in mononuclear cells from normolipidemic and hypercholesterolemic individuals treated with atorvastatin

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Cerda Alvaro

2011-11-01

Full Text Available Abstract Background Apolipoprotein E (apoE is a key component of the lipid metabolism. Polymorphisms at the apoE gene (APOE have been associated with cardiovascular disease, lipid levels and lipid-lowering response to statins. We evaluated the effects on APOE expression of hypercholesterolemia, APOE ε2/ε3/ε4 genotypes and atorvastatin treatment in Brazilian individuals. The relationship of APOE genotypes and plasma lipids and atorvastatin response was also tested in this population. Methods APOE ε2/ε3/ε4 and plasma lipids were evaluated in 181 normolipidemic (NL and 181 hypercholesterolemic (HC subjects. HC individuals with indication for lowering-cholesterol treatment (n = 141 were treated with atorvastatin (10 mg/day/4-weeks. APOE genotypes and APOE mRNA in peripheral blood mononuclear cells (PBMC were analyzed by TaqMan real time PCR. Results HC had lower APOE expression than NL group (p APOE expression showed higher plasma total and LDL cholesterol and apoB, as well as higher apoAI (p APOE genotypes did not affect APOE expression and atorvastatin response. Atorvastatin treatment do not modify APOE expression, however those individuals without LDL cholesterol goal achievement after atorvastatin treatment according to the IV Brazilian Guidelines for Dyslipidemia and Atherosclerosis Prevention had lower APOE expression than patients with desirable response after the treatment (p Conclusions APOE expression in PBMC is modulated by hypercholesterolemia and the APOE mRNA level regulates the plasma lipid profile. Moreover the expression profile is not modulated neither by atorvastatin nor APOE genotypes. In our population, APOE ε2 allele confers protection against hypercholesterolemia and a less atherogenic lipid profile. Moreover, low APOE expression after treatment of patients with poor response suggests a possible role of APOE level in atorvastatin response.

Apolipoprotein M

DEFF Research Database (Denmark)

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

2006-01-01

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...

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100

International Nuclear Information System (INIS)

Soria, L.F.; Ludwig, E.H.; Clarke, H.R.G.; McCarthy, B.J.; Vega, G.L.; Grundy, S.M.

1989-01-01

Familial defective apolipoprotein (apo) B-100 is a genetic disease that leads to hypercholesterolemia and to an increased serum concentration of low density lipoproteins that bind defectively to the apoB,E(LDL) receptor. The disorder appears to result from a mutation in the gene for apoB-100. Extensive sequence analysis of the two alleles of one subject heterozygous for the disorder has revealed a previously unreported mutation in the codon for amino acid 3500 that results in the substitution of glutamine for arginine. This same mutant allele occurs in six other, unrelated subjects and in eight affected relatives in two of these families. A partial haplotype of this mutant apoB-100 allele was constructed by sequence analysis and restriction enzyme digestion at positions where variations in the apoB-100 are known to occur. This haplotype is the same in three probands and four affected members of one family and lacks a polymorphic Xba I site whose presence has been correlated with high cholesterol levels. Thus, it appears that the mutation in the codon for amino acid 3500 (CGG → CAG), a CG mutational hot spot, defines a minor apoB-100 allele associated with defective low density lipoproteins and hypercholesterolemia

Whole Body Vibration Retards Progression of Atherosclerosis via Insulin-Like Growth Factor 1 in Apolipoprotein E-Deficient Mice.

Science.gov (United States)

Wu, He; Zhang, Yibo; Yang, Xuan; Li, Xian; Shao, Zhenya; Zhou, Zipeng; Li, Yuanlong; Pan, Shuwen; Liu, Chang

2018-01-01

Whole body vibration (WBV) has a marked impact on lipid metabolism and the endocrine system, which is related to the progression of atherosclerosis (AS). To investigate the effects of WBV, we measured the atherosclerotic plaque area of apolipoprotein E-knockout (ApoE -/- ) AS mice, which were trained by WBV (15 Hz, 30 min) for 12 weeks. Simultaneously, serum levels of lipids, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 1 receptor (IGF-1R), interleukin 6 (IL-6), and the mRNA and protein levels of the same in the aorta were compared between the control and WBV groups. The results indicated that WBV significantly reduced the atherosclerotic plaque area with lower very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (ox-LDL) in the blood. Moreover, the levels of IGF-1 in serum and expression of IL-6, IGF-1R, and p-IGF-1R protein in the mice aorta decreased significantly in the WBV group. In addition, we found that serum IGF-1 in mice increased to the highest concentration in 30 min after WBV for 10, 30, 60, and 120 minutes. These results suggested that appropriate WBV may delay the progression of AS, which was associated with acutely elevated serum IGF-1 and lower levels of IGF-1 and IL-6 in the aorta for long-term treatment.

High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization.

Science.gov (United States)

Shah, P K; Yano, J; Reyes, O; Chyu, K Y; Kaul, S; Bisgaier, C L; Drake, S; Cercek, B

2001-06-26

Repeated doses of recombinant apolipoprotein A-I(Milano) phospholipid complex (apoA-I(m)) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I(m) could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice. High cholesterol-fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (n=16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; n=14), or 400 mg/kg of recombinant apoA-I(m) complexed with DPPC (1:2.7 weight ratio; n=18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux-promoting capacity was nearly 2-fold higher in recombinant apoA-I(m)-treated mice compared with saline and DPPC-treated mice (P<0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-I(m) injection, and it remained significantly elevated at 48 hours (P<0.01). Mice receiving recombinant apoA-I(m) had 40% to 50% lower lipid content (P<0.01) and 29% to 36% lower macrophage content (P<0.05) in their plaques compared with the saline- and DPPC-treated mice, respectively. A single high dose of recombinant apoA-I(m) rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype.

Context-dependent associations between variation in risk of ischemic heart disease and variation in the 5' promoter region of the apolipoprotein E gene in Danish women

DEFF Research Database (Denmark)

Stengård, Jari H; Dyson, Greg; Frikke-Schmidt, Ruth

2010-01-01

that acknowledges the complex pathobiology of IHD, we identified a subsample of 764 elderly women (> or =65 years) with hypertriglyceridemia who had a history of smoking, a history of hypertension, or a history of both in which the A(560)T(832)/A(560)T(832) and A(560)T(832)/A(560)G(832) 5' 2-SNP genotypes had...... a higher cumulative incidence of IHD (172/1000) compared to the incidence of 70/1000 in the total sample of women. CONCLUSIONS: Our study validates that 5' apolipoprotein E genotypes improve the prediction of IHD and documents that the improvement is greatest in a subset defined by a particular combination...

Mimetic Theory for Cell-Centered Lagrangian Finite Volume Formulation on General Unstructured Grids

Energy Technology Data Exchange (ETDEWEB)

Sambasivan, Shiv Kumar [Los Alamos National Laboratory; Shashkov, Mikhail J. [Los Alamos National Laboratory; Burton, Donald E. [Los Alamos National Laboratory; Christon, Mark A. [Los Alamos National Laboratory

2012-07-19

A finite volume cell-centered Lagrangian scheme for solving large deformation problems is constructed based on the hypo-elastic model and using the mimetic theory. Rigorous analysis in the context of gas and solid dynamics, and arbitrary polygonal meshes, is presented to demonstrate the ability of cell-centered schemes in mimicking the continuum properties and principles at the discrete level. A new mimetic formulation based gradient evaluation technique and physics-based, frame independent and symmetry preserving slope limiters are proposed. Furthermore, a physically consistent dissipation model is employed which is both robust and inexpensive to implement. The cell-centered scheme along with these additional new features are applied to solve solids undergoing elasto-plastic deformation.

Endothelial surface layer degradation by chronic hyaluronidase infusion induces proteinuria in apolipoprotein E-deficient mice.

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Marijn C Meuwese

Full Text Available OBJECTIVE: Functional studies show that disruption of endothelial surface layer (ESL is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model. METHODS: Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 weeks received continuous active or heat-inactivated hyaluronidase (10 U/hr, i.v. through an osmotic minipump during 4 weeks. Blood chemistry and anatomic changes in both macrovasculature and kidneys were examined. RESULTS: Infusion with active hyaluronidase resulted in decreased ESL (0.32±0.22 mL and plasma volume (1.03±0.18 mL compared to inactivated hyaluronidase (0.52±0.29 mL and 1.28±0.08 mL, p<0.05 respectively.Active hyaluronidase increased proteinuria compared to inactive hyaluronidase (0.27±0.02 vs. 0.15±0.01 µg/µg protein/creatinin, p<0.05 without changes in glomerular morphology or development of tubulo-interstitial inflammation. Atherosclerotic lesions in the aortic branches showed increased matrix production (collagen, 32±5 vs. 18±3%; glycosaminoglycans, 11±5 vs. 0.1±0.01%, active vs. inactive hyaluronidase, p<0.05. CONCLUSION: ESL degradation in apoE deficient mice contributes to reduced increased urinary protein excretion without significant changes in renal morphology. Second, the induction of compositional changes in atherogenic plaques by hyaluronidase point towards increased plaque vulnerability. These findings support further efforts to evaluate whether ESL restoration is a valuable target to prevent (micro vascular disease progression.

Development of new quantitative mass spectrometry and semi-automatic isofocusing methods for the determination of Apolipoprotein E typing.

Science.gov (United States)

Hirtz, Christophe; Vialaret, Jerome; Nouadje, Georges; Schraen, Susanna; Benlian, Pascale; Mary, Sandrine; Philibert, Pascal; Tiers, Laurent; Bros, Pauline; Delaby, Constance; Gabelle, Audrey; Lehmann, Sylvain

2016-02-15

Apolipoprotein E (Apo E) is a 36 Kda glycoprotein involved in lipid transport. It exists in 3 major isoforms: E2, E3 and E4. ApoE status is known to be a major risk factor for late-onset Alzheimer's and cardiovascular diseases. Genotyping is commonly used to obtain ApoE status but can show technical issues with ambiguous determinations. Phenotyping can be an alternative, not requiring genetic material. We evaluated the ability to accurately type ApoE isoforms by 2 phenotyping tests in comparison with genotyping. Two phenotyping techniques were used: (1) LC-MS/MS detection of 4 ApoE specific peptides (6490 Agilent triple quadripole): After its denaturation, serum was either reduced and alkylated, or only diluted, and then trypsin digested. Before analysis, desalting, evaporation and resuspension were performed. (2) Isoelectric focusing and immunoprecipitation: serum samples were neuraminidase digested, delipidated and electrophoresed on Hydragel ApoE (Sebia agarose gel) using Hydrasys 2 Scan instrument (Sebia, Lisses, France). ApoE isoforms bands were directly immunofixed in the gel using a polyclonal anti human ApoE antibody. Then, incubation of the gel with HRP secondary antibody followed by TTF1/TTF2 substrate allowed the visualization of ApoE bands. The results of the two techniques were compared to genotyping. Sera from 35 patients previously genotyped were analyzed with the 2 phenotyping techniques. 100% concordance between both phenotyping assays was obtained for the tested phenotypes (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4). When compared to genotyping, 3 samples were discordant. After reanalyzing them by both phenotyping tests and DNA sequencing, 2/3 discrepancies were confirmed. Those can be explained by variants or rare ApoE alleles or by unidentified technical issues. 102 additional samples were then tested on LC-MS/MS only and compared to genotyping. The data showed 100% concordance. Our 2 phenotyping methods represent a valuable alternative to

Electroimmunoassay, radioimmunoassay, and radial immunodiffusion assay evaluated for quantification of human apolipoprotein B

International Nuclear Information System (INIS)

Curry, M.D.; Gustafson, A.; Alaupovic, P.; McConathy, W.J.

1978-01-01

We examined three immunoassay techniques for measuring apolipoprotein B in serum and major lipoprotein density fractions from normolipidemic and hyperlipoproteinemic persons, comparing values by electroimmunoassay, radioimmunoassay, and radial immunodiffusion assay with those determined gravimetrically. Electroimmunoassay is faster and simpler than radioimmunoassay, and equally precise (within- and between-assay coefficients of variation for both were 5 and 7%, respectively). All the immunoassays gave results that agreed with those by gravimetry for normolipidemic sera and the corresponding lipoprotein density fractions, but only electroimmunoassay results agreed with those by gravimetry for apolipoprotein B in lipoproteins of d < 1.019 g/ml isolated from hypertriglyceridemic patients. Concentrations of apolipoprotein B in plasma, determined by electroimmunoassay in a population of normal persons and patients with primary hyperlipoproteinemias, were: normals, 980 +- 200; type 1, 700 +- 160; type IIa, 2000 +- 260; type IIb, 2180 +- 300; type III, 1300 +- 340; type IV, 1470 +- 400; and type V, 1550 +- 390 mg/liter (mean +- SD). Lipoprotein density fractions from the hyperlipoproteinemic patients each had a characteristic distribution of free and associated forms of lipoprotein family B. The absolute concentration and distribution of apolipoprotein B between the free and associated forms of lipoprotein B may represent a useful indicator of the underlying biochemical defect

Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

Science.gov (United States)

Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

2012-01-01

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. PMID:23300939

Effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and on atherogenesis in apolipoprotein E knock-out mice

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Portugal L.R.

2006-01-01

Full Text Available Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Several studies have reported a decrease in serum cholesterol during the consumption of large doses of fermented dairy products or lactobacillus strains. The proposed mechanism for this effect is the removal or assimilation of intestinal cholesterol by the bacteria, reducing cholesterol absorption. Although this effect was demonstrated in vitro, its relevance in vivo is still controversial. Furthermore, few studies have investigated the role of lactobacilli in atherogenesis. The aim of the present study was to determine the effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and the possible hypocholesterolemic and antiatherogenic action of these bacteria using atherosclerosis-prone apolipoprotein E (apo E knock-out (KO mice. For this purpose, Swiss/NIH germ-free mice were monoassociated with L. delbrueckii and fed a hypercholesterolemic diet for four weeks. In addition, apo E KO mice were fed a normal chow diet and treated with L. delbrueckii for 6 weeks. There was a reduction in cholesterol excretion in germ-free mice, which was not associated with changes in blood or liver cholesterol concentration. In apo E KO mice, no effect of L. delbrueckii was detected in blood, liver or fecal cholesterol. The atherosclerotic lesion in the aorta was also similar in mice receiving or not these bacteria. In conclusion, these results suggest that, although L. delbrueckii treatment was able to reduce cholesterol excretion in germ-free mice, no hypocholesterolemic or antiatherogenic effect was observed in apo E KO mice.

