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Sample records for amyloid-beta peptide levels

  1. Tau/Amyloid Beta 42 Peptide Test (Alzheimer Biomarkers)

    Science.gov (United States)

    ... helpful? Also known as: Alzheimer Biomarkers Formal name: Tau Protein and Amyloid Beta 42 Peptide Related tests: Phosporylated ... should know? How is it used? Tests for Tau protein and Aß42 may be used as supplemental tests ...

  2. Plasma amyloid beta peptides and oligomers antibodies in Alzheimer's disease

    OpenAIRE

    Zhou, L.; Chu, LW; Kwan, JSC; Ho, JWM; Lam, KSL; Ho, PWL; Chan, KH

    2011-01-01

    INTRODUCTION: Various forms of amyloid beta (Aβ) including Aβ peptides, oligomers, protofibrils and fibrils are thought to be pathogenic in Alzheimer’s disease (AD). The exact pathophysiological role of endogenous Aβ autoantibodies (Ab) in healthy subjects and AD patients are uncertain. Potential protective role ...

  3. Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers

    CERN Document Server

    Mobley, D L; Singh, R R P; Maddox, M W; Longo, M J; Mobley, David L.; Cox, Daniel L.; Singh, Rajiv R. P.; Maddox, Michael W.; Longo, Marjorie L.

    2003-01-01

    Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A-beta), can insert into cell membranes and form harmful ion channels, we model insertion of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular A-beta peptide as well as mutants causing familial Alzheimer's disease. We present our results and develop the hypothesis that partial insertion into the membrane, leaving the peptide in one leaflet, increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior, and also explains why, normally, A-beta 42 is more toxic to some cultured cells than A-beta 40, but the E22Q mutation reverses this effect. We further apply this model to various artificial A-beta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard ...

  4. PARP-1 modulates amyloid beta peptide-induced neuronal damage.

    Directory of Open Access Journals (Sweden)

    Sara Martire

    Full Text Available Amyloid beta peptide (Aβ causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose polymerase (PARP-1. To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25-35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed.

  5. Effects of Low-Dose Pioglitazone on Serum Levels of Adiponectin, Dehydroepiandrosterone, Amyloid Beta Peptide, and Lipid Profile in Elderly Japanese People with Type 2 Diabetes

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    Yuji Aoki

    2015-01-01

    Full Text Available This study was performed to see how pioglitazone at low doses could affect blood biomarkers related to atherosclerosis and aging. The effects of an add-on treatment with pioglitazone (15 mg for males and 7.5 mg for females for 6 months were assessed in 24 outpatients (12 males, 12 females with type 2 diabetes aged ≥ 70 years. As doses of sulfonylurea were reduced in 10 patients, no significant differences in HbA1c and glucose levels were seen. After the treatment, serum levels of HDL cholesterol, arachidonic acid (predominant in males, and high-molecular-weight adiponectin significantly increased. The level of dehydroepiandrosterone sulfate significantly decreased. No significant changes were seen in those of small dense LDL cholesterol, high-sensitivity C-reactive protein, and amyloid beta peptides 1–40 and 1–42. There was a slight but significant increase in body weight, but apparent adverse effects were not observed. In conclusion, pioglitazone at low doses increased serum adiponectin, HDL cholesterol, and arachidonic acid levels but decreased serum dehydroepiandrosterone level, not associated with glycemia, in elderly Japanese people with type 2 diabetes. An optimal dose of pioglitazone should be sought for to minimize its adverse effects and to fully exert its pleiotropic effects such as antiatherosclerotic and antiaging effects.

  6. Amyloid beta peptide immunotherapy in Alzheimer disease.

    Science.gov (United States)

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  7. The novel amyloid-beta peptide aptamer inhibits intracellular amyloid-beta peptide toxicity

    Institute of Scientific and Technical Information of China (English)

    Xu Wang; Yi Yang; Mingyue Jia; Chi Ma; Mingyu Wang; Lihe Che; Yu Yang; Jiang Wu

    2013-01-01

    Amyloid β peptide binding alcohol dehydrogenase (ABAD) decoy peptide (DP) can competitively antagonize binding of amyloid β peptide to ABAD and inhibit the cytotoxic effects of amyloid β peptide. Based on peptide aptamers, the present study inserted ABAD-DP into the disulfide bond of human thioredoxin (TRX) using molecular cloning technique to construct a fusion gene that can express the TRX1-ABAD-DP-TRX2 aptamer. Moreover, adeno-associated virus was used to allow its stable expression. Immunofluorescent staining revealed the co-expression of the transduced fusion gene TRX1-ABAD-DP-TRX2 and amyloid β peptide in NIH-3T3 cells, indicating that the TRX1-ABAD-DP-TRX2 aptamer can bind amyloid β peptide within cells. In addition, cell morphology and MTT results suggested that TRX1-ABAD-DP-TRX2 attenuated amyloid β peptide-induced SH-SY5Y cell injury and improved cell viability. These findings confirmed the possibility of constructing TRX-based peptide aptamer using ABAD-DP. Moreover, TRX1-ABAD-DP-TRX2 inhibited the cytotoxic effect of amyloid β peptide.

  8. Amyloid Beta Peptides Differentially Affect Hippocampal Theta Rhythms In Vitro

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    Armando I. Gutiérrez-Lerma

    2013-01-01

    Full Text Available Soluble amyloid beta peptide (Aβ is responsible for the early cognitive dysfunction observed in Alzheimer's disease. Both cholinergically and glutamatergically induced hippocampal theta rhythms are related to learning and memory, spatial navigation, and spatial memory. However, these two types of theta rhythms are not identical; they are associated with different behaviors and can be differentially modulated by diverse experimental conditions. Therefore, in this study, we aimed to investigate whether or not application of soluble Aβ alters the two types of theta frequency oscillatory network activity generated in rat hippocampal slices by application of the cholinergic and glutamatergic agonists carbachol or DHPG, respectively. Due to previous evidence that oscillatory activity can be differentially affected by different Aβ peptides, we also compared Aβ25−35 and Aβ1−42 for their effects on theta rhythms in vitro at similar concentrations (0.5 to 1.0 μM. We found that Aβ25−35 reduces, with less potency than Aβ1−42, carbachol-induced population theta oscillatory activity. In contrast, DHPG-induced oscillatory activity was not affected by a high concentration of Aβ25−35 but was reduced by Aβ1−42. Our results support the idea that different amyloid peptides might alter specific cellular mechanisms related to the generation of specific neuronal network activities, instead of exerting a generalized inhibitory effect on neuronal network function.

  9. Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

    NARCIS (Netherlands)

    Giacomelli, CE; Norde, W

    2003-01-01

    The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that dena

  10. PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation

    DEFF Research Database (Denmark)

    Brambilla, Davide; Verpillot, Romain; Le Droumaguet, Benjamin;

    2012-01-01

    We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the...

  11. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Chun Yang; Yufeng Liu; Peng Li; Huiying Yang; Jingxing Dai; Rongmei Qu; Lin Yuan

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei-mer’s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer’s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg-radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer’s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer’s disease treatment.

  12. Sex-dependent actions of amyloid beta peptides on hippocampal choline carriers of postnatal rats

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Říčný, Jan; Kozmiková, I.; Řípová, D.; Zach, P.; Klaschka, Jan

    2006-01-01

    Roč. 31, č. 3 (2006), s. 351-360. ISSN 0364-3190 R&D Projects: GA ČR(CZ) GA305/03/1547 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z10300504 Keywords : amyloid beta peptide * high affinity choline transport * rat hippocampus Subject RIV: ED - Physiology Impact factor: 2.139, year: 2006

  13. DCP-LA neutralizes mutant amyloid beta peptide-induced impairment of long-term potentiation and spatial learning.

    Science.gov (United States)

    Nagata, Tetsu; Tomiyama, Takami; Tominaga, Takemi; Mori, Hiroshi; Yaguchi, Takahiro; Nishizaki, Tomoyuki

    2010-01-01

    Long-term potentiation (LTP) was monitored from the CA1 region of the intact rat hippocampus by delivering high frequency stimulation (HFS) to the Schaffer collateral commissural pathway. Intraventricular injection with mutant amyloid beta(1-42) peptide lacking glutamate-22 (Abeta(1-42)E22Delta), favoring oligomerization, 10 min prior to HFS, inhibited expression of LTP, with the potency more than wild-type amyloid beta(1-42) peptide. Intraperitoneal injection with the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) 70 min prior to HFS neutralized mutant Abeta(1-42)E22Delta peptide-induced LTP inhibition. In the water maze test, continuous intraventricular injection with mutant Abeta(1-42)E22Delta peptide for 14 days prolonged the acquisition latency as compared with that for control, with the potency similar to wild-type Abeta(1-42) peptide, and intraperitoneal injection with DCP-LA shortened the prolonged latency to control levels. The results of the present study indicate that DCP-LA neutralizes mutant Abeta(1-42)E22Delta peptide-induced impairment of LTP and spatial learning. PMID:19716848

  14. Designed amyloid beta peptide fibril - a tool for high-throughput screening of fibril inhibitors.

    Science.gov (United States)

    Dolphin, Gunnar T; Ouberai, Myriam; Dumy, Pascal; Garcia, Julian

    2007-11-01

    Amyloid beta peptide (Abeta) fibril formation is widely believed to be the causative event of Alzheimer's disease pathogenesis. Therapeutic approaches are therefore in development that target various sites in the production and aggregation of Abeta. Herein we present a high-throughput screening tool to generate novel hit compounds that block Abeta fibril formation. This tool is an application for our fibril model (Abeta(16-37)Y(20)K(22)K(24))(4), which is a covalent assembly of four Abeta fragments. With this tool, screening studies are complete within one hour, as opposed to days with native Abeta(1-40). A Z' factor of 0.84+/-0.03 was determined for fibril formation and inhibition, followed by the reporter molecule thioflavin T. Herein we also describe the analysis of a broad range of reported inhibitors and non-inhibitors of Abeta fibril formation to test the validity of the system. PMID:17876751

  15. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  16. Inhibitory Effect of Curcumin-Cu(II) and Curcumin-Zn(II) Complexes on Amyloid-Beta Peptide Fibrillation

    OpenAIRE

    Rona Banerjee

    2014-01-01

    Mononuclear complexes of Curcumin with Cu(II) and Zn(II) have been synthesized and, characterized and their effects on the fibrillization and aggregation of amyloid-beta (Aβ) peptide have been studied. FTIR spectroscopy and atomic force microscopy (AFM) observations demonstrate that the complexes can inhibit the transition from less structured oligomers to β-sheet rich protofibrils which act as seeding factors for further fibrillization. The metal complexes also impart more improved inhibitor...

  17. The mechanism of the low-density lipoprotein receptor- related protein (LRP) in the production of amyloid-[Beta] peptide

    OpenAIRE

    Chen, Eunice Chungyu

    2008-01-01

    Alzheimer's disease (AD) is the most common form of neurodegenerative disorder affecting the elderly, presenting symptoms such as memory impairment and dementia. AD is pathologically characterized by the development of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). The plaques are composed of amyloid-[Beta] peptide (A[Beta]) and the NFTs are composed of a hyperphosphorylated form of the tau protein. A[Beta] is formed by sequential proteolytic processing of the a...

  18. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

    OpenAIRE

    Portelius, Erik; Andreasson, Ulf; Ringman, John M.; Buerger, Katharina; Daborg, Jonny; Buchhave, Peder; Hansson, Oskar; Harmsen, Andreas; Gustavsson, Mikael K; Hanse, Eric; Galasko, Douglas; Hampel, Harald; Blennow, Kaj; Zetterberg, Henrik

    2010-01-01

    Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (A beta) in the brain, which is reflected by low concentration of the A beta 1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional A beta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of A beta. Here, we test the hypothesis that AD is characterized by a specific CSF A beta isoform pattern that is distinct when comparing ...

  19. Lower levels of cerebrospinal fluid amyloid beta (Abeta) in non-demented Indian controls.

    Science.gov (United States)

    Subramanian, Sarada; Sandhyarani, Boya; Shree, A N Divya; Murthy, K Krishna; Kalyani, K; Kumar, S Praveen; Pradeep; Noone, Mohin Jeslie; Taly, A B

    2006-10-23

    Prevalence of Alzheimer's disease in Indian population is lower than in developed countries. To determine whether limitation of amyloid beta (Abeta) concentration may be responsible for lower rate of incidence, we measured the levels of Abeta in cerebrospinal fluid (CSF) collected from 72 non-demented individuals ranging in the age from 20 years to 65 years. These samples were segregated into three groups ranging from 20-35 years, 36-50 years and 51-65 years of age. Levels of Abeta could be detected in all the age groups and they were much lower than the values reported in literature from the developed countries. No significant difference in the average level of Ass was observed with increase in age. PMID:16978775

  20. Chronic exposure of NG108-15 cells to amyloid beta peptide (A beta(1-42)) abolishes calcium influx via N-type calcium channels

    Czech Academy of Sciences Publication Activity Database

    Kašparová, Jana; Lisá, Věra; Tuček, Stanislav; Doležal, Vladimír

    2001-01-01

    Roč. 26, 8-9 (2001), s. 1079-1084. ISSN 0364-3190 R&D Projects: GA MZd NF5183 Institutional research plan: CEZ:AV0Z5011922 Keywords : amyloid beta peptide * Alzheimer's disease * calcium Subject RIV: FH - Neurology Impact factor: 1.638, year: 2001

  1. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

    DEFF Research Database (Denmark)

    Hansson Petersen, Camilla A; Alikhani, Nyosha; Behbahani, Homira;

    2008-01-01

    The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to...... investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane...... potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by...

  2. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering

    Science.gov (United States)

    Zhang-Haagen, Bo; Biehl, Ralf; Nagel-Steger, Luitgard; Radulescu, Aurel; Richter, Dieter; Willbold, Dieter

    2016-01-01

    Small proteins like amyloid beta (Aβ) monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS) is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP) by using SANS and dynamic light scattering (DLS). We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1–40 and 1.6±0.1 nm for Aβ1–42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1–40 and 3.2±0.4 nm for Aβ1–42 including a surface layer of dHFIP solvent molecules. PMID:26919121

  3. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

    Directory of Open Access Journals (Sweden)

    Bo Zhang-Haagen

    Full Text Available Small proteins like amyloid beta (Aβ monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP by using SANS and dynamic light scattering (DLS. We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

  4. CD147 is a regulatory subunit of the gamma-secretase complex inAlzheimer's disease amyloid beta-peptide production

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Shuxia; Zhou, Hua; Walian, Peter J.; Jap, Bing K.

    2005-04-06

    {gamma}-secretase is a membrane protein complex that cleaves the {beta}-amyloid precursor protein (APP) within the transmembrane region, following prior processing by {beta}-secretase, producing amyloid {beta}-peptides (A{beta}{sub 40} and A{beta}{sub 42}). Errant production of A{beta}-peptides that substantially increases A{beta}{sub 42} production has been associated with the formation of amyloid plaques in Alzheimer's disease patients. Biophysical and genetic studies indicate that presenilin-1 (Psn-1), which contains the proteolytic active site, and three other membrane proteins, nicastrin (Nct), APH-1, and PEN-2 are required to form the core of the active {gamma}-secretase complex. Here, we report the purification of the native {gamma}-secretase complexes from HeLa cell membranes and the identification of an additional {gamma}-secretase complex subunit, CD147, a transmembrane glycoprotein with two immunoglobulin-like domains. The presence of this subunit as an integral part of the complex itself was confirmed through co-immunoprecipitation studies of the purified protein from HeLa cells and solubilized complexes from other cell lines such as neural cell HCN-1A and HEK293. Depletion of CD147 by RNA interference was found to increase the production of A{beta} peptides without changing the expression level of the other {gamma}-secretase components or APP substrates while CD147 overexpression had no statistically significant effect on amyloid {beta}-peptide production, other {gamma}-secretase components or APP substrates, indicating that the presence of the CD147 subunit within the {gamma}-secretase complex directly down-modulates the production of A{beta}-peptides. {gamma}-secretase was first recognized through its role in the production of the A{beta} peptides that are pathogenic in Alzheimer's disease (AD) (1). {gamma}-secretase is a membrane protein complex with unusual aspartyl protease activity that cleaves a variety of type I membrane proteins

  5. Einfluß einer In-vitro- und In-vivo-Cholesterol-Modulation in Hirnmembranen auf die zellulären Effekte von Amyloid-beta-Peptid

    OpenAIRE

    Kirsch, Christopher

    2003-01-01

    Die exzessive Bildung und Ablagerung von aggregiertem Amyloid beta-Peptid im Gehirn von Alzheimer Patienten wird allgemein als zentrales Ereignis im Rahmen des Neurodegenerationsprozesses der Alzheimer Demenz betrachtet. Der Amyloid-Stoffwechsel ist dabei in sehr vielfältiger Weise mit dem zellulären Cholesterol-Stoffwechsel verknüpft. Hohe Cholesterolspiegel in spezifischen Membrandomänen wie Lipid-Rafts forcieren sehr wahrscheinlich die zelluläre Produktion als auch die Fibrillogenese von A...

  6. Low levels of amyloid-beta and its transporters in neonatal rats with and without hydrocephalus

    Directory of Open Access Journals (Sweden)

    Silverberg Gerald D

    2009-05-01

    Full Text Available Abstract Background Previous studies in aging animals have shown that amyloid-beta protein (Aβ accumulates and its transporters, low-density lipoprotein receptor-related protein-1 (LRP-1 and the receptor for advanced glycation end products (RAGE are impaired during hydrocephalus. Furthermore, correlations between astrocytes and Aβ have been found in human cases of normal pressure hydrocephalus (NPH and Alzheimer's disease (AD. Because hydrocephalus occurs frequently in children, we evaluated the expression of Aβ and its transporters and reactive astrocytosis in animals with neonatal hydrocephalus. Methods Hydrocephalus was induced in neonatal rats by intracisternal kaolin injections on post-natal day one, and severe ventriculomegaly developed over a three week period. MRI was performed on post-kaolin days 10 and 21 to document ventriculomegaly. Animals were sacrificed on post-kaolin day 21. For an age-related comparison, tissue was used from previous studies when hydrocephalus was induced in a group of adult animals at either 6 months or 12 months of age. Tissue was processed for immunohistochemistry to visualize LRP-1, RAGE, Aβ, and glial fibrillary acidic protein (GFAP and with quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR to quantify expression of LRP-1, RAGE, and GFAP. Results When 21-day post-kaolin neonatal hydrocephalic animals were compared to adult (6–12 month old hydrocephalic animals, immunohistochemistry demonstrated levels of Aβ, RAGE, and LRP-1 that were substantially lower in the younger animals; in contrast, GFAP levels were elevated in both young and old hydrocephalic animals. When the neonatal hydrocephalic animals were compared to age-matched controls, qRT-PCR demonstrated no significant changes in Aβ, LRP-1 and RAGE. However, immunohistochemistry showed very small increases or decreases in individual proteins. Furthermore, qRT-PCR indicated statistically significant increases in GFAP

  7. Stoichiometric inhibition of amyloid beta-protein aggregation with peptides containing alternating alpha,alpha-disubstituted amino acids.

    Science.gov (United States)

    Etienne, Marcus A; Aucoin, Jed P; Fu, Yanwen; McCarley, Robin L; Hammer, Robert P

    2006-03-22

    We have prepared two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid beta-protein (Abeta) that contain alpha,alpha-disubstituted amino acids at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus). We have studied the effects of AMY-1 and AMY-2 on the aggregation of Abeta and find that, at stoichiometric concentrations, both peptides completely stop Abeta fibril growth. Equimolar mixtures of AMY-1 and Abeta form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillar or fibrillar material even after prolonged periods of time (4.5 months). Also, 10 mol % of AMY-1 prevents Abeta self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillar or fibrillar aggregates. Circular dichroism spectroscopy of equimolar mixtures of AMY-1 and Abeta show that the secondary structure of the mixture changes over time and progresses to a predominantly beta-sheet structure, which is consistent with the design of these inhibitors preferring a sheet-like conformation. Changing the position of the charged tail on the peptide, AMY-2 interacts with Abeta differently in that equimolar mixtures form large ( approximately 1 mum) globular aggregates which do not progress to fibrils, but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the inhibitors act as cosurfactants that interfere with the native ability of Abeta to self-assemble by disrupting hydrophobic interactions either at the C-terminus or N-terminus of Abeta. PMID:16536517

  8. Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity.

    Science.gov (United States)

    Ott, Stanislav; Vishnivetskaya, Anastasia; Malmendal, Anders; Crowther, Damian C

    2016-05-01

    Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibire(TS) flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress. PMID:27103517

  9. Evaluation of the amyloid beta-GFP fusion protein as a model of amyloid beta peptides-mediated aggregation: A study of DNAJB6 chaperone

    OpenAIRE

    Rasha Mohamed Hussein; Rashed, Laila A

    2015-01-01

    Alzheimer’s disease is a progressive neurodegenerative disease characterized by the accumulation and aggregation of extracellular amyloid β (Aβ) peptides and intracellular aggregation of hyper-phosphorylated tau protein. Recent evidence indicates that accumulation and aggregation of intracellular amyloid β peptides may also play a role in disease pathogenesis. This would suggest that intracellular Heat Shock Proteins (HSP) that maintain cellular protein homeostasis might be candidates for dis...

  10. Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide.

    Science.gov (United States)

    Gomez-Brouchet, Anne; Pchejetski, Dimitri; Brizuela, Leyre; Garcia, Virginie; Altié, Marie-Françoise; Maddelein, Marie-Lise; Delisle, Marie-Bernadette; Cuvillier, Olivier

    2007-08-01

    We examined the role of sphingosine kinase-1 (SphK1), a critical regulator of the ceramide/sphingosine 1-phosphate (S1P) biostat, in the regulation of death and survival of SH-SY5Y neuroblastoma cells in response to amyloid beta (Abeta) peptide (25-35). Upon incubation with Abeta, SH-SY5Y cells displayed a marked down-regulation of SphK1 activity coupled with an increase in the ceramide/S1P ratio followed by cell death. This mechanism was redox-sensitive; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited Abeta-induced cell death. SphK1 overexpression impaired the cytotoxicity of Abeta, whereas SphK1 silencing by RNA interference mimicked Abeta-induced cell death, thereby establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well established cytoprotective action of insulin-like growth factor (IGF-I) against Abeta toxicity. A dominant-negative form of SphK1 or its pharmacological inhibition not only abrogated IGF-I-triggered stimulation of SphK1 but also hampered IGF-I protective effect. Similarly to IGF-I, the neuroprotective action of TGF-beta1 was also dependent on SphK1 activity; activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Taken together, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of Abeta-treated cells. PMID:17522181

  11. Chronic cladribine administration increases amyloid beta peptide generation and plaque burden in mice.

    Directory of Open Access Journals (Sweden)

    Crystal D Hayes

    Full Text Available BACKGROUND: The clinical uses of 2-chloro-2'-deoxyadenosine (2-CDA or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS. Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known. METHODOLOGY: Here we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm. CONCLUSIONS: Taken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2

  12. Iron and aluminum interaction with amyloid-beta peptides associated with Alzheimer’s disease

    International Nuclear Information System (INIS)

    An elevation in the concentration of heavy metal ions in Alzheimer’s disease (AD) brain has been demonstrated in many studies. Aβ precipitation and toxicity in AD brains seem to be caused by abnormal interactions with neocortical metal ions, especially iron, copper, zinc, and aluminum [1–3]. There is increasing evidence that iron and aluminum ions are involved in the mechanisms that underlie the neurodegenerative diseases [4,5]. However, evidence was brought to demonstrate that some Aβ fragments, at physiological pH, are not able to form binary complexes with Fe(III) ions of sufficient stability to compete with metal hydroxide precipitation [6]. On the contrary, multiple metal ions are known to interact with Aβ peptides [7]. Consequently, we investigated here the interaction of Fe(II/III) and Al(III) ions with some amyloid-β peptides and fragments that results in peptide aggregation and fibrillation [8,9]. Infrared spectroscopy, atomic force microscopy, scanning electron microscopy, electrophoresis and mass spectrometry demonstrated conformational changes of peptides in the presence of such metals

  13. Iron and aluminum interaction with amyloid-beta peptides associated with Alzheimer’s disease

    Energy Technology Data Exchange (ETDEWEB)

    Drochioiu, Gabi; Ion, Laura [Alexandru Ioan Cuza University of Iasi, 11 Carol I, Iasi 700506 (Romania); Murariu, Manuela; Habasescu, Laura [Petru Poni Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, Iasi 700487 (Romania)

    2014-10-06

    An elevation in the concentration of heavy metal ions in Alzheimer’s disease (AD) brain has been demonstrated in many studies. Aβ precipitation and toxicity in AD brains seem to be caused by abnormal interactions with neocortical metal ions, especially iron, copper, zinc, and aluminum [1–3]. There is increasing evidence that iron and aluminum ions are involved in the mechanisms that underlie the neurodegenerative diseases [4,5]. However, evidence was brought to demonstrate that some Aβ fragments, at physiological pH, are not able to form binary complexes with Fe(III) ions of sufficient stability to compete with metal hydroxide precipitation [6]. On the contrary, multiple metal ions are known to interact with Aβ peptides [7]. Consequently, we investigated here the interaction of Fe(II/III) and Al(III) ions with some amyloid-β peptides and fragments that results in peptide aggregation and fibrillation [8,9]. Infrared spectroscopy, atomic force microscopy, scanning electron microscopy, electrophoresis and mass spectrometry demonstrated conformational changes of peptides in the presence of such metals.

  14. Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide

    OpenAIRE

    de Melo, Joana Barbosa; Agostinho, Paula; Oliveira, Catarina Resende

    2003-01-01

    Acetylcholinesterase (AChE) activity is increased within and around amyloid plaques, which are present in Alzheimer's disease (AD) patient's brain. In this study, using cultured retinal cells as a neuronal model, we analyzed the effect of the synthetic peptide A[beta]25-35 on the activity of AChE, the degradation enzyme of acetylcholine, as well as the involvement of oxidative stress in this process. The activity of AChE was increased when retinal cells were incubated with A[beta]25-35 (25 [m...

  15. Multiple mechanisms of iron-induced amyloid beta-peptide accumulation in SHSY5Y cells: protective action of negletein.

    Science.gov (United States)

    Banerjee, Priyanjalee; Sahoo, Arghyadip; Anand, Shruti; Ganguly, Anirban; Righi, Giuliana; Bovicelli, Paolo; Saso, Luciano; Chakrabarti, Sasanka

    2014-12-01

    The increased accumulation of iron in the brain in Alzheimer's disease (AD) is well documented, and excess iron is strongly implicated in the pathogenesis of the disease. The adverse effects of accumulated iron in AD brain may include the oxidative stress, altered amyloid beta-metabolism and the augmented toxicity of metal-bound amyloid beta 42. In this study, we have shown that exogenously added iron in the form of ferric ammonium citrate (FAC) leads to considerable accumulation of amyloid precursor protein (APP) without a corresponding change in the concerned gene expression in cultured SHSY5Y cells during exposure up to 48 h. This phenomenon is also associated with increased β-secretase activity and augmented release of amyloid beta 42 in the medium. Further, the increase in β-secretase activity, in SHSY5Y cells, upon exposure to iron apparently involves reactive oxygen species (ROS) and NF-κB activation. The synthetic flavone negletein (5,6-dihydroxy-7-methoxyflavone), which is a known chelator for iron, can significantly prevent the effects of FAC on APP metabolism in SHSY5Y cells. Further, this compound inhibits the iron-dependent formation of ROS and also blocks the iron-induced oligomerization of amyloid beta 42 in vitro. In concentrations used in this study, negletein alone appears to have only marginal toxic effects on cell viability, but, on the other hand, the drug is capable of ameliorating the iron-induced loss of cell viability considerably. Our results provide the initial evidence of potential therapeutic effects of negletein, which should be explored in suitable animal models of AD. PMID:25249289

  16. Amyloid-beta peptide degradation in cell cultures by mycoplasma contaminants

    Directory of Open Access Journals (Sweden)

    Davies Peter

    2008-06-01

    Full Text Available Abstract Background Cell cultures have become an indispensable tool in Alzheimer's disease research for studying amyloid-β (Aβ metabolism. It is estimated that up to 35% of cell cultures in current use are infected with various mycoplasma species. In contrast with common bacterial and fungal infections, contaminations of cell cultures with mycoplasmas represent a challenging issue in terms of detectability and prevention. Mycoplasmas are the smallest and simplest self-replicating bacteria and the consequences of an infection for the host cells are variable, ranging from no apparent effect to induction of apoptosis. Findings Here we present evidence that mycoplasmas from a cell culture contamination are able to efficiently and rapidly degrade extracellular Aβ. As a result, we observed no accumulation of Aβ in the conditioned medium of mycoplasma-positive cells stably transfected with the amyloid-β precursor protein (APP. Importantly, eradication of the mycoplasma contaminant – identified as M. hyorhinis – by treatments with a quinolone-based antibiotic, restored extracellular Aβ accumulation in the APP-transfected cells. Conclusion These data show that mycoplasmas degrade Aβ and thus may represent a significant source of variability when comparing extracellular Aβ levels in different cell lines. On the basis of these results, we recommend assessment of mycoplasma contaminations prior to extracellular Aβ level measurements in cultured cells.

  17. Accumulation of Exogenous Amyloid-Beta Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

    Directory of Open Access Journals (Sweden)

    Sergio Rosales-Corral

    2012-01-01

    Full Text Available Amyloid-beta (Aβ pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS. Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer’s disease (AD brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.

  18. Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35)-induced cell injury: Anti-inflammatory effects☆

    OpenAIRE

    Xi, Feifei; Sang, Feng; Zhou, Chunxiang; Ling, Yun

    2012-01-01

    In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-β peptide (25–35), as a model of Alzheimer’s disease, to evaluate the protective effects of 10-3–10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-β peptide-induced injury, and lowered levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and ...

  19. Regulation of adenosine triphosphate-sensitive potassium channels suppresses the toxic effects of amyloid-beta peptide (25-35)

    Institute of Scientific and Technical Information of China (English)

    Min Kong; Maowen Ba; Hui Liang; Peng Shao; Tianxia Yu; Ying Wang

    2013-01-01

    In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide (25-35) for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide (25-35) decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nω-nitro-L-arginine, also protected PC12 cells from intracellular reactive oxygen species levels. However, the H2O2-degrading enzyme catalase could that the increases in both mitochondrial membrane potential and reactive oxygen species levels adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β

  20. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

    OpenAIRE

    Portelius, Erik; Andreasson, Ulf; Ringman, John M.; Buerger, Katharina; Daborg, Jonny; Buchhave, Peder; Hansson, Oskar; Harmsen, Andreas; Gustavsson, Mikael K; Hanse, Eric; Galasko, Douglas; Hampel, Harald; Blennow, Kaj; Zetterberg, Henrik

    2010-01-01

    Abstract Background Alzheimer's disease (AD) is associated with deposition of amyloid β (Aβ) in the brain, which is reflected by low concentration of the Aβ1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Aβ peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Aβ. Here, we test the hypothesis that AD is characterized by a specific CSF Aβ isoform pattern that is ...

  1. Local atomic structure and oxidation processes of Cu(I) binding site in amyloid beta peptide: XAS Study

    Science.gov (United States)

    Kremennaya, M. A.; Soldatov, M. A.; Stretsov, V. A.; Soldatov, A. V.

    2016-05-01

    There are two different motifs of X-ray absorption spectra for Cu(I) K-edge in amyloid-β peptide which could be due to two different configurations of local Cu(I) environment. Two or three histidine ligands can coordinate copper ion in varying conformations. On the other hand, oxidation of amyloid-β peptide could play an additional role in local copper environment. In order to explore the peculiarities of local atomic and electronic structure of Cu(I) binding sites in amyloid-β peptide the x-ray absorption spectra were simulated for various Cu(I) environments including oxidized amyloid-β and compared with experimental data.

  2. Expression of secreted human single-chain fragment variable antibody against human amyloid beta peptide in Pichia pastoris

    Institute of Scientific and Technical Information of China (English)

    Jiong Cai; Fang Li; Shizhen Wang

    2008-01-01

    BACKGROUND: Studies have shown that monoclonal or polyclonal antibody injections ofamyloid β peptide arc effective in removing amyloid β peptide overload in the brain.OBJECTIVE: Based on successful screening of a human single-chain fragment variable antibody specific to amyloid β peptide, this paper aimed to express recombinant human single-chain variable antibody against amyloid β peptide.DESIGN, TIME AND SETTING: A single sample experiment was performed at the Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Hospital (Beijing, China) from January to July 2006.MATERIALS: Human single-chain fragment variable antibody gene against amyloid β peptide was screened from a human phage-display antibody library.METHODS: Human single-chain fragment variable antibody gene was mutated to eliminate a BamHI restriction site and cloned into a Teasy plasmid for pT-seFvAβ construction, which was identified by PCR amplification and endonuclease digestion. Plasmid pT-scFvA β was cut by EcoRl and Notl endonucleases, and the antibody gene was cloned into pPIC9K plasmid to construct pPIC9K-scFvA β expression vector, which was confirmed by gene sequencing. Linearized pPICgK-scFvA β was used to transform a Pichia pastoris GS115 cell line, and the recombinant was induced by 0.5 % methanol to express human single-chain fragment variable antibody specific to amyloid β peptide.MAIN OUTCOME MEASURES: Protein electrophoresis was used to identify PCR products, gene sequencing was uscd to verify the pPIC9K-scFvA sequence, and SDS-PAGE was used to detect recombinant expression of human single-chain fragment variable antibody specific to amyloid β peptide in Pichia pastoris.RESULTS: Gene sequencing confirmed pPICgK-scFvA β orientation. Rccomhinants were obtained by lineadzed pPIC9K-scFvA β transformation. After induction with 0.5% methanol, the recombinant yeast cells secreted proteins of 33-ku size

  3. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R;

    2000-01-01

    -Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases...

  4. Characterization of D-enantiomeric peptides binding to monomeric Amyloid beta (1-42) identified by a competitive mirror image phage display

    OpenAIRE

    Rudolph, Stephan; Kutzsche, Janine; Klein, Antonia Nicole; Frenzel, Daniel; Willbold, Dieter

    2014-01-01

    Alzheimer's disease (AD) is the most prominent type of dementia in elderly people. Until now there is no curative therapy available.Amyloid beta (Aβ) is assumed to play a major role in the development and progression of the disease. Freely diffusible, toxic Aβ oligomers seem to have a major toxicological impact.

  5. Molecular Dynamics Simulation of Amyloid Beta Dimer Formation

    CERN Document Server

    Urbanc, B; Ding, F; Sammond, D; Khare, S; Buldyrev, S V; Stanley, H E; Dokholyan, N V

    2004-01-01

    Recent experiments with amyloid-beta (Abeta) peptide suggest that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation: (1) we use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations, and (2) we employ all-atom molecular mechanics simulations to estimate the thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts ten different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40...

  6. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer's disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates.

    Directory of Open Access Journals (Sweden)

    Agustín Ruiz

    Full Text Available Plasma amyloid beta (Aβ levels are being investigated as potential biomarkers for Alzheimer's disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer's disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment. We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i Aβ directly accessible (DA in the plasma, ii Aβ recovered from the plasma matrix (RP after diluting the plasma sample in a formulated buffer, and iii associated with the remaining cellular pellet (CP. We confirmed that diastolic blood pressure (DBP is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032. These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<<0.001 and to a lesser extent to urea, age, hematocrit, uric acid and homocysteine (p<0.001. DBP and the rest of statistical significant correlates identified should be considered as potential confounder factors in studies investigating blood Aβ levels as potential AD biomarker. Remarkably, the factors affecting Aβ levels in plasma (DA, RP and blood cell compartments (CP seem completely different.

  7. The role of mutated amyloid beta 1-42 stimulating dendritic cells in a PDAPP transgenic mouse

    Directory of Open Access Journals (Sweden)

    LI Jia-lin

    2012-06-01

    Full Text Available Background Amyloid plaque is one of the pathological hallmarks of Alzheimer's disease (AD. Anti-beta-amyloid (Aβ immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. To avoid severe adverse effects such as meningoencephalitis induced by amyloid beta vaccine with adjuvant, and take advantage of amyloid beta antibody's therapeutic effect on Alzheimer's disease sufficiently, our group has developed a new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating dendritic cells (DC. Our previous work has confirmed that DC vaccine can induce adequate anti-amyloid beta antibody in PDAPP Tg mice safely and efficiently. The DC vaccine can improve impaired learning and memory in the Alzheimer's animal model, and did not cause microvasculitis, microhemorrhage or meningoencephalitis in the animal model. However, the exact mechanism of immunotherapy which reduces Aβ deposition remains unknown. In this report, we studied the mechanism of the vaccine, thinking that this may have implications for better understanding of the pathogenesis of Alzheimer's disease. Methods A new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating DC which were obtained from C57/B6 mouse bone marrow was developed. Amyloid beta with Freund's adjuvant was inoculated at the same time to act as positive control. After the treatment was done, the samples of brains were collected, fixed, cut. Immunohistochemical staining was performed to observe the expression of the nuclear hormone liver X receptor (LXR, membrane-bound protein tyrosine phosphatase (CD45, the ATP-binding cassette family of active transporters (ABCA1, receptor for advanced glycation end products (RAGE, β-site APP-cleaving enzyme (BACE and Aβ in mouse brain tissue. Semi-quantitative analysis was used to defect CA1, CA2, CA3, DG, Rad in hippocampus region and positive neuron in cortex region. Results Aβ was significantly reduced in the

  8. Laser-Induced In-Source Decay Applied to the Determination of Amyloid-Beta in Alzheimer's Brains.

    Science.gov (United States)

    Kelley, Andrea R; Perry, George; Castellani, Rudolph J; Bach, Stephan B H

    2016-03-16

    A method for the analysis of amyloid-beta peptides in isolated plaques and intact tissue sections affected by Alzheimer's disease (AD) is presented. This method employs matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry and the inherent laser-induced in-source decay (ISD) that occurs coupled with imaging mass spectrometry (IMS) to investigate the composition of these samples eliminating the need for other confirmational MS/MS techniques. These results demonstrate this technique's usefulness for the identification of amyloid-beta peptides in tissue and isolated senile plaques from AD patients using the reproducible fragmentation pattern demonstrated via the laser-induced ISD of synthetic amyloid-beta peptide clips (1-40, 1-42). Clear differences between the hippocampal AD tissue and the control hippocampal tissue regarding the presence of amyloid-beta have been identified. These are based on laser-induced ISD of standard amyloid-beta clips as controls as well as the analysis of isolated senile plaques as a confirmation before tissue analysis. Using the resulting observed peptide clip masses from the control data, we present mass spectrometry based identification of the amyloid-beta peptides in both isolated plaques and hippocampal regions of those patients diagnosed with AD. PMID:26720297

  9. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.