Effects of radiation and apolipoprotein E on lipid profile among workers of nuclear power plants in Korea

International Nuclear Information System (INIS)

Ki-Eun Moon; Mee-Seon Jung; Suk-Hee Sung; Youn-Koun Chang; Il-Keun Park; Yun-Mi Paek; Tae-In Choi; Soo-Geun Kim

2007-01-01

Complete text of publication follows. Several studies reported that the radiation was positively related to fatty liver, low HDL cholesterol, and hypertriglyceridemia. Genetic polymorphism affect prevalence of chronic disease by molecular epidemiology studies. Apolipoprotein E is an important genetic determinant of cardiovascular disease (CVD), namely through its influence on lipid metabolism. Thus, we investigated whether radiation and apo E polymorphism, and environmental factors contribute to the lipid profile in workers of nuclear power plants in Korea. DNA was extracted from the whole blood of 6896 study subjects (6357 males and 359 females), and apo E polymorphism was investigated using PCR. Plasma lipid profiles were measured by standardized enzymatic procedures and radiation dose was measured by the thermoluminescence dosemeter (TLD). Environmental factors such as exercise, smoking were measured from health management database of KHNP. Total of 6802 subjects (aged 20-58) were investigated and radiation exposure dose was 168.51±463.94 mSv in the recent 1-year dose and 248.24±559.21 mSv in the total accumulative dose. In addition, Apo E polymorphism was associated with significant differences in total cholesterol, HDL cholesterol, radiation dose, AI but others no significant. The multiple regression model showed that total cholesterol was positively correlated with age, SBP, BMI, AI, fasting glucose. HDL cholesterol was negatively correlated with AI. LDL cholesterol was positively correlated with age, BMI, fasting glucose. And triglyceride was significantly correlated in the BMI, AI, somking dose, vegetables but others no significant. Metabolic syndrome did not show any relation to the others; only age, SBP, DBP, BMI, fasting glucose, HOMA-IR influenced. However, there was no significant association between radiation dose and lipid profile. In conclusion, Apo E and well-known variables such as SBP, BMI were significantly associated with lipid profile level

Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases

OpenAIRE

Park, Sung-Jun; Ahmad, Faiyaz; Philp, Andrew; Baar, Keith; Williams, Tishan; Luo, Haibin; Ke, Hengming; Rehmann, Holger; Taussig, Ronald; Brown, Alexandra L.; Kim, Myung K.; Beaven, Michael A.; Burgin, Alex B.; Manganiello, Vincent; Chung, Jay H.

2012-01-01

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca2...

A study of serum lipid profile and serum apolipoproteins A1 and B in Indian male violent criminal offenders.

Science.gov (United States)

Chakrabarti, Nandini; Sinha, V K

2006-01-01

High cholesterol has been advanced as the most important factor in the development of coronary artery disease. Most panels have recommended population-wide dietary restrictions, yet a body of evolving data yields evidence of the hazards of low cholesterol, including links to aggression and hostility. The aim of this study was to compare the serum lipid profile and serum apolipoproteins A1 and B of men with a violent criminal record and men with no criminal history. Fasting blood samples were collected from 30 men with a known history of violent crime and 30 men with no criminal record. Serum lipid profile and serum apolipoproteins A1 and B were measured in each sample, and compared between the two groups. The group with the violent criminal record showed significantly lower total cholesterol, lower LDL cholesterol, higher apolipoprotein A1 and lower apolipoprotein B compared with the control group. Lower total cholesterol, lower LDL cholesterol, higher apolipoprotein A1 and lower apolipoprotein B could predispose to violence. Future research might explore the possibility that diets offered in prison could affect relevant pathways in lipid metabolism. Copyright (c) 2006 John Wiley & Sons, Ltd.

Mimetics of Suppressor of cytokine signalling 3: novel potential therapeutics in triple breast cancer.

Science.gov (United States)

La Manna, Sara; Lee, Eunmi; Ouzounova, Maria; Di Natale, Concetta; Novellino, Ettore; Merlino, Antonello; Korkaya, Hasan; Marasco, Daniela

2018-05-11

Suppressor of cytokine signaling (SOCS) family of proteins plays critical role in the regulation of immune responses controlling JAK/STAT mediated inflammatory cytokines. Among the members, SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) and SOCS3 binds to JAK/STAT/gp130 complex by inhibiting the downstream signaling and suppressing inflammatory cytokines. Loss or reduced levels of SOCS3 have been linked to cancer-associated inflammation and suppressive immunity leading to enhanced tumour growth and metastasis. In line with these reports, we previously demonstrated that proteolytic degradation of SOCS3 in triple negative breast cancer (TNBC) subtype drives the expression of inflammatory cytokines. Therefore, we postulated that SOCS3 mimetics might suppress the inflammatory cytokine production in TNBC subtype and inhibit tumor growth and metastasis. Here we designed and characterized five linear peptides derived from the N-terminal region of SOCS3 encompassing regions that interface with the JAK2/gp130 complex by using the Circular Dichroism and Surface Plasmon Resonance spectroscopies. The KIRESS peptide resulted the sequence containing the most part of the hot-spots required for binding to JAK2 and was further investigated in vivo in mouse xenografts of MDA-MB-231-luci tumours as models of human TNBC subtype. Expectedly, this peptide showed a significant inhibition of primary tumour growth and pulmonary metastasis. Our studies suggest that SOCS3 peptidomimetics may possess a therapeutic potential in aggressive cancers, such as TNBC subtype, with activated inflammatory cytokines. This article is protected by copyright. All rights reserved. © 2018 UICC.

Age-dependent effect of apolipoprotein E4 on functional outcome after controlled cortical impact in mice.

Science.gov (United States)

Mannix, Rebekah C; Zhang, Jimmy; Park, Juyeon; Zhang, Xuan; Bilal, Kiran; Walker, Kendall; Tanzi, Rudolph E; Tesco, Giuseppina; Whalen, Michael J

2011-01-01

The apolipoprotein E4 (APOE4) gene leads to increased brain amyloid beta (Aβ) and poor outcome in adults with traumatic brain injury (TBI); however, its role in childhood TBI is controversial. We hypothesized that the transgenic expression of human APOE4 worsens the outcome after controlled cortical impact (CCI) in adult but not immature mice. Adult and immature APOE4 mice had worse motor outcome after CCI (P<0.001 versus wild type (WT)), but the Morris water maze performance was worse only in adult APOE4 mice (P=0.028 at 2 weeks, P=0.019 at 6 months versus WT), because immature APOE4 mice had performance similar to WT for up to 1 year after injury. Brain lesion size was similar in adult APOE4 mice but was decreased (P=0.029 versus WT) in injured immature APOE4 mice. Microgliosis was similar in all groups. Soluble brain Aβ(40) was increased at 48 hours after CCI in adult and immature APOE4 mice and in adult WT (P<0.05), and was dynamically regulated during the chronic period by APOE4 in adults but not immature mice. The data suggest age-dependent effects of APOE4 on cognitive outcome after TBI, and that therapies targeting APOE4 may be more effective in adults versus children with TBI.

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

DEFF Research Database (Denmark)

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

2010-01-01

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...

Selective oxidation of methionine residues in apolipoprotein A-I and its potential biological consequences

International Nuclear Information System (INIS)

Panzenboeck, U.; Waldeck, R.; Rye, K.A.; Sloane, T.; Kritharides, L.; Stocker, R.

1998-01-01

The earliest stages of HDL oxidation are accompanied by the oxidation of specific Met residues in apolipoprotein AI and AII and the formation of Met sulfoxides (Met(O)) has been proposed to play a significant role in the reduction and hence detoxification of lipid hydroperoxides associated with HDL. Oxidation of HDL may generally decrease the anti-atherogenic properties of this lipoprotein, although both, the inhibition and the enhancement of cholesterol removal from cells has been reported for different types of oxidation. In light of these findings we have investigated the secondary structure, lipid affinity, LCAT activation and cholesterol-efflux promoting properties of native and selectively oxidized apo A-I(apo A-I +32 , containing Met(O) at Met l12 and Met l48 ) in purified or reconstituted forms. Data obtained by circular dichroism revealed that selective oxidation of Met residues 112 and 148 does not alter alpha helicity of the protein in solution, indicating that this oxidation is not sufficient to influence significantly this type of secondary structure of apo A-I in its 'lipid-free' form. The lipid affinity of native apo A-I and apo A-I +32 was determined as the rate of clearance of DMPC multilamellar to small unilamellar vesicles. Compared with the native protein, apo A-I +32 induced a 2-3 fold faster rate of clearance, suggesting that the increased hydrophilicity due Met(O) increased the rate for protein-lipid interactions. Met residues 112 and 148 reside in the hydrophobic faces of helices 5 and 7, and both these regions have been suggested to be important for both, LCAT activation and cholesterol efflux. Kinetic experiments have revealed that the affinity for LCAT is comparable for HDL reconstituted with either apo A-I or apo A-I +32 . Efflux of [ 3 H]-cholesterol from lipid-laden human monocytederived macrophages to isolated apolipoproteins was enhanced for apo A-I +32 compared with apo A-I, consistent with the DMPC clearance data. Together these

Skeletal muscle apolipoprotein B expression reduces muscular triglyceride accumulation

DEFF Research Database (Denmark)

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

2014-01-01

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 t...... accumulation and attenuates peripheral insulin resistance in obese mice........ 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......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...

Lack of association of apolipoprotein E (Apo E) polymorphism with the prevalence of metabolic syndrome: the National Heart, Lung and Blood Institute Family Heart Study.

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Lai, Lana Y H; Petrone, Andrew B; Pankow, James S; Arnett, Donna K; North, Kari E; Ellison, R Curtis; Hunt, Steven C; Rosenzweig, James L; Djoussé, Luc

2015-09-01

Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidaemia, elevated blood pressure and insulin resistance, is a major public health concern in the United States. The effects of apolipoprotein E (Apo E) polymorphism on MetS are not well established. We conducted a cross-sectional study consisting of 1551 participants from the National Heart, Lung and Blood Institute Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. MetS was defined according to the American Heart Association-National Heart, Lung and Blood Institute-International Diabetes Federation-World Health Organization harmonized criteria. We used generalized estimating equations to estimate adjusted odds ratios (ORs) for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis. Our study population had a mean age (standard deviation) of 56.5 (11.0) years, and 49.7% had MetS. There was no association between the Apo E genotypes and the MetS. The multivariable adjusted ORs (95% confidence interval) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62-1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47) and 1.87 (0.91-3.85) for the Ɛ3/Ɛ3, Ɛ2/Ɛ2, Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4 and Ɛ4/Ɛ4 genotypes, respectively. In a secondary analysis, Ɛ2/Ɛ3 genotype was associated with 41% lower prevalence odds of low high-density lipoprotein [multivariable adjusted ORs (95% confidence interval) = 0.59 (0.36-0.95)] compared with Ɛ3/Ɛ3 genotype. Our findings do not support an association between Apo E polymorphism and MetS in a multicentre population-based study of predominantly White US men and women. Copyright © 2015 John Wiley & Sons, Ltd.

Apolipoproteins A-I, B, and C-III and Obesity in Young Adult Cherokee

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Wenyu Wang

2017-01-01

Full Text Available Since young adult Cherokee are at increased risk for both diabetes and cardiovascular disease, we assessed association of apolipoproteins (A-I, B, and C-III in non-HDL and HDL with obesity and related risk factors. Obese participants (BMI ≥ 30 aged 20–40 years (n=476 were studied. Metabolically healthy obese (MHO individuals were defined as not having any of four components of the ATP-III metabolic syndrome after exclusion of waist circumference, and obese participants not being MHO were defined as metabolically abnormal obese (MAO. Associations were evaluated by correlation and regression modeling. Obesity measures, blood pressure, insulin resistance, lipids, and apolipoproteins were significantly different between groups except for total cholesterol, LDL-C, and HDL-apoC-III. Apolipoproteins were not correlated with obesity measures with the exception of apoA-I with waist and the waist : height ratio. In a logistic regression model apoA-I and the apoB : apoA-I ratio were significantly selected for identifying those being MHO, and the result (C-statistic = 0.902 indicated that apoA-I and the apoB : apoA-I ratio can be used to identify a subgroup of obese individuals with a significantly less atherogenic lipid and apolipoprotein profile, particularly in obese Cherokee men in whom MHO is more likely.

Modest vasomotor dysfunction induced by low doses of C60 fullerenes in apolipoprotein E knockout mice with different degree of atherosclerosis

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Loft Steffen

2009-02-01

Full Text Available Abstract Background Exposure to small size particulate matter in urban air is regarded as a risk factor for cardiovascular effects, whereas there is little information about the impact on the cardiovascular system by exposure to pure carbonaceous materials in the nano-size range. C60 fullerenes are nano-sized particles that are expected to have a widespread use, including cosmetics and medicines. Methods We investigated the association between intraperitoneal injection of pristine C60 fullerenes and vasomotor dysfunction in the aorta of 11–13 and 40–42 weeks old apolipoprotein E knockout mice (apoE-/- with different degree of atherosclerosis. Results The aged apoE-/-mice had lower endothelium-dependent vasorelaxation elicited by acetylcholine in aorta segments mounted in myographs and the phenylephrine-dependent vasoconstriction response was increased. One hour after an intraperitoneal injection of 0.05 or 0.5 mg/kg of C60 fullerenes, the young apoE-/- mice had slightly reduced maximal endothelium-dependent vasorelaxation. A similar tendency was observed in the old apoE-/- mice. Hampered endothelium-independent vasorelaxation was also observed as slightly increased EC50 of sodium nitroprusside-induced vasorelaxation response in young apoE-/- mice. Conclusion Treatment with C60 fullerenes affected mainly the response to vasorelaxation in young apoE-/- mice, whereas the vasomotor dysfunction in old apoE-/- mice with more advanced atherosclerosis was less affected by acute C60 fullerene treatment. These findings represent an important step in the hazard characterization of C60 fullerenes by showing that intraperitoneal administration is associated with a moderate decrease in the vascular function of mice with atherosclerosis.

Apolipoprotein A-V is present in bile and its secretion increases with lipid absorption in Sprague-Dawley rats.

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Zhang, Linda S; Sato, Hirokazu; Yang, Qing; Ryan, Robert O; Wang, David Q-H; Howles, Philip N; Tso, Patrick

2015-12-01

Apolipoprotein (apo) A-V is a protein synthesized only in the liver that dramatically modulates plasma triglyceride levels. Recent studies suggest a novel role for hepatic apoA-V in regulating the absorption of dietary triglycerides, but its mode of action on the gut remains unknown. The aim of this study was to test for apoA-V in bile and to determine whether its secretion is regulated by dietary lipids. After an overnight recovery, adult male Sprague-Dawley bile fistula rats indeed secreted apoA-V into bile at a constant rate under fasting conditions. An intraduodenal bolus of intralipid (n = 12) increased the biliary secretion of apoA-V but not of other apolipoproteins, such as A-I, A-IV, B, and E. The lipid-induced increase of biliary apoA-V was abolished under conditions of poor lymphatic lipid transport, suggesting that the stimulation is regulated by the magnitude of lipids associated with chylomicrons transported into lymph. We also studied the secretion of apoA-V into bile immediately following bile duct cannulation. Biliary apoA-V increased over time (∼6-fold increase at hour 16, n = 8) but the secretions of other apolipoproteins remained constant. Replenishing luminal phosphatidylcholine and taurocholate (n = 9) only enhanced apoA-V secretion in bile, suggesting that the increase was not due to depletion of phospholipids or bile salts. This is the first study to demonstrate that apoA-V is secreted into bile, introducing a potential route of delivery of hepatic apoA-V to the gut lumen. Our study also reveals the uniqueness of apoA-V secretion into bile that is regulated by mechanisms different from other apolipoproteins. Copyright © 2015 the American Physiological Society.

Cognitive function and apolipoprotein E in very old adults: findings from the Nun Study.

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Riley, K P; Snowdon, D A; Saunders, A M; Roses, A D; Mortimer, J A; Nanayakkara, N

2000-03-01

The epsilon4 allele of apolipoprotein E (APOE) has been associated with Alzheimer' s disease and with milder forms of cognitive impairment. We investigated the possibility that the absence of the epsilon4 allele may predict the maintenance of high cognitive function among very old individuals. Our data are from the Nun Study, a longitudinal study of aging and Alzheimer's disease in 678 Catholic sisters. All sisters participate in annual functional exams that include the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests. High cognitive function was defined as intact scores on five of the CERAD tests. A total of 241 participants aged 75 to 98 met this criterion at the first exam. Findings showed that 62% of the 241 participants maintained intact scores on the five CERAD tests throughout their participation in the study. Life table analyses indicated that those without the APOE epsilon4 allele spent more time with intact cognitive function than those with the epsilon4 allele (p = .007). Cox regression analyses indicated that those without the epsilon4 allele had half the risk of losing their intact status during the study when compared with those with the epsilon4 allele (p < .01). Our findings suggest that the APOE epsilon4 allele may be included among the variables that predict high cognitive function in cognitively intact, very old adults. Although the presence or absence of the epsilon4 allele is known to be related to the risk of dementia, it also appears to be related to maintaining high levels of cognitive function in old age.

A FDG-PET Study of Metabolic Networks in Apolipoprotein E ε4 Allele Carriers.

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Zhijun Yao

Full Text Available Recently, some studies have applied the graph theory in brain network analysis in Alzheimer's disease (AD and Mild Cognitive Impairment (MCI. However, relatively little research has specifically explored the properties of the metabolic network in apolipoprotein E (APOE ε4 allele carriers. In our study, all the subjects, including ADs, MCIs and NCs (normal controls were divided into 165 APOE ε4 carriers and 165 APOE ε4 noncarriers. To establish the metabolic network for all brain regions except the cerebellum, cerebral glucose metabolism data obtained from FDG-PET (18F-fluorodeoxyglucose positron emission tomography were segmented into 90 areas with automated anatomical labeling (AAL template. Then, the properties of the networks were computed to explore the between-group differences. Our results suggested that both APOE ε4 carriers and noncarriers showed the small-world properties. Besides, compared with APOE ε4 noncarriers, the carriers showed a lower clustering coefficient. In addition, significant changes in 6 hub brain regions were found in between-group nodal centrality. Namely, compared with APOE ε4 noncarriers, significant decreases of the nodal centrality were found in left insula, right insula, right anterior cingulate, right paracingulate gyri, left cuneus, as well as significant increases in left paracentral lobule and left heschl gyrus in APOE ε4 carriers. Increased local short distance interregional correlations and disrupted long distance interregional correlations were found, which may support the point that the APOE ε4 carriers were more similar with AD or MCI in FDG uptake. In summary, the organization of metabolic network in APOE ε4 carriers indicated a less optimal pattern and APOE ε4 might be a risk factor for AD.

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

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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.

Apolipoprotein nanodiscs with telodendrimer

Energy Technology Data Exchange (ETDEWEB)

Luo, Juntao; He, Wei; Lam, Kit S.; Henderson, Paul; Coleman, Matthew; Cheng, R. Holland; Xing, Li

2017-05-09

The present invention provides a nanodisc with a membrane scaffold protein. The nanodisc includes a membrane scaffold protein, a telodendrimer and a lipid. The membrane scaffold protein can be apolipoprotein. The telodendrimer has the general formula PEG-L-D-(R).sub.n, wherein D is a dendritic polymer; L is a bond or a linker linked to the focal point group of the dendritic polymer; each PEG is a poly(ethylene glycol) polymer; each R is and end group of the dendritic polymer, or and end group with a covalently bound hydrophobic group, hydrophilic group, amphiphilic compound, or drug; and subscript n is an integer from 2 to 20. Cell free methods of making the nanodiscs are also provided.

Circulating Apolipoprotein A1, Haptoglobin and Α2 Macroglobulin ...

African Journals Online (AJOL)

α2-MG), Apolipoprotein A1 (Apo-1) and Haptoglobin (HP) as non-invasive index of the presence of cirrhosis in chronic hepatitis C patients in relation to the histopathological findings. Subjects and Methods: The study was carried out on 20 ...

Discrete conservation properties for shallow water flows using mixed mimetic spectral elements

NARCIS (Netherlands)

Lee, D.; Palha, A.; Gerritsma, M.

2018-01-01

A mixed mimetic spectral element method is applied to solve the rotating shallow water equations. The mixed method uses the recently developed spectral element histopolation functions, which exactly satisfy the fundamental theorem of calculus with respect to the standard Lagrange basis functions in

Influence of apolipoproteins on the association between lipids and insulin sensitivity

DEFF Research Database (Denmark)

Baldi, Simona; Bonnet, Fabrice; Laville, Martine

2013-01-01

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....

The conversion in the René Girard’s mimetic theory

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Agustín Moreno Fernández

2014-12-01

Full Text Available One of the specific peculiarities of René Girard’s mimetic theory is the recovery of the concept of conversion. In this article we expose, in a detailed way, the three senses of the conversion according to his thinking: novelistic, religious and epistemological. There is an interaction between the three senses and also different significations for each other.

Identification of novel small-molecule Ulex europaeus I mimetics for targeted drug delivery.

Science.gov (United States)

Hamashin, Christa; Spindler, Lisa; Russell, Shannon; Schink, Amy; Lambkin, Imelda; O'Mahony, Daniel; Houghten, Richard; Pinilla, Clemencia

2003-11-17

Lectin mimetics have been identified that may have potential application towards targeted drug delivery. Synthetic multivalent polygalloyl constructs effectively competed with Ulex europaeus agglutinin I (UEA1) for binding to intestinal Caco-2 cell membranes.

Functional network endophenotypes unravel the effects of apolipoprotein E epsilon 4 in middle-aged adults.

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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.

Human placenta secretes apolipoprotein B-100-containing lipoproteins

DEFF Research Database (Denmark)

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

2004-01-01

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....

Celastrol inhibits TGF-β1-induced epithelial–mesenchymal transition by inhibiting Snail and regulating E-cadherin expression

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Kang, Hyereen; Lee, Minjae [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Jang, Sung-Wuk, E-mail: swjang@amc.seoul.kr [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of)

2013-08-09

Highlights: •We investigated the effects of celastrol on TGF-β1-induced EMT in epithelial cells. •Celastrol regulates TGF-β1-induced morphological changes and E-cadherin expression. •Celastrol inhibits TGF-β1-induced Snail expression. •Celastrol strongly suppresses TGF-β1-induced invasion in MDCK and A549 cells. -- Abstract: The epithelial–mesenchymal transition (EMT) is a pivotal event in the invasive and metastatic potentials of cancer progression. Celastrol inhibits the proliferation of a variety of tumor cells including leukemia, glioma, prostate, and breast cancer; however, the possible role of celastrol in the EMT is unclear. We investigated the effect of celastrol on the EMT. Transforming growth factor-beta 1 (TGF-β1) induced EMT-like morphologic changes and upregulation of Snail expression. The downregulation of E-cadherin expression and upregulation of Snail in Madin–Darby Canine Kidney (MDCK) and A549 cell lines show that TGF-β1-mediated the EMT in epithelial cells; however, celastrol markedly inhibited TGF-β1-induced morphologic changes, Snail upregulation, and E-cadherin expression. Migration and invasion assays revealed that celastrol completely inhibited TGF-β1-mediated cellular migration in both cell lines. These findings indicate that celastrol downregulates Snail expression, thereby inhibiting TGF-β1-induced EMT in MDCK and A549 cells. Thus, our findings provide new evidence that celastrol suppresses lung cancer invasion and migration by inhibiting TGF-β1-induced EMT.

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

2010-01-01

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)....

Chimeric design, synthesis, and biological assays of a new nonpeptide insulin-mimetic vanadium compound to inhibit protein tyrosine phosphatase 1B.

Science.gov (United States)

Scior, Thomas; Guevara-García, José Antonio; Melendez, F J; Abdallah, Hassan H; Do, Quoc-Tuan; Bernard, Philippe

2010-09-24

Prior to its total synthesis, a new vanadium coordination compound, called TSAG0101, was computationally designed to inhibit the enzyme protein tyrosine phosphatase 1B (PTP1B). The PTP1B acts as a negative regulator of insulin signaling by blocking the active site where phosphate hydrolysis of the insulin receptor takes place. TSAG001, [V(V)O(2)(OH)(picolinamide)], was characterized by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy; IR: ν/cm(-1) 3,570 (NH), 1,627 (C=O, coordinated), 1,417 (C-N), 970/842 (O=V=O), 727 δ̣ (pyridine ring); (13)C NMR: 5 bands between 122 and 151 ppm and carbonyl C shifted to 180 ppm; and (1)H NMR: 4 broad bands from 7.6 to 8.2 ppm and NH(2) shifted to 8.8 ppm. In aqueous solution, in presence or absence of sodium citrate as a biologically relevant and ubiquitous chelator, TSAG0101 undergoes neither ligand exchange nor reduction of its central vanadium atom during 24 hours. TSAG0101 shows blood glucose lowering effects in rats but it produced no alteration of basal- or glucose-induced insulin secretion on β cells during in vitro tests, all of which excludes a direct mechanism evidencing the extrapancreatic nature of its activity. The lethal dose (LD(50)) of TSAG0101 was determined in Wistar mice yielding a value of 412 mg/kg. This value is one of the highest among vanadium compounds and classifies it as a mild toxicity agent when compared with literature data. Due to its nonsubstituted, small-sized scaffold design, its remarkable complex stability, and low toxicity; TSAG0101 should be considered as an innovative insulin-mimetic principle with promising properties and, therefore, could become a new lead compound for potential nonpeptide PTP1B inhibitors in antidiabetic drug research. In view of the present work, the inhibitory concentration (IC(50)) and extended solution stability will be tested.

Anti-tumor activity of a novel HS-mimetic-vascular endothelial growth factor binding small molecule.

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Kazuyuki Sugahara

Full Text Available The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl-3H-imidazole-4-carbaldehyde was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS, which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7 which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor.

In vivo magnetic resonance imaging of atherosclerotic lesions with a newly developed Evans blue-DTPA-gadolinium contrast medium in apolipoprotein-E-deficient mice.

Science.gov (United States)

Yasuda, Satoshi; Ikuta, Kenjiro; Uwatoku, Toyokazu; Oi, Keiji; Abe, Kohtaro; Hyodo, Fuminori; Yoshimitsu, Kengo; Sugimura, Kohtaro; Utsumi, Hideo; Katayama, Yoshiki; Shimokawa, Hiroaki

2008-01-01

Magnetic resonance imaging (MRI) contrast agents that specifically detect atherosclerotic plaque may be useful for the noninvasive detection of the plaque. We have recently developed a new contrast agent, Evans blue-DTPA-gadolinium (EB-DTPA-Gd), which selectively accumulates vascular lesions with endothelial removal. In this study, we examined whether EB-DTPA-Gd is also useful for in vivo imaging of atherosclerotic plaques. We used male apolipoprotein-E-deficient (ApoE-/-) mice of different ages (3, 6 and 12 months old) and age-matched male wild-type mice. After a single intravenous administration of EB-DTPA-Gd (160 microM/kg body weight), MRI T(1) signal was obtained in vivo. Increased signal intensity in the aortic wall was noted within 10-20 min after intravenous injection of EB-DTPA-Gd and was maintained for 30 min. The MRI enhancement in the aorta of ApoE-/- mice was increased in accordance with age, whereas no such enhancement was noted in wild-type mice. Histological examination demonstrated that there was a topological correlation between the site of MRI enhancement and that of atherosclerotic plaque. These results indicate that EB-DTPA-Gd is a useful MRI contrast medium for the in vivo detection of atherosclerotic plaques. Copyright (c) 2007 S. Karger AG, Basel.

Board composition, mimetic behaviour and corporate voluntary disclosures

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Roshayani Arshad

2008-11-01

Full Text Available This study examines the effects of board composition and mimetic behaviour on the extent and credibility of corporate voluntary disclosure. The investigation is based on the annual reports of 155 Malaysian listed companies during the period when these companies faced new corporate governance regulation. This study provides evidence that under the influence of dominant owners on board, management voluntary disclosure decisions are driven by incentives to conform when their company is structured to meet expectations of good corporate governance. Such incentive seems to override incentives to disclose credible information to outside investors

Targeting annexin A7 by a small molecule suppressed the activity of phosphatidylcholine-specific phospholipase C in vascular endothelial cells and inhibited atherosclerosis in apolipoprotein E⁻/⁻mice.