    Science.gov (United States)

    Castellani, Rudy J; Lee, Hyoung-gon; Siedlak, Sandra L; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition. PMID:19584435

  10. Mutation-based structural modification and dynamics study of amyloid beta peptide (1–42: An in-silico-based analysis to cognize the mechanism of aggregation

    Directory of Open Access Journals (Sweden)

    Pritam Kumar Panda

    2016-03-01

    Full Text Available Alzheimer's disease is the prevalent cause of premature senility, a progressive mental disorder due to degeneration in brain and deposition of amyloid β peptide (1–42, a misfolded protein in the form of aggregation that prevails for a prolonged time and obstructs every aspect of life. One of the primary hallmarks of the neuropathological disease is the accretion of amyloid β peptide in the brain that leads to Alzheimer's disease, but the mechanism is still a mystery. Several investigations have shown that mutations at specific positions have a significant impact in stability of the peptide as predicted from aggregation profiles. Here in our study, we have analyzed the mutations by substituting residues at position A22G, E22G, E22K, E22Q, D23N, L34V and molecular dynamics have been performed to check the deviation in stability and conformation of the peptide. The results validated that the mutations at specific positions lead to instability and the proline substitution at E22P and L34P stalled the aggregation of the peptide.

  11. Rescue of amyloid-Beta-induced inhibition of nicotinic acetylcholine receptors by a peptide homologous to the nicotine binding domain of the alpha 7 subtype.

    Directory of Open Access Journals (Sweden)

    Arthur A Nery

    Full Text Available Alzheimer's disease (AD is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs. Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.

  12. New Insights in the Amyloid-Beta Interaction with Mitochondria

    OpenAIRE

    Carlos Spuch; Saida Ortolano; Carmen Navarro

    2012-01-01

    Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both...

  13. Amyloid-beta Alzheimer targets — protein processing, lipid rafts, and amyloid-beta pores

    Science.gov (United States)

    Arbor, Sage C.; LaFontaine, Mike; Cumbay, Medhane

    2016-01-01

    Amyloid beta (Aβ), the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review.

  14. Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.

    Science.gov (United States)

    Arbor, Sage C; LaFontaine, Mike; Cumbay, Medhane

    2016-03-01

    Amyloid beta (Aβ), the hallmark of Alzheimer's Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review. PMID:27505013

  15. MMPBSA Decomposition of the Binding Energy throughout a Molecular Dynamics Simulation of Amyloid-Beta (Aß10−35 Aggregation

    Directory of Open Access Journals (Sweden)

    Josep M. Campanera

    2010-04-01

    Full Text Available Recent experiments with amyloid-beta (Aβ peptides indicate that the formation of toxic oligomers may be an important contribution to the onset of Alzheimer’s disease. The toxicity of Aβ oligomers depend on their structure, which is governed by assembly dynamics. However, a detailed knowledge of the structure of at the atomic level has not been achieved yet due to limitations of current experimental techniques. In this study, replica exchange molecular dynamics simulations are used to identify the expected diversity of dimer conformations of Aβ10−35 monomers. The most representative dimer conformation has been used to track the dimer formation process between both monomers. The process has been characterized by means of the evolution of the decomposition of the binding free energy, which provides an energetic profile of the interaction. Dimers undergo a process of reorganization driven basically by inter-chain hydrophobic and hydrophilic interactions and also solvation/desolvation processes.

  16. Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells

    Science.gov (United States)

    Drews, Anna; Flint, Jennie; Shivji, Nadia; Jönsson, Peter; Wirthensohn, David; De Genst, Erwin; Vincke, Cécile; Muyldermans, Serge; Dobson, Chris; Klenerman, David

    2016-01-01

    Local delivery of amyloid beta oligomers from the tip of a nanopipette, controlled over the cell surface, has been used to deliver physiological picomolar oligomer concentrations to primary astrocytes or neurons. Calcium influx was observed when as few as 2000 oligomers were delivered to the cell surface. When the dosing of oligomers was stopped the intracellular calcium returned to basal levels or below. Calcium influx was prevented by the presence in the pipette of the extracellular chaperone clusterin, which is known to selectively bind oligomers, and by the presence a specific nanobody to amyloid beta. These data are consistent with individual oligomers larger than trimers inducing calcium entry as they cross the cell membrane, a result supported by imaging experiments in bilayers, and suggest that the initial molecular event that leads to neuronal damage does not involve any cellular receptors, in contrast to work performed at much higher oligomer concentrations. PMID:27553885

  17. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  18. Amyloid-beta: a crucial factor in Alzheimer's disease.

    Science.gov (United States)

    Sadigh-Eteghad, Saeed; Sabermarouf, Babak; Majdi, Alireza; Talebi, Mahnaz; Farhoudi, Mehdi; Mahmoudi, Javad

    2015-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia which affects people older than 60 years of age. In AD, the dysregulation of the amyloid-beta (Aβ) level leads to the appearance of senile plaques which contain Aβ depositions. Aβ is a complex biological molecule which interacts with many types of receptors and/or forms insoluble assemblies and, eventually, its nonphysiological depositions alternate with the normal neuronal conditions. In this situation, AD signs appear and the patients experience marked cognitional disabilities. In general, intellect, social skills, personality, and memory are influenced by this disease and, in the long run, it leads to a reduction in quality of life and life expectancy. Due to the pivotal role of Aβ in the pathobiology of AD, a great deal of effort has been made to reveal its exact role in neuronal dysfunctions and to finding efficacious therapeutic strategies against its adverse neuronal outcomes. Hence, the determination of its different molecular assemblies and the mechanisms underlying its pathological effects are of interest. In the present paper, some of the well-established structural forms of Aβ, its interactions with various receptors and possible molecular and cellular mechanisms underlying its neurotoxicity are discussed. In addition, several Aβ-based rodent models of AD are reviewed. PMID:25471398

  19. A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.

    Directory of Open Access Journals (Sweden)

    Takako Niikura

    Full Text Available Humanin (HN, a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD-related cytotoxicities, including exposure to amyloid beta (Abeta, in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe, tau(P310L, and PS-1(M146V that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

  20. Screening for a human single chain Fv antibody against epitope on amyloid-beta 1-40 from a human phage display library

    Institute of Scientific and Technical Information of China (English)

    ZHAO Zhen-fu; GAO Guo-quan; LIU Shu; ZOU Jun-tao; XIE Yao; YUAN Qun-fang; WANG Hua-qiao; YAO Zhi-bin

    2007-01-01

    @@ Amyloid-beta peptides (Aβ) are believed to be responsible for the mental decline in patients with Alzheimer's disease (AD). In 1999, Schenk et al1 reported that immunization with Aβ attenuated AD-like pathology in the PDAPP mouse, and developed a new vaccination approach to AD.

  1. The nicotinic alpha7 acetylcholine receptor agonist ssr180711 is unable to activate limbic neurons in mice overexpressing human amyloid-beta1-42

    DEFF Research Database (Denmark)

    Søderman, Andreas; Thomsen, Morten S; Hansen, Henrik H;

    2008-01-01

    Recent studies have demonstrated that amyloid-beta1-42 (Abeta1-42) binds to the nicotinergic alpha7 acetylcholine receptor (alpha7 nAChR) and that the application of Abeta1-42 to cells inhibits the function of the alpha7 nAChR. The in vivo consequences of the pharmacological activation of the alp...... that clinical trials testing alpha7 nAChR agonists should be related to the content of Abeta peptides in the patient's nervous system....... systemic administration of the alpha7 nAChR agonist SSR180711 (10 mg/kg) result in a significant increase in Fos protein levels in the shell of nucleus accumbens in wild-type mice, but has no effect in the transgene mice. There were fewer cell bodies expressing Fos in the prefrontal cortex of transgene...

  2. Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Lambracht-Washington D

    2013-08-01

    Full Text Available Doris Lambracht-Washington, Roger N Rosenberg Department of Neurology and Neurotherapeutics, Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Immunotherapy might provide an effective treatment for Alzheimer's disease (AD. A unique feature of AD immunotherapies is that an immune response against a self-antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focused on two possible targets in this regard. One is the inhibition of accumulation and deposition of amyloid beta 1–42 (Aβ42, which is one of the major peptides found in senile plaques, and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations is already in several stages of clinical trials, tau-based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phosphorylated tau have been found, high interest has again focused on further development of tau-based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. Last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects, as these two pathologies are likely synergistic; this is an approach that has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, and present an overview on halted, ongoing, and upcoming clinical trials together with ongoing preclinical studies targeting tau

  3. Time Until Neuron Death After Initial Puncture From an Amyloid-Beta Oligomer

    CERN Document Server

    Horton, Tanner

    2015-01-01

    Hardy and Higgins first proposed the amyloid cascade hypothesis in 1992, stating that the decrease in neuronal function observed in Alzheimer's Disease (AD) is due to a process initiated by the oligomerization of amyloid-beta peptides. One hypothesis states that toxicity arises from the aggregation of amyloid-beta into a pore structure, which can then puncture the brain cell membrane; this allow toxic calcium ions to flood through the opening, causing eventual cell death. In 2007, neurobiologist Ruth Nussinov calculated the three pore sizes most likely to occur within the brain. Based on her findings, we constructed a method to determine the time it takes for a cell to die after the cell is punctured by the pore. Our findings have shown that cell death occurs within one second after the oligomer makes contact with the cell. We believe this is important because instant cell death has been one criticism of Nussinov's model, and we have calculated a concrete time value for that criticism. We identify two potenti...

  4. Poor Memory Performance in Aged Cynomolgus Monkeys with Hippocampal Atrophy, Depletion of Amyloid Beta 1-42 and Accumulation of Tau Proteins in Cerebrospinal Fluid

    DEFF Research Database (Denmark)

    Darusman, Huda S; Pandelaki, Jacub; Mulyadi, Rahmad;

    2014-01-01

    performance had evidence of atrophy in the hippocampus and cortical areas, significantly lower cerebrospinal fluid levels of amyloid beta amino acid 1-42 (p<0.001) and higher cerebrospinal fluid total tau levels (p<0.05) compared to the group performing well on the DRT tests. CONCLUSION: Old, memory...

  5. Amyloid-beta Positron Emission Tomography Imaging Probes : A Critical Review

    NARCIS (Netherlands)

    Kepe, Vladimir; Moghbel, Mateen C.; Langstrom, Bengt; Zaidi, Habib; Vinters, Harry V.; Huang, Sung-Cheng; Satyamurthy, Nagichettiar; Doudet, Doris; Mishani, Eyal; Cohen, Robert M.; Hoilund-Carlsen, Poul F.; Alavi, Abass; Barrio, Jorge R.

    2013-01-01

    The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a

  6. Glutamate carboxypeptidase II does not process amyloid-beta peptide

    Czech Academy of Sciences Publication Activity Database

    Sedlák, František; Šácha, Pavel; Blechová, Miroslava; Březinová, Anna; Šafařík, Martin; Šebestík, Jaroslav; Konvalinka, Jan

    2013-01-01

    Roč. 27, č. 7 (2013), s. 2626-2632. ISSN 0892-6638 R&D Projects: GA ČR GAP304/12/0847 Institutional support: RVO:61388963 Keywords : PSMA * Alzheimer's disease * disaggregation * exopeptidase * substrate specificity * depsipeptide Subject RIV: CE - Biochemistry Impact factor: 5.480, year: 2013

  7. ToF-SIMS analysis of amyloid beta aggregation on different lipid membranes.

    Science.gov (United States)

    Yokoyama, Yuta; Aoyagi, Satoka; Shimanouchi, Toshinori; Iwamura, Miki; Iwai, Hideo

    2016-06-01

    Amyloid beta (Aβ) peptides are considered to be strongly related to Alzheimer's disease. Aβ peptides form a β-sheet structure on hard lipid membranes and it would aggregate to form amyloid fibrils, which are toxic to cells. However, the aggregation mechanism of Aβ is not fully understood. To evaluate the influence of the lipid membrane condition for Aβ aggregation, the adsorption forms of Aβ (1-40) on mixture membranes of lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol β-d-glucoside (β-CG) were investigated by time-of-flight secondary ion mass spectrometry. As a result, Aβ adsorbed along the localized DMPC lipid on the mixture lipid membranes, whereas it was adsorbed homogeneously on the pure DMPC and β-CG membranes. Moreover, amino acid fragments that mainly existed in the n-terminal of Aβ (1-40) peptide were strongly detected on the localized DMPC region. These results suggested that the Aβ was adsorbed along the localized DMPC lipid with a characteristic orientation. These findings suggest that the hardness of the membrane is very sensitive to coexisting materials and that surface hardness is important for aggregation of Aβ. PMID:26822505

  8. Low background and high contrast PET imaging of amyloid-{beta} with [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in Alzheimer's disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska Hospital, AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Eriksdotter, Maria; Freund-Levi, Yvonne [Karolinska Institutet, Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital, Department of Geriatric Medicine, Stockholm (Sweden); Jeppsson, Fredrik [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Stockholm (Sweden)

    2013-04-15

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-{beta} in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-{beta} PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-{beta}. [{sup 3}H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [{sup 11}C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [{sup 11}C]AZD2995 was greater in areas with lower amyloid-{beta} load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-{beta} with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [{sup 11}C]AZD2184 seems to be an amyloid-{beta} radioligand with higher uptake and better group separation when compared to [{sup 11}C]AZD2995. However, the very low nonspecific binding of [{sup 11}C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-{beta}. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

  9. Multifunctional cholinesterase and amyloid Beta fibrillization modulators. Synthesis and biological investigation.

    Science.gov (United States)

    Butini, Stefania; Brindisi, Margherita; Brogi, Simone; Maramai, Samuele; Guarino, Egeria; Panico, Alessandro; Saxena, Ashima; Chauhan, Ved; Colombo, Raffaella; Verga, Laura; De Lorenzi, Ersilia; Bartolini, Manuela; Andrisano, Vincenza; Novellino, Ettore; Campiani, Giuseppe; Gemma, Sandra

    2013-12-12

    In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Aβ). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Aβ aggregation and with the Aβ self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of hAChE-induced Aβ aggregation since they physically hamper Aβ binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Aβ self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Aβ aggregation. PMID:24900626

  10. Amyloid Beta: Multiple Mechanisms of Toxicity and Only Some Protective Effects?

    Directory of Open Access Journals (Sweden)

    Paul Carrillo-Mora

    2014-01-01

    Full Text Available Amyloid beta (Aβ is a peptide of 39–43 amino acids found in large amounts and forming deposits in the brain tissue of patients with Alzheimer’s disease (AD. For this reason, it has been implicated in the pathophysiology of damage observed in this type of dementia. However, the role of Aβ in the pathophysiology of AD is not yet precisely understood. Aβ has been experimentally shown to have a wide range of toxic mechanisms in vivo and in vitro, such as excitotoxicity, mitochondrial alterations, synaptic dysfunction, altered calcium homeostasis, oxidative stress, and so forth. In contrast, Aβ has also shown some interesting neuroprotective and physiological properties under certain experimental conditions, suggesting that both physiological and pathological roles of Aβ may depend on several factors. In this paper, we reviewed both toxic and protective mechanisms of Aβ to further explore what their potential roles could be in the pathophysiology of AD. The complete understanding of such apparently opposed effects will also be an important guide for the therapeutic efforts coming in the future.

  11. Detection of Alzheimer’s disease amyloid-beta plaque deposition by deep brain impedance profiling

    Science.gov (United States)

    Béduer, Amélie; Joris, Pierre; Mosser, Sébastien; Fraering, Patrick C.; Renaud, Philippe

    2015-04-01

    Objective. Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Aß) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. Approach. In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Aß peptides by localized impedance measurements. Main results. We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Aβ plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. Significance. We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Aβ-plaques, which is complementary with existing imaging techniques. This method does not require prior Aβ staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection.

  12. Low-power laser irradiation inhibits amyloid beta-induced cell apoptosis

    Science.gov (United States)

    Zhang, Heng; Wu, Shengnan

    2011-03-01

    The deposition and accumulation of amyloid-β-peptide (Aβ) in the brain are considered a pathological hallmark of Alzheimer's disease(AD). Apoptosis is a contributing pathophysiological mechanism of AD. Low-power laser irradiation (LPLI), a non-damage physical therapy, which has been used clinically for decades of years, is shown to promote cell proliferation and prevent apoptosis. Recently, low-power laser irradiation (LPLI) has been applied to moderate AD. In this study, Rat pheochromocytoma (PC12) cells were treated with amyloid beta 25-35 (Aβ25-35) for induction of apoptosis before LPLI treatment. We measured cell viability with CCK-8 according to the manufacture's protocol, the cell viability assays show that low fluence of LPLI (2 J/cm2 ) could inhibit the cells apoptosis. Then using statistical analysis of proportion of apoptotic cells by flow cytometry based on Annexin V-FITC/PI, the assays also reveal that low fluence of LPLI (2 J/cm2 ) could inhibit the Aβ-induced cell apoptosis. Taken together, we demonstrated that low fluence of LPLI (2 J/cm2 ) could inhibit the Aβ-induced cell apoptosis, these results directly point to a therapeutic strategy for the treatment of AD through LPLI.

  13. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    International Nuclear Information System (INIS)

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

  14. Anti-acetylcholinesterase and Antioxidant Activities of Inhaled Juniper Oil on Amyloid Beta (1-42)-Induced Oxidative Stress in the Rat Hippocampus.

    Science.gov (United States)

    Cioanca, Oana; Hancianu, Monica; Mihasan, Marius; Hritcu, Lucian

    2015-05-01

    Juniper volatile oil is extracted from Juniperus communis L., of the Cupressaceae family, also known as common juniper. Also, in aromatherapy the juniper volatile oil is used against anxiety, nervous tension and stress-related conditions. In the present study, we identified the effects of the juniper volatile oil on amyloid beta (1-42)-induced oxidative stress in the rat hippocampus. Rats received a single intracerebroventricular injection of amyloid beta (1-42) (400 pmol/rat) and then were exposed to juniper volatile oil (200 μl, either 1 or 3 %) for controlled 60 min period, daily, for 21 continuous days. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Additionally, the acetylcholinesterase activity in the hippocampus was assessed. The amyloid beta (1-42)-treated rats exhibited the following: increase of the acetylcholinesterase, superoxide dismutase and catalase specific activities, decrease of glutathione peroxidase specific activity and the total content of the reduced glutathione along with an elevation of malondialdehyde and protein carbonyl levels. Inhalation of the juniper volatile oil significantly decreases the acetylcholinesterase activity and exhibited antioxidant potential. These findings suggest that the juniper volatile oil may be a potential candidate for the development of therapeutic agents to manage oxidative stress associated with Alzheimer's disease through decreasing the activity of acetylcholinesterase and anti-oxidative mechanism. PMID:25743585

  15. Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome.

    Directory of Open Access Journals (Sweden)

    Juliet A Moncaster

    Full Text Available Down syndrome (DS, trisomy 21 is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21 encoding the Alzheimer's disease (AD amyloid precursor protein (APP. Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta, early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta

  16. Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis

    DEFF Research Database (Denmark)

    Zheng, Lin; Kågedal, Katarina; Dehvari, Nodi; Benedikz, Eirikur; Cowburn, Richard; Marcusson, Jan; Terman, Alexei

    2009-01-01

    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (Abeta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads to int...

  17. Neuroinflammation and Complexes of 17 beta-Hydroxysteroid Dehydrogenase type 10-Amyloid beta in Alzheimer's Disease

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Řípová, D.; Bartoš, A.; Bocková, Markéta; Hegnerová, Kateřina; Říčný, J.; Čechová, L.; Vrajová, M.; Homola, Jiří

    2013-01-01

    Roč. 10, č. 2 (2013), s. 165-173. ISSN 1567-2050 R&D Projects: GA MZd(CZ) NT11225 Institutional support: RVO:67985882 Keywords : Amyloid beta * mitochondrial enzyme * Alzheimer 's disease Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.796, year: 2013

  18. In silico study of amyloid beta-protein folding relevant to Alzheimer's disease

    Science.gov (United States)

    Lam Ng, Alfonso Ramon

    Amyloid beta-protein (Abeta) folding is the initial step in the formation of the early toxic Abeta assemblies that are critically linked to Alzheimer's disease (AD). Abeta exists in two main alloforms, Abeta40 and Abeta42, composed of 40 and 42 residues, respectively. Abeta42 aggregates faster, forms more toxic assemblies, and is linked more strongly to AD. Two amino acids of Abeta42, I41 and A42, profoundly affect the behavior of Abeta40 and Abeta42. To examine why this happens, I study Abeta40 and Abeta42 folding using discrete molecular dynamics and a four-bead protein model with backbone hydrogen bonding and residue-specific effective hydropathic and electrostatic interactions. In particular, I explore a range of values of the hydropathic (EHP) and electrostatic (ECH) potential energies. For each peptide, I create a hundred different initial conformations for each set of parameters (EHP,E CH). I investigate the Abeta40 and Abeta42 monomer folding in a wide temperature range and quantify the folded structures by calculating the secondary structure propensities and the intramolecular contact maps. For each set of parameters (EHP,ECH), I calculate an average beta-strand secondary structure propensity in the Abeta40 and Abeta42 monomers as a function of temperature. I compare these simulated results with experimental circular dichroism measurements and estimate the model physiological temperature and the model parameters (E HP,ECH) that best fit the experimental conditions. The results show that in the temperature range [278K,350K], the average beta-strand in Abeta42 is larger than that of Abeta40, which is in agreement with experiments. The model predicts that the average beta-strand propensity should decrease for T>350K. At low temperatures, both Abeta40 and Abeta42 adopt a predominantly collapsed-coil conformation with small amounts of an beta-helical secondary structure (<1%). At high temperatures, beta-strand rich structures are more prominent (19%). Also, the

  19. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease

    OpenAIRE

    Reddy, P. Hemachandra; Beal, M. Flint

    2008-01-01

    Recent studies of postmortem brains from Alzheimer’s disease (AD) patients and transgenic AD mice suggest that oxidative damage, induced by amyloid beta, is associated with mitochondria early in AD progression. Amyloid beta and amyloid precursor protein are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species produ...

  20. S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein***

    Institute of Scientific and Technical Information of China (English)

    Xue Li; Wencong Zhao; Hongqi Yang; Junhong Zhang; Jianjun Ma

    2013-01-01

    Humanin is a potential therapeutic agent for Alzheimer’s disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer’s disease-relevant insults. Alt-hough effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibril ar amyloid-beta 40 disturbed cel ular ho-meostasis through the cel membrane, increasing intracel ular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these re-sponses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cel membrane, and restored the disturbed cel ular homeostasis, thereby exerting a neuroprotective effect on hippocampal neurons.

  1. Amyloid-Beta Related Angiitis of the Central Nervous System: Case Report and Topic Review

    Directory of Open Access Journals (Sweden)

    JoseBiller

    2014-02-01

    Full Text Available Amyloid-beta related angiitis (ABRA of the central nervous system (CNS is a rare disorder with overlapping features of primary angiits of the CNS (PACNS and cerebral amyloid angiopathy (CAA. We evaluated a 74-year-old man with intermittent left sided weakness and MRI findings of leptomeningeal enhancement, vasogenic edema and subcortical white matter disease proven to have ABRA. We discuss clinicopathological features and review the topic of ABRA.

  2. The role of animal models in advancing amyloid-beta immunotherapy to the clinic

    OpenAIRE

    Games, Dora; Seubert, Peter

    2010-01-01

    The amyloid-beta (Aβ) hypothesis of Alzheimer's disease (AD) causality is now well into its third decade and is finally entering a phase of rigorous clinical testing in numerous late stage clinical trials. The use of Aβ-based animal models of AD has been essential to the discovery and/or preclinical validation of many of these therapeutic approaches. While several neuropathologically based results from preclinical studies have translated nicely into AD patients, the full clinical value of Aβ-...

  3. AMYLOID BETA ACCUMULATION IN HIV-1-INFECTED BRAIN: THE ROLE OF THE BLOOD BRAIN BARRIER

    OpenAIRE

    András, Ibolya E.; Toborek, Michal

    2012-01-01

    In recent years we face an increase in the aging of the HIV-1-infected population, which is not only due to effective antiretroviral therapy but also to new infections among older people. Even with the use of the antiretroviral therapy, HIV-associated neurocognitive disorders represent an increasing problem as the HIV-1-infected population ages. Increased amyloid beta (Aβ) deposition is characteristic of HIV-1-infected brains, and it has been hypothesized that brain vascular dysfunction contr...

  4. Insulin Promotes Survival of Amyloid-Beta Oligomers Neuroblastoma Damaged Cells via Caspase 9 Inhibition and Hsp70 Upregulation

    Directory of Open Access Journals (Sweden)

    M. Di Carlo

    2010-01-01

    Full Text Available Alzheimer's disease (AD and type 2 diabetes are connected in a way that is still not completely understood, but insulin resistance has been implicated as a risk factor for developing AD. Here we show an evidence that insulin is capable of reducing cytotoxicity induced by Amyloid-beta peptides (A-beta in its oligomeric form in a dose-dependent manner. By TUNEL and biochemical assays we demonstrate that the recovery of the cell viability is obtained by inhibition of intrinsic apoptotic program, triggered by A-beta and involving caspase 9 and 3 activation. A protective role of insulin on mitochondrial damage is also shown by using Mito-red vital dye. Furthermore, A-beta activates the stress inducible Hsp70 protein in LAN5 cells and an overexpression is detectable after the addition of insulin, suggesting that this major induction is the necessary condition to activate a cell survival program. Together, these results may provide opportunities for the design of preventive and therapeutic strategies against AD.

  5. Amyloid beta oligomers induce neuronal elasticity changes in age-dependent manner: a force spectroscopy study on living hippocampal neurons

    Science.gov (United States)

    Ungureanu, Andreea-Alexandra; Benilova, Iryna; Krylychkina, Olga; Braeken, Dries; De Strooper, Bart; Van Haesendonck, Chris; Dotti, Carlos G.; Bartic, Carmen

    2016-01-01

    Small soluble species of amyloid-beta (Aβ) formed during early peptide aggregation stages are responsible for several neurotoxic mechanisms relevant to the pathology of Alzheimer’s disease (AD), although their interaction with the neuronal membrane is not completely understood. This study quantifies the changes in the neuronal membrane elasticity induced by treatment with the two most common Aβ isoforms found in AD brains: Aβ40 and Aβ42. Using quantitative atomic force microscopy (AFM), we measured for the first time the static elastic modulus of living primary hippocampal neurons treated with pre-aggregated Aβ40 and Aβ42 soluble species. Our AFM results demonstrate changes in the elasticity of young, mature and aged neurons treated for a short time with the two Aβ species pre-aggregated for 2 hours. Neurons aging under stress conditions, showing aging hallmarks, are the most susceptible to amyloid binding and show the largest decrease in membrane stiffness upon Aβ treatment. Membrane stiffness defines the way in which cells respond to mechanical forces in their environment and has been shown to be important for processes such as gene expression, ion-channel gating and neurotransmitter vesicle transport. Thus, one can expect that changes in neuronal membrane elasticity might directly induce functional changes related to neurodegeneration. PMID:27173984

  6. Computational identification of potential multitarget treatments for ameliorating the adverse effects of amyloid-beta on synaptic plasticity

    Directory of Open Access Journals (Sweden)

    ThomasJ.Anastasio

    2014-05-01

    Full Text Available The leading hypothesis on Alzheimer Disease (AD is that it is caused by buildup of the peptide amyloid-beta (Abeta, which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Abeta buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Abeta on synapses and of suggesting pharmacological means to prevent it. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Abeta of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Abeta dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it.

  7. APP17肽调节胰岛素受体底物1在糖尿病小鼠脑内分布及对脑海马区神经元退行性变的作用%Effects of amyloid beta protein precursor 17 peptide on distribution of insulin receptor substrate-1 in brain and degeneration of neurons in hippocampus of diabetic mice

    Institute of Scientific and Technical Information of China (English)

    陆珊; 雷亚平; 崔艳君; 王蓬文; 盛树力

    2006-01-01

    BACKGROUND: In brain insulin does its work through the insulin receptor substrate (IRS). Amyloid beta protein precursor 17 (APP17) peptide has the neurotrophic function, which may improve diabetic encephalopathy resulted from insulin deficiency by affecting insulin receptor substrate.OBJECTIVE: The mouse diabetic model was produced to observe the effect of APP17 peptide on the distribution of IRS-1 in brain tissues.DESIGN: Randomized control animal experiment.SETTING: Staff Room of Pathology, College of Basic Medical Sciences,Capital University of Medical Sciences; Beijing Research Laboratory for Brain Aging of Xuanwu Hospital.MATERIALS: The experiment was performed in Staff Room of Pathology,College of Basic Medical Sciences, Capital University of Medical Sciences and Beijing Research Laboratory for Brain Aging of Xuanwu Hospital from September to October 2003. Totally 18 male kunming mice were employed,and randomly assigned into control group, diabetic group and APP17 peptide treatment group with 6 mice in each group.METHODS: ①The mice were subjected to intraperitoneal injection of streptozotocin (STZ, Sigma) by 200 mg/kg, and 3 days later, the tail blood was sampled to examine non-fasting blood glucose, and the blood glucose over 15 mmol/L was set as the criteria for successful diabetic model establishment. ②In APP17 + diabetes mellitus group, the mice received subcutaneous injection of 0.35 μg APP17 peptide once daily for 2 weeks. The mice in the normal control group were not interfered. ③Then brain was removed and crystat sections were prepared. Immunohistochemical staining was done for IRS-1 at four weeks after giving streptozotocin.MAIN OUTCOME MEASURES: Pattern and distribution of IRS-1 positive cells of mice in each group.RESULTS: Totally 18 mice were involved in the result analysis. ①In the brains of diabetic mice the IRS-1 immunohistochemical positive cells distributed at cortex, hippocampus, thalamus, hypothalamus and so on, while the positive

  8. Telencephalin protects PAJU cells from amyloid beta protein-induced apoptosis by activating the ezrin/radixin/moesin protein family/phosphatidylinositol-3-kinase/protein kinase B pathway

    Institute of Scientific and Technical Information of China (English)

    Heping Yang; Dapeng Wu; Xiaojie Zhang; Xiang Wang; Yi Peng; Zhiping Hu

    2012-01-01

    Telencephalin is a neural glycoprotein that reduces apoptosis induced by amyloid beta protein in the human neural tumor cell line PAJU.In this study,we examined the role of the ezrin/radixin/moesin protein family/phosphatidylinositol-3-kinase/protein kinase B pathway in this process.Western blot analysis demonstrated that telencephalin,phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B were not expressed in PAJU cells transfected with empty plasmid,while they were expressed in PAJU cells transfected with a telencephalin expression plasmid.After treatment with 1.0 nM amyloid beta protein 42,expression of telencephalin and phosphorylated phosphatidylinositol-3-kinase/protein kinase B in the transfected cells gradually diminished,while levels of phosphorylated ezrin/radixin/moesin increased.In addition,the high levels of telencephalin,phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B expression in PAJU cells transfected with a telencephalin expression plasmid could be suppressed by the phosphatidylinositol-3-kinase inhibitor LY294002.These findings indicate that telencephalin activates the ezrin/radixin/moesin family/phosphatidylinositol-3-kinase/protein kinase B pathway and protects PAJU cells from amyloid beta protein-induced apoptosis.

  9. A 'danse macabre': tau and Fyn in STEP with amyloid beta to facilitate induction of synaptic depression and excitotoxicity.

    Science.gov (United States)

    Boehm, Jannic

    2013-06-01

    Alzheimer's disease, with its two most prominent pathological factors amyloid beta and tau protein, can be described as a disease of the synapse. It therefore comes as little surprise that NMDA receptor-related synaptic dysfunction had been thought for several years to underlie the synaptic pathophysiology seen in Alzheimer's disease. In this review I will summarise recent evidence showing that the NMDA receptor links the effects of extracellular amyloid beta with intracellular tau protein. Furthermore, the antagonistic roles of Fyn and STEP in NMDA receptor regulation, synaptic plasticity and induction of synaptic depression will be discussed. PMID:23773061

  10. Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons.

    Science.gov (United States)

    Hu, Hongtao; Li, Mo

    2016-09-01

    Mitochondrial defects including excess reactive oxygen species (ROS) production and compromised ATP generation are featured pathology in Alzheimer's disease (AD). Amyloid beta (Aβ)-mediated mitochondrial ROS overproduction disrupts intra-neuronal Redox balance, in turn exacerbating mitochondrial dysfunction leading to neuronal injury. Previous studies have found the beneficial effects of mitochondria-targeted antioxidants in preventing mitochondrial dysfunction and neuronal injury in AD animal and cell models, suggesting that mitochondrial ROS scavengers hold promise for the treatment of this neurological disorder. In this study, we have determined that mitotempo, a novel mitochondria-targeted antioxidant protects mitochondrial function from the toxicity of Aβ in primary cultured neurons. Our results showed that Aβ-promoted mitochondrial superoxide production and neuronal lipid oxidation were significantly suppressed by the application of mitotempo. Moreover, mitotempo also demonstrated protective effects on mitochondrial bioenergetics evidenced by preserved mitochondrial membrane potential, cytochrome c oxidase activity as well as ATP production. In addition, the Aβ-induced mitochondrial DNA (mtDNA) depletion and decreased expression levels of mtDNA replication-related DNA polymerase gamma (DNA pol γ) and Twinkle were substantially mitigated by mitotempo. Therefore, our study suggests that elimination of excess mitochondrial ROS rescues mitochondrial function in Aβ-insulted neruons; and mitotempo has the potential to be a promising therapeutic agent to protect mitochondrial and neuronal function in AD. PMID:27444386

  11. Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

    Directory of Open Access Journals (Sweden)

    Michalina Hebda

    2016-03-01

    Full Text Available Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM. Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM, and it inhibits amyloid beta aggregation (35.8% at 10 μM. Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.

  12. PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

    Science.gov (United States)

    Wang, Hong-Mei; Zhao, Yan-Xin; Zhang, Shi; Liu, Gui-Dong; Kang, Wen-Yan; Tang, Hui-Dong; Ding, Jian-Qing; Chen, Sheng-Di

    2010-01-01

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes. PMID:20413894

  13. Amyloid beta protein and tau in cerebrospinal fluid and plasma as biomarkers for dementia: a review of recent literature.

    NARCIS (Netherlands)

    Frankfort, S.V.; Tulner, L.R.; Campen, J.P. van; Verbeek, M.M.; Jansen, R.W.; Beijnen, J.H.

    2008-01-01

    This review addresses recent developments in amyloid beta (Abeta), total tau (t-tau), and phosporylated tau (p-tau) protein analysis, in cerebrospinal fluid (CSF) and plasma as biomarkers for dementia. Recent research focused on the protection of patients with mild cognitive impairment (MCI) into de

  14. The coding sequence of amyloid-beta precursor protein APP contains a neural-specific promoter element.

    NARCIS (Netherlands)

    Collin, R.W.J.; Martens, G.J.M.

    2006-01-01

    The amyloid-beta precursor protein APP is generally accepted to be involved in the pathology of Alzheimer's disease. Since its physiological role is still unclear, we decided to study the function of APP via stable transgenesis in the amphibian Xenopus laevis. However, the application of constructs

  15. Reduced amyloidogenic processing of the amyloid beta-protein precursor by the small-molecule Differentiation Inducing Factor-1.

    Science.gov (United States)

    Myre, Michael A; Washicosky, Kevin; Moir, Robert D; Tesco, Giuseppina; Tanzi, Rudolph E; Wasco, Wilma

    2009-04-01

    The detection of cell cycle proteins in Alzheimer's disease (AD) brains may represent an early event leading to neurodegeneration. To identify cell cycle modifiers with anti-Abeta properties, we assessed the effect of Differentiation-Inducing Factor-1 (DIF-1), a unique, small-molecule from Dictyostelium discoideum, on the proteolysis of the amyloid beta-protein precursor (APP) in a variety of different cell types. We show that DIF-1 slows cell cycle progression through G0/G1 that correlates with a reduction in cyclin D1 protein levels. Western blot analysis of DIF-treated cells and conditioned medium revealed decreases in the levels of secreted APP, mature APP, and C-terminal fragments. Assessment of conditioned media by sandwich ELISA showed reduced levels of Abeta40 and Abeta42, also demonstrating that treatment with DIF-1 effectively decreases the ratio of Abeta42 to Abeta40. In addition, DIF-1 significantly diminished APP phosphorylation at residue T668. Interestingly, site-directed mutagenesis of APP residue Thr668 to alanine or glutamic acid abolished the effect of DIF-1 on APP proteolysis and restored secreted levels of Abeta. Finally, DIF-1 prevented the accumulation of APP C-terminal fragments induced by the proteasome inhibitor lactacystin, and calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN). Our findings suggest that DIF-1 affects G0/G1-associated amyloidogenic processing of APP by a gamma-secretase-, proteasome- and calpain-insensitive pathway, and that this effect requires the presence of residue Thr668. PMID:19154786

  16. Effect of copper (II) ion against elongation behavior of amyloid {beta} fibrils on liposome membranes

    Energy Technology Data Exchange (ETDEWEB)

    Shimanouchi, T.; Onishi, R.; Kitaura, N.; Umakoshi, H.; Kuboi, R. [Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka (Japan)

    2012-01-15

    The fibril growth behavior of amyloid {beta} protein (A{beta}) on cell membranes is relating to the progression of Alzheimer's disease. This growth behavior of A{beta} fibrils is sensitively affected by the metal ions, neurotransmitters, or bioreactive substrate. The inhibitory effect of those materials was quantitatively estimated from the viewpoints of ''crystal growth''. In a bulk aqueous solution, copper (II) ion showed the strong inhibitory effect on the growth of A{beta} fibrils. Meanwhile, the addition of a closed-phospholipid bilayer membrane (liposome) could reduce the above inhibitory effect of copper (II) ion. (copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  17. Indirubin-3′-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation

    Institute of Scientific and Technical Information of China (English)

    Shu-gang Zhang; Xiao-shan Wang; Ying-dong Zhang; Qing Di; Jing-ping Shi; Min Qian; Li-gang Xu; Xing-jian Lin; Jie Lu

    2016-01-01

    Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apopto-sis in Alzheimer’s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SH-SY5Y cells exposed to amyloid-beta 25–35 (Aβ25–35), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β (GSK-3β). Our results suggest that in-dirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylationvia a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer’s disease.