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Li, H; Huang, S; Wang, S; Zhao, J; Su, L; Zhao, B; Zhang, Y; Zhang, S; Miao, J

2013-09-19

Phosphatidylcholine-specific phospholipase C (PC-PLC) is a key factor in apoptosis and autophagy of vascular endothelial cells (VECs), and involved in atherosclerosis in apolipoprotein E⁻/⁻ (apoE⁻/⁻) mice. But the endogenous regulators of PC-PLC are not known. We recently found a small chemical molecule (6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine, ABO) that could inhibit oxidized low-density lipoprotein (oxLDL)-induced apoptosis and promote autophagy in VECs, and further identified ABO as an inhibitor of annexin A7 (ANXA7) GTPase. Based on these findings, we hypothesize that ANXA7 is an endogenous regulator of PC-PLC, and targeting ANXA7 by ABO may inhibit atherosclerosis in apoE⁻/⁻ mice. In this study, we tested our hypothesis. The results showed that ABO suppressed oxLDL-induced increase of PC-PLC level and activity and promoted the co-localization of ANXA7 and PC-PLC in VECs. The experiments of ANXA7 knockdown and overexpression demonstrated that the action of ABO was ANXA7-dependent in cultured VECs. To investigate the relation of ANXA7 with PC-PLC in atherosclerosis, apoE⁻/⁻ mice fed with a western diet were treated with 50 or 100 mg/kg/day ABO. The results showed that ABO decreased PC-PLC levels in the mouse aortic endothelium and PC-PLC activity in serum, and enhanced the protein levels of ANXA7 in the mouse aortic endothelium. Furthermore, both dosages of ABO significantly enhanced autophagy and reduced apoptosis in the mouse aortic endothelium. As a result, ABO significantly reduced atherosclerotic plaque area and effectively preserved a stable plaques phenotype, including reduced lipid deposition and pro-inflammatory macrophages, increased anti-inflammatory macrophages, collagen content and smooth muscle cells, and less cell death in the plaques. In conclusion, ANXA7 was an endogenous regulator of PC-PLC, and targeting ANXA7 by ABO inhibited atherosclerosis in apoE⁻/⁻ mice.

Demonstration Of An Abnormality Of Apolipoprotein Ciii And Genetic ...

African Journals Online (AJOL)

Gout is the principal clinical manifestation of hyperuricaemia and leading cause of inflammatory arthritis in adult men. Lipids and apolipoproteins therefore plays an important role in the pathophysiology of the changes seen in hyperuricaemia. We conducted a study on the relationship between APOC3 SstI polymorphism ...

Binding of recombinant apolipoprotein(a) to extracellular matrix proteins

NARCIS (Netherlands)

van der Hoek, Y. Y.; Sangrar, W.; Côté, G. P.; Kastelein, J. J.; Koschinsky, M. L.

1994-01-01

Elevated levels of lipoprotein(a), which consists of apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein-like moiety, is an independent risk factor for the development of atherosclerosis. We show that a recombinant form of apo(a) [r-apo(a)] binds strongly to fibronectin and

Apolipoprotein E genotype is associated with temporal and hippocampal atrophy rates in healthy elderly adults: a tensor-based morphometry study.

Science.gov (United States)

Lu, Po H; Thompson, Paul M; Leow, Alex; Lee, Grace J; Lee, Agatha; Yanovsky, Igor; Parikshak, Neelroop; Khoo, Theresa; Wu, Stephanie; Geschwind, Daniel; Bartzokis, George

2011-01-01

Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer's disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy "younger elderly" volunteers, aged 55-75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively "normal" at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.

Self-assembly of fibronectin mimetic peptide-amphiphile nanofibers

Science.gov (United States)

Rexeisen, Emilie Lynn

Many therapeutic strategies incorporate peptides into their designs to mimic the natural protein ligands found in vivo. A few examples are the short peptide sequences RGD and PHSRN that mimic the primary and synergy-binding domains of the extracellular matrix protein, fibronectin, which is recognized by the cell surface receptor, alpha5beta 1 integrin. Even though scaffold modification with biomimetic peptides remains one of the most promising approaches for tissue engineering, the use of these peptides in therapeutic tissue-engineered products and drug delivery systems available on the commercial market is limited because the peptides are not easily able to mimic the natural protein. The design of a peptide that can effectively target the alpha5beta1 integrin would greatly increase biomimetic scaffold therapeutic potential. A novel peptide containing both the RGD primary binding domain and PHSRN synergy-binding domain for fibronectin joined with the appropriate linker should bind alpha 5beta1 integrin more efficiently and lead to greater cell adhesion over RGD alone. Several fibronectin mimetic peptides were designed and coupled to dialkyl hydrocarbon tails to make peptide-amphiphiles. The peptides contained different linkers connecting the two binding domains and different spacers separating the hydrophobic tails from the hydrophilic headgroups. The peptide-amphiphiles were deposited on mica substrates using the Langmuir-Blodgett technique. Langmuir isotherms indicated that the peptide-amphiphiles that contained higher numbers of serine residues formed a more tightly packed monolayer, but the increased number of serines also made transferring the amphiphiles to the mica substrate more difficult. Atomic force microscopy (AFM) images of the bilayers showed that the headgroups might be bent, forming small divots in the surface. These divots may help expose the PHSRN synergy-binding domain. Parallel studies undertaken by fellow group members showed that human

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

DEFF Research Database (Denmark)

Dahlbäck, B; Nielsen, Lars Bo

2009-01-01

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. ApoM r......; possible mechanisms include increased formation of pre-ss HDL, enhanced cholesterol mobilization from foam cells, and increased antioxidant properties....

Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

Science.gov (United States)

Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A.; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.

2014-01-01

There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis. PMID:24752272

Apolipoprotein A5 in health and disease

Czech Academy of Sciences Publication Activity Database

Hubáček, J. A.; Adámková, V.; Vrablík, M.; Kadlecová, Michaela; Zicha, Josef; Kuneš, Jaroslav; Piťha, J.; Suchánek, P.; Poledne, R.

2009-01-01

Roč. 58, Suppl.2 (2009), S101-S109 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0510 Grant - others:IKEM(CZ) 00023001; GA MŠk(CZ) MEB060808; GA MZd(CZ) NR8895; GAMZd(CZ) NR9393 Institutional research plan: CEZ:AV0Z50110509 Keywords : apolipoprotein A5 * plasma triglycerides * myocardial infarction Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.430, year: 2009

The relation between dietary intake of vegetable oils and serum lipids and apolipoprotein levels in central Iran

Directory of Open Access Journals (Sweden)

Hossein Khosravi Boroujeni

2012-01-01

Full Text Available BACKGROUND: The detrimental effects of partially hydrogenated vegetable oils (PHVOs on apolipoproteins have been reported from several parts of the world. However, little data is available in this regard from the understudied region of the Middle East. The present study therefore tried to evaluate the association between type of vegetable oils and serum lipids and apolipoprotein levels among Iranians. METHODS: In this cross-sectional study, data from 1772 people (795 men and 977 women aged 19-81 years, who were selected with multistage cluster random sampling method from three cities of Isfahan, Najaf Abad and Arak in "Isfahan Healthy Heart Program" (IHHP, was used. To assess participants' usual dietary intakes, a validated food frequency questionnaire was used. Hydrogenated vegetable oil (commonly consumed for cooking in Iran and margarine were considered as the category of PHVOs. Soy, sunflower, corn, olive and canola oils were considered as non-HVOs. After an overnight fasting, serum cholesterol (total, low density lipoprotein (LDL and high density lipoprotein (HDL cholesterol and triglyceride as well as apolipoproteins A and B were measured using standard methods. RESULTS: Participants with the highest intakes of non-HVOs and PHVOs were younger and had lower weight than those with lowest intakes. High consumption of non-HVOs and PHVOs was associated with lower intakes of energy, carbohydrate, dietary fiber, and higher intakes of fruits, vegetables, meat, milk and grains. No overall significant differences were found in serum lipids and apolipoprotein levels across the quartiles of non-HVOs and PHVOs after controlling for potential confounding. CONCLUSION: We did not find any significant associations between hydrogenated or non-hydrogenated vegetable oil and serum lipid and apolipoprotein levels. Thus, further studies are needed in this region to explore this association. Keywords: Vegetable Oils, Cardiovascular Risk Factors, Lipids

Oligomeric protein complexes of apolipoproteins stabilize the internal fluid environment of organism in redfins of the Tribolodon genus [Pisces; Cypriniformes, Cyprinidae].

Science.gov (United States)

Andreeva, Alla M; Serebryakova, Marina V; Lamash, Nina E

2017-06-01

One of the most important functions of plasma proteins in vertebrates is their participation in osmotic homeostasis in the organism. Modern concepts about plasma proteins and their capillary filtration are based on a model of large monomeric proteins that are able to penetrate the interstitial space. At the same time, it was revealed that a considerable amount of oligomeric complexes are present in the low-molecular-weight (LM) protein fraction in the extracellular fluids of fishes. The functions of these complexes are unknown. In the present study, we investigated the LM-fraction proteins in the plasma and interstitial fluid (IF) of redfins of the genus Tribolodon. This fish alternatively spends parts of its life cycle in saline and fresh waters. We identified the protein Wap65, serpins and apolipoproteins in this fraction. By combining the methods of 2D-E under native and denaturing conditions with MALDI, we demonstrated that only apolipoproteins formed complexes. We showed that serum apolipoproteins (АроА-I, Аро-14) were present in the form of homooligomeric complexes that were dissociated with the release of monomeric forms of proteins in the course of capillary filtration to IF. Dissociation of homooligomers is not directly correlated with the change in salinity but is correlated with seasonal dynamics. We found that there was a significant decrease in the total protein concentration in IF relative to plasma. Therefore, we suggested that dissociation of homooligomeric complexes from various apolipoproteins supports the isoosmoticity of extracellular fluids relative to capillary wall stabilization through a fluid medium in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of the Relationship between Estradiol and Follicle-Stimulating Hormone Concentrations and Polymorphisms of Apolipoprotein E and LeptinGenes in Women Post-Menopause

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Aleksandra Rył

2016-05-01

Full Text Available Background: Menopause is the permanent cessation of menstruation due to loss of ovarian follicular activity. A review of the available literature indicates that correlations between the changes that take place in a woman’s body after menopause and different genetic variants are still being sought. Methods: The study was conducted in 252 women who had completed physiological menopause. The women were divided into groups according to the time elapsed since menopause. The total concentrations of estradiol and follicle-stimulating hormone were determined by means of electrochemiluminescence. The apolipoprotein E (APOE and lepitn (LEP genotypes were determined by real-time PCR and polymerase chain reaction–restriction fragment length polymorphism, respectively. Results: We observed that people with the APOE3/E3 genotype entered menopause insignificantly later compared to other genotypes. Additionally, in the group of patients with the APOE3/E3 genotypes, differences in the E2 concentration were significantly related to the time since their last menstruation. There is no association found in the literature between these polymorphisms of the LEP gene and hormones. Conclusions: To date, attempts to formulate a model describing the association between E2 and FSH concentration with the polymorphisms of various genes of menopause in women have not been successful. This relationship is difficult to study because of the number of nongenetic factors. Environmental factors can explain variation in postmenopausal changes in hormone levels.

Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling

Science.gov (United States)

2012-01-01

Background Abnormal proteostasis due to alterations in protein turnover has been postulated to play a central role in several neurodegenerative diseases. Therefore, the development of techniques to quantify protein turnover in the brain is critical for understanding the pathogenic mechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry to measure the clearance of proteins in the mouse brain. Results Cohorts of mice were pulse labeled with 13 C6-leucine and the brains were isolated after pre-determined time points. The extent of label incorporation was measured over time using mass spectrometry to measure the ratio of labeled to unlabeled apolipoprotein E (apoE) and amyloid β (Aβ). The fractional clearance rate (FCR) was then calculated by analyzing the time course of disappearance for the labeled protein species. To validate the technique, apoE clearance was measured in mice that overexpress the low-density lipoprotein receptor (LDLR). The FCR in these mice was 2.7-fold faster than wild-type mice. To demonstrate the potential of this technique for understanding the pathogenesis of neurodegenerative disease, we applied our SILK technique to determine the effect of ATP binding cassette A1 (ABCA1) on both apoE and Aβ clearance. ABCA1 had previously been shown to regulate both the amount of apoE in the brain, along with the extent of Aβ deposition, and represents a potential molecular target for lowering brain amyloid levels in Alzheimer's disease patients. The FCR of apoE was increased by 1.9- and 1.5-fold in mice that either lacked or overexpressed ABCA1, respectively. However, ABCA1 had no effect on the FCR of Aβ, suggesting that ABCA1 does not regulate Aβ metabolism in the brain. Conclusions Our SILK strategy represents a straightforward, cost-effective, and efficient method to measure the clearance of proteins in the mouse brain. We expect that

Metal stabilization of collagen and de novo designed mimetic peptides

OpenAIRE

Parmar, Avanish S.; Xu, Fei; Pike, Douglas H.; Belure, Sandeep V.; Hasan, Nida F.; Drzewiecki, Kathryn E.; Shreiber, David I.; Nanda, Vikas

2015-01-01

We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacen...

Mimetic Divergence and the Speciation Continuum in the Mimic Poison Frog Ranitomeya imitator

DEFF Research Database (Denmark)

Twomey, Evan; Vestergaard, Jacob Schack; Venegas, Pablo J.

2016-01-01

While divergent ecological adaptation can drive speciation, understanding the factors that facilitate or constrain this process remains a major goal in speciation research. Here, we study two mimetic transition zones in the poison frog Ranitomeya imitator, a species that has undergone a Mullerian...

Discovering the enzyme mimetic activity of metal-organic framework (MOF) for label-free and colorimetric sensing of biomolecules.

Science.gov (United States)

Wang, Ying; Zhu, Yingjing; Binyam, Atsebeha; Liu, Misha; Wu, Yinan; Li, Fengting

2016-12-15

A label-free sensing strategy based on the enzyme-mimicking activity of MOF was demonstrated for colorimetric detection of biomolecules. Firstly obvious blue color was observed due to the high efficiency of peroxidase-like catalytic activity of Fe-MIL-88A (an ion-based MOF material) toward 3,3',5,5'-tetramethylbenzidine (TMB). Then in the presence of target biomolecule and corresponding aptamer, the mimetic activity of Fe-MIL-88A can be strongly inhibited and used directly to realize the colorimetric detection. On the basis of the interesting findings, we designed a straightforward, label-free and sensitive colorimetric method for biomolecule detection by using the enzyme mimetic property of MOF coupling with molecular recognition element. Compared with the existed publications, our work breaks the routine way by setting up an inorganic-organic MOF-aptamer hybrid platform for colorimetric determination of biomolecules, expanding the targets scope from H2O2 or glucose to biomolecules. As a proof of concept, thrombin and thrombin aptamer was used as a model analyte. The limit of detection of 10nM can be achieved with naked eyes and ultrahigh selectivity of thrombin toward numerous interfering substances with 10-fold concentration was demonstrated significantly. Of note, the method was further applied for the detection of thrombin in human serum samples, showing the results in agreement with those values obtained in an immobilization buffer by the colorimetric method. This inorganic-organic MOF-aptamer sensing strategy may in principle be universally applicable for the detection of a range of environmental or biomedical molecules of interests. Copyright © 2016 Elsevier B.V. All rights reserved.

Mitochondrial function is involved in regulation of cholesterol efflux to apolipoprotein (apoA-I from murine RAW 264.7 macrophages

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Allen Anne Marie

2012-12-01

Full Text Available Abstract Background Mitochondrial DNA damage, increased production of reactive oxygen species and progressive respiratory chain dysfunction, together with increased deposition of cholesterol and cholesteryl esters, are hallmarks of atherosclerosis. This study investigated the role of mitochondrial function in regulation of macrophage cholesterol efflux to apolipoprotein A-I, by the addition of established pharmacological modulators of mitochondrial function. Methods Murine RAW 264.7 macrophages were treated with a range of concentrations of resveratrol, antimycin, dinitrophenol, nigericin and oligomycin, and changes in viability, cytotoxicity, membrane potential and ATP, compared with efflux of [3H]cholesterol to apolipoprotein (apo A-I. The effect of oligomycin treatment on expression of genes implicated in macrophage cholesterol homeostasis were determined by quantitative polymerase chain reaction, and immunoblotting, relative to the housekeeping enzyme, Gapdh, and combined with studies of this molecule on cholesterol esterification, de novo lipid biosynthesis, and induction of apoptosis. Significant differences were determined using analysis of variance, and Dunnett’s or Bonferroni post t-tests, as appropriate. Results The positive control, resveratrol (24 h, significantly enhanced cholesterol efflux to apoA-I at concentrations ≥30 μM. By contrast, cholesterol efflux to apoA-I was significantly inhibited by nigericin (45%; ppAbca1 mRNA. Oligomycin treatment did not affect cholesterol biosynthesis, but significantly inhibited cholesterol esterification following exposure to acetylated LDL, and induced apoptosis at ≥30 μM. Finally, oligomycin induced the expression of genes implicated in both cholesterol efflux (Abca1, Abcg4, Stard1 and cholesterol biosynthesis (Hmgr, Mvk, Scap, Srebf2, indicating profound dysregulation of cholesterol homeostasis. Conclusions Acute loss of mitochondrial function, and in particular Δψm, reduces

Nuclear microprobe investigation into the trace elemental contents of carotid artery walls of apolipoprotein E deficient mice

International Nuclear Information System (INIS)

Ren Minqin; Huang En; Beck, Konstanze; Rajendran, Reshmi; Wu, Ben J.; Halliwell, Barry; Watt, Frank; Stocker, Roland

2007-01-01

Atherosclerosis is a progressive disease that causes lesions in large and medium-sized arteries. There is increasing evidence that the function of vascular endothelial cells is impaired by oxidation reactions, and that metal ions may participate in these processes. The nuclear microscopy facility in NUS, which has the ability to focus a 2 MeV proton beam down to sub micron spot sizes, was used to investigate the trace elemental changes (e.g. Zn and Fe) in atherosclerotic lesions in the common carotid artery of apolipoprotein E deficient mice fed a high fat diet. In this preliminary study, which is part of a larger study to investigate the effects of probucol on carotid artery atherosclerosis, two sets of mice were used; a test set fed a high fat diet +1% probucol, and a control set which was fed a high fat diet only. The results show that the Zn/Fe ratio was significantly higher in the media of arteries of probucol treated animals without overlying lesion (4.3) compared to the media with overlying lesion (1.3) (p = 0.004) for test mice. For the control mice, the arterial Zn/Fe ratio was 1.8 for media without overlying lesion, compared with 1.0 for media with overlying lesion (p = 0.1). Thus, for media without overlying lesion, the Zn/Fe ratio was significantly higher (p = 0.009) in probucol-treated (4.3) than control mice (1.8), whereas there was little difference in the ratios between the two groups in media with overlying lesion (1.3 compared with 1.0). These preliminary results are consistent with the idea that the levels of iron and zinc concentrations within the artery wall may influence the formation of atherosclerotic plaque in the carotid artery

Effects of red grape juice consumption on high density lipoprotein-cholesterol, apolipoprotein AI, apolipoprotein B and homocysteine in healthy human volunteers.

Science.gov (United States)

Khadem-Ansari, Mohammad H; Rasmi, Yousef; Ramezani, Fatemeh

2010-01-01

It has suggested that grape juice consumption has lipid- lowering effect and it is associated with a decreased risk of heart disease. We aimed to evaluate the effects of red grape juice (RGj) consumption on high density lipoprotein-cholesterol (HDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB) and homocysteine (Hcy) levels in healthy human volunteers. Twenty six healthy and nonsmoking males, aged between 25-60 years, who were under no medication asked to consume 150 ml of RGj twice per day for one month. Serum HDL-C, apoAI, apoB and plasma Hcy levels were measured before and after one month RGj consumption. HDL-C levels after RGj consumption were significantly higher than the corresponding levels before the RGj consumption (41.44 ± 4.50 and 44.37 ± 4.30 mg/dl; P0.05). Hcy levels were decreased after RGj consumption (7.70 ± 2.80 and 6.20 ± 2.30 µmol/l; P<0.001). The present study demonstrates that RGj consumption can significantly increase serum HDL-C levels and decrease Hcy levels. These findings may have important implications for the prevention of atherosclerosis in healthy individuals.

Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4.

Science.gov (United States)

Argyri, Letta; Dafnis, Ioannis; Theodossiou, Theodossis A; Gantz, Donald; Stratikos, Efstratios; Chroni, Angeliki

2014-05-02

The apolipoprotein (apo) E4 isoform has consistently emerged as a susceptibility factor for late-onset Alzheimer disease (AD), although the exact mechanism is not clear. A rare apoE4 mutant, apoE4[L28P] Pittsburgh, burdens carriers with an added risk for late-onset AD and may be a useful tool for gaining insights into the role of apoE4 in disease pathogenesis. Toward this end, we evaluated the effect of the L28P mutation on the structural and functional properties of apoE4. ApoE4[L28P] was found to have significantly perturbed thermodynamic properties, to have reduced helical content, and to expose a larger portion of the hydrophobic surface to the solvent. Furthermore, this mutant is thermodynamically destabilized and more prone to proteolysis. When interacting with lipids, apoE4[L28P] formed populations of lipoprotein particles with structural defects. The structural perturbations brought about by the mutation were accompanied by aberrant functions associated with the pathogenesis of AD. Specifically, apoE4[L28P] promoted the cellular uptake of extracellular amyloid β peptide 42 (Aβ42) by human neuroblastoma SK-N-SH cells as well as by primary mouse neuronal cells and led to increased formation of intracellular reactive oxygen species that persisted for at least 24 h. Furthermore, lipoprotein particles containing apoE4[L28P] induced intracellular reactive oxygen species formation and reduced SK-N-SH cell viability. Overall, our findings suggest that the L28P mutation leads to significant structural and conformational perturbations in apoE4 and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. We propose that these structural and functional changes underlie the observed added risk for AD development in carriers of apoE4[L28P].

Effects of the potential lithium-mimetic, ebselen, on impulsivity and emotional processing.

Science.gov (United States)

Masaki, Charles; Sharpley, Ann L; Cooper, Charlotte M; Godlewska, Beata R; Singh, Nisha; Vasudevan, Sridhar R; Harmer, Catherine J; Churchill, Grant C; Sharp, Trevor; Rogers, Robert D; Cowen, Philip J

2016-07-01

Lithium remains the most effective treatment for bipolar disorder and also has important effects to lower suicidal behaviour, a property that may be linked to its ability to diminish impulsive, aggressive behaviour. The antioxidant drug, ebselen, has been proposed as a possible lithium-mimetic based on its ability in animals to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. The aim of the study was to determine whether treatment with ebselen altered emotional processing and diminished measures of risk-taking behaviour. We studied 20 healthy participants who were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, randomized, cross-over design. Three hours after the final dose of ebselen/placebo, participants completed the Cambridge Gambling Task (CGT) and a task that required the detection of emotional facial expressions (facial emotion recognition task (FERT)). On the CGT, relative to placebo, ebselen reduced delay aversion while on the FERT, it increased the recognition of positive vs negative facial expressions. The study suggests that at the dosage used, ebselen can decrease impulsivity and produce a positive bias in emotional processing. These findings have implications for the possible use of ebselen in the disorders characterized by impulsive behaviour and dysphoric mood.

Apolipoprotein a5 and hypertriglyceridemia in prague hypertriglyceridemic rats

Czech Academy of Sciences Publication Activity Database

Kadlecová, Michaela; Hojná, Silvie; Bohuslavová, R.; Hubáček, J. A.; Zicha, Josef; Kuneš, Jaroslav

2006-01-01

Roč. 55, č. 4 (2006), s. 373-379 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0510; GA ČR(CZ) GA305/03/0769 Institutional research plan: CEZ:AV0Z50110509 Keywords : metabolic syndrome * apolipoprotein A5 * rat Subject RIV: ED - Physiology Impact factor: 2.093, year: 2006

Superstretchable Nacre-Mimetic Graphene/Poly(vinyl alcohol) Composite Film Based on Interfacial Architectural Engineering.

Science.gov (United States)

Zhao, Nifang; Yang, Miao; Zhao, Qian; Gao, Weiwei; Xie, Tao; Bai, Hao

2017-05-23

Through designing hierarchical structures, particularly optimizing the chemical and architectural interactions at its inorganic/organic interface, nacre has achieved an excellent combination of contradictory mechanical properties such as strength and toughness, which is highly demanded yet difficult to achieve by most synthetic materials. Most techniques applied to develop nacre-mimetic composites have been focused on mimicking the "brick-and-mortar" structure, but the interfacial architectural features, especially the asperities and mineral bridges of "bricks", have been rarely concerned, which are of equal importance for enhancing mechanical properties of nacre. Here, we used a modified bidirectional freezing method followed by uniaxial pressing and chemical reduction to assemble a nacre-mimetic graphene/poly(vinyl alcohol) composite film, with both asperities and bridges introduced in addition to the lamellar layers to mimic the interfacial architectural interactions found in nacre. As such, we have developed a composite film that is not only strong (up to ∼150.9 MPa), but also tough (up to ∼8.50 MJ/m 3 ), and highly stretchable (up to ∼10.44%), difficult to obtain by other methods. This was all achieved by only interfacial architectural engineering within the traditional "brick-and-mortar" structure, without introducing a third component or employing chemical cross-linker as in some other nacre-mimetic systems. More importantly, we believe that the design principles and processing strategies reported here can also be applied to other material systems to develop strong and stretchable materials.

The Mimetic Principle in the Underground Economy

Directory of Open Access Journals (Sweden)

Cristina Voicu

2009-08-01

Full Text Available There has been in the recent years an increased preoccupation at international level for the research of the mechanism of development of the underground economy. The numerous vain attempts to measure the dimension of the underground economy persuaded us to embark on a qualitative research of this economic phenomenon. In our investigation on the roots of the underground economy we drew very close to the psychological and sociological aspects of the phenomenon itself. The process of humanizing that has at its origin components of the mimetic principle, like acquisitive mimesis, prompt us to ponder over J.M. Keynes’ words: „The avoidance of taxes is the only intellectual ambition that one feels rewarded for.”

Mimetic Theory and the evolutionary paradox of schizophrenia: The archetypal scapegoat hypothesis.

Science.gov (United States)

Riordan, Daniel Vincent

2017-10-01

Schizophrenia poses an evolutionary paradox, being genetically mediated yet associated with reduced fecundity. Numerous hypotheses have attempted to address this, but few describe how the schizophrenic phenotype itself might constitute an evolutionary adaptation. This paper draws on René Girard's theory on human origins, which claims that humans evolved a tendency to mimic both the desires and the behaviours of each other (mimetic theory). This would have promoted social cohesion and co-operation, but at the cost of intra-group rivalry and conflict. The mimetic dynamic would have escalated such conflicts into reciprocal internecine violence, threatening the survival of the entire group. Girard theorised that the "scapegoat mechanism" emerged, by which means such violence was curtailed by the unanimity of "all against one", thus allowing the mimetic impulse to safely evolve further, making language and complex social behaviours possible. Whereas scapegoating may have emerged in the entire population, and any member of a community could be scapegoated if necessary, this paper proposes that the scapegoat mechanism would have worked better in groups containing members who exhibited traits, recognised by all others, which singled them out as victims. Schizophrenia may be a functional adaptation, similar in evolutionary terms to altruism, in that it may have increased inclusive fitness, by providing scapegoat victims, the choice of whom was likely to be agreed upon unanimously, even during internecine conflict, thus restoring order and protecting the group from self-destruction. This evolutionary hypothesis, uses Girardian anthropology to combine the concept of the schizophrenic as religious shaman with that of the schizophrenic as scapegoat. It may help to reconcile divergent philosophical concepts of mental illness, and also help us to better understand, and thus counter, social exclusion and stigmatisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA

Directory of Open Access Journals (Sweden)

Paul Halley

2014-01-01

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.

A mimetic finite difference method for the Stokes problem with elected edge bubbles

Energy Technology Data Exchange (ETDEWEB)

Lipnikov, K [Los Alamos National Laboratory; Berirao, L [DIPARTMENTO DI MATERMATICA

2009-01-01

A new mimetic finite difference method for the Stokes problem is proposed and analyzed. The unstable P{sub 1}-P{sub 0} discretization is stabilized by adding a small number of bubble functions to selected mesh edges. A simple strategy for selecting such edges is proposed and verified with numerical experiments. The discretizations schemes for Stokes and Navier-Stokes equations must satisfy the celebrated inf-sup (or the LBB) stability condition. The stability condition implies a balance between discrete spaces for velocity and pressure. In finite elements, this balance is frequently achieved by adding bubble functions to the velocity space. The goal of this article is to show that the stabilizing edge bubble functions can be added only to a small set of mesh edges. This results in a smaller algebraic system and potentially in a faster calculations. We employ the mimetic finite difference (MFD) discretization technique that works for general polyhedral meshes and can accomodate non-uniform distribution of stabilizing bubbles.