  18. Cortical Amyloid beta in cognitively normal elderly adults is associated with decreased network efficiency within the cerebro-cerebellar system.

    Directory of Open Access Journals (Sweden)

    Stefanie eSteininger

    2014-03-01

    Full Text Available Deposition of cortical amyloid beta (Aβ is a correlate of aging and a risk factor for Alzheimer Disease (AD. While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using Pittsburgh Compound-B positron-emission-tomography (PiB-PET late frame signals. Volumes of brain structures were assessed by applying an automated parcellation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent (BOLD resting state functional magnetic resonance imaging (fMRI at the high field strength of 7 Tesla for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling.Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro

  19. Alzheimer's disease and amyloid beta-peptide deposition in the brain: a matter of 'aging'?

    DEFF Research Database (Denmark)

    Moro, Maria Luisa; Collins, Matthew J; Cappellini, Enrico

    2010-01-01

    Biomolecules can experience aging processes that limit their long-term functionality in organisms. Typical markers of protein aging are spontaneous chemical modifications, such as AAR (amino acid racemization) and AAI (amino acid isomerization), mainly involving aspartate and asparagine residues...... changes associated with molecular aging also have significant long-term consequences for Abeta folding and turnover. New fast, reproducible and accurate methods for the screening of protein aging markers in biological samples may contribute to improve diagnostic and therapeutic approaches in AD....

  20. Complex of amyloid beta peptides with 24-hydroxycholesterol and its effect on hemicholinium-3 sensitive carriers

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Kopecký, V. Jr.; Hofbauerová, Kateřina; Hovorková, P.; Řípová, D.

    2008-01-01

    Roč. 33, č. 3 (2008), s. 412-421. ISSN 0364-3190 Grant ostatní: GA Mšk(CZ) MZOPCP2005 Institutional research plan: CEZ:AV0Z50200510 Keywords : aging * hippocampus * choline carriers Subject RIV: EE - Microbiology, Virology Impact factor: 2.260, year: 2008

  1. Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production

    OpenAIRE

    Lovell, Mark A.; Erin Abner; Richard Kryscio; Liou Xu; Fister, Shuling X.; Lynn, Bert C.

    2015-01-01

    Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteri...

  2. Determining the Effect of Aluminum Oxide Nanoparticles on the Aggregation of Amyloid-Beta in Transgenic Caenorhabditis elegans

    Science.gov (United States)

    Patel, Suhag; Matticks, John; Howell, Carina

    2014-03-01

    The cause of Alzheimer's disease has been linked partially to genetic factors but the predicted environmental components have yet to be determined. In Alzheimer's, accumulation of amyloid-beta protein in the brain forms plaques resulting in neurodegeneration and loss of mental functions. It has been postulated that aluminum influences the aggregation of amyloid-beta. To test this hypothesis, transgenic Caenorhabditis elegans, CL2120, was used as a model organism to observe neurodegeneration in nematodes exposed to aluminum oxide nanoparticles. Behavioral testing, fluorescent staining, and fluorescence microscopy were used to test the effects of aggregation of amyloid-beta in the nervous systems of effected nematodes exposed to aluminum oxide nanoparticles. Energy-dispersive x-ray spectroscopy was used to quantify the total concentration of aluminum oxide that the worms were exposed to during the experiment. Exposure of transgenic and wild type worms to a concentration of 4 mg mL-1 aluminum oxide showed a decrease in the sinusoidal motion, as well as an infirmity of transgenic worms when compared to control worms. These results support the hypothesis that aluminum may play a role in neurodegeneration in C. elegans, and may influence and increase the progression of Alzheimer's disease. This work was supported by National Science Foundation grants DUE-1058829, DMR-0923047 DUE-0806660 and Lock Haven FPDC grants.

  3. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2010-06-01

    Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

  4. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2012-02-01

    Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

  5. Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses

    Directory of Open Access Journals (Sweden)

    Armando Romani

    2013-01-01

    Full Text Available The role of amyloid-beta (Aβ in brain function and in the pathogenesis of Alzheimer’s disease remains elusive. Recent publications reported that an increase in Aβ concentration perturbs pre-synaptic release in hippocampal neurons. In particular, it was shown in vitro that Aβ is an endogenous regulator of synaptic transmission at the CA3-CA1 synapse, enhancing its release probability. How this synaptic modulator influences neuronal output during physiological stimulation patterns, such as those elicited in vivo, is still unknown. Using a realistic model of hippocampal CA1 pyramidal neurons, we first implemented this Aβ-induced enhancement of release probability and validated the model by reproducing the experimental findings. We then demonstrated that this synaptic modification can significantly alter synaptic integration properties in a wide range of physiologically relevant input frequencies (from 5 to 200 Hz. Finally, we used natural input patterns, obtained from CA3 pyramidal neurons in vivo during free exploration of rats in an open field, to investigate the effects of enhanced Aβ on synaptic release under physiological conditions. The model shows that the CA1 neuronal response to these natural patterns is altered in the increased-Aβ condition, especially for frequencies in the theta and gamma ranges. These results suggest that the perturbation of release probability induced by increased Aβ can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during Alzheimer’s disease.

  6. Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.

    Science.gov (United States)

    Liu, Yu-Hui; Wang, Ye-Ran; Xiang, Yang; Zhou, Hua-Dong; Giunta, Brian; Mañucat-Tan, Noralyn B; Tan, Jun; Zhou, Xin-Fu; Wang, Yan-Jiang

    2015-02-01

    Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies. PMID:24733588

  7. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease?

    Science.gov (United States)

    Murray, Melissa E; Dickson, Dennis W

    2014-01-01

    Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Aβ) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Aβ senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Aβ plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Aβ deposition in pathological aging. PMID:25031637

  8. Nanoscale-alumina induces oxidative stress and accelerates amyloid beta (Aβ) production in ICR female mice

    Science.gov (United States)

    Shah, Shahid Ali; Yoon, Gwang Ho; Ahmad, Ashfaq; Ullah, Faheem; Amin, Faiz Ul; Kim, Myeong Ok

    2015-09-01

    The adverse effects of nanoscale-alumina (Al2O3-NPs) have been previously demonstrated in both in vitro and in vivo studies, whereas little is known about their mechanism of neurotoxicity. It is the goal of this research to determine the toxic effects of nano-alumina on human neuroblastoma SH-SY5Y and mouse hippocampal HT22 cells in vitro and on ICR female mice in vivo. Nano-alumina displayed toxic effects on SH-SY5Y cell lines in three different concentrations also increased aluminium abundance and induced oxidative stress in HT22 cells. Nano-alumina peripherally administered to ICR female mice for three weeks increased brain aluminium and ROS production, disturbing brain energy homeostasis, and led to the impairment of hippocampus-dependent memory. Most importantly, these nano-particles induced Alzheimer disease (AD) neuropathology by enhancing the amyloidogenic pathway of Amyloid Beta (Aβ) production, aggregation and implied the progression of neurodegeneration in the cortex and hippocampus of these mice. In conclusion, these data demonstrate that nano-alumina is toxic to both cells and female mice and that prolonged exposure may heighten the chances of developing a neurodegenerative disease, such as AD.

  9. Gene expression profile of amyloid beta protein-injected mouse model for Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Ling-na KONG; Ping-ping ZUO; Liang MU; Yan-yong LIU; Nan YANG

    2005-01-01

    Aim: To investigate the gene expression profile changes in the cerebral cortex of mice injected icv with amyloid beta-protein (Aβ) fragment 25-35 using cDNA microarray. Methods: Balb/c mice were randomly divided into a control group and Aβ-treated group. The Morris water maze test was performed to detect the effect of Aβ-injection on the learning and memory of mice. Atlas Mouse 1.2 Expression Arrays containing 1176 genes were used to investigate the gene expression pattern of each group. Results: The gene expression profiles showed that 19 genes including TBX1, NF-κB, AP-1/c-Jun, cadherin, integrin, erb-B2, and FGFR1 were up-regulated after 2 weeks oficv administration of Aβ; while 12 genes were downregulated, including NGF, glucose phosphate isomerase 1, AT motif binding factor 1, Na+/K+-ATPase, and Akt. Conclusions: The results provide important leads for pursuing a more complete understanding of the molecular events of Aβ-injection into mice with Alzheimer disease.

  10. Low Cerebrospinal Fluid Amyloid-Beta Concentration Is Associated with Poorer Delayed Memory Recall in Women

    Directory of Open Access Journals (Sweden)

    Fanni Haapalinna

    2016-07-01

    Full Text Available Background: Data on the association of memory performance with cerebrospinal fluid (CSF biomarkers of Alzheimer's disease (AD are inconsistent. The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NB is a commonly used validated cognitive tool; however, only few studies have examined its relationship with CSF biomarkers for AD. We studied the correlation of pathological changes in CSF biomarkers with various CERAD-NB subtests and total scores. Methods: Out of 79 subjects (36 men, mean age 70.5 years, 63 had undergone an assessment of cognitive status with CERAD-NB and a CSF biomarker analysis due to a suspected memory disorder, and 16 were controls with no memory complaint.Results: In women we found a significant correlation between CSF amyloid-beta (Aβ1-42 and several subtests measuring delayed recall. Word List Recall correlated with all markers: Aβ1-42 (r = 0.323, p = 0.035, tau (r = -0.304, p = 0.050 and hyperphosphorylated tau (r = -0.331, p = 0.046. No such correlations were found in men. Conclusions: CSF biomarkers correlate with delayed memory scores in CERAD-NB in women, and women may have more actual AD pathology at the time of the investigations than men.

  11. Polarization properties of amyloid-beta plaques in Alzheimer's disease (Conference Presentation)

    Science.gov (United States)

    Baumann, Bernhard; Wöhrer, Adelheid; Ricken, Gerda; Pircher, Michael; Kovacs, Gabor G.; Hitzenberger, Christoph K.

    2016-03-01

    In histopathological practice, birefringence is used for the identification of amyloidosis in numerous tissues. Amyloid birefringence is caused by the parallel arrangement of fibrous protein aggregates. Since neurodegenerative processes in Alzheimer's disease (AD) are also linked to the formation of amyloid-beta (Aβ) plaques, optical methods sensitive to birefringence may act as non-invasive tools for Aβ identification. At last year's Photonics West, we demonstrated polarization-sensitive optical coherence tomography (PS-OCT) imaging of ex vivo cerebral tissue of advanced stage AD patients. PS-OCT provides volumetric, structural imaging based on both backscatter contrast and tissue polarization properties. In this presentation, we report on polarization-sensitive neuroimaging along with numerical simulations of three-dimensional Aβ plaques. High speed PS-OCT imaging was performed using a spectral domain approach based on polarization maintaining fiber optics. The sample beam was interfaced to a confocal scanning microscope arrangement. Formalin-fixed tissue samples as well as thin histological sections were imaged. For comparison to the PS-OCT results, ray propagation through plaques was modeled using Jones analysis and various illumination geometries and plaque sizes. Characteristic polarization patterns were found. The results of this study may not only help to understand PS-OCT imaging of neuritic Aβ plaques but may also have implications for polarization-sensitive imaging of other fibrillary structures.

  12. Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus

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    Patel Sunil

    2012-03-01

    Full Text Available Abstract Background Idiopathic normal pressure hydrocephalus (iNPH is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42 ratio in ventricular CSF and shunt outcome in patients with iNPH. Methods We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort. Results We found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios. Conclusions Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology

  13. Copper Exposure Perturbs Brain Inflammatory Responses and Impairs Clearance of Amyloid-Beta.

    Science.gov (United States)

    Kitazawa, Masashi; Hsu, Heng-Wei; Medeiros, Rodrigo

    2016-07-01

    Copper promotes a toxic buildup of amyloid-beta (Aβ) and neurofibrillary tangle pathology in the brain, and its exposure may increase the risk for Alzheimer's disease (AD). However, underlying molecular mechanisms by which copper triggers such pathological changes remain largely unknown. We hypothesized that the copper exposure perturbs brain inflammatory responses, leading to impairment of Aβ clearance from the brain parenchyma. Here, we investigated whether copper attenuated Aβ clearance by microglial phagocytosis or by low-density lipoprotein-related receptor protein-1 (LRP1) dependent transcytosis in both in vitro and in vivo When murine monocyte BV2 cells were exposed to copper, their phagocytic activation induced by fibrillar Aβ or LPS was significantly reduced, while the secretion of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, were increased. Interestingly, not only copper itself but also IL-1β, IL-6, or TNF-α were capable of markedly reducing the expression of LRP1 in human microvascular endothelial cells (MVECs) in a concentration-dependent manner. While copper-mediated downregulation of LRP1 was proteasome-dependent, the cytokine-induced loss of LRP1 was proteasome- or lysosome-independent. In the mouse model, copper exposure also significantly elevated neuroinflammation and downregulated LRP1 in the brain, consistent with our in vitro results. Taken together, our findings support the pathological impact of copper on inflammatory responses and Aβ clearance in the brain, which could serve as key mechanisms to explain, in part, the copper exposure as an environmental risk factor for AD. PMID:27122238

  14. Urinary Peptide Levels in Patients with Chronic Renal Failure

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    Mungli Prakash

    2010-10-01

    Full Text Available Introduction: Peptide levels in urine are found to be decreased in renal failure. In the current study urinary peptide levels were determined in chronic renal failure (CRF patients. Method: 86 CRF patients and 80 healthy controls were selected for the study. Urinary proteins and peptide levels were determined by spectrophotometer based Lowry and Bradford methods. Urinary creatinine levels were determined by clinical chemistry analyzer. Results: There was significant decrease in urinary peptide levels in CRF patients and Urinary % peptides were significantly decreased in CRF patients as compared to healthy controls. Urinary % peptides correlated negatively with proteinuria. Conclusion: we have found decrease in urinary peptides and % urinary peptides in CRF patients and possibly measurement of % urinary peptides may possibly serve as better indicator in early detection of impairment in renal function.

  15. Protective effects of components of the Chinese herb grassleaf sweetlfag rhizome on PC12 cells incubated with amyloid-beta42

    Institute of Scientific and Technical Information of China (English)

    Zi-hao Liang; Xiao-hui Cheng; Zhi-gang Ruan; Han Wang; Shan-shan Li; Jing Liu; Guo-ying Li; Su-min Tian

    2015-01-01

    The major ingredients of grassleaf sweetlfag rhizome areβ-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms ofβ-asarone and eugenol, components of the Chinese herb grassleaf sweetlfag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations (between 1 × 10–10 M and 1 × 10–5 M) ofβ-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions (1 × 10–6 Mβ-asarone and eugenol). The survival rates of PC12 cells significantly increased, while expression levels of the mRNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl mRNA increased. In addition, the combination ofβ-asarone with eugenol achieved better results than either component alone. Our experimental ifndings indicate that bothβ-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

  16. Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42

    Directory of Open Access Journals (Sweden)

    Zi-hao Liang

    2015-01-01

    Full Text Available The major ingredients of grassleaf sweetflag rhizome are β-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of β-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations (between 1 × 10 -10 M and 1 × 10 -5 M of β-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions (1 × 10 -6 M β-asarone and eugenol. The survival rates of PC12 cells significantly increased, while expression levels of the mRNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl mRNA increased. In addition, the combination of β-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both β-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

  17. Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold

    Directory of Open Access Journals (Sweden)

    Hof Patrick R

    2011-09-01

    Full Text Available Abstract Background Memory deficits in Alzheimer's disease (AD manifest together with the loss of synapses caused by the disruption of the postsynaptic density (PSD, a network of scaffold proteins located in dendritic spines. However, the underlying molecular mechanisms remain elusive. Since it was shown that ProSAP2/Shank3 scaffold assembly within the PSD is Zn2+-dependent and that the amyloid beta protein (Aβ is able to bind Zn2+, we hypothesize that sequestration of Zn2+ ions by Aβ contributes to ProSAP/Shank platform malformation. Results To test this hypothesis, we designed multiple in vitro and in vivo assays demonstrating ProSAP/Shank dysregulation in rat hippocampal cultures following Aβ oligomer accumulation. These changes were independent from alterations on ProSAP/Shank transcriptional level. However, application of soluble Aβ prevented association of Zn2+ ions with ProSAP2/Shank3 in a cell-based assay and decreased the concentration of Zn2+ clusters within dendrites. Zn2+ supplementation or saturation of Aβ with Zn2+ ions prior to cell treatment was able to counter the effects induced by Aβ on synapse density and ProSAP2/Shank3 levels at the PSD. Interestingly, intracellular Zn2+ levels in APP-PS1 mice and human AD hippocampus are reduced along with a reduction in synapse density and synaptic ProSAP2/Shank3 and Shank1 protein levels. Conclusions We conclude that sequestration of Zn2+ ions by Aβ significantly contributes to changes in ProSAP2/Shank3 platforms. These changes in turn lead to less consolidated (mature synapses reflected by a decrease in Shank1 protein levels at the PSD and decreased synapse density in hippocampal neurons.

  18. Urinary Peptide Levels in Patients with Chronic Renal Failure

    OpenAIRE

    Mungli Prakash; Phani, Nagaraj M; Kavya R; Supriya M

    2010-01-01

    Introduction: Peptide levels in urine are found to be decreased in renal failure. In the current study urinary peptide levels were determined in chronic renal failure (CRF) patients. Method: 86 CRF patients and 80 healthy controls were selected for the study. Urinary proteins and peptide levels were determined by spectrophotometer based Lowry and Bradford methods. Urinary creatinine levels were determined by clinical chemistry analyzer. Results: There was significant decrease in urinary pepti...

  19. Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer’s Disease Treatment: Rethinking the Current Strategy

    Directory of Open Access Journals (Sweden)

    Siddhartha Mondragón-Rodríguez

    2012-01-01

    Full Text Available Alzheimer’s disease (AD is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβ and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment.

  20. NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression.

    Directory of Open Access Journals (Sweden)

    Albert Tamburri

    Full Text Available Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

  1. Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction and oxidative stress.

    Science.gov (United States)

    Chiang, Ming-Chang; Nicol, Christopher J; Cheng, Yi-Chuan; Lin, Kuan-Hung; Yen, Chia-Hui; Lin, Chien-Hung

    2016-04-01

    Neuronal cell impairment, such as that induced by amyloid-beta (Aβ) protein, is a process with limited therapeutic interventions and often leads to long-term neurodegeneration common in disorders such as Alzheimer's disease. Interestingly, peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor whose ligands control many physiological and pathologic processes, and may be neuroprotective. We hypothesized that rosiglitazone, a PPARγ agonist, would prevent Aβ-mediated effects in human neural stem cells (hNSCs). Here, we show that rosiglitazone reverses, via PPARγ-dependent downregulation of caspase 3 and 9 activity, the Aβ-mediated decreases in hNSC cell viability. In addition, Aβ decreases hNSC messenger RNA (mRNA) levels of 2 neuroprotective factors (Bcl-2 and CREB), but co-treatment with rosiglitazone significantly rescues these effects. Rosiglitazone co-treated hNSCs also showed significantly increased mitochondrial function (reflected by levels of adenosine triphosphate and Mit mass), and PPARγ-dependent mRNA upregulation of PGC1α and mitochondrial genes (nuclear respiratory factor-1 and Tfam). Furthermore, hNSCs co-treated with rosiglitazone were significantly rescued from Aβ-induced oxidative stress and correlates with reversal of the Aβ-induced mRNA decrease in oxidative defense genes (superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 1). Taken together, these novel findings show that rosiglitazone-induced activation of PPARγ-dependent signaling rescues Aβ-mediated toxicity in hNSCs and provide evidence supporting a neuroprotective role for PPARγ activating drugs in Aβ-related diseases such as Alzheimer's disease. PMID:26973118

  2. Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer's disease by accelerating the clearance of amyloid-beta.

    Science.gov (United States)

    Song, Qingxiang; Huang, Meng; Yao, Lei; Wang, Xiaolin; Gu, Xiao; Chen, Juan; Chen, Jun; Huang, Jialin; Hu, Quanyin; Kang, Ting; Rong, Zhengxing; Qi, Hong; Zheng, Gang; Chen, Hongzhuan; Gao, Xiaoling

    2014-03-25

    Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer's disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically inspired nanostructure, apolipoprotein E3-reconstituted high density lipoprotein (ApoE3-rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3-rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3-rHDL gained access to the brain. Four-week daily treatment with ApoE3-rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes, and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of a biomimetic nanostructure crossing the blood-brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3-rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy. PMID:24527692

  3. A new DNA vaccine fused with the C3d-p28 induces a Th2 immune response against amyloid-beta*

    Institute of Scientific and Technical Information of China (English)

    Wanshu Guo; Sha Sha; Tongzi Jiang; Xiaona Xing; Yunpeng Cao

    2013-01-01

    To enhance anti-amyloid-beta (Aβ) antibody generation and induce a Th2 immune response, we constructed a new DNA vaccine p(Aβ3-10 )10-C3d-p28.3 encoding ten repeats of Aβ3-10 and three copies of C3d-p28 as a molecular adjuvant. In this study, we administered this adjuvant intramus-cularly to female C57BL/6J mice at 8-10 weeks of age. Enzyme linked immunosorbent assay was used to detect the titer of serum anti-Aβ antibody, isotypes, and cytokines in splenic T cel s. A 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to detect the prolifera-tion rate of splenic T cel s. Brain sections from a 12-month-old APP/PS1 transgenic mouse were used for detecting the binding capacities of anti-Aβ antibodies to Aβ plaques. The p(Aβ3-10)10-C3d-p28.3 vaccine induced high titers of anti-amyloid-βantibodies, which bound to Aβplaques in APP/PS1 transgenic mouse brain tissue, demonstrating that the vaccine is effective against plaques in a mouse model of Alzheimer’s disease. Moreover, the vaccine elicited a pre-dominantly IgG1 humoral response and low levels of interferon-γ in ex vivo cultured splenocytes, indicating that the vaccine could shift the cel ular immune response towards a Th2 phenotype. This indicated that the vaccine did not elicit a detrimental immune response and had a favorable safety profile. Our results indicate that the p(Aβ3-10)10-C3d-p28.3 vaccine is a promising immunothera-peutic option for Aβvaccination in Alzheimer’s disease.

  4. Regional Fluid-Attenuated Inversion Recovery (FLAIR at 7 Tesla correlates with Amyloid beta in Hippocampus and Brainstem of cognitively normal elderly subjects.

    Directory of Open Access Journals (Sweden)

    Xinyang Liu

    2014-09-01

    Full Text Available Background: Accumulation of amyloid beta (Aβ may occur during healthy aging and is a risk factor for Alzheimer Disease (AD. While individual Aβ-accumulation can be measured non-invasively using Pittsburgh compound-B positron-emission-tomography (PiB-PET, Fluid-Attenuated Inversion Recovery (FLAIR is a Magnetic Resonance Imaging (MRI sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR- intensity. Methods: 14 healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T. Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho, followed by Holm-Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right:rho=0.86; left:rho=0.84, Brainstem (rho=0.85 and left Basal Ganglia vessel region (rho=0.82. Conclusions: Our finding of a significant relationship between PiB- and FLAIR-intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative

  5. Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration.

    Science.gov (United States)

    Aboelnour, Asmaa; Kam, Jaimie Hoh; Elnasharty, M A; Sayed-Ahmed, Ahmed; Jeffery, Glen

    2016-06-01

    Extra-cellular deposition including amyloid beta (Aβ) is a feature of retinal ageing. It has been documented for Bruch's membrane (BM) where Aβ is elevated in complement factor H knockout mice (Cfh(-/-)) proposed as a model for age related macular degeneration. However, arterial deposition in choroidal vessels prior to perfusion across BM has not been examined. Aβ is associated with tau phosphorylation and these are linked in blood vessels in Alzheimers Disease where they can drive perivascular pathology. Here we ask if Aβ, tau and phosphorylated tau are features of ageing in choroidal vessels in 12 month C57 BL/6 and Cfh(-/-) mice, using immune staining and Western blot analysis. Greater levels of Aβ and phosphorylated tau are found in choroidal vessels in Cfh(-/-) mice. Western blot revealed a 40% increase in Aβ in Cfh(-/-) over C57 BL/6 mice. Aβ deposits coat around 55% of the luminal wall in Cfh(-/-) compared to only about 40% in C57 BL/6. Total tau was similar in both groups, but phosphorylated tau increased by >100% in Cfh(-/-) compared to C57 BL/6 and covered >75% of the luminal wall compared to 50% in C57 BL/6. Hence, phosphorylated tau is a marked choroidal feature in this mouse model. Aβ deposition was clumped in Cfh(-/-) mice and likely to influence blood flow dynamics. Disturbed flow is associated with atherogenesis and may be related to the accumulation of membrane attack complex recently identified between choroidal vessels in those at high risk of macular degeneration due to complement factor H polymorphisms. PMID:27181225

  6. The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs

    Directory of Open Access Journals (Sweden)

    Akira Yano

    2015-01-01

    Full Text Available The reduction of brain amyloid beta (Aβ peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer’s disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβ antibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ40, and Aβ42 compared to Aβ fibrils. The levels of serum anti-Aβ antibodies and plasma Aβ peptides increased in both animals and decreased the brain Aβ40 level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβ antibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβ peptides and their toxic effects via clearance of Aβ peptides by generated antibodies.

  7. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

    OpenAIRE

    Zhang, Xueli; Tian, Yanli; Zhang, Can; Tian, Xiaoyu; Ross, Alana W.; Moir, Robert D.; Sun, Hongbin; Tanzi, Rudolph E.; Moore, Anna; Ran, Chongzhao

    2015-01-01

    Drug development for Alzheimer’s disease (AD) has been largely unsuccessful to date. Although numerous agents are reportedly effective in vitro, only an inadequate number of them have been tested in vivo, partially because of the lack of reliable and cost-efficient imaging methods to monitor their in vivo therapeutic effectiveness. Several amyloid beta (Aβ)-specific PET tracers have been used for clinical studies. However, their application for monitoring drug treatment in small animals is li...

  8. 670 nm laser light and EGCG complementarily reduce amyloid-{beta} aggregates in human neuroblastoma cells: basis for treatment of Alzheimer's disease?

    OpenAIRE

    Sommer, A.P.; Bieschke, J.; Friedrich, R.P.; Zhu, D.; Wanker, E. E.; Fecht, H.J.; Mereles, D; Hunstein, W

    2012-01-01

    Objective: The aim of the present study is to present the results of in vitro experiments with possible relevance in the treatment of Alzheimer's disease (AD). Background Data: Despite intensive research efforts, there is no treatment for AD. One root cause of AD is the extra- and intracellular deposition of amyloid-beta (A{beta}) fibrils in the brain. Recently, it was shown that extracellular A{beta} can enter brain cells, resulting in neurotoxicity. Methods: After internalization of A{beta}...

  9. Neurogenic Responses to Amyloid-Beta Plaques in the Brain of Alzheimer's Disease-Like Transgenic (pPDGF-APPSw,Ind) Mice

    OpenAIRE

    Gan, Li; Qiao, Shuhong; Lan, Xun; Chi, Liying; Luo, Chun; Lien, Lindsey; Liu, Qing Yan; Liu, Rugao

    2007-01-01

    Formation and accumulation of amyloid-beta (Aβ) plaques are associated with declined memory and other neurocognitive function in Alzheimer's Disease (AD) patients. However, the effects of Aβ plaques on neural progenitor cells (NPCs) and neurogenesis from NPCs remain largely unknown. The existing data on neurogenesis in AD patients and AD-like animal models remain controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ (pNes-LacZ) reporter transgenic mice ...

  10. Icariin Prevents Amyloid Beta-Induced Apoptosis via the PI3K/Akt Pathway in PC-12 Cells

    Directory of Open Access Journals (Sweden)

    Dongdong Zhang

    2015-01-01

    Full Text Available Icariin is a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum that exerts a variety of pharmacological activities and shows promise in the treatment and prevention of Alzheimer’s disease. In this study, we investigated the neuroprotective effects of icariin against amyloid beta protein fragment 25–35 (Aβ25–35 induced neurotoxicity in cultured rat pheochromocytoma PC12 cells and explored potential underlying mechanisms. Our results showed that icariin dose-dependently increased cell viability and decreased Aβ25–35-induced apoptosis, as assessed by MTT assay and Annexin V/propidium iodide staining, respectively. Results of western blot analysis revealed that the selective phosphatidylinositol 3-kinase (PI3K inhibitor LY294002 suppressed icariin-induced Akt phosphorylation, suggesting that the protective effects of icariin are associated with activation of the PI3K/Akt signaling pathway. LY294002 also blocked the icariin-induced downregulation of proapoptotic factors Bax and caspase-3 and upregulation of antiapoptotic factor Bcl-2 in Aβ25–35-treated PC12 cells. These findings provide further evidence for the clinical efficacy of icariin in the treatment of Alzheimer’s disease.

  11. A systematic review of amyloid-beta peptides as putative mediators of the association between affective disorders and Alzheimer's disease

    DEFF Research Database (Denmark)

    Abbasowa, L.; Heegaard, N. H. H.

    2014-01-01

    Background: Affective disorders are associated with an increased occurrence of cognitive deficits and have been linked to cognitive impairment and Alzheimer's disease. The putative molecular mechanisms involved in these associations are however not clear. The aim of this systematic review was to ...

  12. Analysis of the complex between amyloid beta peptides and mitochondrial enzyme 17beta-HSD in cerebrospinal fluid

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Hegnerová, Kateřina; Bocková, Markéta; Vaisocherová, Hana; Bartoš, A.; Říčný, J.; Řípová, D.; Homola, J.

    2008-01-01

    Roč. 275, podzim (2008), s. 249-249. ISSN 1742-464X. [EUROPTRODE /9./. Dublin, 30.03.2008-02.04.2008] Institutional research plan: CEZ:AV0Z20670512 Keywords : surface plasmon resonance * alzheimer disease * 17beta-HSD10 Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.139, year: 2008

  13. Cholesterol enhances amyloid {beta} deposition in mouse retina by modulating the activities of A{beta}-regulating enzymes in retinal pigment epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jiying [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Ohno-Matsui, Kyoko, E-mail: k.ohno.oph@tmd.ac.jp [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Morita, Ikuo [Section of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer Cholesterol-treated RPE produces more A{beta} than non-treated RPE. Black-Right-Pointing-Pointer Neprilysin expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer {alpha}-Secretase expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer Cholesterol-enriched diet induced subRPE deposits in aged mice. Black-Right-Pointing-Pointer A{beta} were present in cholesterol-enriched-diet-induced subRPE deposits in aged mice. -- Abstract: Subretinally-deposited amyloid {beta} (A{beta}) is a main contributor of developing age-related macular degeneration (AMD). However, the mechanism causing A{beta} deposition in AMD eyes is unknown. Hypercholesterolemia is a significant risk for developing AMD. Thus, we investigated the effects of cholesterol on A{beta} production in retinal pigment epithelial (RPE) cells in vitro and in the mouse retina in vivo. RPE cells isolated from senescent (12-month-old) C57BL/6 mice were treated with 10 {mu}g/ml cholesterol for 48 h. A{beta} amounts in culture supernatants were measured by ELISA. Activity and expression of enzymes and proteins that regulate A{beta} production were examined by activity assay and real time PCR. The retina of mice fed cholesterol-enriched diet was examined by transmission electron microscopy. Cholesterol significantly increased A{beta} production in cultured RPE cells. Activities of A{beta} degradation enzyme; neprilysin (NEP) and anti-amyloidogenic secretase; {alpha}-secretase were significantly decreased in cell lysates of cholesterol-treated RPE cells compared to non-treated cells, but there was no change in the activities of {beta}- or {gamma}-secretase. mRNA levels of NEP and {alpha}-secretase (ADAM10 and ADAM17) were significantly lower in cholesterol-treated RPE cells than non-treated cells. Senescent (12-month-old) mice fed cholesterol-enriched chow developed subRPE deposits containing A{beta}, whereas

  14. Effect of combination of extracts of ginseng and ginkgo biloba on acetylcholine in amyloid beta-protein-treated rats determined by an improved HPLC

    Institute of Scientific and Technical Information of China (English)

    Jian-xun LIU; Wei-hong CONG; Li XU; Jian-nong WANG

    2004-01-01

    AIM: To determine the concentration of acetylcholine (ACh) in amyloid beta-protein (Aβ) treated rats and offer a method determining ACh as well. METHODS: A 1-month combination of extrats of ginseng and ginkgo biloba(Naoweikang) ig administration to rats was performed daily after bilateral injection of Aβ1-40 (4 g/L, 1 μL for each side) into hippocampus. After decollation, homogenizing, and centrifuging and extracting, a high pressure liquid chromatographic (HPLC) method using electrochemical detection (ECD) combined with two immobilized enzyme reactors was used to determine ACh in rat whole brain. RESULTS: With a mobile phase consisting of disodium hydrogen orthophosphate, tetramethylammonium chloride (TMAC1), octanesulfonic acid sodium salt (OSA) and"Reagent MB" at a final pH of 8.0, ACh was determined while removing the interfering choline in less than 10 min at a flow rate of 0.35 mL/min on a platinum (Pt) working electrode at a potential of +300 mV vs a solid-state palladium (Pd) reference electrode. Linear regression analysis of peak area vs concentration demonstrated linearity in the 28.01 to 1400.06 μg/L injection range. The r-value was 0.9978. The limit of detection (LOD) is 0.28 ng on column. ACh in whole brain decreased by 20.34 % (from 162.1±32.7 to 134.7±14.0 μg/L, P<0.05) after bilateral injection of Aβ into rat hippocampus. After Naoweikang administration (31 and 15.5 mg/kg, respectively), ACh increased by 19.97 % (from 134.7+14.0 to 161.6+26.2 μg/L, P<0.05) and 18.56 % (from 134.7+14.0 to 159.7+22.9 μg/L, P<0.05), respectively. CONCLUSION: Naoweikang significantly increased the level of ACh in whole brain of Aβ treated rats. And a sensitive, selective and reliable method for routinely determining ACh in rat whole brain was established in this study.

  15. Development of a high-sensitivity immunoassay for amyloid-beta 1-42 using a silicon microarray platform.

    Science.gov (United States)

    Gagni, Paola; Sola, Laura; Cretich, Marina; Chiari, Marcella

    2013-09-15

    In this work, we present a highly sensitive immunoassay for the detection of the Alzheimer's disease (AD) biomarker amyloid-beta 1-42 (Aβ42) based on a label/label-free microarray platform that utilises silicon/silicon oxide (Si/SiO2) substrates. Due to constructive interference, Si/SiO2 layered slides allow enhancement of the fluorescence intensity on the surface with significant improvements in sensitivity of detection. The same substrate allows the label-free multiplexed detection of targets using the Interferometric Reflectance Imaging Sensor (IRIS), a platform amenable to high-throughput detection of mass changes on microarray substrates. Silicon chips are coated with copoly(DMA-NAS-MAPS), a ter-copolymer made from dimethylacrylamide (DMA), 3-(trimethoxysilyl)propyl methacrylate (MAPS) and N-Acryloyloxy succinimide (NAS). Aβ42 aggregation was studied by circular dichroism (CD), and an optimal antibody pair was selected based on specificity of recognition, binding yield and spot morphology of the capture antibody on the coated silicon surface as analysed by IRIS. Finally, incubation conditions were optimised, and an unprecedented Aβ42 detection sensitivity of 73pg/mL was achieved using an artificial cerebrospinal fluid (CSF) sample. Because of their multiplexing capability, low volume sample consumption and efficient sample-to-result time for population-wide screening, microarrays are ideal tools for the identification of individuals with preclinical AD who are still cognitively healthy. The high sensitivity of this assay format, potentially coupled to a pre-concentration step or signal-enhancing modifications, could lead to a non-invasive, inexpensive diagnostic tool for population-wide screening of AD biomarkers in biological fluids other than CSF, such as serum or plasma. PMID:23624018

  16. Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.

    Science.gov (United States)

    Yao, Lei; Gu, Xiao; Song, Qingxiang; Wang, Xiaolin; Huang, Meng; Hu, Meng; Hou, Lina; Kang, Ting; Chen, Jun; Chen, Hongzhuan; Gao, Xiaoling

    2016-03-28

    Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest global healthcare challenges. However, an effective therapy is still lacking. Accumulation of amyloid-beta (Aβ) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Aβ clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Aβ clearance. However, the in vivo application of α-M is limited due to its hydrophobic nature, poor aqueous solubility and stability, and thus low bioavailability and accumulation in the target organs. To overcome this limitation, α-M was encapsulated into the core of poly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(α-M)]. Such nanoencapsulation improved the biodistribution of α-M in both the brain and liver, enhanced the brain clearance of (125)I-radiolabeled Aβ1-42 in an LDLR-dependent manner, reduced Aβ deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified the concept that polyphenol-mediated modulation of LDLR expression might serve as a safe and efficient disease-modifying therapy for AD by accelerating Aβ clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD. PMID:26836197

  17. Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia.

    NARCIS (Netherlands)

    Jong, D. de; Jansen, R.W.M.M.; Kremer, H.P.H.; Verbeek, M.M.

    2006-01-01

    BACKGROUND: The differentiation of Alzheimer's disease (AD) from vascular dementia (VaD) is hampered by clinical diagnostic criteria with disappointing sensitivity and specificity. The objective of this study was to investigate whether cerebrospinal fluid (CSF) levels of total tau protein (t-tau), a

  18. Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2

    Directory of Open Access Journals (Sweden)

    Koutaro Takamatsu

    2014-11-01

    Full Text Available The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS cell-derived macrophage-like cells for Alzheimer's disease (AD. In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aβ added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aβ. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aβ. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2, which is a protease with Aβ-degrading activity. In vitro, expression of NEP2 but not anti-Aβ scFv enhanced the effect to reduce the level of soluble Aβ oligomer in the culture medium and to alleviate the neurotoxicity of Aβ. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2 in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aβ in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.