Caffeine Increases Apolipoprotein A-1 and Paraoxonase-1 but not Paraoxonase-3 Protein Levels in Human-Derived Liver (HepG2) Cells.

Science.gov (United States)

Sayılan Özgün, Gülben; Özgün, Eray; Tabakçıoğlu, Kıymet; Süer Gökmen, Selma; Eskiocak, Sevgi; Çakır, Erol

2017-12-01

Apolipoprotein A-1, paraoxonase-1 and paraoxonase-3 are antioxidant and anti-atherosclerotic structural high-density lipoprotein proteins that are mainly synthesized by the liver. No study has ever been performed to specifically examine the effects of caffeine on paraoxonase enzymes and on liver apolipoprotein A-1 protein levels. To investigate the dose-dependent effects of caffeine on liver apolipoprotein A-1, paraoxonase-1 and paraoxonase-3 protein levels. In vitro experimental study. HepG2 cells were incubated with 0 (control), 10, 50 and 200 μM of caffeine for 24 hours. Cell viability was evaluated by 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apolipoprotein A-1, paraoxonase-1 and paraoxonase-3 protein levels were measured by western blotting. We observed a significant increase on apolipoprotein A-1 and paraoxonase-1 protein levels in the cells incubated with 50 µM of caffeine and a significant increase on paraoxonase-1 protein level in the cells incubated with 200 µM of caffeine. Our study showed that caffeine does not change paraoxonase-3 protein level, but the higher doses used in our study do cause an increase in both apolipoprotein A-1 and paraoxonase-1 protein levels in liver cells.

Diversity of apolipoprotein E genetic polymorphism significance on cardiovascular risk is determined by the presence of metabolic syndrome among hypertensive patients.

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Teixeira, Andrei Alkmim; Marrocos, Mauro Sergio; Quinto, Beata Marie Redublo; Dalboni, Maria Aparecida; Rodrigues, Cassio Jose de Oliveira; Carmona, Silmara de Melo; Kuniyoshi, Mariana; Batista, Marcelo Costa

2014-11-20

Hypertension has a significant relevance as a cardiovascular risk factor. A consistent increase on world's Metabolic Syndrome (MetS) incidence has been associated with an epidemic cardiovascular risk in different populations. Dislipidemia plays a major role determining the epidemic CV burden attributed to MetS. Apolipoprotein E (ApoE) is involved on cholesterol and triglycerides metabolism regulation. Once ApoE polymorphism may influence lipid metabolism, it is possible that it brings on individual susceptibility consequences for the development of MetS and cardiovascular risk. The objective of the study is to measure the discriminatory power of ApoE polymorphism in determining cardiovascular risk stratification based on the presence MetS in a cohort of hypertensive patients. It was enrolled 383 patients, divided in two groups, classified by MetS presence (IDF criteria): Group 1: 266 patients with MetS (MetS +) and Group 2: 117 patients without Mets (MetS -). Patient's data were collected by clinical evaluation, physical exam, file reviews and laboratory testing. Polymorphic ApoE analysis was performed by PCR amplification. Groups were compared on clinical and laboratory characteristics as well as allele and genotype distribution towards ApoE polymorphism. Mets CVD prevalence was analysed according to E4 allele prevalence. The results evidenced 184 men (48%), 63,7% whites, 45,1% diabetics and 11,7% of patients were smokers. Mean age was 64,0 ± 12,0 years. When genotypic distribution was analyzed, E3/3 genotype and E3 allele frequencies were more prevalent. Among patients with MetS, we observed an independent association between CVD prevalence and E4 allele frequency (OR 2.42 (1.17- 5.0, p < 0,05)). On the opposite direction, in those without MetS, there was lesser CVD burden in E4 allele carriers (OR 0,14 (0,02-0,75)). These associations remained significant even after confounding factor corrections. The results presented demonstrate that the association

Selective improvement of pulmonary arterial hypertension with a dual ETA/ETB receptors antagonist in the apolipoprotein E-/- model of PAH and atherosclerosis.

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Renshall, Lewis; Arnold, Nadine; West, Laura; Braithwaite, Adam; Pickworth, Josephine; Walker, Rachel; Alfaidi, Mabruka; Chamberlain, Janet; Casbolt, Helen; Thompson, A A Roger; Holt, Cathy; Iglarz, Marc; Francis, Sheila; Lawrie, Allan

2018-01-01

Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE -/- ) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE -/- mice with macitentan, a dual ET A /ET B receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE -/- mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ET A /ET B antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE -/- mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ET A /ET B receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis.

Apolipoprotein M mediates sphingosine-1-phosphate efflux from erythrocytes

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Christensen, Pernille M.; Bosteen, Markus H.; Hajny, Stefan

2017-01-01

Sphingosine-1-phosphate (S1P) is a bioactive lipid implicated in e.g. angiogenesis, lymphocyte trafficking, and endothelial barrier function. Erythrocytes are a main source of plasma S1P together with platelets and endothelial cells. Apolipoprotein M (apoM) in HDL carries 70% of plasma S1P, whereas...... 30% is carried by albumin. The current aim was to investigate the role of apoM in export of S1P from human erythrocytes. Erythrocytes exported S1P more efficiently to HDL than to albumin, particularly when apoM was present in HDL. In contrast, export of sphingosine to HDL was unaffected...... by the presence of apoM. The specific ability of apoM to promote export of S1P was independent of apoM being bound in HDL particles. Treatment with MK-571, an inhibitor of the ABCC1 transporter, effectively reduced export of S1P from human erythrocytes to apoM, whereas the export was unaffected by inhibitors...

Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

NARCIS (Netherlands)

Dallinga-Thie, G. M.; van Tol, A.; Hattori, H.; van Vark-van der Zee, L. C.; Jansen, H.; Sijbrands, E. J. G.

2006-01-01

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 patients with type

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

Bio-mimetic mineralization potential of collagen hydrolysate obtained from chromium tanned leather waste

International Nuclear Information System (INIS)

Banerjee, Pradipta; Madhu, S.; Chandra Babu, N.K.; Shanthi, C.

2015-01-01

Hydroxyapatite (HA) ceramics serve as an alternative to autogenous-free bone grafting by virtue of their excellent biocompatibility. However, chemically synthesized HA lacks the strong load-bearing capacity as required by bone. The bio-mimetic growth of HA crystals on collagen surface provides a feasible solution for synthesizing bone substitutes with the desired properties. This study deals with the utilization of the collagen hydrolysate recovered from leather waste as a substrate for promoting HA crystal growth. Bio-mimetic growth of HA was induced by subjecting the hydrolysate to various mineralization conditions. Parameters that would have a direct effect on crystal growth were varied to determine the optimal conditions necessary. Maximum mineralization was achieved with a combination of 10 mM of CaCl 2 , 5 mM of Na 2 HPO 4 , 100 mM of NaCl and 0.575% glutaraldehyde at a pH of 7.4. The metal–protein interactions leading to formation of HA were identified through Fourier-transform infrared (FTIR) spectroscopy and x-ray diffraction (XRD) studies. The crystal dimensions were determined to be in the nanoscale range by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The size and crystallinity of bio-mimetically grown HA indicate that hydrolysate from leather waste can be used as an ideal alternative substrate for bone growth. - Highlights: • Collagen hydrolysate, extracted from leather industry waste is subjected to biomineralization. • Optimal conditions required for HA growth are identified. • FTIR studies reveal higher Ca−COO − and low C−N stretch with higher HA formation. • AFM and SEM studies reveal nanometer ranged HA crystals

Expression of apolipoprotein B in the kidney attenuates renal lipid accumulation

DEFF Research Database (Denmark)

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

2010-01-01

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...

Clinical application of human serum apolipoprotein B ria

International Nuclear Information System (INIS)

He Rongxia

1988-01-01

The serum apolipoprotein B (Apo B) was measured in 89 normal subjects with radioimmunoassay method established by the authors, among them 50 patients with coronary heart disease (CHD), 19 patients with cerebrae-vascular accident (CVA) and 46 patients with hyperlipemia. Meanwhile the serum cholesterol and triglyceride were also measured. Although cholesterol, triglyceride, and Apo B levels in disease groups were all significantly higher than control group, there are more overlap between the control and disease group for cholesterol and triglyceride. The Apo B level was 723.9 +- 195.9 mg/L in control group, 1097 +- 236.0 mg/L in CHD group and in CVA group, and this difference was highly significant (P < 0.001). Besides, less overlap of the Apo B value between disease and countrol group was observed in both disease groups. When the Apo B was used as single parameter for the diagnosis CHD, the accuracy rate reached 82%. The results of this study indicated that measurement of Apo B can offer important prediction for coronary artery disease, especially in those having normal levels of plasma cholesterol. In conclusion, the study of apolipoprotein is more significant than lipid component in discriminating between atherosclerotic patients and normal persons

Cardioprotection by Conditioning Mimetic Drugs.

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Santillo, Elpidio; Migale, Monica; Postacchini, Demetrio; Balestrini, Fabrizio; Incalzi, Raffaele Antonelli

2016-01-01

At present, ischemic heart disease (IHD) is one of the main causes of morbidity and mortality world-wide. An important insight into both IHD pathophysiology and cardioprotection was achieved in 1986 when Murry et al. described for the first time the ischemic preconditioning (IP). IP can be defined as an innate phenomenon by which brief episodes of ischemia confer protection to a tissue from a subsequent more protracted ischemic insult. Suggested mechanisms explaining IP comprise the action of circulating substances (e.g. adenosine, bradykinin, nitric oxide). These mediators are released after a prolonged ischemic stress, causing activation of molecular pathways that induce favorable posttranslational changes of proteins and adaptive modifications in genetic expression. Briefly review evidences from clinical studies on drugs that exert their effects by mimicking IP, discussing their therapeutic properties and the potential clinical employment in order to obtain cardioprotection. Literature regarding IP mimicking pharmacological agents was searched in Medline and Google Scholar. Authors reviewed relevant researches in English language including both clinical studies and reviews of clinical studies published from 1986 to 2016. Several pharmacological agents reproducing IP protective actions have been evaluated in many clinical trials. Examined molecules include adenosine, nicorandil and atrial natriuretic peptide. Interestingly IP mimicking effects of drugs have been also analyzed perioperatively in the context of ischaemia-reperfusion heart injury. Moreover evidences suggest that also some anaesthetic drugs (especially volatile agents) are able to provide myocardial protection by inducing IP. Drugs capable of mimicking IP exhibit a high therapeutic potential because of their properties of eliciting an effective cardioprotective signaling. Future studies should clarify the optimal doses and timing of administration of IP mimetic agents in order to favor the advent of

Prostaglandin E(2) synthase inhibition as a therapeutic target.

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Iyer, Jitesh P; Srivastava, Punit K; Dev, Rishabh; Dastidar, Sunanda G; Ray, Abhijit

2009-07-01

Most NSAIDs function by inhibiting biosynthesis of PGE(2) by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Apolipoprotein E gene polymorphisms are associated with primary hyperuricemia in a Chinese population.

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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

Coupling of an indicator-free electrochemical DNA biosensor with polymerase chain reaction for the detection of DNA sequences related to the apolipoprotein E

Energy Technology Data Exchange (ETDEWEB)

Lucarelli, Fausto; Marrazza, Giovanna; Palchetti, Ilaria; Cesaretti, S.; Mascini, Marco

2002-09-26

This paper describes a disposable indicator-free electrochemical DNA biosensor applied to the detection of apolipoprotein E (apoE) sequences in PCR samples. In the indicator-free assays, the duplex formation was detected by measuring the electrochemical signal of the guanine base of nucleic acids. The biosensor format involved the immobilisation of an inosine-modified (guanine-free) probe onto a screen-printed electrode (SPE) transducer and the detection of the duplex formation in connection with the square-wave voltammetric measurement of the oxidation peak of the guanine of the target sequence. The indicator-free scheme has been characterised using 23-mer oligonucleotides as model: parameters affecting the hybridisation assay such as probe immobilisation conditions, hybridisation time, use of hybridisation accelerators were examined and optimised. The analysis of PCR samples (244 bp DNA fragments, obtained by amplification of DNA extracted from human blood) required a further optimisation of the experimental procedure. In particular, a lower steric hyndrance of the probe modified surface was essential to allow an efficient hybridisation of the target DNA fragment. Negative controls have been performed using the PCR blank and amplicons unrelated to the immobilised probe. A 10 min hybridisation time allowed a full characterisation of each sample.

Nickel Inhibits Mitochondrial Fatty Acid Oxidation

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Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

2015-01-01

Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

Metabolism of apolipoproteins C-II, C-III, and B in hypertriglyceridemic men. Changes after heparin-induced lipolysis

International Nuclear Information System (INIS)

Huff, M.W.; Breckenridge, W.C.; Strong, W.L.; Wolfe, B.M.

1988-01-01

The C apolipoproteins are normally transferred to high density lipoproteins (HDL) after lipolysis of very low density lipoprotein (VLDL) triglyceride. In previous studies, a loss of plasma C apolipoproteins was documented after heparin-induced lipolysis in hypertriglyceridemic subjects. The present studies were designed to determine if this decline in plasma C apolipoproteins was due to their clearance with VLDL remnants. Five Type IV hypertriglyceridemic and two normal subjects were injected with 125I-VLDL and 131I-low density lipoproteins (LDL) to document kinetically an excess of VLDL apolipoprotein (apo) B flux relative to LDL apo B flux in the Type IV subjects. A mean of 46% VLDL apo B was cleared from the circulation, without conversion to intermediate density lipoprotein (IDL) or LDL. Heparin was then infused (9000 IU over 4 hours) to generate an excess of VLDL remnants that were not converted to IDL or LDL. VLDL triglyceride, apo B, and apo C concentrations fell at a similar rate. VLDL apo B declined by 42% (p less than 0.01). However, no increases were observed in IDL or LDL apo B in the Type IV subjects. This resulted in a 14% (p less than 0.01) decline in plasma apo B concentrations, indicating a clearance of VLDL remnants. VLDL apo C-II and C-III concentrations fell by 42% (p less than 0.025) and 52% (p less than 0.01), respectively. During the first 2.5 hours of infusion, they were almost quantitatively recovered in HDL. Thereafter, the C apolipoproteins declined in HDL during which time VLDL apo C concentrations continued to decline

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

DEFF Research Database (Denmark)

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

2006-01-01

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, gene......D alleles, genotypes or haplotypes to be associated with disease. However, we did find that long-term clinical outcome was associated with the ApoD polymorphism rs7659 (P = 0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.......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...

Convergent and divergent effects of apolipoprotein E ε4 and ε2 alleles on amygdala functional networks in nondemented older adults.

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Gong, Liang; Shu, Hao; He, Cancan; Ye, Qing; Bai, Feng; Xie, Chunming; Zhang, Zhijun

2017-06-01

Traditionally, in the context of Alzheimer's disease, the apolipoprotein E ε2 (APOEε2) allele is a protective factor and the APOEε4 allele is a destructive factor. However, this inverse relationship has recently been challenged, and the neural mechanisms underlying the effects of APOE genotype on Alzheimer's disease remain unclear. A resting-state functional magnetic resonance imaging study was conducted to investigate the effects of APOE genotype and age on amygdala functional connectivity (AFC) networks in 84 patients with amnestic mild cognitive impairment and 124 cognitively normal order adults. The results indicated that the APOEε2 and APOEε4 alleles produced convergent effects in the right AFC network but divergent effects in the left AFC network. As age increased, APOEε2 carriers showed stable AFC, whereas APOEε4 carriers exhibited decreased AFC in all participants. Furthermore, mediation analysis revealed that connectivity strength regulates the effects of APOE genotype and age on cognitive function in amnestic mild cognitive impairment patients. Our findings suggest that the APOEε2 and APOEε4 alleles produce both convergent and divergent topological effects on brain function. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor

OpenAIRE

Fang, Pengfei; Han, Hongyan; Wang, Jing; Chen, Kaige; Chen, Xin; Guo, Min

2015-01-01

Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits P. falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report 3 crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all 3 structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of...

Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

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Mingzhu Zhuang

Full Text Available Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease.

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Wolk, David A; Dickerson, Bradford C

2010-06-01

The epsilon4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer's disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the epsilon4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of epsilon4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer's Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.

Does Apolipoprotein e4 Status Moderate the Association of Family Environment with Long-Term Child Functioning following Early Moderate to Severe Traumatic Brain Injury? A Preliminary Study.

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Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Wade, Shari L; Kurowski, Brad G

2016-09-01

To examine whether apolipoprotein e4 (APOE) status moderates the association of family environment with child functioning following early traumatic brain injury (TBI). Sixty-five children with moderate to severe TBI and 70 children with orthopedic injury (OI) completed assessments 6, 12, 18 months, and 3.5 and 6.8 years post injury. DNA was extracted from saliva samples and genotyped for APOE e4 status. Linear mixed models examined moderating effects of APOE e4 status on associations between two family environment factors (parenting style, home environment) and three child outcomes (executive functioning, behavioral adjustment, adaptive functioning). Children with TBI who were carriers of the e4 allele showed poorer adaptive functioning relative to non-carriers with TBI and children with OI in the context of low authoritarianism. At high levels of authoritarianism, non-carriers with TBI showed the poorest adaptive functioning among groups. There were no main effects or interactions involving APOE and executive functioning or behavioral adjustment. The APOE e4 allele was detrimental for long-term adaptive functioning in the context of positive parenting, whereas in less optimal parenting contexts, being a non-carrier was detrimental. We provide preliminary evidence for an interaction of APOE e4 status and parenting style in predicting long-term outcomes following early TBI. (JINS, 2016, 22, 859-864).

Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy

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Monteiro Pedro

2011-03-01

Full Text Available Abstract Background The risk of coronary heart disease (CHD is related to environmental factors and genetic variants. Apolipoprotein E (apoE polymorphisms are heritable determinants of total and low-density lipoprotein cholesterol, with some authors suggesting an association between the ε4 allele and CHD. We investigated the relationship between apoE genotype and age at referral to a specialized lipid clinic by the primary care physician and whether the benefits of treatment with statin differed between genotypes. Methods We assessed individual apoE genotypes and lipid blood profile in a total of 463 patients followed at a specialized lipid clinic due to dyslipidemia, with a 3-year median follow-up time. The primary care physician at the time of the referral had no access to the apoE genotyping results. Carriers of apoE ε4/ε2 genotype were excluded. Results The frequencies of ε2, ε3 and ε4 alleles were 7.8, 78.9 and 13.3%, respectively. There were no significant differences between genders. Although with similar lipid profiles and antidyslipidemic drug usage at baseline, ε4-carriers were referred to the clinic at a younger age (44.2 ± 14.7 years compared with non-ε4 carriers (50.6 ± 13.8 years (p Conclusion Our findings support the concept that there is a reduced response to anti-dyslipidemic treatment in ε4 carriers; this can be a contributing factor for the earlier referral of these patients to our specialized lipid clinic and reinforces the usefulness of apoE genotyping in predicting patients response to lipid lowering therapies.

Using superoxide dismutase/catalase mimetics to manipulate the redox environment of neural precursor cells

International Nuclear Information System (INIS)

Limoli, C. L.; Giedzinski, E.; Baure, J.; Doctrow, S. R.; Rola, R.; Fike, J. R.

2006-01-01

Past work has shown that neural precursor cells are predisposed to redox sensitive changes, and that oxidative stress plays a critical role in the acute and persistent changes that occur within the irradiated CNS. Irradiation leads to a marked rise in reactive oxygen species (ROS) that correlates with oxidative endpoints in vivo and reductions in neuro-genesis. To better understand the impact of oxidative stress on neural precursor cells, and to determine if radiation-induced oxidative damage and precursor cell loss after irradiation could be reduced, a series of antioxidant compounds (EUK-134, EUK-163, EUK-172, EUK-189) were tested, three of which possess both superoxide dismutase (SOD) and catalase activities and one (EUK-163) whose only significant activity is SOD. Our results show that these SOD/catalase mimetics apparently increase the oxidation of a ROS-sensitive fluorescent indicator dye, particularly after short (12 h) treatments, but that longer treatments (24 h) decrease oxidation attributable to radiation-induced ROS. Similarly, other studies found that cells incubated with CuZnSOD showed some increase in intracellular ROS levels. Subsequent data suggested that the dye-oxidising capabilities of the EUK compounds were linked to differences in their catalase activity and, most likely, their ability to catalyse per-oxidative pathways. In unirradiated mice, the EUK-134 analogue induced some decrease of proliferating precursor cells and immature neurons 48 h after radiation, an effect that may be attributable to cytotoxicity and/or inhibition of precursor proliferation. In irradiated mice, a single injection of EUK-134 was not found to be an effective radioprotector at acute times (48 h). The present results support continued development of our in vitro model as a tool for predicting certain in vivo responses, and suggest that in some biological systems the capability to scavenge superoxide but produce excess H 2 O 2 , as is known for CuZnSOD, may be

Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the Alzheimer's disease brain.

Science.gov (United States)

Love, Julia E; Day, Ryan J; Gause, Justin W; Brown, Raquel J; Pu, Xinzhu; Theis, Dustin I; Caraway, Chad A; Poon, Wayne W; Rahman, Abir A; Morrison, Brad E; Rohn, Troy T

2017-01-01

Although harboring the apolipoprotein E4 ( APOE4 ) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment. In addition, this antibody also detected a ~17 kDa amino-terminal fragment of apoE4 following incubation with collagenase and matrix metalloproteinase-9 (MMP-9), but did not react with full-length apoE4. Application of this amino-terminal apoE cleavage-fragment (nApoECFp17) antibody, revealed nuclear labeling within glial cells and labeling of a subset of neurofibrillary tangles in the human AD brain. A quantitative analysis indicated that roughly 80% of labeled nuclei were microglia. To confirm these findings, cultured BV2 microglia cells were incubated with the amino-terminal fragment of apoE4 corresponding to the cleavage site at D151. The results indicated efficient uptake of this fragment and trafficking to the nucleus that also resulted in significant cell death. In contrast, a similarly designed apoE3 fragment showed no toxicity and primarily localized within the cytoplasm. These data suggest a novel cleavage event by which apoE4 is cleaved by the extracellular proteases, collagenase and MMP-9, generating an amino-terminal fragment that is then taken up by microglia, traffics to the nucleus and promotes cell death. Collectively, these findings provide important mechanistic insights into the mechanism by which harboring the APOE4 allele may elevate dementia risk observed in AD.

Stick–slip friction of gecko-mimetic flaps on smooth and rough surfaces

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Das, Saurabh; Cadirov, Nicholas; Chary, Sathya; Kaufman, Yair; Hogan, Jack; Turner, Kimberly L.; Israelachvili, Jacob N.

2015-01-01

The discovery and understanding of gecko ‘frictional-adhesion’ adhering and climbing mechanism has allowed researchers to mimic and create gecko-inspired adhesives. A few experimental and theoretical approaches have been taken to understand the effect of surface roughness on synthetic adhesive performance, and the implications of stick–slip friction during shearing. This work extends previous studies by using a modified surface forces apparatus to quantitatively measure and model frictional forces between arrays of polydimethylsiloxane gecko footpad-mimetic tilted microflaps against smooth and rough glass surfaces. Constant attachments and detachments occur between the surfaces during shearing, as described by an avalanche model. These detachments ultimately result in failure of the adhesion interface and have been characterized in this study. Stick–slip friction disappears with increasing velocity when the flaps are sheared against a smooth silica surface; however, stick–slip was always present at all velocities and loads tested when shearing the flaps against rough glass surfaces. These results demonstrate the significance of pre-load, shearing velocity, shearing distances, commensurability and shearing direction of gecko-mimetic adhesives and provide us a simple model for analysing and/or designing such systems. PMID:25589569

Methods and Experimental Protocols to Design a Simulated Bio-Mimetic Quadruped Robot

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Hadi El Daou

2013-05-01

Full Text Available Abstract This paper presents a bio-mimetic approach to design and simulate a tortoise-like virtual robot. This study takes a multidisciplinary approach: from in vivo and in vitro experiments on animals, data are collected and used to design, control and simulate a bio-mimetic virtual robot using MD ADAMS platform. From the in vitro experiments, the geometrical and inertial properties of body limbs are measured, and a model of tortoise kinematics is derived. From the in vivo experiments the contact forces between each limb and the ground are measured. The contributions of hind and forelimbs in the generation of propelling and braking forces are studied. The motion of the joints between limb segments are recorded and used to solve the inverse kinematics problem. A virtual model of a tortoise-like robot is built; it is a linkage of 15 rigid bodies articulated by 22 degrees of freedom. This model is referred to as TATOR II. It has the inertial and geometrical properties measured during the in vitro experiments. TATOR II motion is achieved using a Proportional-Derivative controller copying the joint angle trajectories calculated from the in vivo experiments.

Whole Body Vibration Retards Progression of Atherosclerosis via Insulin-Like Growth Factor 1 in Apolipoprotein E-Deficient Mice

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He Wu

2018-01-01

Full Text Available Whole body vibration (WBV has a marked impact on lipid metabolism and the endocrine system, which is related to the progression of atherosclerosis (AS. To investigate the effects of WBV, we measured the atherosclerotic plaque area of apolipoprotein E-knockout (ApoE−/− AS mice, which were trained by WBV (15 Hz, 30 min for 12 weeks. Simultaneously, serum levels of lipids, insulin-like growth factor 1 (IGF-1, insulin-like growth factor 1 receptor (IGF-1R, interleukin 6 (IL-6, and the mRNA and protein levels of the same in the aorta were compared between the control and WBV groups. The results indicated that WBV significantly reduced the atherosclerotic plaque area with lower very low-density lipoprotein (VLDL and oxidized low-density lipoprotein (ox-LDL in the blood. Moreover, the levels of IGF-1 in serum and expression of IL-6, IGF-1R, and p-IGF-1R protein in the mice aorta decreased significantly in the WBV group. In addition, we found that serum IGF-1 in mice increased to the highest concentration in 30 min after WBV for 10, 30, 60, and 120 minutes. These results suggested that appropriate WBV may delay the progression of AS, which was associated with acutely elevated serum IGF-1 and lower levels of IGF-1 and IL-6 in the aorta for long-term treatment.

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.

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.

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

DEFF Research Database (Denmark)

Benn, Marianne

2009-01-01

capturing the entire variation in APOB cannot be identified, and thus most polymorphisms must be evaluated separately in association studies; (3) APOB mutations and polymorphisms are associated with a range of apolipoprotein B and LDL cholesterol levels, although the magnitude of effect sizes of common...... for the E4154K polymorphism that possibly predicts a reduction in risk of ischemic cerebrovascular disease and ischemic stroke, common APOB polymorphisms with modest effect sizes on lipid levels do not predict risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease...

Overcoming EMT-driven therapeutic resistance by BH3 mimetics.

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Keitel, Ulrike; Scheel, Christina; Dobbelstein, Matthias

2014-01-01

Epithelial-mesenchymal transition (EMT) contributes to the progression of cancer through enhanced invasion and stem-like properties of cancer cells. Additionally, EMT confers resistance towards many chemotherapeutics. We recently described a mechanism that mediates EMT-driven chemoresistance through augmented levels of Bcl-xL, an anti-apoptotic member of the Bcl-2 family (Keitel et al., Oncotarget, in press). Here, we elaborate on how these findings pertain to cancer cells dispersed in the tumor-adjacent stroma of breast cancer tissues, and how BH3-mimetics may provide a therapeutic strategy to eliminate cancer cell populations that have passed through an EMT.

Asymmetries in global-local processing ability in elderly people with the apolipoprotein e-epsilon4 allele.