  19. Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Saak V. Ovsepian

    2013-12-01

    Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

  20. New Alzheimer amyloid beta responsive genes identified in human neuroblastoma cells by hierarchical clustering.

    Directory of Open Access Journals (Sweden)

    Markus Uhrig

    Full Text Available Alzheimer's disease (AD is characterized by neuronal degeneration and cell loss. Abeta(42, in contrast to Abeta(40, is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Abeta(40 and Abeta(42 levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Abeta(40 and Abeta(42 levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2 and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Abeta(42/Abeta(40 ratio. Importantly however, an increased Abeta(42/Abeta(40 ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Abeta(42/Abeta(40 ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Abeta(42/Abeta(40 ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes.

  1. New Alzheimer amyloid beta responsive genes identified in human neuroblastoma cells by hierarchical clustering.

    Science.gov (United States)

    Uhrig, Markus; Ittrich, Carina; Wiedmann, Verena; Knyazev, Yuri; Weninger, Annette; Riemenschneider, Matthias; Hartmann, Tobias

    2009-01-01

    Alzheimer's disease (AD) is characterized by neuronal degeneration and cell loss. Abeta(42), in contrast to Abeta(40), is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Abeta(40) and Abeta(42) levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids) in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Abeta(40) and Abeta(42) levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2) and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Abeta(42)/Abeta(40) ratio. Importantly however, an increased Abeta(42)/Abeta(40) ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Abeta(42)/Abeta(40) ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Abeta(42)/Abeta(40) ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes. PMID:19707560

  2. Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation

    Directory of Open Access Journals (Sweden)

    Podlisny Marcia

    2011-01-01

    Full Text Available Abstract Background Previously we reported 1 μM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. Results Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aβ dimers and trimers (Aβd/t induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aβ1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50 in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Aβd/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state, lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Aβ monomers are not active, suggesting oxidized SDS-stable Aβ1-42 dimers in a low-n state are the most active rod-inducing species. Aβd/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Aβd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aβd/t, whereas overexpression of a cofilin kinase inhibits Aβd/t-induced rod formation. Conclusions Together these data support a mechanism by which Aβd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.

  3. Molecular modeling approach to explore the role of cathepsin B from Hordeum vulgare in the degradation of Aβ peptides.

    Science.gov (United States)

    Dhanavade, Maruti J; Parulekar, Rishikesh S; Kamble, Subodh A; Sonawane, Kailas D

    2016-01-01

    The pathological hallmark of Alzheimer's disease is the accumulation of Aβ peptides in human brains. These Aβ peptides can be degraded by several enzymes such as hACE, hECE, hIDE and cathepsin B. Out of which cathepsin B also belongs to the papain super family and has been found in human brains, it has a role in Aβ peptide degradation through limited proteolysis. The Aβ concentrations are maintained properly by its production and clearance via receptor-mediated cellular uptake and direct enzymatic degradation. However, the reduced production of Aβ degrading enzymes as well as their Aβ degrading activity in human brains initiate the process of accumulation of Aβ peptides. So it becomes essential to investigate the molecular interactions involved in the process of Aβ degradation in detail at the atomic level. Hence, homology modeling, molecular docking and molecular dynamics simulation techniques have been used to explore the possible role of cathepsin B from Hordeum vulgare in the degradation of amyloid beta (Aβ) peptides. The homology model of cathepsin B from Hordeum vulgare shows good similarity with human cathepsin B. Molecular docking and MD simulation results revealed that the active site residues Cys32, HIS112, HIS113 are involved in the catalytic activity of cathepsin B. The sulfhydryl group of the Cys32 residue of cathepsin B from Hordeum vulgare cleaves the Aβ peptide from the carboxylic end of Glu11. Hence, this structural study might be helpful in designing alternative strategies for the treatment of AD. PMID:26568474

  4. The soluble transcobalamin receptor (sCD320) is present in cerebrospinal fluid and correlates to dementia-related biomarkers tau proteins and amyloid-beta

    DEFF Research Database (Denmark)

    Abuyaman, Omar; Nexo, Ebba

    2015-01-01

    in cerebrospinal fluid (CSF) and show its correlations to dementia-related biomarkers tau proteins and amyloid-beta. METHODS: We collected 223 cerebrospinal fluid samples and corresponding plasma samples (n = 46). We measured CSF and plasma sCD320, holoTC and total TC employing in-house ELISA methods...... and CSF phospho-tau (181P) (p-tau), total tau (t-tau) and amyloid-beta 1-42 (Aβ) (n = 177) employing commercial ELISA kits (Innogenetics Company). Size exclusion chromatography was performed on a Superdex 200 column. RESULTS: The median sCD320 concentration in CSF (14 pmol/L) is around five times.......01). Interestingly, sCD320 correlates to p-tau and t-tau (Rs = 0.599, 0.569 (n = 173, 176) respectively, p < 0.001) and to Aβ (Rs = 0.265, p < 0.001 (n = 177)). CONCLUSION: We document for the first time the occurrence of sCD320 in human CSF. We report that the concentration of sCD320 correlates to the dementia...

  5. Gastrointestinal peptide levels in obese and anorexic females

    Energy Technology Data Exchange (ETDEWEB)

    Pasley, J.N.; Rice, R.L.; McCullough, S.S.; McKay, D.W.; Rayford, P.L. (Univ. of Arkansas for Medical Sciences, Little Rock (USA))

    1989-01-01

    The role of gastrointestinal peptides in eating disorders has yet to be determined. Methods: In this study we examined plasma levels of gastrin (G), cholecystokinin (CCK), and pancreatic polypeptide (PP) in adolescent anorexic, and obese female subjects hospitalized for feeding behavior disorders. Six anorexic, six obese and six control young females (ages 13-26) were studied after an overnight fast and after consuming a liquid test meal. The liquid test meal (Ensure, Ross Laboratories; Columbus OH) consisted of 14% calories as protein, 31.5% calories as fat and 54.5% calories as carbohydrate in a 240ml volume. Plasma levels of gastrointestinal peptides, G, CCK and PP were determined by specific radioimmunoassay. The data were analyzed by one way analysis of variance and the Student's t-test. Results: show that fasting levels of G were greater in control and obese groups than the anorexic subjects. Postprandial G levels for controls were higher than the anorexic, and obese groups respectively. When fasting and postprandial G levels were compared among the same groups only the controls increased after eating. Fasting CCK levels were lower in control and anorexic groups than the obese group. Postprandial CCK levels were higher among control patients compared to anorexic and obese subjects. When fasting and postprandial CCK levels were compared among groups, only control levels increased after eating. Fasting and postprandial PP levels were not different between groups. Postprandial PP levels increased over fasting PP levels only in controls.

  6. Gastrointestinal peptide levels in obese and anorexic females

    International Nuclear Information System (INIS)

    The role of gastrointestinal peptides in eating disorders has yet to be determined. Methods: In this study we examined plasma levels of gastrin (G), cholecystokinin (CCK), and pancreatic polypeptide (PP) in adolescent anorexic, and obese female subjects hospitalized for feeding behavior disorders. Six anorexic, six obese and six control young females (ages 13-26) were studied after an overnight fast and after consuming a liquid test meal. The liquid test meal (Ensure, Ross Laboratories; Columbus OH) consisted of 14% calories as protein, 31.5% calories as fat and 54.5% calories as carbohydrate in a 240ml volume. Plasma levels of gastrointestinal peptides, G, CCK and PP were determined by specific radioimmunoassay. The data were analyzed by one way analysis of variance and the Student's t-test. Results: show that fasting levels of G were greater in control and obese groups than the anorexic subjects. Postprandial G levels for controls were higher than the anorexic, and obese groups respectively. When fasting and postprandial G levels were compared among the same groups only the controls increased after eating. Fasting CCK levels were lower in control and anorexic groups than the obese group. Postprandial CCK levels were higher among control patients compared to anorexic and obese subjects. When fasting and postprandial CCK levels were compared among groups, only control levels increased after eating. Fasting and postprandial PP levels were not different between groups. Postprandial PP levels increased over fasting PP levels only in controls

  7. Control of Alzheimer's amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila.

    Directory of Open Access Journals (Sweden)

    Reiko Sanokawa-Akakura

    Full Text Available FK506 binding proteins (FKBPs, also called immunophilins, are prolyl-isomerases (PPIases that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP. Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Abeta toxicity. Towards this goal, we generated Abeta transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Abeta and increased lifespan in Abeta flies, whereas loss of function of FKBP52 exacerbated these Abeta phenotypes. Interestingly, the Abeta pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (-/- cells have increased intracellular copper and higher levels of Abeta. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Abeta peptides.

  8. Repeated intraperitoneal injections of liposomes containing phosphatidic acid and cardiolipin reduce amyloid-β levels in APP/PS1 transgenic mice

    DEFF Research Database (Denmark)

    Ordóñez-Gutiérrez, Lara; Re, Francesca; Bereczki, Erika;

    2015-01-01

    UNLABELLED: The accumulation of extracellular amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). It is thought that an equilibrium exists between Aβ in the brain and in the peripheral blood and th...

  9. Genetic Variation in the Natriuretic Peptide System, Circulating Natriuretic Peptide Levels, and Blood Pressure

    DEFF Research Database (Denmark)

    Jeppesen, Jørgen L; Nielsen, Søren J; Torp-Pedersen, Christian; Hansen, Tine W; Olsen, Michael H; Linneberg, Allan; Madsbad, Sten; Fenger, Mogens; Berg, Nikolaj D

    2012-01-01

    BackgroundIn a large collaborative study (n > 50,000), common variants in the natriuretic peptide (NP) genes were found to be associated with circulating NP levels and also with blood pressure (BP) levels based on office BP measurements (OBPMs). It is unknown if determining an individual's BP by 24......-h ambulatory BP measurements (ABPMs) will influence the effect of NP gene variations on BP levels.MethodsWe used rs632793 at the NPPB (NP precursor B) locus to investigate the relationship between genetically determined serum N-terminal pro-brain NP (NT-proBNP) concentrations and BP levels...... participants with the G:G genotype (geometric mean (95% confidence interval (CI)): 34.8 (31.5-38.4) pg/ml vs. 48.1 (41.9-55.3) pg/ml, P = 0.0002), but higher 24-h ambulatory BP levels (mean difference (95% CI): 2.0 (0.1-4.1) mm Hg, P = 0.043, for systolic BP and 1.7 (0.4-3.1) mm Hg, P = 0.011, for diastolic BP...

  10. Intracellular accumulation of amyloid-beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Thomas A Bayer

    2010-03-01

    Full Text Available Despite of long-standing evidence that beta-amyloid (Aβ peptides have detrimental effects on synaptic function, the relationship between Aβ, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Aβ peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer’s disease (AD which have been proven to be valuable model system in modern AD research. The present review discusses the impact of intraneuronal Aβ accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

  11. Characterization of D-enatiomeric peptides derived from D3 for treatment of Alzheimer`s disease

    OpenAIRE

    Klein, Antonia Nicole; Tusche, Markus; Schlosser, Christine; Bartnik, Dirk; Kutzsche, Janine; Willbold, Dieter

    2014-01-01

    Alzheimer's disease (AD) is the most prominent neurodegenerative disease affecting more than 24 million people worldwide. Currently, it is the sixth-leading cause of death, but until now there is no causal therapy available. The amyloid-beta (Aβ) peptide plays an important role in the pathology of the disease. Especially the soluble, most harmful neurotoxic oligomers of Aβ are discussed to be responsible for the development and progression of the disease. In our group we identified the D-enan...

  12. High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer β-amyloid peptide

    OpenAIRE

    Rauth, Sabine; Hinz, Dominik; Börger, Michael; Uhrig, Markus; Mayhaus, Manuel; Riemenschneider, Matthias; Skerra, Arne

    2016-01-01

    Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutatio...

  13. 7.0T nuclear magnetic resonance evaluation of the amyloid beta (1-40) animal model of Alzheimer’s disease:comparison of cytology veriifcation

    Institute of Scientific and Technical Information of China (English)

    Lei Zhang; Shuai Dong; Guixiang Zhao; Yu Ma

    2014-01-01

    3.0T magnetic resonance spectroscopic imaging is a commonly used method in the research of brain function in Alzheimer’s disease. However, the role of 7.0T high-ifeld magnetic resonance spectroscopic imaging in brain function of Alzheimer’s disease remains unclear. In this study, 7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer’s disease rats, the N-acetylaspartate wave crest was reduced, and the creatine and choline wave crest was elevated. This ifnding was further supported by hematoxylin-eosin staining, which showed a loss of hippocampal neurons and more glial cells. Moreover, electron microscopy showed neuronal shrinkage and mitochondrial rupture, and scanning electron microscopy revealed small size hippocampal synaptic vesicles, incomplete synaptic structure, and reduced number. Overall, the results revealed that 7.0T high-ifeld nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer’s disease rats in vivo, allowing the possibility for assessing the success rate and grading of the amyloid beta (1-40) animal model of Alzheimer’s disease.

  14. Antiamnesic Effect of Broccoli (Brassica oleracea var. italica) Leaves on Amyloid Beta (Aβ)1-42-Induced Learning and Memory Impairment.

    Science.gov (United States)

    Park, Seon Kyeong; Ha, Jeong Su; Kim, Jong Min; Kang, Jin Yong; Lee, Du Sang; Guo, Tian Jiao; Lee, Uk; Kim, Dae-Ok; Heo, Ho Jin

    2016-05-01

    To examine the antiamnesic effects of broccoli (Brassica oleracea var. italica) leaves, we performed in vitro and in vivo tests on amyloid beta (Aβ)-induced neurotoxicity. The chloroform fraction from broccoli leaves (CBL) showed a remarkable neuronal cell-protective effect and an inhibition against acetylcholinesterase (AChE). The ameliorating effect of CBL on Aβ1-42-induced learning and memory impairment was evaluated by Y-maze, passive avoidance, and Morris water maze tests. The results indicated improving cognitive function in the CBL group. After the behavioral tests, antioxidant effects were detected by superoxide dismutase (SOD), oxidized glutathione (GSH)/total GSH, and malondialdehyde (MDA) assays, and inhibition against AChE was also presented in the brain. Finally, oxo-dihydroxy-octadecenoic acid (oxo-DHODE) and trihydroxy-octadecenoic acid (THODE) as main compounds were identified by quadrupole time-of-flight ultraperformance liquid chromatography (Q-TOF UPLC-MS) analysis. Therefore, our studies suggest that CBL could be used as a natural resource for ameliorating Aβ1-42-induced learning and memory impairment. PMID:27079470

  15. Influence of ionizing radiation on gastrointestinal peptide levels

    International Nuclear Information System (INIS)

    Exposure of the gut to ionising radiation may induce gastrointestinal damage and dysfunction. Early effects such as nausea, vomiting and diarrhea, anorexia may be observed within the first 24 h after irradiation. Such symptoms are seen even with doses as low as 1 Gy. later effects and the onset of the gastrointestinal syndrome are seen at higher doses (10 Gy) and include gastric emptying inhibition, intestinal hemorrhages, disturbances in water and electrolytes balance and septicemia. The severity of which depends on the nature, dose and dose rate received. The mechanism underlying these changes was unclear; it has long been known that exposure to ionising radiation affects intestinal morphology usually because of inhibition of mitotic activity at the level of the crypt enterocyst. The various physiological functions of the gastrointestinal tract are controlled by a wide variety of agents as neurotransmitters, neuropeptides. Radiation induces alterations in hormonal release and response. The present study carried out in the rat focuses on Gastrin Releasing Peptide (GRP), a gastrointestinal neuropeptide present in the central nervous system and in the gut endocrine cells were released into blood. The GRP controls food intake, pancreatic enzyme secretions, gastric emptying, intestinal motility and cellular proliferation. The aim was to investigate the effects of gamma and neutron/gamma on plasma and gastrointestinal tissue levels of GRP

  16. Influence of ionizing radiation on gastrointestinal peptide levels

    Energy Technology Data Exchange (ETDEWEB)

    Wysocki, J.; Esposito, V.; Linard, C. [CEA Fontenay-aux-Roses, 92 (France). Inst. de Protection et de Surete Nucleaire

    1997-03-01

    Exposure of the gut to ionising radiation may induce gastrointestinal damage and dysfunction. Early effects such as nausea, vomiting and diarrhea, anorexia may be observed within the first 24 h after irradiation. Such symptoms are seen even with doses as low as 1 Gy. later effects and the onset of the gastrointestinal syndrome are seen at higher doses (10 Gy) and include gastric emptying inhibition, intestinal hemorrhages, disturbances in water and electrolytes balance and septicemia. The severity of which depends on the nature, dose and dose rate received. The mechanism underlying these changes was unclear; it has long been known that exposure to ionising radiation affects intestinal morphology usually because of inhibition of mitotic activity at the level of the crypt enterocyst. The various physiological functions of the gastrointestinal tract are controlled by a wide variety of agents as neurotransmitters, neuropeptides. Radiation induces alterations in hormonal release and response. The present study carried out in the rat focuses on Gastrin Releasing Peptide (GRP), a gastrointestinal neuropeptide present in the central nervous system and in the gut endocrine cells were released into blood. The GRP controls food intake, pancreatic enzyme secretions, gastric emptying, intestinal motility and cellular proliferation. The aim was to investigate the effects of gamma and neutron/gamma on plasma and gastrointestinal tissue levels of GRP

  17. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease.

    Science.gov (United States)

    Calkins, Marcus J; Manczak, Maria; Reddy, P Hemachandra

    2012-01-01

    In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer's disease (AD). Mounting evidence from multiple Alzheimer's disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. PMID:23226091

  18. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Directory of Open Access Journals (Sweden)

    Jia Meng

    Full Text Available With the trend of an increasing aged population worldwide, Alzheimer's disease (AD, an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC inhibitor, suberoylanilidehydroxamic acid (SAHA, may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  19. Droplet-based magnetic bead immunoassay using microchannel-connected multiwell plates (μCHAMPs) for the detection of amyloid beta oligomers.

    Science.gov (United States)

    Park, Min Cheol; Kim, Moojong; Lim, Gun Taek; Kang, Sung Min; An, Seong Soo A; Kim, Tae Song; Kang, Ji Yoon

    2016-06-21

    Multiwell plates are regularly used in analytical research and clinical diagnosis but often require laborious washing steps and large sample or reagent volumes (typically, 100 μL per well). To overcome such drawbacks in the conventional multiwell plate, we present a novel microchannel-connected multiwell plate (μCHAMP) that can be used for automated disease biomarker detection in a small sample volume by performing droplet-based magnetic bead immunoassay inside the plate. In this μCHAMP-based immunoassay platform, small volumes (30-50 μL) of aqueous-phase working droplets are stably confined within each well by the simple microchannel structure (200-300 μm in height and 0.5-1 mm in width), and magnetic beads are exclusively transported into an adjacent droplet through the oil-filled microchannels assisted by a magnet array aligned beneath and controlled by a XY-motorized stage. Using this μCHAMP-based platform, we were able to perform parallel detection of synthetic amyloid beta (Aβ) oligomers as a model analyte for the early diagnosis of Alzheimer's disease (AD). This platform easily simplified the laborious and consumptive immunoassay procedure by achieving automated parallel immunoassay (32 assays per operation in 3-well connected 96-well plate) within 1 hour and at low sample consumption (less than 10 μL per assay) with no cumbersome manual washing step. Moreover, it could detect synthetic Aβ oligomers even below 10 pg mL(-1) concentration with a calculated detection limit of ∼3 pg mL(-1). Therefore, the μCHAMP and droplet-based magnetic bead immunoassay, with the combination of XY-motorized magnet array, would be a useful platform in the diagnosis of human disease, including AD, which requires low consumption of the patient's body fluid sample and automation of the entire immunoassay procedure for high processing capacity. PMID:27185215

  20. Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps.

    Science.gov (United States)

    Sajadi, Ahmadali; Provost, Chloé; Pham, Brendon; Brouillette, Jonathan

    2016-01-01

    Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aβo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aβo correlate with memory deficits in AD models and humans. The Aβo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aβo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aβo-induced memory deficits at the onset of AD. Since soluble Aβo aggregate relatively fast into insoluble Aβ fibrils that correlate poorly with the clinical state of patients, soluble Aβo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aβo and continuous infusion of Aβo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aβo in pre-dementia patients. PMID:27585306

  1. [18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer's disease

    International Nuclear Information System (INIS)

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the 18F-labeled Pittsburgh compound B (PIB) derivative [18F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [18F]FMM and [11C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [18F]FMM PET 85 min after injection, 60-min dynamic [11C]PIB PET, and cognitive testing. [18F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [18F]FMM scans had a sensitivity of 97.2 % and specificity of 85.3 % in distinguishing AD patients from older HC subjects, and a specificity of 100 % for young and transitional HC subjects. The [11C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p 18F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [11C]PIB PET. (orig.)

  2. Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages.

    Directory of Open Access Journals (Sweden)

    Jaimie Hoh Kam

    Full Text Available BACKGROUND: Amyloid beta (Aβ accumulates in the ageing central nervous system and is associated with a number of age-related diseases, including age-related macular degeneration (AMD in the eye. AMD is characterised by accumulation of extracellular deposits called drusen in which Aβ is a key constituent. Aβ activates the complement cascade and its deposition is associated with activated macrophages. So far, little is known about the quantitative measurements of Aβ accumulation and definitions of its relative sites of ocular deposition in the normal ageing mouse. METHODOLOGY/PRINCIPAL FINDINGS: We have traced Aβ accumulation quantitatively in the ageing mouse retina using immunohistochemistry and Western blot analysis. We reveal that it is not only deposited at Bruch's membrane and along blood vessels, but unexpectedly, it also coats photoreceptor outer segments. While Aβ is present at all sites of deposition from 3 months of age, it increases markedly from 6 months onward. Progressive accumulation of deposits on outer segments was confirmed with scanning electron microscopy, revealing age-related changes in their morphology. Such progress of accumulation of Aβ on photoreceptor outer segments with age was also confirmed in human retinae using immunohistochemistry. We also chart the macrophage response to increases in Aβ showing up-regulation in their numbers using both confocal laser imaging of the eye in vivo followed by in vitro immunostaining. With age macrophages become bloated with cellular debris including Aβ, however, their increasing numbers fail to stop Aβ accumulation. CONCLUSIONS: Increasing Aβ deposition in blood vessels and Bruch's membrane will impact upon retinal perfusion and clearance of cellular waste products from the outer retina, a region of very high metabolic activity. This accumulation of Aβ may contribute to the 30% reduction of photoreceptors found throughout life and the shortening of those that remain. The

  3. The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain.

    Science.gov (United States)

    Fossati, Silvia; Giannoni, Patrizia; Solesio, Maria E; Cocklin, Sarah L; Cabrera, Erwin; Ghiso, Jorge; Rostagno, Agueda

    2016-02-01

    Mitochondrial dysfunction has been recognized as an early event in Alzheimer's disease (AD) pathology, preceding and inducing neurodegeneration and memory loss. The presence of cytochrome c (CytC) released from the mitochondria into the cytoplasm is often detected after acute or chronic neurodegenerative insults, including AD. The carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) was identified among a library of drugs as an inhibitor of CytC release and proved to be neuroprotective in Huntington's disease and stroke models. Here, using neuronal and glial cell cultures, in addition to an acute model of amyloid beta (Aβ) toxicity, which replicates by intra-hippocampal injection the consequences of interstitial and cellular accumulation of Aβ, we analyzed the effects of MTZ on neuronal and glial degeneration induced by the Alzheimer's amyloid. MTZ prevented DNA fragmentation, CytC release and activation of caspase 9 and caspase 3 induced by Aβ in neuronal and glial cells in culture through the inhibition of mitochondrial hydrogen peroxide production. Moreover, intraperitoneal administration of MTZ prevented neurodegeneration induced by intra-hippocampal Aβ injection in the mouse brain and was effective at reducing caspase 3 activation in neurons and microglia in the area surrounding the injection site. Our results, delineating the molecular mechanism of action of MTZ against Aβ-mediated mitochondrial dysfunction and caspase activation, and demonstrating its efficiency in a model of acute amyloid-mediated toxicity, provide the first combined in vitro and in vivo evidence supporting the potential of a new therapy employing FDA-approved CAIs in AD. PMID:26581638

  4. K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus.

    OpenAIRE

    Heurteaux, C; Bertaina, V; Widmann, C; Lazdunski, M

    1993-01-01

    Transient global forebrain ischemia induces in rat brain a large increase of expression of the immediate early genes c-fos and c-jun and of the mRNAs for the 70-kDa heat-shock protein and for the form of the amyloid beta-protein precursor including the Kunitz-type protease-inhibitor domain. At 24 hr after ischemia, this increased expression is particularly observed in regions that are vulnerable to the deleterious effects of ischemia, such as pyramidal cells of the CA1 field in the hippocampu...

  5. The Relationship between Different Assays for Detection and Quantification of Amyloid Beta 42 in Human Cerebrospinal Fluid

    Directory of Open Access Journals (Sweden)

    Teresa A. Ellis

    2012-01-01

    Full Text Available Alzheimer's disease (AD, which is characterized by a degeneration of neurons and their synapses, is one of the most common forms of dementia. CSF levels of amyloid 42 (A42 have been recognized as a strong candidate to serve as an AD biomarker. There are a number of commercial assays that are routinely employed for measuring A42; however, these assays give diverse ranges for the absolute levels of CSF A42. In order to employ CSF A42 as a biomarker across multiple laboratories, studies need to be performed to understand the relationship between the different platforms. We have analyzed CSF samples from both diseased and nondiseased subjects with two different widely used assay platforms. The results showed that different values for the levels of CSF A42 were reported, depending on the assay used. Nonetheless, both assays clearly demonstrated statistically significant differences in the levels of A42 in CSF from AD relative to age-matched controls (AMC. This paper provides essential data for establishing the relationship between these assays and provides an important step towards the validation of A42 as a biomarker for AD.

  6. Relationship between N-terminal pro-B-type natriuretic peptide levels and metabolic syndrome

    OpenAIRE

    Bao, Yuanyuan; Shang, Xiliang; Zhou, Linuo; Hu, Renming; Li, Yiming; Ding, Wei

    2011-01-01

    Introduction Previous studies have shown that obese individuals have reduced natriuretic peptide levels. But conflicting data exist on the relation of natriuretic peptide levels to other metabolic risk factors. Material and methods We investigated the relationship between plasma N-terminal pro-B-type natriuretic peptide levels (NT-proBNP) and metabolic syndrome (MetS) and metabolic risk factors in 469 patients free of heart failure. Two hundred thirty diagnosed MetS cases and 239 non-MetS cas...

  7. Glycemia and Levels of Cerebrospinal Fluid Amyloid and Tau in Patients Attending a Memory Clinic

    NARCIS (Netherlands)

    Exalto, Lieza G.; van der Flier, Wiesje M.; Scheltens, Phillip; Biessels, Geert Jan

    2010-01-01

    OBJECTIVES: To determine the association between markers of glycemia and cerebrospinal fluid (CSF) amyloid beta 1-42 (A beta 42) and tau levels in patients attending a memory clinic. DESIGN: Cross-sectional study. SETTING: Memory clinic. PARTICIPANTS: Two hundred forty-five consecutive patients atte

  8. [{sup 18}F]Flutemetamol amyloid-beta PET imaging compared with [{sup 11}C]PIB across the spectrum of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Hatashita, Shizuo; Yamasaki, Hidetomo [Shonan-Atsugi Hospital, Neurology, PET Center, Atsugi (Japan); Suzuki, Yutaka; Wakebe, Daichi; Hayakawa, Hideki [Shonan-Atsugi Hospital, Radiology, PET Center, Atsugi (Japan); Tanaka, Kumiko [Shonan-Atsugi Hospital, Pharmacology, PET Center, Atsugi (Japan)

    2014-02-15

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the {sup 18}F-labeled Pittsburgh compound B (PIB) derivative [{sup 18}F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [{sup 18}F]FMM and [{sup 11}C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [{sup 18}F]FMM PET 85 min after injection, 60-min dynamic [{sup 11}C]PIB PET, and cognitive testing. [{sup 18}F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [{sup 18}F]FMM scans had a sensitivity of 97.2 % and specificity of 85.3 % in distinguishing AD patients from older HC subjects, and a specificity of 100 % for young and transitional HC subjects. The [{sup 11}C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p < 0.01). Of the MCI patients, 68 had a bimodal distribution of SUVR, and 29 of them (42.6 %) had positive scans. Cortical FMM SUVR values were strongly correlated with PIB DVR (r = 0.94, n = 145, p < 0.001). [{sup 18}F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [{sup 11}C]PIB PET. (orig.)

  9. Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia.

    Science.gov (United States)

    Muradashvili, Nino; Tyagi, Reeta; Metreveli, Naira; Tyagi, Suresh C; Lominadze, David

    2014-09-01

    Increased blood level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) accompanies many cognitive disorders including Alzheimer's disease. We hypothesized that HHcy-enhanced cerebrovascular permeability occurs via activation of matrix metalloproteinase-9 (MMP9) and leads to an increased formation of fibrinogen-β-amyloid (Fg-Aβ) complex. Cerebrovascular permeability changes were assessed in C57BL/6J (wild type, WT), cystathionine-β-synthase heterozygote (Cbs+/-, a genetic model of HHcy), MMP9 gene knockout (Mmp9-/-), and Cbs and Mmp9 double knockout (Cbs+/-/Mmp9-/-) mice using a dual-tracer probing method. Expression of vascular endothelial cadherin (VE-cadherin) and Fg-Aβ complex formation was assessed in mouse brain cryosections by immunohistochemistry. Short-term memory of mice was assessed with a novel object recognition test. The cerebrovascular permeability in Cbs+/- mice was increased via mainly the paracellular transport pathway. VE-cadherin expression was the lowest and Fg-Aβ complex formation was the highest along with the diminished short-term memory in Cbs+/- mice. These effects of HHcy were ameliorated in Cbs+/-/Mmp9-/- mice. Thus, HHcy causes activation of MMP9 increasing cerebrovascular permeability by downregulation of VE-cadherin resulting in an enhanced formation of Fg-Aβ complex that can be associated with loss of memory. These data may lead to the identification of new targets for therapeutic intervention that can modulate HHcy-induced cerebrovascular permeability and resultant pathologies. PMID:24865997

  10. Cratoxylum formosum Extract Protects against Amyloid-Beta Toxicity in a Caenorhabditis elegans Model of Alzheimer's Disease.

    Science.gov (United States)

    Keowkase, Roongpetch; Weerapreeyakul, Natthida

    2016-04-01

    Amyloid-β, one of the hallmarks of Alzheimer's disease, is toxic to neurons and causes cell death in the brain. Oxidative stress is known to play an important role in Alzheimer's disease, and there is strong evidence linking oxidative stress to amyloid-β. The herbal plant "Tiew kon" (Cratoxylum formosum ssp. pruniflorum) is an indigenous vegetable that is grown in Southeast Asia. Many reports suggested that the twig extract from C. formosum possesses an antioxidant property. The purpose of this study was to investigate the protective effect of the twig extract from C. formosum against amyloid-β toxicity using the transgenic Caenorhabditis elegans model. This study demonstrated that the extract significantly delayed amyloid-β-induced paralysis in the C. elegans model of Alzheimer's disease. Using a genetic approach, we found that DAF-16/FOXO transcription factor, heat shock factor 1, and SKN-1 (Nrf2 in mammals) were required for the extract-mediated delayed paralysis. The extract ameliorated oxidative stress by reducing the level of H2O2, which appeared to account for the protective action of the extract. The extract possesses antioxidant activity against juglone-induced oxidative stress as it was shown to increase survival of the stressed worms. In addition, C. formosum decreased the expression of the heat shock protein-16.2 gene which was induced by thermal stress, indicating its ability to reduce cellular stress. The results from this study support the C. elegans model in the search for disease-modifying agents to treat Alzheimer's disease and indicate the potential of the extract from C. formosum ssp. pruniflorum as a source for the development of anti-Alzheimer's drugs. PMID:26845710

  11. Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer’s Disease

    Science.gov (United States)

    Sung, Hye Youn; Choi, Byung-Ok; Jeong, Jee Hyang; Kong, Kyoung Ae; Hwang, Jinha; Ahn, Jung-Hyuck

    2016-01-01

    To identify epigenetically regulated genes involved in the pathogenesis of Alzheimer’s disease (AD) we analyzed global mRNA expression and methylation profiles in amyloid precursor protein (APP)-Swedish mutant-expressing AD model cells, H4-sw and selected heme oxygenase-1 (HMOX1), which is associated with pathological features of AD such as neurofibrillary tangles and senile plaques. We examined the epigenetic regulatory mechanism of HMOX1 and its application as a diagnostic and prognostic biomarker for AD. Our results show that HMOX1 mRNA and protein expression was approximately 12.2-fold and 7.9-fold increased in H4-sw cells, respectively. Increased HMOX1 expression was also detected in the brain, particularly the hippocampus, of AD model transgenic mice. However, the methylation of specific CpG sites within its promoter, particularly at CpG located −374 was significantly decreased in H4-sw cells. Treatment of neuroglioma cells with the demethylating agent 5-aza-2′-deoxycytidine resulted in reduced methylation of HMOX1 promoter accompanied by enhanced HMOX1 expression strongly supporting DNA methylation-dependent transcriptional regulation of HMOX1. Toxic Aβ-induced aberrant hypomethylation of HMOX1 at −374 promoter CpG site was correlated with increased HMOX1expression. In addition to neuroglioma cells, we also found Aβ-induced epigenetic regulation of HMOX1 in human T lymphocyte Jurkat cells. We evaluated DNA methylation status of HMOX1 at −374 promoter CpG site in blood samples from AD patients, patients with mild cognitive impairment (MCI), and control individuals using quantitative methylation-specific polymerase chain reaction. We observed lower methylation of HMOX1 at the −374 promoter CpG site in AD patients compared to MCI and control individuals, and a correlation between Mini-Mental State Examination score and demethylation level. Receiver operating characteristics analysis revealed good discrimination of AD patients from MCI patients and

  12. Increased expression of ApoE and protection from amyloid-beta toxicity in transmitochondrial cybrids with haplogroup K mtDNA.

    Science.gov (United States)

    Thaker, Kunal; Chwa, Marilyn; Atilano, Shari R; Coskun, Pinar; Cáceres-Del-Carpio, Javier; Udar, Nitin; Boyer, David S; Jazwinski, S Michal; Miceli, Michael V; Nesburn, Anthony B; Kuppermann, Baruch D; Kenney, M Cristina

    2016-09-01

    Mitochondrial (mt) DNA haplogroups, defined by specific single nucleotide polymorphism (SNP) patterns, represent populations of diverse geographic origins and have been associated with increased risk or protection of many diseases. The H haplogroup is the most common European haplogroup while the K haplogroup is highly associated with the Ashkenazi Jewish population. Transmitochondrial cybrids (cell lines with identical nuclei, but mtDNA from either H (n=8) or K (n=8) subjects) were analyzed by the Seahorse flux analyzer, quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry (IHC). Cybrids were treated with amyloid-β peptides and cell viabilities were measured. Other cybrids were demethylated with 5-aza-2'-deoxycytidine (5-aza-dC) and expression levels for APOE and NFkB2 were measured. Results show K cybrids have (a) significantly lower mtDNA copy numbers, (b) higher expression levels for MT-DNA encoded genes critical for oxidative phosphorylation, (c) lower Spare Respiratory Capacity, (d) increased expression of inhibitors of the complement pathway and important inflammasome-related genes; and (e) significantly higher levels of APOE transcription that were independent of methylation status. After exposure to amyloid-β1-42 peptides (active form), H haplogroup cybrids demonstrated decreased cell viability compared to those treated with amyloid-β42-1 (inactive form) (p<0.0001), while this was not observed in the K cybrids (p=0.2). K cybrids had significantly higher total global methylation levels and differences in expression levels for two acetylation genes and four methylation genes. Demethylation with 5-aza-dC altered expression levels for NFkB2, while APOE transcription patterns were unchanged. Our findings support the hypothesis that mtDNA-nuclear retrograde signaling may mediate expression levels of APOE, a key factor in many age-related diseases. Future studies will focus on identification of the mitochondrial-nuclear retrograde signaling

  13. Plasma glucagon-like peptide 1 and peptide YY levels are not altered in symptomatic fructose-sorbitol malabsorption

    DEFF Research Database (Denmark)

    Valeur, Jørgen; Øines, Eliann; Morken, Mette Helvik; Holst, Jens Juul; Berstad, Arnold

    2008-01-01

    excretion and plasma glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) levels were measured during the next 3 h. Both habitual and post-test symptoms were assessed. RESULTS: Malabsorption of fructose and sorbitol was present in 61% of the patients and 73% of the controls. Nevertheless, the patients......OBJECTIVE: Carbohydrate malabsorption causes more symptoms in patients with functional gastrointestinal disorders than in healthy individuals. The purpose of this study was to investigate whether this could be explained by differences in ileal brake hormone secretion. MATERIAL AND METHODS: Eighteen...... consecutive patients with functional abdominal complaints, referred to our clinic for investigation of self-reported food hypersensitivity, were included in the study and compared with 15 healthy volunteers. All subjects ingested a mixture of 25 g fructose and 5 g sorbitol. Pulmonary hydrogen and methane...

  14. Fasting Serum C‐Peptide Levels Predict Cardiovascular and Overall Death in Nondiabetic Adults

    OpenAIRE

    Patel, Nileshkumar; Taveira, Tracey H.; Choudhary, Gaurav; Whitlatch, Hilary; Wu, Wen‐Chih

    2012-01-01

    Background Insulin resistance, characterized by hyperinsulinemia and normal or elevated serum glucose, is an established precursor to diabetes and cardiovascular disease. Despite fasting serum C‐peptide levels being an accurate and stable marker of endogenous insulin production used in patients with diabetes, it is unknown whether C‐peptide could serve as a marker of insulin resistance and predict outcomes in patients without diabetes. Method and Results This is a retrospective cohort study u...

  15. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion

    DEFF Research Database (Denmark)

    Hagemann, Dirk; Holst, Jens Juul; Gethmann, Arnica;

    2007-01-01

    INTRODUCTION: Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion of the...... ghrelin levels 150 and 360 min after meal ingestion (p<0.05). The patterns of ghrelin concentrations in the experiments with GLP-1 and placebo administration were inversely related to the respective plasma levels of insulin and C-peptide. CONCLUSIONS: GLP-1 reduces the rise in ghrelin levels in the late...... meal was served. Venous blood was drawn frequently for the determination of glucose, insulin, C-peptide, GLP-1 and ghrelin. RESULTS: During the infusion of exogenous GLP-1 and placebo, GLP-1 plasma concentrations reached steady-state levels of 139+/-15 pmol/l and 12+/-2 pmol/l, respectively (p<0...

  16. β-淀粉样蛋白25-35致伤对PC12神经元突触相关蛋白表达的影响%Effects of amyloid-beta 25-35 on expression of synapse-associated proteins in PC12 neurons Effects of amyloid-beta 25-35 on expression of synapse-associated proteins in PC12 neurons

    Institute of Scientific and Technical Information of China (English)

    张爽; 黄昕艳; 刘爽; 李艳君; 赵锦程

    2016-01-01

    背景:脑内β-淀粉样蛋白的聚集可诱导神经细胞凋亡,大量神经元及突触的缺失和功能的损害尚无有效的干预手段,提高突触可塑性为治疗早期阿尔茨海默病提供重要方向。目的:筛选最佳的阿尔茨海默病模型,检测β-淀粉样蛋白25-35致伤PC12神经元的突触相关蛋白表达。方法:采用50μg/L神经生长因子诱导PC12细胞分化为神经元样细胞,以不同浓度β-淀粉样蛋白25-35致伤PC12神经元样细胞。应用CCK8法检测细胞生存率。神经颗粒素、神经调节素免疫荧光染色观察模型细胞的形态学变化,Western blot法检测神经颗粒素、CAMKⅡ、PSD-95蛋白表达水平。结果与结论:随着β-淀粉样蛋白25-35浓度增高和作用时间的延长,PC12神经元生存率呈剂量依赖性降低;可见突触长度变短、神经元萎缩、神经元彼此连接疏松;神经颗粒素、CAMK Ⅱ、PSD-95蛋白表达均下调。结果提示,10μmol/Lβ-淀粉样蛋白25-35、48 h是筛选早期PC12神经元阿尔茨海默病细胞模型的最佳干预浓度和时间。%BACKGROUND:An amyloid-beta (Aβ) aggregation in the brain can induce nerve cel apoptosis, loss of synapses and functional damage. However, there is stil no effective intervention. Improving the synaptic plasticity provides an important direction for the treatment of early Alzheimer’s disease. OBJECTIVE: To screen the best model of Alzheimer’s disease and to explore the expression of synapse-associated proteins in Aβ25-35-injured PC12 neurons. METHODS:PC12 cels were induced by 50 μg/L nerve growth factor to differentiate into neuronal-like cels. Then, these cels were treated with Aβ25-35 at different concentrations. Consequently, cel survival rate was detected using cel counting kit-8; neurogranin and neuregulin immunofluorescence stainings were used to observe morphological changes of model cels; western blot used to detect the expression level of

  17. Neurohypophyseal peptide levels in CSF and plasma during passive avoidance behavior in rats

    NARCIS (Netherlands)

    Mens, W.B.J.; Egmond, M.A.H. van; Rotte, A.A. de; Wimersma Greidanus, T.B. van

    1982-01-01

    Levels of vasopressin (AVP), oxytocin (OXT), and neurophysin (NP) in CSF and plasma of rats were determined during acquisition and retention of passive avoidance behavior. None of the levels of neurohypophyseal peptides in CSF were changed either during the adaptation period, or during acquisition o

  18. Effect of Curcumin on the metal ion induced fibrillization of Amyloid-β peptide

    Science.gov (United States)

    Banerjee, Rona

    2014-01-01

    The effect of Curcumin on Cu(II) and Zn(II) induced oligomerization and protofibrillization of the amyloid-beta (Aβ) peptide has been studied by spectroscopic and microscopic methods. Curcumin could significantly reduce the β-sheet content of the peptide in a time dependent manner. It also plays an antagonistic role in β-sheet formation that is promoted by metal ions like Cu(II) and Zn(II) as observed by Circular Dichroism (CD) spectroscopy. Atomic force microscopic (AFM) images show that spontaneous fibrillization of the peptide occurs in presence of Cu(II) and Zn(II) but is inhibited on incubation of the peptide with Curcumin indicating the beneficial role of Curcumin in preventing the aggregation of Aβ peptide.

  19. Optimization of heavy chain and light chain signal peptides for high level expression of therapeutic antibodies in CHO cells.

    Directory of Open Access Journals (Sweden)

    Ryan Haryadi

    Full Text Available Translocation of a nascent protein from the cytosol into the ER mediated by its signal peptide is a critical step in protein secretion. The aim of this work was to develop a platform technology to optimize the signal peptides for high level production of therapeutic antibodies in CHO cells. A database of signal peptides from a large number of human immunoglobulin (Ig heavy chain (HC and kappa light chain (LC was generated. Most of the HC signal peptides contain 19 amino acids which can be divided into three domains and the LC signal peptides contain 22 amino acids. The signal peptides were then clustered according to sequence similarity. Based on the clustering, 8 HC and 2 LC signal peptides were analyzed for their impacts on the production of 5-top selling antibody therapeutics, namely, Herceptin, Avastin, Remicade, Rituxan, and Humira. The best HC and LC signal peptides for producing these 5 antibodies were identified. The optimized signal peptides for Rituxan is 2-fold better compared to its native signal peptides which are available in the public database. Substitution of a single amino acid in the optimized HC signal peptide for Avastin reduced its production significantly. Mass spectrometry analyses revealed that all optimized signal peptides are accurately removed in the mature antibodies. The results presented in this report are particularly important for the production of these 5 antibodies as biosimilar drugs. They also have the potential to be the best signal peptides for the production of new antibodies in CHO cells.

  20. Optimization of heavy chain and light chain signal peptides for high level expression of therapeutic antibodies in CHO cells.

    Science.gov (United States)

    Haryadi, Ryan; Ho, Steven; Kok, Yee Jiun; Pu, Helen X; Zheng, Lu; Pereira, Natasha A; Li, Bin; Bi, Xuezhi; Goh, Lin-Tang; Yang, Yuansheng; Song, Zhiwei

    2015-01-01

    Translocation of a nascent protein from the cytosol into the ER mediated by its signal peptide is a critical step in protein secretion. The aim of this work was to develop a platform technology to optimize the signal peptides for high level production of therapeutic antibodies in CHO cells. A database of signal peptides from a large number of human immunoglobulin (Ig) heavy chain (HC) and kappa light chain (LC) was generated. Most of the HC signal peptides contain 19 amino acids which can be divided into three domains and the LC signal peptides contain 22 amino acids. The signal peptides were then clustered according to sequence similarity. Based on the clustering, 8 HC and 2 LC signal peptides were analyzed for their impacts on the production of 5-top selling antibody therapeutics, namely, Herceptin, Avastin, Remicade, Rituxan, and Humira. The best HC and LC signal peptides for producing these 5 antibodies were identified. The optimized signal peptides for Rituxan is 2-fold better compared to its native signal peptides which are available in the public database. Substitution of a single amino acid in the optimized HC signal peptide for Avastin reduced its production significantly. Mass spectrometry analyses revealed that all optimized signal peptides are accurately removed in the mature antibodies. The results presented in this report are particularly important for the production of these 5 antibodies as biosimilar drugs. They also have the potential to be the best signal peptides for the production of new antibodies in CHO cells. PMID:25706993

  1. Comparison of the effects of pantethine and fursultiamine on plasma gastrointestinal peptide levels in healthy volunteers.

    Science.gov (United States)

    Suzuki, Yosuke; Itoh, Hiroki; Abe, Tomohide; Nishimura, Fumihiro; Sato, Yuhki; Takeyama, Masaharu

    2011-01-01

    Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal obstruction. In recent years, the actions of drugs used to treat gastrointestinal diseases have been elucidated pharmacologically from the viewpoints of gastrointestinal peptide levels. We examined the effects of pantethine and fursultiamine on plasma levels of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, motilin- and substance P (SP)-like immunoreactive substances (IS) in healthy subjects. An open-labeled study was conducted on five healthy volunteers. Each subject was administered a single oral dose of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 min after each administration. Plasma peptide levels were measured using a highly sensitive enzyme immunoassay. A single oral dose of pantethine resulted in significant increases of plasma CGRP- and VIP-IS levels compared to placebo. Furthermore, areas under the plasma concentration-time curves (AUC(0-240)) of CGRP- and VIP-IS were significantly higher after pantethine administration compared with placebo. On the other hand, fursultiamine had no effect on plasma levels and AUC(0-240) of CGRP-, VIP-, motilin- and SP-IS. This study demonstrated the different effects of pantethine and fursultiamine from the viewpoint of plasma gastrointestinal peptide changes. The pharmacological effects of pantethine may be closely related to the changes in plasma CGRP- and VIP-IS levels. PMID:21963510

  2. Type III procollagen peptide and PZ-peptidase serum levels in pre-cirrhotic liver diseases.

    Science.gov (United States)

    Morelli, A; Vedovelli, A; Fiorucci, S; Angelini, G P; Fini, C; Palmerini, C A; Floridi, A

    1985-05-30

    To obtain a dynamic and non-invasive picture of hepatic fibrosis in pre-cirrhotic liver diseases we measured both the concentration of the N-terminal peptide of procollagen III, as a marker of collagen synthesis, and the activity of PZ-peptidase, an enzyme involved in collagen degradation, in the serum of alcoholic or chronic viral hepatitis patients. Peptide serum levels were similar in chronic persistent hepatitis and controls, but significantly higher in chronic active hepatitis. Chronic persistent hepatitis patients had PZ-peptidase levels higher than controls, but similar to chronic active hepatitis. The increase in collagen synthesis without a parallel increase in collagen degradation seen in chronic active hepatitis could be regarded as a sign of impending cirrhosis, whereas the unbalanced rise in PZ-peptidase observed in chronic persistent hepatitis is consistent with the non-progressive character of this disorder. In alcoholic hepatitis both peptide concentration and PZ-peptidase activity were elevated, thus suggesting that both collagen synthesis and degradation are activated. However, the greater increase in PZ-peptidase than in peptide serum levels seen in some patients seems to indicate a minor tendency to progressive fibrosis or a trend towards resolution. Unlike liver disease patients, normal peptide and PZ-peptidase levels were found in patients with pancreatic fibrosis. Since circulating inhibitors and activators of the PZ-peptidase activity can be excluded, as proved by this study, joint peptide and PZ-peptidase serum measurements would seem to offer a simple reliable non-invasive method for differentiating and monitoring progressive and non-progressive forms of hepatic fibrosis. PMID:3888456

  3. Neurohypophyseal peptide levels in CSF and plasma during passive avoidance behavior in rats

    OpenAIRE

    Mens, W.B.J.; Egmond, M.A.H. van; Rotte, A.A. de; Wimersma Greidanus, T.B. van

    1982-01-01

    Levels of vasopressin (AVP), oxytocin (OXT), and neurophysin (NP) in CSF and plasma of rats were determined during acquisition and retention of passive avoidance behavior. None of the levels of neurohypophyseal peptides in CSF were changed either during the adaptation period, or during acquisition or the retention of this behavior. Moreover, no differences were found in hormone levels in CSF of the various groups of rats subjected to different shock intensities during the acquisition trial. T...

  4. Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells.

    Science.gov (United States)

    Chng, Jake; Wang, Tianhua; Nian, Rui; Lau, Ally; Hoi, Kong Meng; Ho, Steven C L; Gagnon, Peter; Bi, Xuezhi; Yang, Yuansheng

    2015-01-01

    Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells. Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expression of 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines. HC and LC were linked by different 2A peptides both in the absence and presence of GSG linkers. Insertion of a furin recognition site upstream of 2A allowed removal of 2A residues that would otherwise be attached to the HC. Different 2A peptides exhibited different cleavage efficiencies that correlated to the mAb expression level. The relative cleavage efficiency of each 2A peptide remains similar for expression of different IgG1 mAbs in different CHO cells. While complete cleavage was not observed for any of the 2A peptides, GSG linkers did enhance the cleavage efficiency and thus the mAb expression level. T2A with the GSG linker (GT2A) exhibited the highest cleavage efficiency and mAb expression level. Stably amplified CHO DG44 pools generated using GT2A had titers 357, 416 and 600 mg/L for the 3 mAbs in shake flask batch cultures. Incomplete cleavage likely resulted in incorrectly processed mAb species and aggregates, which were removed with a chromatin-directed clarification method and protein A purification. The vector and methods presented provide an easy process beneficial for both mAb development and manufacturing. PMID:25621616

  5. Increased plasma levels and blunted effects of brain natriuretic peptide in rats with congestive heart failure.

    Science.gov (United States)

    Hoffman, A; Grossman, E; Keiser, H R

    1991-07-01

    The hemodynamic and renal effects of brain natriuretic peptide (BNP) were studied in conscious rats with experimental congestive heart failure (CHF) produced by an aortocaval fistula. The peptide had potent hypotensive, diuretic, and natriuretic effects in control rats, all of which were abolished in CHF. Plasma levels of BNP increased time-dependently during the development of CHF, and were more than four-fold higher in sodium retaining rats than in control rats. The data suggest that BNP secretion from the atria is increased in CHF, and that resistance to BNP, in addition to the relative resistance to atrial natriuretic factor, may contribute to sodium retention in CHF. PMID:1831369

  6. A Dynamic Noise Level Algorithm for Spectral Screening of Peptide MS/MS Spectra

    Directory of Open Access Journals (Sweden)

    Xu Hua

    2010-08-01

    Full Text Available Abstract Background High-throughput shotgun proteomics data contain a significant number of spectra from non-peptide ions or spectra of too poor quality to obtain highly confident peptide identifications. These spectra cannot be identified with any positive peptide matches in some database search programs or are identified with false positives in others. Removing these spectra can improve the database search results and lower computational expense. Results A new algorithm has been developed to filter tandem mass spectra of poor quality from shotgun proteomic experiments. The algorithm determines the noise level dynamically and independently for each spectrum in a tandem mass spectrometric data set. Spectra are filtered based on a minimum number of required signal peaks with a signal-to-noise ratio of 2. The algorithm was tested with 23 sample data sets containing 62,117 total spectra. Conclusions The spectral screening removed 89.0% of the tandem mass spectra that did not yield a peptide match when searched with the MassMatrix database search software. Only 6.0% of tandem mass spectra that yielded peptide matches considered to be true positive matches were lost after spectral screening. The algorithm was found to be very effective at removal of unidentified spectra in other database search programs including Mascot, OMSSA, and X!Tandem (75.93%-91.00% with a small loss (3.59%-9.40% of true positive matches.

  7. Alteration of Plasma Brain Natriuretic Peptide Level After Acute Moderate Exercise in Professional Athletes

    OpenAIRE

    Homa Sheikhani; Mohammad Ali Babaee Beygi; Farhad Daryanoosh; Bijan Jafari

    2011-01-01

    Background: Cardiac fatigue or myocardial damage following exercise until complete exhaustion can increase blood levels of brain natriuretic peptide (BNP) in athletes. Objectives: The aim of the present study was to investigate the effect of resistance and acute moderate aerobic exercise on alterations in BNP levels in professional athletes. Materials and Methods: Forty professional athletes who had at least 3 years of a championship background in track and field (aerobic group) or bo...

  8. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-03-05

    ..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

  9. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    International Nuclear Information System (INIS)

    β-endorphin, [met]enkephalin, and [leu]enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO4 or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. β-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; [met]enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; [leu]-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs

  10. Proteasome inhibitors alter levels of intracellular peptides in HEK293T and SH-SY5Y cells.

    Directory of Open Access Journals (Sweden)

    Sayani Dasgupta

    Full Text Available The proteasome cleaves intracellular proteins into peptides. Earlier studies found that treatment of human embryonic kidney 293T (HEK293T cells with epoxomicin (an irreversible proteasome inhibitor generally caused a decrease in levels of intracellular peptides. However, bortezomib (an antitumor drug and proteasome inhibitor caused an unexpected increase in the levels of most intracellular peptides in HEK293T and SH-SY5Y cells. To address this apparent paradox, quantitative peptidomics was used to study the effect of a variety of other proteasome inhibitors on peptide levels in HEK293T and SH-SY5Y cells. Inhibitors tested included carfilzomib, MG132, MG262, MLN2238, AM114, and clasto-Lactacystin β-lactone. Only MG262 caused a substantial elevation in peptide levels that was comparable to the effect of bortezomib, although carfilzomib and MLN2238 elevated the levels of some peptides. To explore off-target effects, the proteosome inhibitors were tested with various cellular peptidases. Bortezomib did not inhibit tripeptidyl peptidase 2 and only weakly inhibited cellular aminopeptidase activity, as did some of the other proteasome inhibitors. However, potent inhibitors of tripeptidyl peptidase 2 (butabindide and cellular aminopeptidases (bestatin did not substantially alter the peptidome, indicating that the increase in peptide levels due to proteasome inhibitors is not a result of peptidase inhibition. Although we cannot exclude other possibilities, we presume that the paradoxical increase in peptide levels upon treatment with bortezomib and other inhibitors is the result of allosteric effects of these compounds on the proteasome. Because intracellular peptides are likely to be functional, it is possible that some of the physiologic effects of bortezomib and carfilzomib arise from the perturbation of peptide levels inside the cell.

  11. Rabeprazole's influence on duodenal ulcer patients' serum levels of gastrointestinal peptide hormone and neurotransmitter

    Institute of Scientific and Technical Information of China (English)

    Xiao-Chun Zhong; Hong-Yan Duan; Wang-Qiong Xu

    2015-01-01

    Objective:To observe the effects of rabeprazole of duodenal ulcer, and its influence on the serum levels of gastrointestinal peptide hormone and neurotransmitter.Methods:180 patients with duodenal ulcer were randomly divided into control group and observation group, each group had 90 cases, patients in control group were given routine treatment, and those in observation group were treated with rabeprazole 20 mg/time, 2 times/d, treatment for 4 weeks based on routine treatment. Then gastroscopy and 14C- urea breath test were took before and after treatment for comparison of efficacy between the two groups, and the serum levels of gastrointestinal hormone such as gastrin (Gas), motilin (MTL), somatostatin (SS) and calcitonin gene related peptide (CGRP) and neurotransmitter such as 5- serotonin (5-HT), substance P (SP), nitric oxide (NO), vasoactive intestinal peptide (VIP) of two groups before and after treatment were detected and compared.Results:3, 5 weeks after treatment, the stomach integral of observation group was lower than that of the control group, stomach pain relief time was shorter than control group, Hp eradication rate was higher than control group, and the curative effect of observation group was significantly better than the control group. 3, 5 weeks after treatment, the serum levels of Gas, AM, MTL and 5-HT, SP, NO, VIP level of observation group were significantly lower than that of the control group, while the SS and CGRP were higher than the control group.Conclusion:Rabeprazole can effectively regulate the expression of gastrointestinal peptide hormone and neurotransmitter of patients with duodenal ulcer, shorten the recovery time and improve the curative effect.

  12. Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers

    DEFF Research Database (Denmark)

    Kruuse, C; Iversen, Helle Klingenberg; Jansen-Olesen, I; Edvinsson, L; Olesen, J

    2010-01-01

    calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers...

  13. Changes of serum leptin and c-peptide level in children with type 1 diabetic mellitus

    International Nuclear Information System (INIS)

    To deplore the relationship between leptin and c-peptide in children with type 1 diabetic mellitus (DM). The levels of serum leptin and c-peptide (C-P) in 65 type 1 DM children (including 31 before and after insulin treatment) and 30 normal controls were measured by radioimmunoassay (RIA). The results found that there was significant differences (P < 0.01) in leptin and C-P between DM children and normal controls, also in 31 DM children before and after treatment. It showed a positive correlation between leptin and C-P. The changes of the leptin/C-P ratio in DM children compared with normal controls and that before and after treatment were also significantly different. It suggested that leptin may have close relationship in the development, progress and the occurrence of complications in children with DM and also provide a new clue for their diagnosis treatment and complication occurrence

  14. Study on the relationship between fasting blood sugar and GH, C-peptide levels in patients with DM2

    International Nuclear Information System (INIS)

    Objective: To investigate the relationship between fasting blood sugar (FBG) and growth hormone (GH), C-peptide (CP) levels in patients with type II diabetes mellitus (DM2). Methods: Serum fasting glucose (with biochemical method) GH, C-peptide (with RIA) levels were measured in 64 patients with DM2 and 31 controls. Results: In the 64 patients, 40 were relatively well-controlled (FBG <9.0mmol/L) and 24 were relatively poorly-controlled (FBG ≥ 9.0mmol/L), The serum GH levels in the poorly controlled group were significantly higher than those in the well-controlled group (P<0.01), which, in turn, were significantly higher than those in the controls (P<0.01). The reverse was exactly true for the C-peptide levels. Conclusion: The higher GH and lower C-peptide levels might be a contributory, cause of the inadequate control in these patients. (authors)

  15. Insulin and C peptide response, and antibody levels in hepatitis C related chronic liver disease

    International Nuclear Information System (INIS)

    Objective: Patients with cirrhosis due to hepatitis C (HC) have an increased prevalence of diabetes mellitus. The pathogenic mechanism by which HC predisposes to DM is not clear. The objective of this study was to determine the insulin and C-peptide response to 75 gram oral glucose load and measure anti phospholipid antibody levels in patients with chronic liver disease due to HC. Design: a prospective study. Place and duration of study: This study was conducted at the department of medicine, Jinnah postgraduate medical centre over period of three months. Subjects and methods: An analytical case control study was carried out on 37 patients (m-18,f=19); none of these patients had received interferon. They were divided into four groups: (a) HC cirrhosis with DM (n=9 ), (b) HC cirrhosis without DM (n=11), (c) hepatitis B (HB) cirrhosis without DM (n=7), (d) chronic hepatitis C without DM (n=10). Group C and D were taken as controls. Fasting blood samples were taken and repeated after 2 hours of 75 gram oral glucose load (2 h PG). Result: mean ages of group A,B,C and D were (yr +- SD) 51.3 +- 7.6,48.9 +- 2.4, 33.7 +-10.8 and 31.7 +- 8.8 respectively. There was no statistically significant difference in the age, Pugh score and body mass index of HC cirrhotic patients with and without DM. Patients of group A had higher fasting and 2 h PG glucose levels (P=0.003 and 0.000) and higher fasting insulin level (p=0.045). However, increments in insulin and c peptide levels 2 h PG were much less (p=0.048 and 0.003). HB cirrhotics without diabetes (group C behaved just like HC cirrhotic without diabetes (group B). Patients of group D had normal glucose tolerance and insulin and C peptide levels. All four groups had normal anti phospholipid antibody levels. Conclusion: Patients with cirrhosis due to HC nd HB show evidence of glucose intolerance in spite of hyperinsulinaemia probably due to insulin resistance. HC cirrhotics with diabetes have fasting hyperglycemia in spite of

  16. Mo polyoxometalate nanoclusters capable of inhibiting the aggregation of Aβ-peptide associated with Alzheimer's disease

    Science.gov (United States)

    Chen, Qingchang; Yang, Licong; Zheng, Chuping; Zheng, Wenjing; Zhang, Jingnan; Zhou, Yunshan; Liu, Jie

    2014-05-01

    A neuropathological hallmark of Alzheimer's disease (AD) is aggregation of a forty-residue peptide known as amyloid beta forty (Aβ40). While past work has indicated that blocking Aβ40 aggregation could be an effective strategy for the treatment of AD, developing therapies with this goal has been met with limited success. Polyoxometalates (POMs) have been previously investigated for their anti-viral and anti-tumoral properties and we report here that three representative POM nanoclusters have been synthesized for use against Aβ40 aggregation. Through the use of thioflavin T fluorescence, turbidity, circular dichroism spectroscopy, and transmission electron microscopy (TEM), we found that all three POM complexes can significantly inhibit both natural Aβ40 self-aggregation and metal-ion induced Aβ40 aggregation. We also evaluated the protective effect of POM complexes on Aβ40-induced neurotoxicity in cultured PC12 cells and found that treatment with POM complexes can elevate cell viability, decrease levels of intracellular reactive oxygen species, and stabilize mitochondrial membrane potential. These findings indicate that all three representative POM complexes are capable of inhibiting Aβ40 aggregation and subsequent neurotoxicity. While a complete mechanistic understanding remains to be elucidated, the synthesized POM complexes may work through a synergistic interaction with metal ions and Aβ40. These data indicate that POM complexes have high therapeutic potential for use against one of the primary neuropathological features of AD.A neuropathological hallmark of Alzheimer's disease (AD) is aggregation of a forty-residue peptide known as amyloid beta forty (Aβ40). While past work has indicated that blocking Aβ40 aggregation could be an effective strategy for the treatment of AD, developing therapies with this goal has been met with limited success. Polyoxometalates (POMs) have been previously investigated for their anti-viral and anti-tumoral properties

  17. Restraint stress and repeated CRF receptor activation in the amygdala both increase amyloid β precursor protein (APP) and amyloid-β (Aβ) peptide but have divergent effects on BDNF and pre-synaptic proteins in the prefrontal cortex of rats

    OpenAIRE

    Ray, Balmiki; Gaskins, Denise L.; Sajdyk, Tammy J.; Spence, John P.; Fitz, Stephanie D.; Shekhar, Anantha; Lahiri, Debomoy K.

    2011-01-01

    Both environmental stress and anxiety may represent important risk factors for Alzheimer's disease (AD) pathogenesis. Previous studies demonstrate that restraint stress is associated with increased amyloid beta (Aβ) and decreased brain-derived neurotrophic factor (BDNF) levels in the brain. Aβ deposition, synaptic loss, and neurodegeneration define major hallmarks of AD, and BDNF is responsible for the maintenance of neurons. In contrast to restraint stress, repeated injections of sub-anxioge...

  18. Low plasma levels of brain natriuretic peptide in severe acute heart failure: merely a case?

    Science.gov (United States)

    Brentana, Loretta; Temporelli, Pier Luigi; Corrà, Ugo; Gattone, Marinella; Pistono, Massimo; Imparato, Alessandro; Gnemmi, Marco; Giannuzzi, Pantaleo

    2007-11-30

    Brain natriuretic peptide (BNP) is commonly used for diagnosis and prognosis of patients with congestive heart failure (HF). High levels of BNP are associated with high probability of cardiogenic dyspnea and higher risk of subsequent cardiovascular events. We describe a case of acute HF (worsening chronic HF) in a 74-year-old male with low plasma BNP levels on admission, in whom a rapid and consistent increase in the marker's concentration occurred after administration of diuretics and vasodilators, despite a prompt clinical and hemodynamic improvement. Reports of cardiogenic dyspnea with moderate increase or normal plasma levels of BNP have been recently published: does this signify a pitfall for BNP as a useful diagnostic and prognostic tool? Clinical implications of our observation are discussed, and we conclude that neurohumoral biomarkers do not obviate the need for a careful physical and instrumental examination of patient. PMID:17382416

  19. Levels of circulating peptide and steroid hormones in men with lung cancer

    International Nuclear Information System (INIS)

    Levels of circulating peptide (FSH, LH, prolactin, ACTH, calcitonin, gastrin and insulin-like growth factor-1 [IGF-1]) and steroid (estradiol, progesterone, DHEA-S and testosterone)hormones were estimated by radioimmunoassay (RIA) and immunoradiometric assay (IRMA) in male patients with lung cancer (n=37) pre-therapeutically and compared with 25 age matched healthy controls. In this retrospective study, FSH, LH, prolactin, ACTH, calcitonin, gastrin and IGF-1 were significantly higher with concomitant lower levels of DHEA-S and testosterone, while the difference was statistically non-significant for estradiol and progesterone in patients with lung cancer when compared with controls. Early stage patients (Stage II) exhibited higher levels of gastrin as compared to advanced stage patients (Stages III and IV). It is suggested that hormonal imbalance might play an important role in the development and progression in male patients with lung cancer. (author)

  20. Measurement of insulin and C-peptide excitatory test levels in gestational diabetes mellitus

    International Nuclear Information System (INIS)

    To investigate the function of islet β cells in patients with gestational diabetes mellitus (GDM), serum insulin and C-peptide (C-P) excitatory test levels were measured dynamically by radioimmunoassay in 41 patients with GDM and 30 normal pregnant controls. The results showed that there were significant difference in insulin and C-peptide excitatory test levels between normal pregnancy for 32-40 weeks and patients with GDM (P < 0.001). The secretory peak of insulin occurred at 60 min in normal pregnancy, while at 120 min in patients with GDM, and the recovery postponed in patients with GDM. The peak time for C-P was just as same as that of insulin, but the peak error for C-P between normal pregnant controls and patients with GDM was more larger than that for insulin and it recovered more slowly. It suggested that majority of islet β cells in patients with GDM were good enough for response to islet resistance factors and big stress from pregnancy, and also suggested a relation between pregnancy and islet β cells function

  1. Associates of an Elevated Natriuretic Peptide Level in Stable Heart Failure Patients: Implications for Targeted Management

    Directory of Open Access Journals (Sweden)

    Aftab Jan

    2013-01-01

    Full Text Available Background. Persistently elevated natriuretic peptide (NP levels in heart failure (HF patients are associated with impaired prognosis. Recent work suggests that NP-guided therapy can improve outcome, but the mechanisms behind an elevated BNP remain unclear. Among the potential stimuli for NP in clinically stable patients are persistent occult fluid overload, wall stress, inflammation, fibrosis, and ischemia. The purpose of this study was to identify associates of B-type natriuretic peptide (BNP in a stable HF population. Methods. In a prospective observational study of 179 stable HF patients, the association between BNP and markers of collagen metabolism, inflammation, and Doppler-echocardiographic parameters including left ventricular ejection fraction (LVEF, left atrial volume index (LAVI, and E/e prime (E/e′ was measured. Results. Univariable associates of elevated BNP were age, LVEF, LAVI, E/e′, creatinine, and markers of collagen turnover. In a multiple linear regression model, age, creatinine, and LVEF remained significant associates of BNP. E/e′ and markers of collagen turnover had a persistent impact on BNP independent of these covariates. Conclusion. Multiple variables are associated with persistently elevated BNP levels in stable HF patients. Clarification of the relative importance of NP stimuli may help refine NP-guided therapy, potentially improving outcome for this at-risk population.

  2. Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Sung-Tae Kim

    2011-02-01

    Full Text Available BackgroundRecent studies have revealed that C-peptide induces smooth muscle cell proliferation and causes human atherosclerotic lesions in diabetic patients. The present study was designed to examine whether the basal C-peptide levels correlate with cardiovascular risk in type 2 diabetes mellitus (T2DM patients.MethodsData was obtained from 467 patients with T2DM from two institutions who were followed for four years. The medical findings of all patients were reviewed, and patients with creatinine >1.4 mg/dL, any inflammation or infection, hepatitis, or type 1 DM were excluded. The relationships between basal C-peptide and other clinical values were statistically analyzed.ResultsA simple correlation was found between basal C-peptide and components of metabolic syndrome (MS. Statistically basal C-peptide levels were significantly higher than the three different MS criteria used in the present study, the Adult Treatment Panel III (ATP III of the National Cholesterol Education Program's (NCEP's, World Health Organization (WHO, and the International Diabetes Federation (IDF criteria (NCEP-ATP III, P=0.001; IDF, P<0.001; WHO, P=0.029. The multiple regression analysis between intima-media thickness (IMT and clinical values showed that basal C-peptide significantly correlated with IMT (P=0.043, while the analysis between the 10-year coronary heart disease risk by the United Kingdom Prospective Diabetes Study risk engine and clinical values showed that basal C-peptide did not correlate with IMT (P=0.226.ConclusionBasal C-peptide is related to cardiovascular predictors (IMT of T2DM, suggesting that basal C-peptide does provide a further indication of cardiovascular disease.

  3. Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients

    OpenAIRE

    Sung-Tae Kim; Byung-Joon Kim; Dong-Mee Lim; In-Geol Song; Jang-Han Jung; Kang-Woo Lee; Keun-Young Park; Youn-Zoo Cho; Dae-Ho Lee; Gwan-Pyo Koh

    2011-01-01

    Background Recent studies have revealed that C-peptide induces smooth muscle cell proliferation and causes human atherosclerotic lesions in diabetic patients. The present study was designed to examine whether the basal C-peptide levels correlate with cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. Methods Data was obtained from 467 patients with T2DM from two institutions who were followed for four years. The medical findings of all patients were reviewed, and patients with c...

  4. Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Shu Meguro

    2014-01-01

    Full Text Available Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n=133, 115 men and 18 women; age 64.7±11.5 years; HbA1c 8.1±1.6%. Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2±22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r=−0.450, P<0.01, triglyceride (r=0.445, P<0.01, and high sensitive C-reactive protein (r=0.316, P<0.01 but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (β=−0.411, P<0.01 and high sensitive C-reactive protein (β=0.193, P<0.05. Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus.

  5. Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.

    Science.gov (United States)

    Souza, Leandro Cattelan; Jesse, Cristiano R; Antunes, Michelle S; Ruff, Jossana Rodrigues; de Oliveira Espinosa, Dieniffer; Gomes, Nathalie Savedra; Donato, Franciele; Giacomeli, Renata; Boeira, Silvana Peterini

    2016-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aβ1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aβ-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aβ-induced neuroinflammation. PMID:26965653

  6. Expresssion of bax/bcl-xl by low-power laser irradiation in the Amyloid Beta 25-35 induced apoptosis of PC12 cell

    Science.gov (United States)

    Zhang, Lan; Xing, Da

    2006-09-01

    Apoptosis has been reported as a contributing pathophysiological mechanism of Alzheimer's disease (AD). Recently, the anti-apoptosis function of low-power laser irradiation (LPLI) was proposed, suggesting LPLI may become a new means for AD therapy. In this study, we aimed to demonstrate the anti-apoptosis function of LPLI at molecular level. Aβ 25-35 was used to induce apoptosis of PC12 cell, and then the cells were dealt with LPLI. After irradiation, the molecular level of apoptosis was detected by quantifying the bax I bcl-xl mRNA ratio using a highly sensitive and quantitative polymerase chain reaction (QT-PCR) technique. The primary results show that the bax Ibcl-xl mRNA ratio of the PC12 cell treated with Aβ 25-35 was decreased by LPLI, demonstrating the anti-apoptosis function of LPLI at molecular level.

  7. Changes of Plasma Levels of Brain Natriuretic Peptide in Patients with Chronic Heart Failure

    Institute of Scientific and Technical Information of China (English)

    Pei Xiaoyang; Pan Ying; Hu Xuesong; Li Song; Xu Yawei; Yu Xuejing

    2006-01-01

    Objectives To investigate the changes of plasma brain natriuretic peptide (BNP) levels in patients with chronic heart failure (CHF).Methods Plasma BNP concentrations in patients with CHF (n=56) and in normal controls (n=60) were measured with specific radioimmunoassay. Left ventricular ejection fraction in patients with chronic heart failure was measured with 99mTc gated cardiac blood pool scintigraphy. Results The results showed that Plasma BNP concentrations in patients with CHF were significantly higher than normal controls (223±79 ng/L vs 40±15 ng/L, P < 0.01). Plasma BNP concentrations had a significant negative correlation with left ventricular ejection fractions(r=-0.68, P <0.01 ). Conclusions These results indicates that Plasma BNP levels are increased in patients with CHF, and they markedly increased according to the severity of heart failure classified by NYHA classification. The plasma BNP levels may be a biochemical parameter for evaluating the left ventricular function.

  8. Alteration of Plasma Brain Natriuretic Peptide Level After Acute Moderate Exercise in Professional Athletes

    Directory of Open Access Journals (Sweden)

    Homa Sheikhani

    2011-12-01

    Full Text Available Background: Cardiac fatigue or myocardial damage following exercise until complete exhaustion can increase blood levels of brain natriuretic peptide (BNP in athletes. Objectives: The aim of the present study was to investigate the effect of resistance and acute moderate aerobic exercise on alterations in BNP levels in professional athletes. Materials and Methods: Forty professional athletes who had at least 3 years of a championship background in track and field (aerobic group or body building (resistance group volunteered to participate in the present study. Track and field athletes (n = 20 were requested to run 8 km at 60% to 70% of maximum heart rate. Body building athletes (n = 20 performed a resistance training session of 5 exercises in 3 sets of 10 repetitions at 75% of 1 RM (bench press, seated row, leg extension, leg curl, and leg press. Before and immediately after the exercise, plasma BNP levels of both groups of athletes were measured by PATHFASTTM NT-proBNP assay, an immunochemiluminescent assay using two polyclonal antibodies in sandwich test format, on a PATHFASTTM automated analyzer. Results: Plasma BNP levels immediately following exercise increased significantly as compared with baseline values. Plasma BNP concentrations in the aerobic group were significantly higher than in the resistance group before and after exercise. Moreover, the increase in mean BNP concentrations in aerobic athletes was 7 times more than in resistance athletes. Conclusions: BNP levels in athlete who performed distance exercises increased significantly compared with resistance training. Possibly exercise program type, intensity of exercise, volume of exercise program, and field sport can be factors of changes in BNP levels

  9. Amyloid beta(1-40-induced astrogliosis and the effect of genistein treatment in rat: a three-dimensional confocal morphometric and proteomic study.