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Jacobson, Mark W; Delis, Dean C; Lansing, Amy; Houston, Wes; Olsen, Ryan; Wetter, Spencer; Bondi, Mark W; Salmon, David P

2005-11-01

Previous studies have identified cognitive asymmetries in elderly people at increased risk for Alzheimer's disease (AD) by comparing standardized neuropsychological tests of verbal and spatial abilities in both preclinical AD and apolipoprotein epsilon4+ elderly groups. This prospective study investigated cognitive asymmetries within a single test by comparing cognitively intact elderly (with and without the epsilon4+ allele) on a learning and memory measure that uses global and local visuospatial stimuli. Both groups demonstrated comparable overall learning and recall. But the epsilon4+ group had a significantly larger discrepancy between their global and local learning scores and had a greater proportion of individuals with more than a one standard deviation difference between their immediate recall of the global and local elements, relative to the epsilon4- group. These findings build on previous studies identifying subgroups of elderly people at greater risk for AD who often demonstrate increased cognitive asymmetries relative to groups without significant risk factors. Copyright (c) 2005 APA, all rights reserved.

Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic β-Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet.

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Abderrazak, Amna; El Hadri, Khadija; Bosc, Elodie; Blondeau, Bertrand; Slimane, Mohamed-Naceur; Büchele, Berthold; Simmet, Thomas; Couchie, Dominique; Rouis, Mustapha

2016-06-01

Intraperitoneal injection of arglabin (2.5 ng/g of body weight, twice daily, 13 weeks) into female human apolipoprotein E2 gene knock-in (ApoE2Ki) mice fed a high-fat Western-type diet (HFD) reduced plasma levels of glucose and insulin by ∼20.0% ± 3.5% and by 50.0% ± 2.0%, respectively, in comparison with vehicle-treated mice. Immunohistochemical analysis revealed the absence of active caspase-3 in islet sections from ApoE2Ki mice fed a HFD and treated with arglabin. In addition, arglabin reduced interleukin-1β (IL-1β) production in a concentration-dependent manner in Langerhans islets isolated from ApoE2Ki mice treated with lipopolysaccharide (LPS) and with cholesterol crystals. This inhibitory effect is specific for the inflammasome NOD-like receptor family, pyrin domain-containing 3 (NLRP3) because IL-1β production was abolished in Langerhans islets isolated from Nlrp3(-/-) mice. In the insulin-secreting INS-1 cells, arglabin inhibited, in a concentration-dependent manner, the maturation of pro-IL-1β into biologically active IL-1β probably through the inhibition of the maturation of procaspase-1 into active capsase-1. Moreover, arglabin reduced the susceptibility of INS-1 cells to apoptosis by increasing Bcl-2 levels. Similarly, autophagy activation by rapamycin decreased apoptosis susceptibility while autophagy inhibition by 3-methyladenin treatment promoted apoptosis. Arglabin further increased the expression of the autophagic markers Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain 3 II (LC3-II) in a concentration-dependent manner. Thus, arglabin reduces NLRP3-dependent inflammation as well as apoptosis in pancreatic β-cells in vivo and in the INS-1 cell line in vitro, whereas it increases autophagy in cultured INS-1 cells, indicating survival-promoting properties of the compound in these cells. Hence, arglabin may represent a new promising compound to treat inflammation and type 2 diabetes mellitus development

Inhibition of adipocytogenesis by canonical WNT signaling in human mesenchymal stem cells

International Nuclear Information System (INIS)

Shen, Longxiang; Glowacki, Julie; Zhou, Shuanhu

2011-01-01

The WNT signaling pathway plays important roles in the self-renewal and differentiation of mesenchymal stem cells (MSCs). Little is known about WNT signaling in adipocyte differentiation of human MSCs. In this study, we tested the hypothesis that canonical and non-canonical WNTs differentially regulate in vitro adipocytogenesis in human MSCs. The expression of adipocyte gene PPARγ2, lipoprotein lipase, and adipsin increased during adipocytogenesis of hMSCs. Simultaneously, the expression of canonical WNT2, 10B, 13, and 14 decreased, whereas non-canonical WNT4 and 11 increased, and WNT5A was unchanged. A small molecule WNT mimetic, SB-216763, increased accumulation of β-catenin protein, inhibited induction of WNT4 and 11 and inhibited adipocytogenesis. In contrast, knockdown of β-catenin with siRNA resulted in spontaneous adipocytogenesis. These findings support the view that canonical WNT signaling inhibits and non-canonical WNT signaling promotes adipocytogenesis in adult human marrow-derived mesenchymal stem cells.

Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice.

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Schroeter, Marco R; Humboldt, Tim; Schäfer, Katrin; Konstantinides, Stavros

2009-07-01

Statins enhance incorporation of bone marrow-derived cells into experimental neointimal lesions. However, the contribution of progenitor cells to progression of spontaneous atherosclerotic plaques, and the possible modulatory role of statins in this process, remain poorly understood. We compared the effects of rosuvastatin (1 and 10mg/kg BW) and pravastatin (10mg/kg) on progenitor cell mobilisation, recruitment into atherosclerotic plaques, and lesion growth. Statins were administered over 8 weeks to apolipoprotein E knockout mice on atherogenic diet. In addition, mice were lethally irradiated, followed by transplantation of bone marrow from LacZ transgenic mice. Rosuvastatin reduced lesion area and intima-to-media ratio at the brachiocephalic artery compared to vehicle, while both parameters were not significantly altered by pravastatin. Rosuvastatin also augmented endothelialisation (P<0.05) and reduced the smooth muscle cells (SMC) content (P=0.042) of lesions. Numbers of c-kit, sca-1 and flk-1, sca-1 double-positive progenitor cells were significantly increased in rosuvastatin compared to control-treated mice, both in the bone marrow and the peripheral blood. Similarly, the number of spleen-derived acLDL, lectin double-positive progenitor cells (P=0.001) and colony-forming units (P=0.0104) was significantly increased in mice treated with rosuvastatin compared to vehicle alone. In the bone marrow, increased Akt and p42/44 MAP kinase phosphorylation and upregulated SDF1alpha mRNA expression were observed. Importantly, rosuvastatin treatment also increased the plasma levels of c-kit ligand (P=0.003), and the number of c-kit-positive cells within atherosclerotic lesions (P=0.041). Our findings suggest that rosuvastatin reduces the size of atherosclerotic plaques, and this effect appears to involve progenitor cell mobilisation and recruitment into vascular lesions.

Mimetic Finite Differences for Flow in Fractures from Microseismic Data

KAUST Repository

Al-Hinai, Omar; Srinivasan, Sanjay; Wheeler, Mary F.

2015-01-01

We present a method for porous media flow in the presence of complex fracture networks. The approach uses the Mimetic Finite Difference method (MFD) and takes advantage of MFD's ability to solve over a general set of polyhedral cells. This flexibility is used to mesh fracture intersections in two and three-dimensional settings without creating small cells at the intersection point. We also demonstrate how to use general polyhedra for embedding fracture boundaries in the reservoir domain. The target application is representing fracture networks inferred from microseismic analysis.

Mimetic Finite Differences for Flow in Fractures from Microseismic Data

KAUST Repository

Al-Hinai, Omar

2015-01-01

We present a method for porous media flow in the presence of complex fracture networks. The approach uses the Mimetic Finite Difference method (MFD) and takes advantage of MFD\\'s ability to solve over a general set of polyhedral cells. This flexibility is used to mesh fracture intersections in two and three-dimensional settings without creating small cells at the intersection point. We also demonstrate how to use general polyhedra for embedding fracture boundaries in the reservoir domain. The target application is representing fracture networks inferred from microseismic analysis.

Simultaneous Quantification of Apolipoprotein A-I and Apolipoprotein B by Liquid-Chromatography–Multiple-Reaction–Monitoring Mass Spectrometry

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Agger, Sean A.; Marney, Luke C.; Hoofnagle, Andrew N.

2011-01-01

BACKGROUND If liquid-chromatography–multiple-reaction–monitoring mass spectrometry (LC-MRM/MS) could be used in the large-scale preclinical verification of putative biomarkers, it would obviate the need for the development of expensive immunoassays. In addition, the translation of novel biomarkers to clinical use would be accelerated if the assays used in preclinical studies were the same as those used in the clinical laboratory. To validate this approach, we developed a multiplexed assay for the quantification of 2 clinically well-known biomarkers in human plasma, apolipoprotein A-I and apolipoprotein B (apoA-I and apoB). METHODS We used PeptideAtlas to identify candidate peptides. Human samples were denatured with urea or trifluoroethanol, reduced and alkylated, and digested with trypsin. We compared reversed-phase chromatographic separation of peptides with normal flow and microflow, and we normalized endogenous peptide peak areas to internal standard peptides. We evaluated different methods of calibration and compared the final method with a nephelometric immunoassay. RESULTS We developed a final method using trifluoroethanol denaturation, 21-h digestion, normal flow chromatography-electrospray ionization, and calibration with a single normal human plasma sample. For samples injected in duplicate, the method had intraassay CVs <6% and interassay CVs <12% for both proteins, and compared well with immunoassay (n = 47; Deming regression, LC-MRM/MS = 1.17 × immunoassay – 36.6; Sx|y = 10.3 for apoA-I and LC-MRM/MS = 1.21 × immunoassay + 7.0; Sx|y = 7.9 for apoB). CONCLUSIONS Multiplexed quantification of proteins in human plasma/serum by LC-MRM/MS is possible and compares well with clinically useful immunoassays. The potential application of single-point calibration to large clinical studies could simplify efforts to reduce day-to-day digestion variability. PMID:20923952

High ethanol and acetaldehyde impair spatial memory in mouse models: opposite effects of aldehyde dehydrogenase 2 and apolipoprotein E on memory.

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Jamal, Mostofa; Ameno, Kiyoshi; Miki, Takanori; Tanaka, Naoko; Ono, Junichiro; Shirakami, Gotaro; Sultana, Ruby; Yu, Nakamura; Kinoshita, Hiroshi

2012-05-01

Aldehyde dehydrogenase 2 deficiency may directly contribute to excess acetaldehyde (AcH) accumulation after ethanol (EtOH) drinking and AcH mediates some of the behavioral effects of EtOH. Apolipoprotein E has been suggested to be involved in the alteration of attention and memory. We have chosen Aldh2-knockout (Aldh2-KO), ApoE-KO, and their wild-type (WT) control mice to examine the effects of EtOH and AcH on spatial memory and to compare the possible relationship between genetic deficiency and memory using two behavioral assessments. Mice were trained for 4 days, with EtOH (0.5, 1.0, 2.0 g/kg) being given intraperitoneally on day 4. A probe trial was given on day 5 in the non-EtOH state in the Morris water maze (MWM). The results showed that 2.0 g/kg EtOH increased errors, indicating memory impairment on the eight-arm radial maze (RAM) for all the mice studied. One gram per kilogram EtOH impaired the performance of Aldh2-KO and ApoE-KO mice, but not WT mice. We found similar effects of EtOH on the MWM performance, with 2.0 g/kg EtOH increasing the latencies. One gram per kilogram EtOH increased the latencies of Aldh2-KO and WT mice, but not ApoE-KO mice. The 2.0 g/kg EtOH-induced memory impairment in Aldh2-KO mice was greater, suggesting an AcH effect. Furthermore, time spent on the probe trial was shorter in mice that had previously received 2.0 g/kg EtOH. ApoE-KO mice learned more slowly, while Aldh2-KO mice learned more quickly. Both the RAM and MWM results suggest that high EtOH and AcH impair spatial memory in mice, while lower doses do not have consistent memory effects. In addition, we conclude that genetic differences might underlie some of EtOH's effects on memory. Copyright © 2012 Elsevier Inc. All rights reserved.

Metabolism of apolipoproteins A-I and A-II in human high-density lipoprotein: a mathematical approach for analysis of their specific activity decay curves

International Nuclear Information System (INIS)

Atmeh, R.F.

1987-01-01

The differential rate equations describing the compartmental model of human high-density lipoprotein (HDL) were integrated by means of Laplace transforms and an exponential equation was obtained for each of the three compartments. These equations were used to fit the observed plasma decay data and give estimates for the rate constants of the system by means of a written computer program. Furthermore, these estimates were used to calculate the exponential constants of the integrated equations. Consequently, the amount of label in any of the intravascular, extravascular, and urine compartments can be calculated as a fraction of the original dose of label at any time point. This method was tested using data for the (AI)HDL subclass because it contains only apolipoprotein A-I as the major apolipoprotein and does not contain apolipoprotein A-II. The calculated plasma and urine radioactivity data were compared with the experimentally obtained data from two normolipoproteinemic subjects and found to be in good agreement. The significance of this method is its application to the analysis of the decay data of the individual apolipoproteins of (AI + AII) HDL subclass where the urinary radioactivity data resulting from the individual apolipoprotein breakdown on the native particle cannot be measured experimentally at present. Such data are essential for the detailed calculation of the kinetic parameters of these apolipoproteins

Lack of association of apolipoprotein E (Apo E ε2/ε3/ε4 polymorphisms with primary open-angle glaucoma: a meta-analysis from 1916 cases and 1756 controls.

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Wei Wang

Full Text Available BACKGROUND: A number of case-control studies were conducted to investigate the association of apolipoprotein E (Apo E polymorphisms with primary open angle glaucoma (POAG. But the results remain controversial. This meta-analysis aims to comprehensively evaluate the relationship between a common ε2/ε3/ε4 polymorphism in Apo E gene on the risk of POAG. METHOD: A comprehensive literature search for studies published up to April 2013 was performed. Summary odds ratios (ORs and 95% confidence intervals (CI were calculated employing random-effects models irrespective of between-study heterogeneity. Publication bias of literatures was evaluated using funnel plots and Egger's test. RESULTS: A total of 12 studies including 1916 cases and 1756 controls meeting the predefined criteria were involved in this meta-analysis. Overall, the Apo E ε2 allele and ε4 allele were not associated with POAG, compared with those carrying ε3 allele, with ORs of 0.98 (95% CI, 0.79 to 1.23; P=0.872 and 1.05 (95% CI, 0.78 to 1.41; P=0.743, respectively. Genotypic analysis also found no significant association between the ε4 carriers (ε3/ε4+ε4/ε4, ε2 carriers (ε2/ε3+ε2/ε2 and POAG, compared with participants with Apo E ε3/3, with ORs of 0.91 (95% CI, 0.66 to 1.25; P=0.543 and 1.08 (95% CI, 0.74 to 1.57; P=0.694, respectively. In the subgroup analysis by ethnicity, source of controls, genotyping methods, Hardy-Weinberg equilibrium or not, or type of the POAG, still no obvious associations were found. CONCLUSIONS: This meta-analysis suggests that Apo E ε2/ε3/ε4 polymorphisms may not be associated with the risk of POAG. However, well-designed studies with larger sample size and more ethnic groups are required to further validate the results.