    Directory of Open Access Journals (Sweden)

    Maryam Bagheri

    Full Text Available Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy and proliferation of astrocytes. Here, we performed 3D confocal microscopy to evaluate the morphological response of reactive astrocytes positive for glial fibrillary acidic protein (GFAP in rats, to the presence of Aβ(1-40 in the rat brain before and after treatment with genistein. In 50 astrocytes per animal, we measured the volume and surface area for the nucleus, cell body, the entire cell, the tissue covered by single astrocytes and quantified the number and length of branches, the density of the astrocytes and the intensity of GFAP immunoreactivity. Injecting Aβ(1-40 into the brain of rats caused astrogliosis indicated by increased values for all measured parameters. Mass spectrometric analysis of hippocampal tissue in Aβ(1-40-injected brain showed decreased amounts of tubulins, enolases and myelin basic protein, and increased amounts of dihydropyrimidinase-related protein 2. In Aβ(1-40-injected rats pretreated with genistein, GFAP intensity was decreased to the sham-operated group level, and Aβ(1-40-induced astrogliosis was significantly ameliorated.

  10. Successful adjuvant-free vaccination of BALB/c mice with mutated amyloid β peptides

    Directory of Open Access Journals (Sweden)

    Wahi Monika M

    2008-02-01

    Full Text Available Abstract Background A recent human clinical trial of an Alzheimer's disease (AD vaccine using amyloid beta (Aβ 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants. The development of a vaccine with mutant Aβ peptides that avoids the use of an adjuvant may result in an effective and safer human vaccine. Results All peptides tested showed high antibody responses, were long-lasting, and demonstrated good memory response. Epitope mapping indicated that peptide mutation did not lead to epitope switching. Mutant peptides induced different inflammation responses as evidenced by cytokine profiles. Ig isotyping indicated that adjuvant-free vaccination with peptides drove an adequate Th2 response. All anti-sera from vaccinated mice cross-reacted with human Aβ in APP/PS1 transgenic mouse brain tissue. Conclusion Our study demonstrated that an adjuvant-free vaccine with different Aβ peptides can be an effective and safe vaccination approach against AD. This study represents the first report of adjuvant-free vaccines utilizing Aβ peptides carrying diverse mutations in the T-cell epitope. These largely positive results provide encouragement for the future of the development of human vaccinations for AD.

  11. Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men

    DEFF Research Database (Denmark)

    Nathanson, D; Zethelius, B; Berne, C;

    2011-01-01

    Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest....

  12. Peptide YY (PYY) Levels and Bone Mineral Density (BMD) in Women with Anorexia Nervosa

    Science.gov (United States)

    Utz, Andrea L.; Lawson, Elizabeth A.; Misra, Madhusmita; Mickley, Diane; Gleysteen, Suzanne; Herzog, David B.; Klibanski, Anne; Miller, Karen K.

    2008-01-01

    Introduction Anorexia nervosa is a psychiatric illness that results in significant bone loss. Studies examining the neuroendocrine dysregulation that occurs in AN may increase understanding of endocrine systems that regulate bone mass. PYY is an anorexigenic peptide derived primarily from the intestine, with actions mediated via activation of Y-receptors. We have previously shown that PYY levels are elevated in adolescents with AN. Y2 receptor knockout mice have increased bone mineral density (BMD) and thus PYY may play a role in regulating bone mass. We hypothesized that PYY levels would be inversely associated with BMD in women with AN. Methods This was a cross-sectional study performed in a General Clinical Research Center of 12 adult women with AN, (mean ± SEM) mean age 30.9 ± 1.8 years, BMI 17.1 ± 0.4 kg/m2, and % ideal body weight 77.5 ± 1.7%. PYY concentrations were measured hourly from 20:00 h to 08:00 h. BMD was measured using dual x-ray absorptiometry (DXA). Results In women with AN, mean overnight PYY levels strongly inversely correlated with BMD at the PA spine (r = −0.77, p = 0.003), lateral spine (r = −0.82, p = 0.002), total hip (r = −0.75, p = 0.005), femoral neck (r = −0.72, p = 0.009), total radius (r = −0.72, p = 0.009) and 1/3 distal radius (r = −0.81, p = 0.002). Body mass index was inversely correlated with PYY level (r = −0.64, p = 0.03). Multivariate stepwise regression analysis was performed to determine the contribution of age, duration of AN, BMI, fat-free mass, and PYY to BMD. For PA and lateral spine, PYY was the primary determinant of BMD, accounting for 59% and 67% of the variability, respectively. Fat-free mass and duration of anorexia nervosa were the primary determinants of BMD at other skeletal sites. Conclusions In women with anorexia nervosa, an elevated PYY level is strongly associated with diminished BMD, particularly at the spine. Therefore further investigation of the hypothesis that PYY may contribute to

  13. Levels of 17beta-Hydroxysteroid Dehydrogenase Type 10 in Cerebrospinal Fluid of People with Mild Cognitive Impairment and Various Types of Dementias

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Říčný, J.; Vyhnálek, M.; Hort, J.; Laczó, J.; Šírová, J.; Klaschka, Jan; Řípová, D.

    2015-01-01

    Roč. 48, č. 1 (2015), s. 105-114. ISSN 1387-2877 R&D Projects: GA ČR(CZ) GBP304/12/G069 Grant ostatní: GA MŠk(CZ) ED2.1.00/03.0078; Prague Psychiatric Center (CZ) MH CZ–DRO: 00023752 Institutional support: RVO:67985807 Keywords : 17beta-HSD10 * Alzheimer’s disease * amyloid-beta peptides * biomarker * cerebrospinal fluid Subject RIV: FH - Neurology Impact factor: 4.151, year: 2014

  14. Interaction between Pirenzepine and Ninjinto, a Traditional Japanese Herbal Medicine, on the Plasma Gut-Regulated Peptide Levels in Humans

    Directory of Open Access Journals (Sweden)

    Yuhki Sato

    2013-01-01

    Full Text Available The Japanese herbal medicine (Kampo Ninjinto has been used for the treatment of gastroenteritis, esogastritis, gastric atony, gastrectasis, vomiting, and anorexia. The pharmacological effects of Ninjinto on the gastrointestine are due to changes in the levels of gut-regulated peptide, such as motilin, somatostatin, calcitonin gene-related peptide (CGRP, substance P, and vasoactive intestinal polypeptide (VIP. The release of these peptides is controlled by acetylcholine (ACh from the preganglionic fibers of the parasympathetic nerve. Thus, we examined the effects of the selective M1 muscarinic receptor antagonist pirenzepine on the elevation of Ninjinto-induced plasma the area under the plasma gut-regulated peptide concentration-time curve from 0 to 240 min ( in humans. Oral pretreatment with pirenzepine significantly reduced the Ninjinto-induced elevation of plasma motilin and substance P release (. Combined treatment with Ninjinto and pirenzepine significantly increased the release of plasma somatostatin ( compared with administration of Ninjinto alone or placebo. Ninjinto appeared to induce the release of substance P and motilin into plasma mainly through the activation of M1 muscarinic receptors, and pirenzepine may affect the pharmacologic action of Ninjinto by the elevation of plasma substance P, motilin, and somatostatin.

  15. Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells

    OpenAIRE

    Chng, Jake; Wang, Tianhua; Nian, Rui; Lau, Ally; Hoi, Kong Meng; Ho, Steven CL; Gagnon, Peter; Bi, Xuezhi; Yang, Yuansheng

    2015-01-01

    Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells. Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expression of 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines. HC and LC ...

  16. Physiological Regulation of Gut Peptide Hormone (PYY) Levels by Age, Sex, Hormonal and Nutritional Status in Rats

    International Nuclear Information System (INIS)

    Peptide YY hormone (PYY) was recently appreciated as an important gut hormonal regulator of appetite. PYY is produced by the gut and released into the circulation after food intake and is found to decrease appetite. The main form of PYY, both stored and circulated, is PYY(3-36), the N-terminal truncated form of the full length peptide so, peripheral injections of PYY(3-36) in rats inhibit food intake in experimental animals as well as in lean and obese human subjects. Also, this hormone has been suggested to be an attractive therapeutic option for obesity. PYY levels are influenced by age and the highest hormone level is achieved in early postnatal life (day 30) and is decreased thereafter. PYY levels were also dependent on thyroid hormone status and being decreased in hyperthyroid rats. The PYY levels observed in acute and chronic food restricted rats indicated that, in situations of decreased energy intake, the lower PYY levels could serve to regulate central pathways and facilitate food intake. Contrary, in pregnant rats, PYY levels were enhanced at late gestation. The aim of this study was to assess the influence of age, sex, thyroid status, pregnancy and food restriction on PYY levels in rats. The underling mechanisms through which PYY levels alternated as a result of sex, age, pregnancy, thyroidal and nutritional status were discussed in the light of recent research outcomes

  17. Relationship between N-terminal probrain natriuretic peptide level and cardiac function in patients with congestive heart failure

    International Nuclear Information System (INIS)

    To study the relationship between N-temrina probarin natriuretic peptide (NT-proBNP) level and cardiac functions in patients with congestive heart failure (CHF), the plasma level of NT-proBNP in 108 patients with CHF and 30 healthy controls were measured by electrochemiluminescence immunoassay (ECLIA) and left ventricular ejection fraction (LVEF) was measured by echocardiography. The results showed that the NT-proBNP level in patients with CHF was significantly higher compared with healthy controls (P<0.01). The NT-proBNP levels increased gradually with NYHA heart function classes increased by degrees (P<0.01). There was negatively correlation between NT-proBNP level and LVEF (r=-0.633, P<0.01). There was a good correlation between the plasma NT-proBNP level and cardiac function. The plasma NT-proBNP level could be as a biochemical marker of cardiac function in CHF patients. (authors)

  18. Effect of sinus rhythm restoration on plasma brain natriuretic peptide (BNP) levels in patients with atrial fibrillation

    International Nuclear Information System (INIS)

    Objective: To study the changes of plasma brain natriuretic peptide (BNP) levels before and after sinus rhythm restoration in patients with paroxysmal or persistent atrial fibrillation (AF) but normal left ventricle function and to explore the role of BNP in AF. Methods: Plasma BNP levels were measured with RIA in 68 patients and 34 controls. Results: Twenty four hours after successful cardioversion, plasma BNP levels decreased significantly in all the patients. The 30 patients with paroxysmal atrial fibrillation were all restored to sinus rhythm and levels of plasma BNP dropped from 96±42pg/ml to 28 ±21pg/ml. Of the 38 patients with persistent atrial fibrillation, 28 of them were restored to sinus rhythm, in whom levels of plasma BNP dropped from 73±38pg/ml to 38±25pg/ml. Conclusion: The presence of AF should be taken into consideration when interpreting plasma BNP levels in patients with heart disease. (authors)

  19. Significance of 111In-DTPA chelate in renal radioactivity levels of 111In-DTPA-conjugated peptides

    International Nuclear Information System (INIS)

    Metabolic studies of 111In-DTPA-labeled polypeptides and peptides showed that the radiolabeled (poly)peptides generated 111In-DTPA-adducts of amino acid that possess long residence times in the lysosomal compartment of the tissues where (poly)peptides accumulated. However, a recent study suggested that metal-chelate-methionine (Met) might possess in vivo behaviors different from metal-chelate adducts of other amino acids. In this study, to elucidate whether some biological characteristics of Met may accelerate the renal elimination rate of 111In-DTPA-adduct of Met into urine, 111In-DTPA-Met1-octreotide was synthesized and the renal handling of 111In-DTPA-Met was investigated using 111In-DTPA-L-Phe1-octreotide (Phe represents phenylalanine), which was reported previously, as a reference. Both 111In-DTPA-conjugated octreotide analogs were stable against 3-h incubation in murine serum at 37 deg. C. Both 111In-DTPA-octreotide analogs also showed rapid clearance of the radioactivity from the blood and similar accumulation of the radioactivity in the kidney. No significant differences were observed in the renal radioactivity levels from 10 min to 24 h postinjection between the two. Metabolic studies indicated that 111In-DTPA-Met1-octreotide and 111In-DTPA-L-Phe1-octreotide generated 111In-DTPA-adducts of Met and Phe, respectively, as the final radiometabolites at similar rates. These findings suggested that the long residence times of the radioactivity in tissues after administration of 111In-DTPA-labeled peptides and polypeptides would be attributed to inherent characteristics of 111In-DTPA chelate

  20. Fast voxel-level dosimetry for 177Lu labelled peptide treatments

    Science.gov (United States)

    Hippeläinen, E.; Tenhunen, M.; Sohlberg, A.

    2015-09-01

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for 177Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions. Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by 177Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared. The photon cross-fire dose from the kidney increased the background’s absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  1. Fast voxel-level dosimetry for 177Lu labelled peptide treatments

    International Nuclear Information System (INIS)

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for 177Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions.Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by 177Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared.The photon cross-fire dose from the kidney increased the background’s absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  2. Mapping the antigenic structure of porcine parvovirus at the level of peptides

    DEFF Research Database (Denmark)

    Kamstrup, Søren; Langeveld, Jan; Bøtner, Anette;

    1998-01-01

    The antigenic structure of the capsid proteins of porcine parvovirus (PPV) was investigated. A total of nine linear epitopes were identified by Pepscan using porcine or rabbit anti-PPV antisera. No sites were identified with a panel of neutralising monoclonal antibodies (MAbs). All epitopes were...... located in the region corresponding to the major capsid protein VP2. Based on this information, and on analogy to other autonomous parvoviruses, 24 different peptides were synthesised, coupled to keyhole limpet haemocyanin (KLH) and used to immunise rabbits. Most antisera were able to bind viral protein...

  3. Increased urine level of amino-terminal peptide derivatives of type III procollagen in patients with liver diseases.

    OpenAIRE

    Koide, Norio; Ukida,Minoru; Kondo, Hideaki; Jitoku,Michihiro; Ono,Ryosaku; Tanabe,Takayoshi; Nagashima,Hideo

    1986-01-01

    The amino-terminal peptides of type III procollagen (PIIIP) in the urine of 40 patients with various liver diseases were determined with a commercial radioimmunoassay kit. The level of urinary PIIIP (uPIIIP) was correlated well with serum PIIIP (sPIIIP) in 9 patients, the coefficient of correlation being r = 0.836 (p less than 0.01) and the regression line being y = 1.42x + 24. Urinary PIIIP consisted of at least 4 different molecular species with molecular weights of 49 k, 18 k, 10 k and 4.6...

  4. Evaluation of Serum Levels of N-terminal Pro Brain Natriuretic Peptide and Atrial Natriuretic Peptide in Neonates with Respiratory Distress

    OpenAIRE

    Noor Mohammad Noori; Sima Savadkoohi; Alireza Teimouri; Fatemeh Alizadeh

    2016-01-01

    Background: Acute respiratory distress (ARD) is a critical respiratory failure due to lung injury of neonates leading to the clinical appearance of poor lung compliance. The aimed of the study was to evaluate the diagnostic values in differentiating respiratory from heart diseases with using of N-terminal pro brain natriuretic peptide (NT-pro BNP) and Atrial natriuretic peptide(ANP) in neonates. Material and Methods: Ninety  neonates  randomly collected from those who hospitalized in the neon...

  5. The potential role of adiponectin- and resistin-like peptides in the regulation of lipid levels in the hemolymph of over-wintering adult females of Osmia bicornis

    OpenAIRE

    Wasielewski, Oskar; Szczepankiewicz, Dawid; Giejdasz, Karol; Wojciechowicz, Tatiana; Bednářová, Andrea; Krishnan, Natraj

    2014-01-01

    The presence and potential role of adiponectin- and resistin-like peptides in mobilizing free lipids of hemolymph during over-wintering was studied in females of the European solitary red mason bee Osmia bicornis L. (Hymenoptera: Megachilidae). The levels of both peptides (as demonstrated both by RIA/ELISA and Western blots) were highest in fat body tissue homogenates during early pre-wintering (September) followed by a gradual and significant decline during wintering and post-wintering month...

  6. Improving protein identification from peptide mass fingerprinting through a parameterized multi-level scoring algorithm and an optimized peak detection.

    Science.gov (United States)

    Gras, R; Müller, M; Gasteiger, E; Gay, S; Binz, P A; Bienvenut, W; Hoogland, C; Sanchez, J C; Bairoch, A; Hochstrasser, D F; Appel, R D

    1999-12-01

    We have developed a new algorithm to identify proteins by means of peptide mass fingerprinting. Starting from the matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) spectra and environmental data such as species, isoelectric point and molecular weight, as well as chemical modifications or number of missed cleavages of a protein, the program performs a fully automated identification of the protein. The first step is a peak detection algorithm, which allows precise and fast determination of peptide masses, even if the peaks are of low intensity or they overlap. In the second step the masses and environmental data are used by the identification algorithm to search in protein sequence databases (SWISS-PROT and/or TrEMBL) for protein entries that match the input data. Consequently, a list of candidate proteins is selected from the database, and a score calculation provides a ranking according to the quality of the match. To define the most discriminating scoring calculation we analyzed the respective role of each parameter in two directions. The first one is based on filtering and exploratory effects, while the second direction focuses on the levels where the parameters intervene in the identification process. Thus, according to our analysis, all input parameters contribute to the score, however with different weights. Since it is difficult to estimate the weights in advance, they have been computed with a generic algorithm, using a training set of 91 protein spectra with their environmental data. We tested the resulting scoring calculation on a test set of ten proteins and compared the identification results with those of other peptide mass fingerprinting programs. PMID:10612280

  7. Correlation of B-type natriuretic peptide levels and echocardiographic parameters in preterm infants with patent ductus arteriosus

    Science.gov (United States)

    Jeong, Hyun Ah; Shin, Jeonghee; Kim, Eunji; Lee, Eun Hee; Son, Chang Sung; Lee, Joo Won

    2016-01-01

    Purpose This study aimed to evaluate the correlation, according to postnatal age, between plasma B-type natriuretic peptide (BNP) levels and echocardiographic parameters for the assessment of patent ductus arteriosus (PDA) in preterm infants with respiratory distress. Methods We enrolled 42 preterm infants with respiratory distress who underwent serial echocardiographic evaluation with simultaneous plasma BNP measurements until ductal closure. The correlations between BNP levels and the following 4 representative echocardiographic parameters were studied: diameter of the ductus arteriosus (DA), ratio of the left atrial diameter to the aortic diameter (LA/Ao), ratio of the PDA diameter to the infant's left pulmonary artery diameter (PDA/LPA), and the antegrade diastolic flow of LPA (DFLPA). Results BNP levels were significantly correlated to the magnitude of the ductal shunt, comprising the DA diameter, PDA/LPA ratio, LA/Ao ratio, and antegrade DFLPA for the overall study period. The earliest significant correlation, starting from postnatal day 2, was observed between the LA/Ao ratio and BNP levels. The PDA/LPA ratio and the antegrade DFLPA showed significant correlations with BNP levels postnatal day 3 onward, and with the DA diameter, postnatal day 5 onward. Conclusion BNP levels and echocardiographic parameters showed a positive correlation, but the significance of the correlations differed according to the postnatal age, especially during the first few days of life. PMID:27186229

  8. Study on clinical value of determination of plasma brain natriuretic peptide levels in patients with chronic congestive heart failure

    International Nuclear Information System (INIS)

    Objective: To evaluate the clinical value of determination of plasma brain natriuretic peptide (BNP) levels in patients with chronic congestive heart failure(CHF). Methods: The levels of plasma BNP were measured with fluorescence immunoassay in 341 patients with chronic CHF and 55 controls. Left ventricular ejection fraction (LVEF), left ventricular end systolic diameter (LVESD) and left ventricular end diastolic diameter (LVEDD) were determined with color doppler ultrasonography in CHF patients. Results: Plasma levels of BNP were significantly increased in patients with CHF as compared with those in controls (P<0.01). There were also significant differences in plasma levels of CHF patients of different clinical stages (P<0.01). There was obvious correlation between plasma levels of BNP and the values of LVEF, LVESD and LVEDD (r was-0.62, +0.54 and +0.60 respectively, P<0.01). Conclusion: Plasma level of BNP is a sensitive indicator for assessment of ventricle function in CHF patients. (authors)

  9. Study on plasma levels of brain natriuretic peptide, angiotensin and aldosterone in patients with congestive heart failure

    International Nuclear Information System (INIS)

    Objective: To investigate the relationship between brain natriuretic peptide (BNP), angiotensin (AT-II), and aldosterone (ALD) levels in patients with congestive heart failure (CHF). Methods: Plasma levels of BNP (with CLIA) and Angiotensin II (AT-II), aldosterone (ALD) (with RIA) were measured in 98 patients with CHF, 76 cardiac patients without heart faclure, and 86 controls. Results: The plasma levels of BNP, AT-II and ALD in patients (with RIA) CHF were significantly higher than those in the controls. The levels of BNP, AT-II and ALD, CHF patients after therapy were markedly dropped and were significantly lower than those patients before therapy (P<0.01). BNP levels were positively correlated with AT-II and ALD in levels CHF (P<0.05). Conclusion: The over activity of RAA systems may be one of the mechanisms of heart failure. Dynamic observation of changes of BNP, AT-II and ALD may be very useful in assessment of severity and prognosis of patients with CHF. (authors)

  10. The predictive value of plasma B-type natriuretic peptide levels on outcome in children with pulmonary hypertension undergoing congenital heart surgery

    Directory of Open Access Journals (Sweden)

    Ayse Baysal

    2014-09-01

    Full Text Available Background and objectives: In children undergoing congenital heart surgery, plasma brain natriuretic peptide levels may have a role in development of low cardiac output syndrome that is defined as a combination of clinical findings and interventions to augment cardiac output in children with pulmonary hypertension. Methods: In a prospective observational study, fifty-one children undergoing congenital heart surgery with preoperative echocardiographic study showing pulmonary hypertension were enrolled. The plasma brain natriuretic peptide levels were collected before operation, 12, 24 and 48 h after operation. The patients enrolled into the study were divided into two groups depending on: (1 Development of LCOS which is defined as a combination of clinical findings or interventions to augment cardiac output postoperatively; (2 Determination of preoperative brain natriuretic peptide cut-off value by receiver operating curve analysis for low cardiac output syndrome. The secondary end points were: (1 duration of mechanical ventilation ≥72 h, (2 intensive care unit stay >7days, and (3 mortality. Results: The differences in preoperative and postoperative brain natriuretic peptide levels of patients with or without low cardiac output syndrome (n = 35, n = 16, respectively showed significant differences in repeated measurement time points (p = 0.0001. The preoperative brain natriuretic peptide cut-off value of 125.5 pg mL−1 was found to have the highest sensitivity of 88.9% and specificity of 96.9% in predicting low cardiac output syndrome in patients with pulmonary hypertension. A good correlation was found between preoperative plasma brain natriuretic peptide level and duration of mechanical ventilation (r = 0.67, p = 0.0001. Conclusions: In patients with pulmonary hypertension undergoing congenital heart surgery, 91% of patients with preoperative plasma brain natriuretic peptide levels above 125.5 pg mL−1 are at risk of developing low cardiac

  11. Amyloid-β peptides time-dependent structural modifications: AFM and voltammetric characterization.

    Science.gov (United States)

    Enache, Teodor Adrian; Chiorcea-Paquim, Ana-Maria; Oliveira-Brett, Ana Maria

    2016-07-01

    The human amyloid beta (Aβ) peptides, Aβ1-40 and Aβ1-42, structural modifications, from soluble monomers to fully formed fibrils through intermediate structures, were investigated, and the results were compared with those obtained for the inverse Aβ40-1 and Aβ42-1, mutant Aβ1-40Phe(10) and Aβ1-40Nle(35), and rat Aβ1-40Rat peptide sequences. The aggregation was followed at a slow rate, in chloride free media and room temperature, and revealed to be a sequence-structure process, dependent on the physicochemical properties of each Aβ peptide isoforms, and occurring at different rates and by different pathways. The fibrilization process was investigated by atomic force microscopy (AFM), via changes in the adsorption morphology from: (i) initially random coiled structures of ∼0.6 nm height, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to (ii) aggregates and protofibrils of 1.5-6.0 nm height and (iii) two types of fibrils, corresponding to the Aβ peptide in a β-sheet configuration. The reactivity of the carbon electrode surface was considered. The hydrophobic surface induced rapid changes of the Aβ peptide conformations, and differences between the adsorbed fibrils, formed at the carbon surface (beaded, thin, 2.0 nm height), were detected. Differential pulse voltammetry showed that, according to their primary structure, the Aβ peptides undergo oxidation in one or two steps, the first step corresponding to the tyrosine amino acids oxidation, and the second one to the histidine and methionine amino acids oxidation. The fibrilization process was electrochemically detected via the decrease of the Aβ peptide oxidation peak currents that occurred in a time dependent manner. PMID:27216391

  12. Analysis of N-terminal pro-brain natriuretic peptide levels in patients with chronic heart failure

    International Nuclear Information System (INIS)

    To investigate the changes and its clinical significance of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with chronic heart failure(CHF), 128 patients with decompensated CHF and 20 patients without structural heart disease were selected as CHF and control group. All subjects were evaluated heart function by New York Heart Association (NYHA) class. The serum NT-proBNP levels were assayed by electrochemiluminescence double antibody sandwich immunoassay. Left ventricular ejection fraction (LVEF) was detected by color Doppler ultrasound. The results showed that the NT-proBNP levels in CHF group were significantly higher than that of in the control group (P<0.05). Further, the NT-proBNP levels showed an increased tendency accompanied by the severity of heart failure (P<0.05) and lowering of LVEF (r=-0.595, P<0.05). The serum NT-proBNP levels can reflect the state of cardiac function in patients with decompensated DHF, and useful in the diagnosis and severity assessment of CHF. (authors)

  13. Growth of Streptococcus mutans in Biofilms Alters Peptide Signaling at the Sub-population Level

    Science.gov (United States)

    Shields, Robert C.; Burne, Robert A.

    2016-01-01

    Streptococcus mutans activates multiple cellular processes in response to the formation of a complex between comX-inducing peptide (XIP) and the ComR transcriptional regulator. Bulk phase and microfluidic experiments previously revealed that ComR-dependent activation of comX is altered by pH and by carbohydrate source. Biofilm formation is a major factor in bacterial survival and virulence in the oral cavity. Here, we sought to determine the response of S. mutans biofilm cells to XIP during different stages of biofilm maturation. Using flow cytometry and confocal microscopy, we showed that exogenous addition of XIP to early biofilms resulted in robust comX activation. However, as the biofilms matured, increasing amounts of XIP were required to activate comX expression. Single-cell analysis demonstrated that the entire population was responding to XIP with activation of comX in early biofilms, but only a sub-population was responding in mature biofilms. The sub-population response of mature biofilms was retained when the cells were dispersed and then treated with XIP. The proportion and intensity of the bi-modal response of mature biofilm cells was altered in mutants lacking the Type II toxins MazF and RelE, or in a strain lacking the (p)ppGpp synthase/hydrolase RelA. Thus, competence signaling is markedly altered in cells growing in mature biofilms, and pathways that control cell death and growth/survival decisions modulate activation of comX expression in these sessile populations. PMID:27471495

  14. Effects of Wen Dan Tang on insomnia-related anxiety and levels of the brain-gut peptide Ghrelin

    Institute of Scientific and Technical Information of China (English)

    Liye Wang; Binghe Guan; Xiaolan Liu; Yuehan Song; Feng Li; Yan Liu; Jie Ma; Meng Mao; Fengzhi Wu; Ying Wu; Sinai Li

    2014-01-01

    Ghrelin, a brain-gut peptide that induces anxiety and other abnormal emotions, contributes to the effects of insomnia on emotional behavior. In contrast, the traditional Chinese Medi-cine remedy Wen Dan Tang reduces insomnia-related anxiety, which may perhaps correspond to changes in the brain-gut axis. This suggests a possible relationship between Wen Dan Tang’s pharmacological mechanism and the brain-gut axis. Based on this hypothesis, a sleep-deprived rat model was induced and Wen Dan Tang was administered using oral gavage during model es-tablishment. Wen Dan Tang signiifcantly reduced insomnia-related anxiety and prevented Ghrelin level decreases following sleep deprivation, especially in the hypothalamus. Increased expression of Ghrelin receptor mRNA in the hypothalamus was also observed, suggesting that reduced anxi-ety may be a result of Wen Dan Tang’s regulation of Ghrelin-Ghrelin receptors.

  15. Effects of atrial and brain natriuretic peptides upon cyclic GMP levels, potassium transport, and receptor binding in rat astrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Beaumont, K.; Tan, P.K. (Univ. of California, San Diego, La Jolla (USA))

    1990-02-01

    The ability of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) to alter cyclic GMP levels and NaKCl cotransport in rat neocortical astrocytes was determined. At concentrations of 10(-9)-10(-6) M, rat ANP99-126 (rANF), rat ANP102-126 (auriculin B), and rat ANP103-126 (atriopeptin III) stimulated 6- to 100-fold increases in cyclic GMP levels. Porcine BNP (pBNP) and rat BNP (rBNP) were 20%-90% as effective as rANF over most of this concentration range, although 10(-6) M pBNP produced a greater effect than rANF. NaKCl cotransport as measured by bumetanide-sensitive 86Rb+ influx was not altered by exposure of astrocytes to 10(-6)M rANF, pBNP, or rBNP. Both pBNP and rBNP, as well as rat ANP103-123 (atriopeptin I) and des(gl18, ser19, gly20, leu21, gly22) ANF4-23-NH2 (C-ANF4-23) strongly competed for specific 125I-rANF binding sites in astrocyte membranes with affinities ranging from 0.03 to 0.4 nM, suggesting that virtually all binding sites measured at subnanomolar concentrations of 125I-rANF were of the ANP-C (ANF-R2) receptor subtype. These receptors are thought to serve a clearance function and may be linked to a guanylate cyclase activity that is chemically and pharmacologically distinct from that coupled to ANP-A (ANF-R1) receptors. ANP receptors on astrocytes may function in limiting the access of ANP and BNP to neurons involved in body fluid and cardiovascular regulation.

  16. Effects of atrial and brain natriuretic peptides upon cyclic GMP levels, potassium transport, and receptor binding in rat astrocytes

    International Nuclear Information System (INIS)

    The ability of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) to alter cyclic GMP levels and NaKCl cotransport in rat neocortical astrocytes was determined. At concentrations of 10(-9)-10(-6) M, rat ANP99-126 (rANF), rat ANP102-126 (auriculin B), and rat ANP103-126 (atriopeptin III) stimulated 6- to 100-fold increases in cyclic GMP levels. Porcine BNP (pBNP) and rat BNP (rBNP) were 20%-90% as effective as rANF over most of this concentration range, although 10(-6) M pBNP produced a greater effect than rANF. NaKCl cotransport as measured by bumetanide-sensitive 86Rb+ influx was not altered by exposure of astrocytes to 10(-6)M rANF, pBNP, or rBNP. Both pBNP and rBNP, as well as rat ANP103-123 (atriopeptin I) and des[gl18, ser19, gly20, leu21, gly22] ANF4-23-NH2 (C-ANF4-23) strongly competed for specific 125I-rANF binding sites in astrocyte membranes with affinities ranging from 0.03 to 0.4 nM, suggesting that virtually all binding sites measured at subnanomolar concentrations of 125I-rANF were of the ANP-C (ANF-R2) receptor subtype. These receptors are thought to serve a clearance function and may be linked to a guanylate cyclase activity that is chemically and pharmacologically distinct from that coupled to ANP-A (ANF-R1) receptors. ANP receptors on astrocytes may function in limiting the access of ANP and BNP to neurons involved in body fluid and cardiovascular regulation

  17. Asymmetric Dimethylarginine and Pro-B-Type Natriuretic Peptide Levels in Patients With Carbon Monoxide Poisoning

    Directory of Open Access Journals (Sweden)

    Murat Eroglu

    2013-04-01

    CONCLUSIONS: Despite COHB level decreased, ADMA increased after oxygen therapy in patients with CO poisoning. We think that CO poisoning induced oxidative stress may cause increased ADMA levels. Further studies are needed to evaluate the importance of ADMA in CO poisoning. [Dis Mol Med 2013; 1(2.000: 21-25

  18. Brain natriuretic peptide and copeptin levels are associated with cardiovascular disease in patients with chronic kidney disease

    Institute of Scientific and Technical Information of China (English)

    LI Xin; YANG Xin-chun; SUN Qian-mei; CHEN Xiang-dong; LI Yan-chun

    2013-01-01

    Background Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD).We explored the relationship between CVD,plasma brain natriuretic peptide (BNP) and copeptin in non-dialysis patients with chronic kidney disease (CKD).Methods BNP and copeptin were measured using ELISA in 86 non-dialysis patients with different degrees of CKD and in 20 control patients.The effects of BNP,copeptin levels and other biochemical indices on carotid ultrasound echocardiography and CVD history were determined using correlation analysis.Results BNP and copeptin levels were significantly higher in the CKD group than in the control group.Both indices increased progressively,in parallel with the decline in glomerular filtration rate (GFR).BNP levels were (184.25±65.18)ng/L in early phase CKD,(975.245±354.09) ng/L in middle phase CKD,and (1463.51±614.92) ng/ml in end phase CKD compared with levels of (101.56±42.76) ng/L in the control group (all P <0.01).Copeptin levels in the middle phase ((20.36±9.47) pmol/L) and end phase groups ((54.26±18.23) pmol/L were significantly higher than in the control group ((9.21±2.64) pmol/L; both P <0.01).There was no difference in copeptin levels between early phase CKD ((10.09±5.23)pmol/L) and control patients.Stepwise multiple regression analysis identified GFR,intima-media thickness (IMT),left ventricular hypertrophy (LVH),and previous history of CVD as independent risk factors for elevated BNP and copeptin levels.Conclusion BNP and copeptin appear to provide sensitive biological markers for the evaluation of atherosclerosis in non-dialysis patients with CKD.

  19. A peptide identification-free, genome sequence-independent shotgun proteomics workflow for strain-level bacterial differentiation

    OpenAIRE

    Wenguang Shao; Min Zhang; Henry Lam; Lau, Stanley C K

    2015-01-01

    Shotgun proteomics is an emerging tool for bacterial identification and differentiation. However, the identification of the mass spectra of peptides to genome-derived peptide sequences remains a key issue that limits the use of shotgun proteomics to bacteria with genome sequences available. In this proof-of-concept study, we report a novel bacterial fingerprinting method that enjoys the resolving power and accuracy of mass spectrometry without the burden of peptide identification (i.e. genome...

  20. Tracer level radiochemistry to clinical dose preparation of 177Lu-labeled cyclic RGD peptide dimer

    International Nuclear Information System (INIS)

    Aim: Integrin αvβ3 plays a significant role in angiogenesis during tumor growth and metastasis, and is a receptor for the extracellular matrix proteins with the exposed arginine(R)-glycine(G)-aspartic acid(D) tripeptide sequence. The over-expression of integrin αvβ3 during tumor growth and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Considering the advantages of 177Lu for targeted radiotherapy and enhanced tumor targeting capability of cyclic RGD peptide dimer, an attempt has been made to optimize the protocol for the preparation of clinical dose of 177Lu labeled DOTA-E[c(RGDfK)]2 (E = Glutamic acid, f = phenyl alanine, K = lysine) as a potential agent for targeted tumor therapy. Methods: 177Lu was produced by thermal neutron bombardment on enriched Lu2O3 (82% in 176Lu) target at a flux of 1 × 1014 n/cm2.s for 21 d. Therapeutic dose of 177Lu-DOTA-E[c(RGDfK)]2 (7.4 GBq) was prepared by adding the aqueous solution of the ligand and 177LuCl3 to 0.1 M NH4OAC buffer containing gentisic acid and incubating the reaction mixture at 90 °C for 30 min. The yield and radiochemical purity of the complex was determined by HPLC technique. Parameters, such as, ligand-to-metal ratio, pH of the reaction mixture, incubation time and temperature were varied using tracer quantity of 177Lu (37 MBq) in order to arrive at the optimized protocol for the preparation of clinical dose. Biological behavior of the radiotracer prepared was studied in C57/BL6 mice bearing melanoma tumors. Results: 177Lu was produced with a specific activity of 950 ± 50 GBq/mg (25.7 ± 1.4 Ci/mg) and radionuclidic purity of 99.98%. A careful optimization of several parameters showed that 177Lu-DOTA-E[c(RGDfK)]2 could be prepared with adequately high radiochemical purity using a ligand-to-metal ratio ∼ 2. Based on these studies therapeutic dose of the agent with 7.4 GBq of 177Lu was formulated in ∼ 63 GBq/μM specific

  1. The dynamic changes of brain natriuretic peptide level in patients with hyperthyroid heart disease after 131I therapy

    International Nuclear Information System (INIS)

    Objective: To investigate the application value of urine brain natriuretic peptide (BNP) level in 131I treatment of hyperthyroid heart disease. Methods: One hundred and eleven hyperthyroidism patients who received 131I therapy were divided into two groups, hyperthyroidism group (51 cases) and hyperthyroid heart disease group (60 cases), and 30 healthy subjects as control. Sixty patients in the hyperthyroid heart disease group all received ultrasonic cardiogram. The hyperthyroid heart disease group was divided into two subgroups according to New York Heart Association (NYHA) functional classification (hyperthyroid heart disease A subgroup and hyperthyroid heart disease B subgroup). The urine and serum BNP level and serum free triiodothyronine (FT3), free thyroxine (FT4) level were measured through chemiluminescence before and after therapy. Results: The urine and serum BNP level before 131I therapy of the hyperthyroid heart disease group were significantly higher than those of hyperthyroidism group (serum: t=8.98 and 9.52, both P<0.01; urine: t=10.83 and 12.73, both P<0.01) and the control group (serum: t=8.97 and 9.52, both P<0.01; urine: t=9.21 and 5.64, both P<0.01). The urine and serum BNP level before and 6, 12 months after 131I therapy of the hyperthyroid heart disease A subgroup were significantly higher than those of hyperthyroid heart disease B subgroup (serum: t=5.98, 5.87 and 6.35, all P<0.01; serum: t=4.33, 4.09 and 5.02, all P<0.01). The urine level of BNP was gradually increased with the severity of cardiac insufficiency and it was positively correlated with the serum level of BNP (r=0.829, P<0.01), the NYHA functional classification (r=0.751, P<0.01) and the serum level of FT3 and FT4 (FT3: r=0.635, P<0.01; FT4: r=0.672, P<0.01). Conclusions: The urine BNP level of hyperthyroid heart disease patient increased with the severity of cardiac insufficiency. The urine BNP level could accurately reflect cardiac function of hyperthyroid heart disease patient

  2. Analysis of changes of serum leptin, C-peptide levels and peripheral fat tissue leptin receptor expression in obesity

    International Nuclear Information System (INIS)

    Objective: To explore the mechanism of obesity and obesity accompanied type two diabetes mellitus by investigating changes of serum leptin, C-peptide (C-P) levels and leptin receptor expression in peripheral adipose tissues. Methods: Peripheral leptin receptor density was measured via radio-ligand binding method, serum leptin and C - P levels were measured via radioimmunoassay in 91 cases (38 in obesity group, 23 in over weight, and 30 in normal controls). Results: With the increase of body mass index (BMI), the peripheral leptin receptor density of the over weight and obese cases decreased and was mash less than that of normal cases (both p<0.01, respectively). There was no statistical differences for Kd value among the three groups, suggesting no associated change between the binding ability of leptin receptor to its ligand. There was a negative correlation between BMI and leptin receptor density (r = -0.70, p < 0.01). The serum leptin and C-P levels in weight excess and obese subjects with type two DM were both increased, but significantly higher in obese group than those in weight excess group (p < 0.01). The increase of C-P was much marked than that of leptin. Serum C-P level was positively correlated with BMI. Conclusion: Changes of serum leptin, C-P levels and peripheral leptin receptor expression in cases with simple obesity and obesity accompanied with type two DM were related closely with BMI. Type 2 DM in obese subjects was related with leptin resistance and insulin resistance

  3. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis

    Directory of Open Access Journals (Sweden)

    Ziegler Thomas R

    2009-04-01

    Full Text Available Abstract Background Vitamin D insufficiency is common in hospitalized patients. Recent evidence suggests that vitamin D may enhance the innate immune response by induction of cathelicidin (LL-37, an endogenous antimicrobial peptide produced by macrophages and neutrophils. Thus, the relationship between vitamin D status and LL-37 production may be of importance for host immunity, but little data is available on this subject, especially in the setting of human sepsis syndrome and other critical illness. Methods Plasma concentrations of 25-hydroxyvitamin D (25(OHD, vitamin D binding protein (DBP and LL-37 in critically ill adult subjects admitted to intensive care units (ICUs with sepsis and without sepsis were compared to healthy controls. Results Critically ill subjects had significantly lower plasma 25(OHD concentrations compared to healthy controls. Mean plasma LL-37 levels were significantly lower in critically ill subjects compared to healthy controls. Vitamin D binding protein levels in plasma were significantly lower in critically ill subjects with sepsis compared to critically ill subjects without sepsis. There was a significant positive association between circulating 25(OHD and LL-37 levels. Conclusion This study demonstrates an association between critical illness and lower 25(OHD and DBP levels in critically ill patients as compared to healthy controls. It also establishes a positive association between vitamin D status and plasma LL-37, which suggests that systemic LL-37 levels may be regulated by vitamin D status. Optimal vitamin D status may be important for innate immunity especially in the setting of sepsis. Further invention studies to examine this association are warranted.

  4. A grape seed extract increases active glucagon-like peptide-1 levels after an oral glucose load in rats.

    Science.gov (United States)

    González-Abuín, Noemi; Martínez-Micaelo, Neus; Margalef, Maria; Blay, Mayte; Arola-Arnal, Anna; Muguerza, Begoña; Ardévol, Anna; Pinent, Montserrat

    2014-09-01

    We have previously reported that procyanidins, a class of flavonoids, improve glycemia and exert an incretin-like effect, which was linked to their proven inhibitory effect on the dipeptidyl-peptidase 4 (DPP4) activity. However, their actual effect on incretin levels has not been reported yet. Therefore, in the present study we have evaluated whether a grape seed extract enriched in procyanidins (GSPE) modulates plasma incretin levels and attempted to determine the mechanisms involved. An acute GSPE treatment in healthy Wistar female rats prior to an oral glucose load induced an increase in plasma active glucagon-like peptide-1 (GLP-1), which was accompanied by an increase in the plasma insulin/glucose ratio and a simultaneous decrease in glucose levels. In agreement with our previous studies, the intestinal DPP4 activity was inhibited by the GSPE treatment. We have also assayed in vitro whether this inhibition occurs in inner intestinal tissues close to GLP-1-producing cells, such as the endothelium of the capillaries. We have found that the main compounds absorbed by intestinal CaCo-2 cells after an acute treatment with GSPE are catechin, epicatechin, B2 dimer and gallic acid, and that they inhibit the DPP4 activity in endothelial HUVEC cells in an additive way. Moreover, an increase in plasma total GLP-1 levels was found, suggesting an increase in GLP-1 secretion. In conclusion, our results show that GSPE improves glycemia through its action on GLP-1 secretion and on the inhibition of the inner intestinal DPP4 activity, leading to an increase in active GLP-1 levels, which, in turn, may affect the insulin release. PMID:25088664

  5. Absorbed dose at subcellular level by Monte Carlo simulation for a 99mTc-peptide with nuclear internalization

    International Nuclear Information System (INIS)

    The utility of radiolabeled peptides for the early and specific diagnosis of cancer is being investigated around the world. Recent investigations have demonstrated the specificity of 99mTc-bombesin conjugates to target breast and prostate cancer cells. The novel idea of adding the Tat (49-57) peptide to the radiopharmaceutical in order to penetrate the cell nucleus is a new proposal for therapy at cellular level. 99mTc radionuclide produces Auger energy of 0.9 keV/decay and internal conversion electron energy of 15.4 keV/decay, which represent 11.4% of the total 99mTc energy released per decay. It is expected that the dose delivered at specific microscopic levels in cancer cells induce a therapeutic effect. The aim of this research was to assess in vitro internalization kinetics in breast and prostate cancer cells of 99mTc-Tat(49-57)-bombesin and to evaluate the radiation absorbed dose at subcellular level simulating the electron transport. The pen main program from the 2006 version of the Penelope code was used to simulate and calculate the absorbed dose by Auger and internal conversion electron contribution in the membrane, cytoplasm and nucleus of Pc-3 prostate cancer and MCF7 and MDA human breast cancer cell lines. Nuclear data were obtained from the 2002 BNM-LNHB 99mTc decay scheme. The spatial distribution of the absorbed doses to the membrane, cytoplasm and nucleus were calculated using a geometric model built from real images of cancer cells. The elemental cell composition was taken from the literature. The biokinetic data were obtained evaluating total disintegrations in each subcellular compartment by integration of the time-activity curves acquired from experimental data. Results showed that 61, 63 and 46% of total disintegrations per cell-bound 99mTc-Tat-Bn activity unit occurred in the nucleus of Pc-3, MCF7 and MDA-MB231 respectively. 99mTc--Tat-Bn absorbed doses were 1.78, 5.76 and 2.59 Gy/Bq in the nucleus of Pc-3, MCF7 and MDA-MB231 correspondingly

  6. B-type natriuretic peptide (BNP serum levels in rats after forced repeated swimming stress

    Directory of Open Access Journals (Sweden)

    Almira Hadžovic-Džuvo

    2011-02-01

    Full Text Available Aim To estimate the effects of forced repeated swimming stress on BNP serum levels in rats. Methods Adult male Wistar rats weighting between 280-330 g were divided into two groups: control group (n =8 and stress group (n =8. Rats in the stress group were exposed to forced swimming stress daily, for 7 days. The rats were forced to swim in plastic tanks (90 cm wide, 120 cm deep containing tap water (temperature ca. 25°C. The depth of water was 40 cm. Duration of each swimming session progressively increased from 10 minutes on the irst day to 40 minutes on days 6 and 7. Rats were sacriiced and blood was drawn from abdominal aorta for BNP analysis immediately after the last swimming session. B-type natriuretic serum level was determined by ELISA method using RAT BNP-32 kit (Phoenix Pharmaceutical Inc.. Results There was no statistically signiicant difference between mean BNP serum level in the stress group after the swimming period (0.81±0.14 ng/ml as compared to the unstressed group of rats (0.8 ±0.08ng/ml. After the swimming period mean body weight slightly decreased in the stress group in comparison with values before stress period (296.3 g vs.272.8 g, but this difference was not statistically signiicant. The stress period had no inluence on food intake in the stress rat group. Conclusion The workload consisting of 40-minutes long swimming session is not suficient to provoke BNP release from myocardium in rats.

  7. Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease

    DEFF Research Database (Denmark)

    Schmidt, Peter T; Ljung, Tryggve; Hartmann, Bolette; Hare, Kristine J; Holst, Jens Juul; Hellström, Per M

    2005-01-01

    BACKGROUND AND AIM: Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in...... the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients. CONCLUSION: The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may...

  8. Adiponectin corrects premature cellular senescence and normalizes antimicrobial peptide levels in senescent keratinocytes.

    Science.gov (United States)

    Jin, Taewon; Kim, Min Jeong; Heo, Won Il; Park, Kui Young; Choi, Sun Young; Lee, Mi-Kyung; Hong, Seung-Phil; Kim, Seong-Jin; Im, Myung; Moon, Nam Ju; Seo, Seong Jun

    2016-09-01

    Stress-induced premature senescence or aging causes dysfunction in the human somatic system. Adiponectin (Acrp30) plays a role in functional recovery, especially with adenosine 3',5'-monophosphate (AMP)-activated protein kinase (AMPK) and silent mating type information regulation 2 homolog 1 (SIRT1). Acrp30 stimulation reduced the premature senescence positive ratio induced by hydrogen peroxide (H2O2) and restituted human β-defensin 2 (hBD-2) levels in senescent keratinocytes. Acrp30 recovered AMPK activity in senescent keratinocytes and increased SIRT1 deacetylation activity. As a result, FoxO1 and FoxO3 transcription activity was recovered. Additionally, Acrp30 stimulation suppresses NFκB p65, which induces abnormal expression of hBD-2 induced by H2O2. In the present study, we have shown that Acrp30 reduces premature senescence and recovers cellular function in keratinocytes. These results suggest a role for Acrp30 as an anti-aging agent to improve impaired skin immune barriers. PMID:27349869

  9. Increased urine level of amino-terminal peptide derivatives of type III procollagen in patients with liver diseases.

    Directory of Open Access Journals (Sweden)

    Koide,Norio

    1986-10-01

    Full Text Available The amino-terminal peptides of type III procollagen (PIIIP in the urine of 40 patients with various liver diseases were determined with a commercial radioimmunoassay kit. The level of urinary PIIIP (uPIIIP was correlated well with serum PIIIP (sPIIIP in 9 patients, the coefficient of correlation being r = 0.836 (p less than 0.01 and the regression line being y = 1.42x + 24. Urinary PIIIP consisted of at least 4 different molecular species with molecular weights of 49 k, 18 k, 10 k and 4.6 k as estimated by column chromatography on Sephadex G-100. Furthermore. uPIIIP was found to be significantly elevated in acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma and other liver diseases, in which the elevation of sPIIIP has been reported by others. The mean values +/- standard deviations of uPIIIP were 44.0 +/- 32.0, 60.4 +/- 32.0, 62.0 +/- 46.5, 53.0 +/- 27.1 and 48.1 +/- 22.8 ng/ml for the respective liver diseases, and 13.2 +/- 4.5 for the non-hepatic disease group.

  10. Peptides from sesame cake extend healthspan of Caenorhabditis elegans via upregulation of skn-1 and inhibition of intracellular ROS levels.

    Science.gov (United States)

    Wang, Zhuanhua; Ma, Xiaoli; Li, Jiao; Cui, Xiaodong

    2016-09-01

    The peptides from sesame cake (PSC) which are the main by-product of agricultural processing of sesame were prepared. To evaluate benefits of PSC for health and longevity, antioxidant activity and anti-aging effects were studied in vitro and in a Caenorhabditis elegans (C. elegans) model system. PSC exhibited antioxidant activity in vitro, and induced beneficial effects on lifespan and several health parameters of C.elegans, including pharyngeal pumping rate, locomotion and lipofuscin accumulation. In a mev-1 mutant, PSC increased lifespan, and it enhanced oxidative stress tolerance in wild-type nematodes. After treatment with PSC, SOD activity, GSH content, and GSH/GSSG ratio were increased, leading to low intracellular ROS levels in C. elegans. PSC up-regulated skn-1 mRNA, and its target gene gcs-1, and abolished the extension of lifespan in skn-1 mutant, indicating that PSC-mediated longevity is dependent on activation of the skn-1/Nrf-2 transcription factor. Current results warrant research into the use of PSC as nutraceuticals for overall health improvement. PMID:27381188

  11. The relationship between repressive and defensive coping styles and monocyte, eosinophile, and serum glucose levels: support for the opioid peptide hypothesis of repression.

    Science.gov (United States)

    Jamner, L D; Schwartz, G E; Leigh, H

    1988-01-01

    The opioid peptide hypothesis of repression (1) predicts that repressive coping is associated with increased functional endorphin levels in the brain, which can result in decreased immunocompetence and hyperglycemia. In a random sample of 312 patients seen at a Yale Medical School outpatient clinic, significant main effects of coping style were found for monocyte and eosinophile counts, serum glucose levels, and self-reports of medication allergies. Specifically, repressive and defensive high-anxious patients demonstrated significantly decreased monocyte counts. In addition, repressive coping was associated with elevated eosinophile counts, serum glucose levels, and self-reported reactions to medications. This behavioral, immunologic, and endocrine profile is consistent with the opioid peptide hypothesis, which provides an integrative framework for relating the attenuated emotional experience of pain and distress characteristic of repressive coping with reduced resistance to infectious and neoplastic disease. PMID:2853404

  12. Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults

    DEFF Research Database (Denmark)

    Dixon, Brian M; Barker, Tyler; McKinnon, Toni;

    2012-01-01

    ABSTRACT: BACKGROUND: Transcription of the cathelicidin antimicrobial peptide (CAMP) gene is induced by binding of the bioactive form of vitamin D, 1,25-dihydroxyvitamin D, to the vitamin D receptor. Significant levels of the protein hCAP18/LL-37 are found in the blood and may protect against...... = 0.63). CONCLUSIONS: We conclude that plasma hCAP18 levels correlate with serum 25(OH)D levels in subjects with concentrations of 25(OH)D 32 ng/ml and that vitamin D status may regulate systemic levels of hCAP18/LL-37....

  13. Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation- induced cardiac hypertrophic growth in experimental rats.

    Science.gov (United States)

    Venkatesan, Balaji; Tumala, Anusha; Subramanian, Vimala; Vellaichamy, Elangovan

    2016-07-01

    Natriuretic peptide receptor-C (NPR-C) is considered as a clearance receptor that maintains the circulatory levels of natriuretic peptides. It has been suggested that augmented expression of NPR-C as a cause for the diminished anti-hypertrophic action of natriuretic peptides in the failing heart. Hence, we sought to determine the level of Npr3 gene (coding for NPR-C) expression in the Isoproterenol (ISO) treated Wistar rats. In addition, we studied the effect of Npr3 gene silencing on the hypertrophic growth. A significant increase in heart weight-to-body weight ratio (HW/BW-24%,Pexpression was significantly increased by 4 fold as compared to control rats. In parallel, the circulatory atrial natriuretic peptide (ANP) level was significantly decreased (2 fold) in ISO treated rats. Upon treatment with siRNA-Npr3, a significant decrease in the cardiac NPR-C protein expression (70%,Pexpression were observed. Interestingly, the circulatory ANP level was increased by 1.5 fold in the siRNA-Npr3 treated rats as compared to ISO treated rats. Moreover, the cardiac collagen content, matrixmetalloprotinases-2 (MMP-2) and enzymatic antioxidant status (P<0.01, respectively) were found to be restored back to near normal upon siRNA-Npr3 treatment. Taken together, the results of this study indicates that specific down-regulation of Npr3 gene improves the circulatory levels of ANP and antioxidant system and there by attenuates the β-adrenoceptor over-activation mediated cardiac hypertrophic growth in experimental rats. PMID:27108789

  14. Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Wei; Hao, Jian; Liu, Rui; Zhang, Zhuo; Lei, Gesheng; Su, Changjun; Miao, Jianting; Li, Zhuyi

    2011-09-23

    Amyloid-beta peptide (Aβ) is believed to be central in the pathogenesis of Alzheimer's disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aβ pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aβ pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aβ1-40 and Aβ1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aβ1-40 and Aβ1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aβ plaque load and fibrillar Aβ plaque load), total Aβ levels (Aβ1-40 and Aβ1-42), as well as insoluble Aβ levels (Aβ1-40 and Aβ1-42). Stepwise multiple regression analysis identified hippocampal soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aβ in middle-aged APPswe/PS1dE9 mice, in which soluble Aβ levels are only a tiny fraction of the amount of total Aβ levels. Consequently, our findings provide further evidence that soluble Aβ might primarily contribute to cognitive deficits in AD, suggesting that reducing

  15. Effect of Teduglutide, a Glucagon-like Peptide 2 Analog, on Citrulline Levels in Patients With Short Bowel Syndrome in Two Phase III Randomized Trials

    OpenAIRE

    Seidner, Douglas L; Joly, Francisca; Youssef, Nader N

    2015-01-01

    Objectives: In clinical trials, treatment with the glucagon-like peptide 2 analog teduglutide was associated with improved fluid and nutrient absorption and increased intestinal villus height and crypt depth in patients with short bowel syndrome (SBS). Plasma citrulline, an amino acid produced by enterocytes, is considered a measure of enterocyte mass. This analysis assessed changes in plasma citrulline levels in patients with SBS in 2 phase III clinical studies of teduglutide. Methods: Both ...

  16. Anticipatory and consummatory effects of (hedonic chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Directory of Open Access Journals (Sweden)

    Antonello E. Rigamonti

    2015-11-01

    Full Text Available Background: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods: To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1, peptide YY (PYY, anandamide (AEA, 2-AG, palmitoylethanolamide (PEA, and oleoylethanolamide (OEA in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results: The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions: When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  17. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    OpenAIRE

    Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Background: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown.Methods: To explore...

  18. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans

    DEFF Research Database (Denmark)

    Meier, J J; Gethmann, A; Götze, O;

    2006-01-01

    AIMS/HYPOTHESIS: Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels...... administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33+/-0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely...

  19. Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing Amyloid-β Peptide and APP-CTFβ Levels in Neuronal Cells.

    Directory of Open Access Journals (Sweden)

    Hye Rin Lee

    Full Text Available Autophagy is a vital pathway for the removal of β-amyloid peptide (Aβ and the aggregated proteins that cause Alzheimer's disease (AD. We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Aβ and C-terminal APP fragment β subunit (APP-CTFβ by up-regulating autophagy.When N2a cells were exposed to soluble Aβ1-42, protein levels of beclin-1, autophagy-related protein5 (Atg5, and SIRT1 decreased significantly. Pretreatment with cilostazol (10-30 μM or resveratrol (20 μM prevented these Aβ1-42 evoked suppressions. LC3-II (a marker of mammalian autophagy levels were significantly increased by cilostazol, and this increase was reduced by 3-methyladenine. To evoke endogenous Aβ overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition. Aβ and APP-CTFβ expressions were increased after 12~24 h in Tet- condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Aβ and APP-CTFβ were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion. After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein, cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Aβ was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Aβ induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Aβ clearance and increases cell viability.

  20. Levels of vasoactive intestinal peptide,cholecystokinin and calcitonin gene-related peptide in plasma and jejunum of rats following traumatic brain injury and underlying significance in gastrointestinal dysfunction

    Institute of Scientific and Technical Information of China (English)

    Chun-Hua Hang; Ji-Xin Shi; Jie-Shou Li; Wei Wu; Wei-Qin Li; Hong-Xia Yin

    2004-01-01

    AIM: To study the alterations of brain-gut peptides following traumatic brain injury (TBI) and to explore the underlying significance of these peptides in the complicated gastrointestinal dysfunction.METHODS: Rat models of focal traumatic brain injury were established by impact insult method, and divided into 6 groups (6 rats each group) including control group with sham operation and TBI groups at postinjury 3, 12, 24, 72 h, and d 7. Blood and proximal jejunum samples were taken at time point of each group and gross observations of gastrointestinal pathology were recorded simultaneously. The levels of vasoactive intestinal peptide (VIP) in plasma, calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) in both plasma and jejunum were measured by enzyme immunoassay (EIA). Radioimmunoassay (RIA) was used to determine the levels of VTP in jejunum. RESULTS: Gastric distension, delayed gastric emptying and intestinal dilatation with a large amount of yellowish effusion and thin edematous wall were found in TBI rats through 12 h and 72 h, which peaked at postinjury 72 h. As compared with that of control group (247.8±29.5 ng/L), plasma VIP levels were significantly decreased at postinjury 3, 12 and 24 h (106.7±34.1 ng/L, 148.7±22.8 ng/L, 132.8±21.6 ng/L,respectively), but significantly increased at 72 h (405.0±29.8 ng/L) and markedly declined on d 7 (130.7±19.3 ng/L).However, Plasma levels CCK and CGRP were significantly increased through 3 h and 7 d following TBT (126-691% increases), with the peak at 72 h. Compared with control (VIP, 13.6±1.4 ng/g; CGRP, 70.6±17.7 ng/g); VIP and CGRP levels in jejunum were significantly increased at 3 h after TBI (VIP, 35.4±5.0 ng/g; CGRP, 103.8±22.1 ng/g), anddeclined gradually at 12 h and 24 h (VIP, 16.5±1.8 ng/g, 5.5±1.4 ng/g; CGRP, 34.9±9.7 ng/g, 18.5±7.7 ng/g), but were significantly increased again at 72 h (VIP, 48.7±9.5 ng/g; CGRP, 142.1±24.3 ng/g), then declined in various degrees on d 7 (VIP, 3.8±1

  1. Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome.

    Science.gov (United States)

    Schupf, Nicole; Lee, Annie; Park, Naeun; Dang, Lam-Ha; Pang, Deborah; Yale, Alexander; Oh, David Kyung-Taek; Krinsky-McHale, Sharon J; Jenkins, Edmund C; Luchsinger, José A; Zigman, Warren B; Silverman, Wayne; Tycko, Benjamin; Kisselev, Sergey; Clark, Lorraine; Lee, Joseph H

    2015-10-01

    We examined the contribution of candidates genes for Alzheimer's disease (AD) to individual differences in levels of beta amyloid peptides in adults with Down syndrom, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30-78 years of age. Genomic deoxyribonucleic acid was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aβ peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race and/or ethnicity, and the presence of the APOE ε4 allele. For Aβ42 levels, the strongest gene-wise association was found for a single nucleotide polymorphism (SNP) on CAHLM1; for Aβ40 levels, the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aβ42/Aβ40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence amyloid precursor protein processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1). PMID:26166206

  2. Penetratin Peptide-Functionalized Gold Nanostars: Enhanced BBB Permeability and NIR Photothermal Treatment of Alzheimer's Disease Using Ultralow Irradiance.

    Science.gov (United States)

    Yin, Tiantian; Xie, Wenjie; Sun, Jing; Yang, Licong; Liu, Jie

    2016-08-01

    The structural changes of amyloid-beta (Aβ) from nontoxic monomers into neurotoxic aggregates are implicated with pathogenesis of Alzheimer's disease (AD). Over the past decades, weak disaggregation ability and low permeability to the blood-brain barrier (BBB) may be the main obstacles for major Aβ aggregation blockers. Here, we synthesized penetratin (Pen) peptide loaded poly(ethylene glycol) (PEG)-stabilized gold nanostars (AuNS) modified with ruthenium complex (Ru@Pen@PEG-AuNS), and Ru(II) complex as luminescent probes for tracking drug delivery. We revealed that Ru@Pen@PEG-AuNS could obviously inhibit the formation of Aβ fibrils as well as dissociate preformed fibrous Aβ under the irradiation of near-infrared (NIR) due to the NIR absorption characteristic of AuNS. More importantly, this novel design could be applied in medicine as an appropriate nanovehicle, being highly biocompatible and hemocompatible. In addition, Ru@Pen@PEG-AuNS had excellent neuroprotective effect on the Aβ-induced cellular toxicity by applying NIR irradiation. Meanwhile, Pen peptide could effectively improve the delivery of nanoparticles to the brain in vitro and in vivo, which overcame the major limitation of Aβ aggregation blockers. These consequences illustrated that the enhanced BBB permeability and efficient photothermolysis of Ru@Pen@PEG-AuNS are promising agents in AD therapy. PMID:27411476

  3. A peptidome-based phylogeny pipeline reveals differential peptides at the strain level within Bifidobacterium animalis subsp. lactis.

    Science.gov (United States)

    Blanco-Míguez, Aitor; Gutiérrez-Jácome, Alberto; Fdez-Riverola, Florentino; Lourenço, Anália; Sánchez, Borja

    2016-12-01

    Bifidobacteria are gut commensal microorganisms belonging to the Actinobacteria group. Some specific strains of Bifidobacterium animalis subsp. lactis are used in functional foods as they are able to exert health-promoting effects in the human host. Due to the limited genetic variability within this subspecies, it is sometimes difficult for a manufacturer to properly track its strain once included in dairy products or functional foods. In this paper, we present a peptidome-based analysis in which the proteomes of a set of B. animalis subsp. lactis strains were digested in silico with human gut endopeptidases. The molecular masses were compared along all the strains to detect strain-specific peptides. These peptides may be interesting towards the development of methodologies for strain identification in the final product. PMID:27554155

  4. Determination of plasma calcitonin gene related peptide (CGRP) levels in patients with deep vein thrombosis (DVT) during treatment with integrated Chinese and Western medicine

    International Nuclear Information System (INIS)

    Objective: To investigate the clinical significance of changes of plasma calcitonin gene related peptide (CGRP) levels during integrated Chinese and Western medical treatment in patients with deep vein thrombosis (DVT). Methods: The plasma CGRP levels were determined dynamically with RIA during the course of integrated treatment in 50 patients with acute DVT and 30 patients with chronic DVT. Results: In patients with acute DVT, the plasma CGRP levels were increased at 6h and reached peak values at 72 h after starting the treatment, roughly corresponding to the time of most active thrombolysis. However, there were little change of CGRP levels in patients with chronic DVT. Conclusion: Plasma CGRP levels might be taken as an indicator of the efficacy of integrated Chinese and western medical treatment for DVT. (authors)

  5. Changes of Leptin Level in Serum, Cord Venous Blood and Placenta in Women with Gestational Diabetes Mellitus and Correlations with Insulin and C-Peptide

    Institute of Scientific and Technical Information of China (English)

    Jin-ming ZHU; Li SHI; Xiao-yuan LU; Rong-rong ZHANG; Min LI; Xiao-ning ZHANG

    2014-01-01

    ObjectiveTo investigate the changes of leptin levels in serum, cord venous blood and placenta and examine the possible relationships among them in women with gestational diabetes mellitus (GDM).Methods This case-control study was performed in 40 women with GDM and 40 normal women. The women with GDM received dietary advice, blood glucose monitoring and insulin treatment when necessary. Maternal serum and venous cord blood leptin, insulin and C-peptide levels were detected by ELISA. The expression level of leptin in placenta was measured by an immunohistochemical method. Results1. Leptin, insulin and C-peptide levels in serum of the women with GDM were significantly higher than those of the normal women (P<0.01,P<0.05, P<0.01). 2. Cord venous blood leptin and insulin in GDM group were significantly higher than in the normal group (P<0.01,P<0.05). No significant difference was found in cord venous blood C-peptide between two groups. 3. The expression of placenta leptin protein was significantly higher in GDM women than in normal women (P<0.01). There were positive correlations between placental leptin, cord venous leptin and insulin, birth weight, ponderal index in GDM women (r=0.37,P<0.05;r=0.39,P<0.05;r=0.53,P<0.01;r=0.54,P<0.01). However, there was no correlation between placental leptin and serum leptin.Conclusion The women with GDM and their fetuses suffer from hyperleptinaemia and hyperinsulinaemia. In the women with GDM, there was disorder in the interaction between leptin and insulin. The GDM women and their fetuses may be prone to insulin resistance and leptin resistance in late pregnancy.

  6. Changes in brain seabream GnRH mRNA and pituitary seabream GnRH peptide levels during ovarian maturation in female barfin flounder.

    Science.gov (United States)

    Amano, Masafumi; Pham, Ky Xuan; Amiya, Noriko; Yamanome, Takeshi; Yamamori, Kunio

    2008-09-01

    The pleuronectid barfin flounder Verasper moseri expresses three forms of gonadotropin-releasing hormones (GnRHs), i.e., seabream GnRH (sbGnRH), salmon GnRH, and chicken GnRH-II. Among these, sbGnRH is the dominant form in the pituitary, indicating that sbGnRH regulates gonadal maturation. In order to clarify the physiological roles of sbGnRH during ovarian maturation in reared female barfin flounder, the changes in brain sbGnRH mRNA levels and pituitary sbGnRH peptide levels were examined by real-time quantitative PCR and time-resolved fluoroimmunoassay, respectively. The fish hatched in April 2002. The gonadosomatic index remained low until August 2004 and increased thereafter until April 2005 when the fish began to ovulate. The sbGnRH mRNA levels per brain increased significantly from April 2004 to April 2005. Pituitary sbGnRH peptide levels also increased significantly during this period. These results indicate that sbGnRH is involved in ovarian maturation and ovulation in the barfin flounder. PMID:18662692

  7. Peptide dendrimers

    Czech Academy of Sciences Publication Activity Database

    Niederhafner, Petr; Šebestík, Jaroslav; Ježek, Jan

    2005-01-01

    Roč. 11, - (2005), 757-788. ISSN 1075-2617 R&D Projects: GA ČR(CZ) GA203/03/1362 Institutional research plan: CEZ:AV0Z40550506 Keywords : multiple antigen peptides * peptide dendrimers * synthetic vaccine * multipleantigenic peptides Subject RIV: CC - Organic Chemistry Impact factor: 1.803, year: 2005

  8. Hormone therapy with tamoxifen reduces plasma levels of NT-B-type natriuretic peptide but does not change ventricular ejection fraction after chemotherapy in women with breast cancer

    Directory of Open Access Journals (Sweden)

    F.B. Silva

    2015-02-01

    Full Text Available The objective of this study was to evaluate the effect of tamoxifen on the plasma concentration of NT-pro-B-type natriuretic peptide (NT-proBNP in women undergoing chemotherapy for breast cancer and to correlate changes in NT-proBNP with the left ventricular ejection fraction (LVEF. Over a period of 12 months, we followed 60 women with a diagnosis of breast cancer. The patients were separated into a group that received only chemotherapy (n=23, a group that received chemotherapy + tamoxifen (n=21, and a group that received only tamoxifen (n=16. Plasma levels of NT-proBNP were assessed at 0 (T0, 6 (T6, and 12 (T12 months of treatment, and echocardiography data were assessed at T0 and T12. Plasma NT-proBNP levels were increased in the chemotherapy-only group at T6 and T12, whereas elevated NT-proBNP levels were only found at T6 in the chemotherapy + tamoxifen group. At T12, the chemotherapy + tamoxifen group exhibited a significant reduction in the peptide to levels similar to the group that received tamoxifen alone. The chemotherapy-only group exhibited a significant decrease in LVEF at T12, whereas the chemotherapy + tamoxifen and tamoxifen-only groups maintained levels similar to those at the beginning of treatment. Treatment with tamoxifen for 6 months after chemotherapy significantly reduced the plasma levels of NT-proBNP and did not change LVEF in women with breast cancer.

  9. Reversible peptide oligomerization over nanoscale gold surfaces

    OpenAIRE

    Kazushige Yokoyama; Christa D. Catalfamo; Minxuan Yuan

    2015-01-01

    A selective oligomeric formation of amyloid beta 1-40 (Ab1-40) monomers over a nanogold colloidal surface was investigated. An unfolded Ab1-40 monomer is considered to construct a dimer or trimer based oligomeric form with its hydrophobic segment placing outward under an acidic condition. Under a basic condition, a conformation of Ab is expected to take a folded monomeric form with its hydrophilic segment folded inward, avoiding the networking with residual colloidal particles. The most proba...

  10. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction

    DEFF Research Database (Denmark)

    Gheorghiade, Mihai; Greene, Stephen J; Butler, Javed; Filippatos, Gerasimos; Lam, Carolyn S P; Maggioni, Aldo P; Ponikowski, Piotr; Shah, Sanjiv J; Solomon, Scott D; Kraigher-Krainer, Elisabeth; Samano, Eliana T; Müller, Katharina; Roessig, Lothar; Pieske, Burkert

    2015-01-01

    weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis......, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined...... as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. INTERVENTIONS: Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12...

  11. Significance of changes of the plasma levels of nitricoxide, endothelin and atrial natriuretic peptide in patients with lupus nephritis complicated with renal failure and receiving hemodialysis

    International Nuclear Information System (INIS)

    Objective: To investigate the clinical significance of changes of plasma levels of nitricoxide(NO), endothelin (ET) and atrial natriuretic peptide (ANP) before and after hemodialysis in lupus nephritis(LN) patients with renal failure. Methods: Plasma NO (with biochemistry) and ET, ANP(with RIA) levels were measured in 32 lupus patients with renal failure both before and after a course of hemodialysis and 32 controls. Results: The plasma levels of NO, ET and ANP in the 32 LN patients with renal failure were significant higher than those in controls (P<0.05) before hemodialysis, the NO, ET and ANP levels were positively correlated with the BUN and creatinine levels. After a course of hemodialysis, plasma NO and ANP decreased significantly (P<0.05), but no significant changes were observed in plasma ET levels. Conclusion: The plasma level of NO, ET and ANP could help to assess the damage of renal function and hemodialysis could lower the level of NO and ANP in LN patients with renal failure. (authors)

  12. Effect of a Single Session of Aerobic and Circuit-Resistance Exercise on Plasma Ghrelin and Agouti-Related Peptide (AgRP) Levels in Well-Trained Females

    OpenAIRE

    Mahdiyeh Ebrahimnia; Amir Rashidlamir; Mehdi Seyed-Alhosseini

    2014-01-01

    Background: Ghrelin and agouti-related protein (AgRP) are orexigenic peptides secreted from stomach mucosa and the arcuate nucleus of the hypothalamus, respectively. Both peptides affect feeding behavior and play a role in energy balance, glucose homeostasis, and adiposity. The purpose of the present study was to investigate the effect of two types of exercises, aerobic and single circuit resistance exercise on plasma ghrelin and AgRP levels. Materials and Methods: The current study is sem...

  13. Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

    DEFF Research Database (Denmark)

    Eftekhari, Sajedeh; Edvinsson, Lars

    2011-01-01

    in a network around fiber bundles in the superficial laminae. CLR and RAMP1 expression were predominately found in fibers in the spinal trigeminal tract region, with some fibers spanning into the superficial laminae. Co-localization between CGRP and its receptor components was not noted. In C1, CGRP......BACKGROUND: Calcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor components, projects peripheral to the intracranial vasculature and central...... trigeminal nucleus (STN) and the C1-level of the spinal cord. Immunohistochemistry was used to study the distribution and relation between CGRP and its receptor components - calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) - in human and rat STN and at the C1-level...

  14. Molecular Bases for the Recognition of Short Peptide Substrates and Cysteine-Directed Modifications of Human Insulin-Degrading Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Malito, Enrico; Ralat, Luis A.; Manolopoulou, Marika; Tsay, Julie L.; Wadlington, Natasha L.; Tang, Wei-Jen (UC)

    2009-12-01

    Insulin degrading enzyme (IDE) utilizes a large catalytic chamber to selectively bind and degrade peptide substrates such as insulin and amyloid {beta} (A{beta}). Tight interactions with substrates occur at an exosite located 30 {angstrom} away from the catalytic center that anchors the N-terminus of substrates to facilitate binding and subsequent cleavages at the catalytic site. However, IDE also degrades peptide substrates that are too short to occupy both the catalytic site and the exosite simultaneously. Here, we use kinins as a model system to address the kinetics and regulation of human IDE with short peptides. IDE specifically degrades bradykinin and kallidin at the Pro/Phe site. A 1.9 {angstrom} crystal structure of bradykinin-bound IDE reveals the binding of bradykinin to the exosite and not to the catalytic site. In agreement with observed high K{sub m} values, this suggests low affinity of bradykinin for IDE. This structure also provides the molecular basis on how the binding of short peptides at the exosite could regulate substrate recognition. We also found that human IDE is potently inhibited by physiologically relevant concentrations of S-nitrosylation and oxidation agents. Cysteine-directed modifications play a key role, since an IDE mutant devoid of all 13 cysteines is insensitive to the inhibition by S-nitrosoglutathione, hydrogen peroxide, or N-ethylmaleimide. Specifically, cysteine 819 of human IDE is located inside the catalytic chamber pointing toward an extended hydrophobic pocket and is critical for the inactivation. Thiol-directed modification of this residue likely causes local structural perturbation to reduce substrate binding and catalysis.

  15. Human anti-Aβ IgGs target conformational epitopes on synthetic dimer assemblies and the AD brain-derived peptide.

    Directory of Open Access Journals (Sweden)

    Alfred T Welzel

    Full Text Available Soluble non-fibrillar assemblies of amyloid-beta (Aβ and aggregated tau protein are the proximate synaptotoxic species associated with Alzheimer's disease (AD. Anti-Aβ immunotherapy is a promising and advanced therapeutic strategy, but the precise Aβ species to target is not yet known. Previously, we and others have shown that natural human IgGs (NAbs target diverse Aβ conformers and have therapeutic potential. We now demonstrate that these antibodies bound with nM avidity to conformational epitopes on plate-immobilized synthetic Aβ dimer assemblies, including synaptotoxic protofibrils, and targeted these conformers in solution. Importantly, NAbs also recognized Aβ extracted from the water-soluble phase of human AD brain, including species that migrated on denaturing PAGE as SDS-stable dimers. The critical reliance on Aβ's conformational state for NAb binding, and not a linear sequence epitope, was confirmed by the antibody's nM reactivity with plate-immobilized protofibrills, and weak uM binding to synthetic Aβ monomers and peptide fragments. The antibody's lack of reactivity against a linear sequence epitope was confirmed by our ability to isolate anti-Aβ NAbs from intravenous immunoglobulin using affinity matrices, immunoglobulin light chain fibrils and Cibacron blue, which had no sequence similarity with the peptide. These findings suggest that further investigations on the molecular basis and the therapeutic/diagnostic potential of anti-Aβ NAbs are warranted.

  16. High-level secretion and very efficient isotopic labeling of tick anticoagulant peptide (TAP) expressed in the methylotrophic yeast, Pichia pastoris.

    Science.gov (United States)

    Laroche, Y; Storme, V; De Meutter, J; Messens, J; Lauwereys, M

    1994-11-01

    Tick anticoagulant peptide (TAP) is a potent and specific inhibitor of the blood coagulation protease Factor Xa. We designed and assembled a synthetic TAP-encoding gene (tapo) based on codons preferentially observed in the highly expressed Pichia pastoris alcohol oxidase 1 gene (AOX1), and fused it to a novel hybrid secretory prepro leader sequence. Expression from this gene yielded biologically active rTAP, which was correctly processed at the amino-terminal fusion site, and accumulated in the medium to approximately 1.7 g/l. This corresponds to a molar concentration of 0.24 mM, and is the highest yet described for a recombinant product secreted from P. pastoris. It also represents a seven-fold improvement in productivity compared to rTAP secretion from Saccharomyces cerevisiae, making P. pastoris an attractive host for the industrial-scale production of this potential therapeutic agent. This system was also used to prepare 21 mg 15N-rTAP, 11 mg 13C-rTAP and 27 mg 15N/13C-rTAP, with isotope incorporation levels higher than 98%, and purities sufficient to allow their use in determining the solution structure of the tick anticoagulant peptide using high field NMR. PMID:7765555

  17. Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy.

    Directory of Open Access Journals (Sweden)

    Martha Trindade Manchini

    Full Text Available Low-level laser therapy (LLLT has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI. However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS and Kallikrein-Kinin System (KKS vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO generation.

  18. Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy.

    Science.gov (United States)

    Manchini, Martha Trindade; Serra, Andrey Jorge; Feliciano, Regiane dos Santos; Santana, Eduardo Tadeu; Antônio, Ednei Luis; de Tarso Camillo de Carvalho, Paulo; Montemor, Jairo; Crajoinas, Renato Oliveira; Girardi, Adriana Castello Costa; Tucci, Paulo José Ferreira; Silva, José Antônio

    2014-01-01

    Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation. PMID:24991808

  19. Urinary Peptides in Rett Syndrome.

    Science.gov (United States)

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  20. Type III procollagen N-terminal peptide (P-III-P), prolyl hydroxylase (PH), and laminin P sub 1 levels in serum and BALF of radiotherapy patients

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Shuichi (Komaki Municipal Hospital, Aichi (Japan)); Shindo, Jo; Horiba, Michiaki; Hara, Michihiro; Inoue, Koji

    1992-01-01

    The etiology of pulmonary fibrosis remains unclear, and at present there are no definite biochemical markers of its activity. We measured serum and BALF levels of type III procollagen N-terminal peptide (P-III-P), prolyl hydroxylase (PH), and laminin P{sub 1} in patients who had undergone radiotherapy for malignant neoplasms, and investigated their value as biochemical markers in a model of pulmonary fibrosis. The following results were obtained: 1) Patients with abnormal liver function had significantly higher serum P-III-P levels and showed a tendency to have higher serum PH levels. If P-III-P or PH are to be used as markers of pulmonary fibrosis, the effect of liver function must be taken into consideration; however, no significant difference was detected with respect to laminin P{sub 1} levels. 2) Serum P-III-P levels were significantly elevated by radiotherapy. 3) Laminin P{sub 1} levels rose in a similar manner to P-III-P levels after radiotherapy, but no significant change was detected. 4) In most cases, the levels of all markers in BALF were below the threshold of detection, nevertheless all three markers were elevated in a patient who developed diffuse radiation pneumonitis during radiotherapy. Increase in the lymphocyte count were found in BALF of this patient. 5) BALF hyaluronic acid levels were negative in the 3 cases assayed. 6) A significant correlation between P-III-P and laminin P{sub 1} in serum was shown, but no significant correlations could be found between the other combinations of markers in serum. Thus it appears that serum P-III-P and laminin P{sub 1} are valid biochemical markers of pulmonary fibrosis. It is expected that they will be useful for the detection of early radiation pneumonitis, the assessment of patients with pulmonary fibrosis, and the monitoring of steroid therapy. (author).

  1. High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer β-amyloid peptide

    Science.gov (United States)

    Rauth, Sabine; Hinz, Dominik; Börger, Michael; Uhrig, Markus; Mayhaus, Manuel; Riemenschneider, Matthias; Skerra, Arne

    2016-01-01

    Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutations targeted at 20 exposed amino acid positions in the four loops that form the natural binding site was performed using both recombinant and synthetic target peptides and resulted in three different Anticalins. Biochemical characterization of the purified proteins produced by periplasmic secretion in Escherichia coli revealed high folding stability in a monomeric state, with Tm values ranging from 53.4°C to 74.5°C, as well as high affinities for Aβ40, between 95 pM and 563 pM, as measured by real-time surface plasmon resonance analysis. The central linear VFFAED epitope within the Aβ sequence was mapped using a synthetic peptide array on membranes and was shared by all three Anticalins, despite up to 13 mutual amino acid differences in their binding sites. All Anticalins had the ability–with varying extent–to inhibit Aβ aggregation in vitro according to the thioflavin-T fluorescence assay and, furthermore, they abolished Aβ42-mediated toxicity in neuronal cell culture. Thus, these Anticalins provide not only useful protein reagents to study the molecular pathology of AD but they also show potential as alternative drug candidates compared with antibodies. PMID:27029347

  2. High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer β-amyloid peptide.

    Science.gov (United States)

    Rauth, Sabine; Hinz, Dominik; Börger, Michael; Uhrig, Markus; Mayhaus, Manuel; Riemenschneider, Matthias; Skerra, Arne

    2016-06-01

    Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutations targeted at 20 exposed amino acid positions in the four loops that form the natural binding site was performed using both recombinant and synthetic target peptides and resulted in three different Anticalins. Biochemical characterization of the purified proteins produced by periplasmic secretion in Escherichia coli revealed high folding stability in a monomeric state, with Tm values ranging from 53.4°C to 74.5°C, as well as high affinities for Aβ40, between 95 pM and 563 pM, as measured by real-time surface plasmon resonance analysis. The central linear VFFAED epitope within the Aβ sequence was mapped using a synthetic peptide array on membranes and was shared by all three Anticalins, despite up to 13 mutual amino acid differences in their binding sites. All Anticalins had the ability-with varying extent-to inhibit Aβ aggregation in vitro according to the thioflavin-T fluorescence assay and, furthermore, they abolished Aβ42-mediated toxicity in neuronal cell culture. Thus, these Anticalins provide not only useful protein reagents to study the molecular pathology of AD but they also show potential as alternative drug candidates compared with antibodies. PMID:27029347

  3. Comparative effects of recombinant human brain natriuretic peptide and dobutamine on acute decompensated heart failure patients with differsent blood BNP levels

    Science.gov (United States)

    2014-01-01

    Background Recombinant human B-type natriuretic peptide (rhBNP) has been indicated for the treatment of acute decompensated heart failure (ADHF). However, the therapeutic efficacy of intravenous rhBNP is not always satisfactory in patients with extremely high blood BNP levels. In this study, we evaluated the effects of rhBNP on patients with different BNP levels. Methods One hundred and five patients with ADHF whose left ventricular ejection fraction (LVEF) was  3000 pg/mL) , depending on their admission plasma BNP levels. Each group was then subdivided into rhBNP or dobutamine subgroups according to intravenous administration with either rhBNP or dobutamine for 24-72h. In the high BNP group, 58 patients were randomized to subgroup rhBNP (n = 28) and subgroup dobutamine (n = 30). In the extra-high BNP group, 47 patients were randomized to subgroup rhBNP (n = 24) and subgroup dobutamine (n = 23). The effects of rhBNP and dobutamine on patients in the high and extra-high BNP groups were compared. Results In the high BNP group, rhBNP was more efficient than dobutamine at improving NYHA classification (P 3000 pg/mL). Trial registration ClinicalTrials.gov Identifier: NCT01837849. PMID:24593826

  4. Responses of plasma cyclic AMP, serum immunoreactive insulin, C-peptide immunoreactivity and blood sugar levels to glucagon in patients with liver diseases.

    Directory of Open Access Journals (Sweden)

    Shimamura,Junnosuke

    1985-10-01

    Full Text Available Levels of plasma cyclic AMP, serum immunoreactive insulin (IRI, serum c-peptide immunoreactivity (CPR and blood sugar (BS were determined 0, 15, 30, 45 and 60 min after a glucagon injection (0.01 mg per kg body weight in normal controls, patients with acute hepatitis and liver cirrhosis. Plasma cyclic AMP responses to glucagon in liver disease patients varied widely in peak value, and only in patients with fulminant hepatitis and decompensated liver cirrhosis with poor prognosis was the response suppressed. The peak response of BS was found significantly later in liver cirrhosis patients than in normal controls. IRI and CPR responses to glucagon were lower in acute hepatitis patients than in normal controls and liver cirrhosis patients. IRI levels and their sum were also lower in acute hepatitis patients, although CPR levels were not significantly different. Thus, the ratio of the sum of CPR from 0 to 60 min to that of IRI was significantly higher in acute hepatitis, indicating impaired pancreatic secretion of insulin to glucagon stimulation as well as increased uptake of insulin by the liver in acute hepatitis.

  5. High N-terminal pro-B-type natriuretic peptide levels are associated with reduced heart rate variability in acute myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Luc Lorgis

    Full Text Available AIM: We investigated the relationships between the autonomic nervous system, as assessed by heart rate variability (HRV and levels of N-terminal Pro-B-type Natriuretic Peptide (Nt-proBNP in patients with acute myocardial infarction (MI. METHODS AND RESULTS: The mean of standard deviation of RR intervals (SDNN, the percentage of RR intervals with >50 ms variation (pNN50, square root of mean squared differences of successive RR intervals (rMSSD, and frequency domain parameters (total power (TP, high frequency and low frequency power ratio (LF/HF were assessed by 24 h Holter ECG monitoring. 1018 consecutive patients admitted <24 h for an acute MI were included. Plasma Nt-proBNP (Elecsys, Roche was measured from blood samples taken on admission. The median (IQR Nt-proBNP level was 681(159-2432 pmol/L. Patients with the highest quartile of Nt-proBNP were older, with higher rate of risk factors and lower ejection fraction. The highest Nt-proBNP quartile group had the lowest SDNN, LF/HF and total power but similar pNN50 and rMSSD levels. Nt-proBNP levels correlated negatively with SDNN (r = -0.19, p<0.001, LF/HF (r = -0.37, p<0.001, and LF (r = -0.29, p<0.001 but not HF (r = -0.043, p = 0.172. Multiple regression analysis showed that plasma propeptide levels remained predictive of LF/HF (B(SE = -0.065(0.015, p<0.001, even after adjustment for confounders. CONCLUSIONS: In conclusion, our population-based study highlights the importance of Nt-proBNP levels to predict decreased HRV after acute MI.

  6. Sardine protein diet increases plasma glucagon-like peptide-1 levels and prevents tissue oxidative stress in rats fed a high-fructose diet.

    Science.gov (United States)

    Madani, Zohra; Sener, Abdullah; Malaisse, Willy J; Dalila, Ait Yahia

    2015-11-01

    The current study investigated whether sardine protein mitigates the adverse effects of fructose on plasma glucagon‑like peptide-1 (GLP-1) and oxidative stress in rats. Rats were fed casein (C) or sardine protein (S) with or without high‑fructose (HF) for 2 months. Plasma glucose, insulin, GLP‑1, lipid and protein oxidation and antioxidant enzymes were assayed. HF rats developed obesity, hyperglycemia, hyperinsulinemia, insulin resistance and oxidative stress despite reduced energy and food intakes. High plasma creatinine and uric acid levels, in addition to albuminuria were observed in the HF groups. The S‑HF diet reduced plasma glucose, insulin, creatinine, uric acid and homeostasis model assessment‑insulin resistance index levels, however increased GLP‑1 levels compared with the C‑HF diet. Hydroperoxides were reduced in the liver, kidney, heart and muscle of S‑HF fed rats compared with C‑HF fed rats. A reduction in liver, kidney and heart carbonyls was observed in S‑HF fed rats compared with C‑HF fed rats. Reduced levels of nitric oxide (NO) were detected in the liver, kidney and heart of the S‑HF fed rats compared with C‑HF fed rats. The S diet compared with the C diet reduced levels of liver hydroperoxides, heart carbonyls and kidney NO. The S‑HF diet compared with the C‑HF diet increased the levels of liver and kidney superoxide dismutase, liver and muscle catalase, liver, heart and muscle glutathione peroxidase and liver ascorbic acid. The S diet prevented and reversed insulin resistance and oxidative stress, and may have benefits in patients with metabolic syndrome. PMID:26398482

  7. Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Masuda Takashi

    2010-05-01

    Full Text Available Abstract Background Glucagon-like peptide-1 (GLP-1 is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility. Metabolic syndrome (MetS is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4 inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP. In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown. Methods To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60 and pre-MetS (n = 37. Results Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P Conclusion Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

  8. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis

    DEFF Research Database (Denmark)

    Gombart, Adrian F; Bhan, Ishir; Borregaard, Niels;

    2009-01-01

    hemodialysis. Case patients (n = 81) were those who died of an infectious disease within 1 year; control patients (n = 198) were those who survived at least 1 year while undergoing dialysis. RESULTS: Mean (+/-SD) baseline levels of hCAP18 in case patients and control patients were 539 +/- 278 ng/mL and 650...

  9. Mosapride citrate, a 5-HT₄ receptor agonist, increased the plasma active and total glucagon-like peptide-1 levels in non-diabetic men.

    Science.gov (United States)

    Aoki, Kazutaka; Kamiyama, Hiroshi; Masuda, Kiyomi; Togashi, Yu; Terauchi, Yasuo

    2013-01-01

    Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion. PMID:23257734

  10. The Association between N-terminal Pro-Brain Natriuretic Peptide Levels in the Umbilical Vein and Amniotic Fluid Volume Abnormalities.

    Science.gov (United States)

    Ersoy, Ali Ozgur; Ozler, Sibel; Oztas, Efser; Ersoy, Ebru; Ergin, Merve; Erkaya, Salim; Uygur, Dilek

    2016-04-01

    Purpose The amniotic fluid volume (AFV) is known as a predictor for the wellness of a fetus. We aimed to investigate whether N-terminal pro-brain natriuretic peptide (NTproBNP) levels reflect AFV abnormalities in otherwise normal fetuses. Methods We recruited 24 women with isolated oligohydramnios, 23 women with isolated polyhydramnios, and 36 women with normal AFV at a tertiary referral center. NT-proBNP levels in umbilical venous samples and the individual characteristics of the three groups were compared. One-way ANOVA and Kruskal-Wallis analysis of variance were used for multi-group comparisons of continuous variables. When a significant difference was detected, the Scheffe test was performed as a post-hoc analysis. Proportions were compared using the Chi-square (χ2) test. Results Maternal age, body mass indices, weight gained in pregnancy and NT-proBNP levels were similar among the three groups. Apgar scores at 1 and 5 minutes significantly correlated with NT-proBNP levels in all newborns (Spearman's r = 0.23; p = 0.03 and Spearman's r = 0.24; p = 0.02, respectively). The umbilical venous NT-proBNP levels did not differ between newborns who needed mechanical ventilation and those who didn't (p = 0.595). Conclusions NT-proBNP is a biomolecule that may provide insights into the pathogenesis of fetal circulatory problems and subsequent renal failure. Further investigations are warranted. PMID:27096950

  11. Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice

    OpenAIRE

    Tohru Hasegawa; Nobuyuki Mikoda; Masashi Kitazawa; LaFerla, Frank M.

    2010-01-01

    Alzheimer's disease (AD) is an age-associated progressive neurodegenerative disorder with dementia, the exact pathogenic mechanisms of which remain unknown. We previously reported that homocysteic acid (HA) may be one of the pathological biomarkers in the brain with AD and that the increased levels of HA may induce the accumulation of intraneuronal amyloid-beta (Abeta) peptides. In this study, we further investigated the pathological role of HA in a mouse model of AD. Four-month-old prepathol...

  12. Lymphocyte Mitochondria: Towards Identification of Peripheral Biomarkers in Progression of Alzheimer Disease

    OpenAIRE

    Sultana, Rukhsana; Baglioni, Mauro; Cecchetti, Roberta; Cai, Jian; Klein, Jon B.; Bastiani, Patrizia; Ruggiero, Carmelinda; Mecocci, Patrizia; Butterfield, D. Allan

    2013-01-01

    Alzheimer disease is an age-related neurodegenerative condition. AD is histopathologically characterized by the presence of three main hallmarks: senile plaque (SP, rich in amyloid-beta peptide), neuronal fibrillary tangles (NFT, rich in phosphorylated tau protein), and synapse loss. However, definitive biomarkers for this devastating disease in living people are still lacking. In the present study, we showed that levels of oxidative stress markers are significantly increased in the mitochond...

  13. The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Zander, M; Madsbad, S; Deacon, C F;

    2006-01-01

    AIM/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) is metabolised by the enzyme dipeptidyl-peptidase 4 (DPP-4), generating a metabolite with potential antagonistic properties. This study was conducted to evaluate the effect of that metabolite on plasma glucose levels in patients with type 2 diabetes...... the metabolite increased from 1+/-3 (SAL) and 2+/-6 (IB) pmol/l to 42+/-4 (LSC), 64+/-8 (IV) and 327+/-16 (HSC) pmol/l, p<0.0001. Mean plasma glucose levels at 6 h decreased from 12.4+/-1.1 (SAL) mmol/l to 10.4+/-1.1 (LSC), 8.6+/-0.6 (IB), 8.8+/-0.8 (IV) and 9.1+/-0.9 (HSC) mmol/l, p<0....... MATERIALS AND METHODS: The randomised crossover study consisted of five regimens: (1) i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1); IV); (2 and 3) s.c. infusion of GLP-1 (2.4 and 9.6 pmol kg(-1) min(-1); LSC, HSC); (4) s.c. infusion of GLP-1 (2.4 pmol kg(-1) min(-1)) in combination with a DPP-4 inhibitor...

  14. Prognostic value of iodine-123-metaiodobenzylguanidine imaging and cardiac natriuretic peptide levels in patients with left ventricular dysfunction resulting from cardiomyopathy

    International Nuclear Information System (INIS)

    This study assessed the prognostic value of Iodine-123-metaiodobenzylguanidine (MIBG) imaging and of the plasma level of cardiac natriuretic peptides in patients with left ventricular dysfunction resulting from cardiomyopathy. Predictors of cardiac death or hospitalization related to progressive heart failure were examined in 171 patients with chronic heart failure (96 patients with idiopathic cardiomyopathy and 75 patients with ischemic cardiomyopathy). All patients underwent MIBG imaging at rest and other hemodynamic studies. During a mean (±SD) follow-up period of 27±11 months, 11 patients died from heat failure and 16 required hospitalization. High MIBG washout was an independent predictor of cardiac death (relative risk [RR]=1.158, p0.0001) and high MIBG washout (relative risk [RR]=1.094, p<0.0001) were predictors of progressive heart failure (ie, combined cardiac death and hospitalization). Accelerated myocardial adrenergic nerve activity as assessed by MIBG imaging and the plasma levels of BNP are powerful predictors of the patient's prognosis. (author)

  15. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function

    Science.gov (United States)

    Yalcin, F.; Aksoy, F. G.; Muderrisoglu, H.; Sabah, I.; Garcia, M. J.; Thomas, J. D.

    2000-01-01

    BACKGROUND: Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease. HYPOTHESIS: This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension. METHODS: Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy. RESULTS: Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.

  16. Influence of atrial fibrillation on plasma von Willebrand factor, soluble E-selectin, and N-terminal pro B-type natriuretic peptide levels in systolic heart failure

    DEFF Research Database (Denmark)

    Freestone, B.; Gustasson, F.; Chong, A.Y.; Corell, P.; Kistorp, C.; Hildebrandt, P.; Lip, G.Y.H.

    2008-01-01

    Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p = 0.003) between patients and control subjects. On Tukey post hoe analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p = 0.0183) but not E-selectin (p = 0.071) levels...... patients with systolic HF. Methods: We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with...... sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. Results: One hundred ninety patients (73% men; mean age, 69...

  17. Syntheses of Sulfo-Glycodendrimers Using Click Chemistry and Their Biological Evaluation

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    Tomohiro Fukuda

    2012-10-01

    Full Text Available A series of novel glycol-clusters containing sulfonated N-acetyl-D-glucosamine (GlcNAc have been synthesized using click chemistry. Three dendrimers with aromatic dendrons were synthesized using chlorination, azidation and click chemistries. The resulting dendrimers were modified with azide-terminated sulfonated GlcNAc using click chemistry. The sulfonated dendrimers showed affinity for proteins, including the lectin wheat germ agglutinin and amyloid beta peptide (1-42. The dendrimers of G1 and G2 in particular showed the largest affinity for the proteins. The addition of the sulfonated GlcNAc dendrimers of G1 and G2 exhibited an inhibition effect on the aggregation of the amyloid beta peptide, reduced the b-sheet conformation, and led to a reduction in the level of nanofiber formation.

  18. Maternal Testosterone Levels are Associated with C-Peptide Levels in the Mexican American Subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Cohort

    OpenAIRE

    Ackerman, C. M.; Lowe, L. P.; Dyer, A R; Hayes, M G; Metzger, B E; Lowe, W. L.; Urbanek, M

    2013-01-01

    Altered sex hormone levels are thought to play an important role in adult-onset diseases including obesity, cardiovascular disease, and diabetes. They contribute to these complex diseases through changes in their availability, which is influenced, in part, by binding proteins. Insulin resistance, which is characteristic of these diseases, along with increased insulin secretion, is a physiologic change that occurs normally during pregnancy. To determine the relationship between insulin resista...

  19. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function

    Science.gov (United States)

    Yalcin, F.; Aksoy, F. G.; Muderrisoglu, H.; Sabah, I.; Garcia, M. J.; Thomas, J. D.

    2000-01-01

    BACKGROUND: Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease. HYPOTHESIS: This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension. METHODS: Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy. RESULTS: Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p < 0.001). Left ventricular mass decreased from 252.4 +/- 8.3 to 205.7 +/- 7.08 g and left atrial volume from 20.4 +/- 5.1 to 17.6 +/- 5.2 ml, respectively (p < 0.001). Transmitral Doppler early and atrial filling velocity ratio (E/A) increased from 0.69 +/- 0.06 to 0.92 +/- 0.05 m/s and plasma ANP level decreased from 71.9 +/- 11.7 to 35.3 +/- 7.8 pg/ml (p < 0.001). Reduction of LV mass correlated positively with a reduction in ANP levels (r = 0.66, p < 0.0005). CONCLUSIONS: Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.

  20. Left ventricular diastolic dysfunction and N-terminal probrain sodium-uretic peptid level in patients with atrial fibrillation

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    Dzyak G.V.

    2013-06-01

    Full Text Available In our study 100 consecutive non-valvular permanent atrial fibrillation patients with NYHA I – III heart failure, 43 - 86 years old (65 men and 35 women were examined. Control group consisted of 30 patients with arterial hypertension and coronary artery disease matched by age, sex with basic group. Relationship of NT-proBNP with echocardiographic parameters of left heart were studied. Transthoracic echocardiography with tissue doppler measurements were performed on echocardiograph “SONOS 7500”. For left ventricular filling pressure assessment ratio Em/Ea was used due to its diagnostic value in atrial fibrillation (regardless of left ventricular ejection fraction. Mean left ventricular filling pressure was increased in patients with heart failure: in atrial fibrillation group and controls as well. In comparison with controls atrial fibrillation group was more likely to have higher both systolic and diastolic left atrial square and volume. According to Em/Ea in 95% of patients with non-valvular atrial fibrillation high left ventricular filling pressure was observed, this testifies to diastolic dysfunction. This parameter correlated well with left atrial square and volume during systole and diastole. Correlation between NT pro-BNP level and NYHA class of heart failure, left ventricular filling pressure was determined in patients with atrial fibrillation. Tissue doppler echocardiography makes it possible to diagnose left ventricular diastolic dysfunction in atrial fibrillation patients.

  1. Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma

    International Nuclear Information System (INIS)

    Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that has been approved for the treatment of metastatic renal cell carcinoma. Although the majority of sunitinib-treated patients receive a clinical benefit, almost a third of the patients will not respond. Currently there is no available marker that can predict for response in these patients. We estimated the plasma levels of NT-pro-BNP (the N-terminal precursor of brain natriuretic peptide) in 36 patients that were treated with sunitinib for metastatic clear-cell renal carcinoma. From the 36 patients, 9 had progressive disease and 27 obtained a clinical benefit (objective response or disease stabilization). Increases in plasma NT-pro-BNP were strongly correlated to clinical outcome. Patients with disease progression increased plasma BNP at statistically significant higher levels than patients that obtained a clinical benefit, and this was evident from the first 15 days of treatment (a three-fold increase in patients with progressive disease compared to stable NT-pro-BNP levels in patients with clinical benefit, p < 0.0001). Median progression-free survival was 12.0 months in patients with less than 1.5 fold increases (n = 22) and 3.9 months in patients with more than 1.5 fold increases in plasma NT-pro-BNP (n = 13) (log-rank test, p = 0.001). This is the first time that a potential 'surrogate marker' has been reported with such a clear correlation to clinical benefit at an early time of treatment. Due to the relative small number of accessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice

  2. Relationship between B-type natriuretic peptide levels and echocardiographic indices of left ventricular filling pressures in post-cardiac surgery patients

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    La Carrubba Salvatore

    2009-10-01

    Full Text Available Abstract Background B-type natriuretic peptide (BNP is increased in post-cardiac surgery patients, however the mechanisms underlying BNP release are still unclear. In the current study, we aimed to assess the relationship between postoperative BNP levels and left ventricular filling pressures in post-cardiac surgery patients. Methods We prospectively enrolled 134 consecutive patients referred to our Center 8 ± 5 days after cardiac surgery. BNP was sampled at hospital admission and related to the following echocardiographic parameters: left ventricular (LV diastolic volume (DV, LV systolic volume (SV, LV ejection fraction (EF, LV mass, relative wall thickness (RWT, indexed left atrial volume (iLAV, mitral inflow E/A ratio, mitral E wave deceleration time (DT, ratio of the transmitral E wave to the Doppler tissue early mitral annulus velocity (E/E'. Results A total of 124 patients had both BNP and echocardiographic data. The BNP values were significantly elevated (mean 353 ± 356 pg/ml, with normal value in only 17 patients (13.7%. Mean LVEF was 59 ± 10% (LVEF ≥50% in 108 pts. There was no relationship between BNP and LVEF (p = 0.11, LVDV (p = 0.88, LVSV (p = 0.50, E/A (p = 0.77, DT (p = 0.33 or RWT (p = 0.50. In contrast, BNP was directly related to E/E' (p iLAV (p = 0.026. At multivariable regression analysis, age and E/E' were the only independent predictors of BNP levels. Conclusion In post-cardiac surgery patients with overall preserved LV systolic function, the significant increase in BNP levels is related to E/E', an echocardiographic parameter of elevated LV filling pressures which indicates left atrial pressure as a major determinant in BNP release in this clinical setting.

  3. Glucagon-Like Peptide-1 Secreting Cell Function as well as Production of Inflammatory Reactive Oxygen Species Is Differently Regulated by Glycated Serum and High Levels of Glucose

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    Alessandra Puddu

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1, an intestinal hormone contributing to glucose homeostasis, is synthesized by proglucagon and secreted from intestinal neuroendocrine cells in response to nutrients. GLP-1 secretion is impaired in type 2 diabetes patients. Here, we aimed at investigating whether diabetic toxic products (glycated serum (GS or high levels of glucose (HG may affect viability, function, and insulin sensitivity of the GLP-1 secreting cell line GLUTag. Cells were cultured for 5 days in presence or absence of different dilutions of GS or HG. GS and HG (alone or in combination increased reactive oxygen species (ROS production and upregulated proglucagon mRNA expression as compared to control medium. Only HG increased total production and release of active GLP-1, while GS alone abrogated secretion of active GLP-1. HG-mediated effects were associated with the increased cell content of the prohormone convertase 1/3 (PC 1/3, while GS alone downregulated this enzyme. HG upregulated Glucokinase (GK and downregulated SYNTHAXIN-1. GS abrogated SYNTHAXIN-1 and SNAP-25. Finally, high doses of GS alone or in combination with HG reduced insulin-mediated IRS-1 phosphorylation. In conclusion, we showed that GS and HG might regulate different pathways of GLP-1 production in diabetes, directly altering the function of neuroendocrine cells secreting this hormone.

  4. Comparison of the Degree of Exercise Tolerance in Children After Surgical Treatment of Complex Cardiac Defects, Assessed Using Ergospirometry and the Level of Brain Natriuretic Peptide

    Science.gov (United States)

    Mazurek, Boguslaw; Szydlowski, Leslaw; Mazurek, Magdalena; Markiewicz-Loskot, Grazyna; Pajak, Jacek; Morka, Aleksandra

    2016-01-01

    Abstract Children who underwent surgery for complex congenital heart defects present worse exercise capacity than their healthy peers. In adults and adolescents, heart failure is assessed on the basis of clinical symptoms using the New York Heart Association (NYHA) score, while in an infant Ross scale; heart failure can also be evaluated by other parameters. The purpose of this study was to compare the degree of exercise tolerance in children after surgery for complex heart defects, assessed by the ratio of maximum oxygen uptake (VO2max) and the brain natriuretic peptide (N-terminal fragment of the prohormone brain-type natriuretic peptide [NT-proBNP]) concentration. The study group consisted of 42 children, ages 9 to 17 years (mean 14.00 ± 2.72). Among them there were 22 children with tetralogy of Fallot (ToF) after total correction, 18 children with transposition of the great arteries (d-TGA) after the arterial switch operation, and 2 children with single ventricle (SV) after the Fontan operation. All but 1 child were in NYHA class I. The control group consisted of 20 healthy children. Outcomes of interest were the ratio of VO2max, determined during ergospirometry, and the level of NT-proBNP. The statistical analysis was performed and the groups were considered significantly different for P < 0.05. There was no statistically significant correlation between NT-proBNP and maximum oxygen uptake (VO2) kg−1 min−1 in the study group compared with the control group. The VO2max in the test group had a mean value less (34.6 ± 8.0) than controls (38.4 ± 7.7), and the differences were statistically significant (P = 0.041). In contrast, the average concentration of NT-proBNP in the study group was higher than controls (117.9 ± 74.3 vs 18.0 ± 24.5), and these differences were statistically significant (P < 0.001). After operations for complex heart defects (ToF, TGA, and SV), children have worse heart function parameters and exercise

  5. N-Terminal Pro-B–Type Natriuretic Peptide Plasma Levels as a Potential Biomarker for Cardiac Damage After Radiotherapy in Patients With Left-Sided Breast Cancer

    International Nuclear Information System (INIS)

    Purpose: Adjuvant radiotherapy (RT) after breast-conserving surgery has been associated with increased cardiovascular mortality. Cardiac biomarkers may aid in identifying patients with radiation-mediated cardiac dysfunction. We evaluated the correlation between N-terminal pro-B–type natriuretic peptide (NT-proBNP) and troponin (TnI) and the dose of radiation to the heart in patients with left-sided breast cancer. Methods and Materials: NT-proBNP and TnI plasma concentrations were measured in 30 left-sided breast cancer patients (median age, 55.0 years) 5 to 22 months after RT (Group I) and in 30 left-sided breast cancer patients (median age, 57.0 years) before RT as control group (Group II). Dosimetric and geometric parameters of heart and left ventricle were determined in all patients of Group I. Seventeen patients underwent complete two-dimensional echocardiography. Results: NT-proBNP levels were significantly higher (p = 0.03) in Group I (median, 90.0 pg/ml; range, 16.7–333.1 pg/ml) than in Group II (median, 63.2 pg/ml; range, 11.0–172.5 pg/ml). TnI levels remained below the cutoff threshold of 0.07 ng/ml in both groups. In patients with NT-proBNP values above the upper limit of 125 pg/ml, there were significant correlations between plasma levels and V3Gy(%) (p = 0.001), the ratios D15cm3(Gy)/Dmean(Gy) (p = 0.01), the ratios D15cm3/D50% (Gy) (p = 0.008) for the heart and correlations between plasma levels and V2Gy (%) (p = 0.002), the ratios D1cm3(Gy)/Dmean(Gy) (p = 0.03), and the ratios D0.5cm3(Gy)/D50%(Gy) (p = 0.05) for the ventricle. Conclusions: Patients with left-sided breast cancer show higher values of NT-pro BNP after RT when compared with non–RT-treated matched patients, increasing in correlation with high doses in small volumes of heart and ventricle. The findings of this study show that the most important parameters are not the mean doses but instead the small percentage of organ volumes (heart or ventricle) receiving high dose levels

  6. Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study

    Science.gov (United States)

    2014-01-01

    Introduction High levels of the oncoprotein survivin may be detected in the majority of patients with early rheumatoid arthritis (RA). Survivin is a sensitive predictor of joint damage and persistent disease activity. Survivin-positive patients are often poor responders to antirheumatic and biological treatment. The aim of this study was to investigate the reproducibility of survivin status and its significance for clinical and immunological assessment of RA patients. Methods Survivin levels were measured in 339 patients from the Better Anti-Rheumatic FarmacOTherapy (BARFOT) cohort of early RA at baseline and after 24 months. The association of survivin status with joint damage (total Sharp-van der Heijde score), disease activity (Disease Activity Score based on evaluation of 28 joints (DAS28)), functional disability (Health Assessment Questionnaire (HAQ)), and pain perception (Visual Analogue Scale (VAS)) was calculated in the groups positive and negative for survivin on both occasions, and for the positive-negative and negative-positive groups. Results In 268 patients (79%) the levels of survivin were similar at baseline and after 24 months, 15% converted from survivin-positive to survivin-negative, and 5% from survivin-negative to survivin-positive. A combination of smoking and antibodies against cyclic citrullinated peptides (aCCP) predicted persistently (baseline and 24 months) high levels of survivin (odds ratio 4.36 (95% CI: 2.64 to 7.20), P < 0.001), positive predictive value 0.66 and specificity 0.83). The independent nature of survivin and aCCP was demonstrated by statistical and laboratory analysis. Survivin positivity on both test occasions was associated with the progression of joint damage, significantly higher DAS28 and lower rate of remission at 24 and 60 months compared to negative-negative patients. Survivin status was less associated with changes in HAQ and VAS. Conclusions Survivin is a relevant and reproducible marker of severe RA

  7. How does serum brain natriuretic peptide level change under nasal continuous positive airway pressure in obstructive sleep apnea-hypopnea syndrome?

    Science.gov (United States)

    Msaad, Sameh; Marrakchi, Rim; Grati, Malek; Gargouri, Rahma; Kammoun, Samy; Jammoussi, Kamel; Yangui, Ilhem

    2016-01-01

    Background Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with cardiovascular morbidity and mortality, which can be improved by using continuous positive airway pressure (CPAP) therapy. However, the pathophysiological links between the two kinds of disease and the mechanism of the CPAP effect remain incompletely understood. We aimed to inquire into the myocardial involvement in this relationship. We suggested that serum brain natriuretic peptide (BNP) is sensitive enough to detect myocardial stress caused by OSAHS. Design and methods Sixty-four subjects without cardiovascular disease (21 controls, 24 normotensive OSAHS patients, and 19 hypertensive OSAHS patients) were analyzed for serum BNP at baseline and serially over 6 months. CPAP was applied to 23 patients with severe OSAHS. Results At baseline, the serum BNP levels were significantly higher (p=0.0001) in the OSAHS group (22.3±14.79 pg/ml) than in the control group (9.2±6.75 pg/ml). Increased serum BNP levels were significantly associated with mean transcutaneous oxygen saturation (SpO2) (psleep time spent with SpO2 lower than 90% (p=0.002). All patients with elevated BNP levels (≥37 pg/ml) had moderate or severe OSAHS (11/43 OSAHS patients). The more severe the OSAHS, the higher the BNP levels were. However, only the difference between severe and mild OSAHS was statistically significant (p=0.029). Hypertensive OSAHS patients had the highest baseline BNP levels (27.7±16.74 pg/ml). They were significantly higher (p=0.001) than in normotensive OSAHS patients (18±11.72 pg/ml) (p=0.039) and the controls (9.2±6.75 pg/ml). As compared with baseline, treatment with CPAP significantly decreased BNP levels in both hypertensive and normotensive OSAHS patients (respectively, from 36±16.10 to 29.7±14.29 pg/ml, p<0.001, and from 20±10.09 to 16±8.98 pg/ml, p<0.001). In contrast, the BNP levels slightly increased in the controls (from 9.2±6.75 to 9.5±7.02 pg/ml, p=0.029), but there was no

  8. MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.

    Science.gov (United States)

    Burgos, Jonathan R; Iresjö, Britt-Marie; Smedh, Ulrika

    2016-04-01

    The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor per se. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid P component (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation. PMID:26780979

  9. SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

    Science.gov (United States)

    Ramirez, Alfredo; van der Flier, Wiesje M; Herold, Christine; Ramonet, David; Heilmann, Stefanie; Lewczuk, Piotr; Popp, Julius; Lacour, André; Drichel, Dmitriy; Louwersheimer, Eva; Kummer, Markus P; Cruchaga, Carlos; Hoffmann, Per; Teunissen, Charlotte; Holstege, Henne; Kornhuber, Johannes; Peters, Oliver; Naj, Adam C; Chouraki, Vincent; Bellenguez, Céline; Gerrish, Amy; Heun, Reiner; Frölich, Lutz; Hüll, Michael; Buscemi, Lara; Herms, Stefan; Kölsch, Heike; Scheltens, Philip; Breteler, Monique M; Rüther, Eckart; Wiltfang, Jens; Goate, Alison; Jessen, Frank; Maier, Wolfgang; Heneka, Michael T; Becker, Tim; Nöthen, Markus M

    2014-12-15

    Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42. PMID:25027320

  10. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

    Science.gov (United States)

    Reddy, I A; Pino, J A; Weikop, P; Osses, N; Sørensen, G; Bering, T; Valle, C; Bluett, R J; Erreger, K; Wortwein, G; Reyes, J G; Graham, D; Stanwood, G D; Hackett, T A; Patel, S; Fink-Jensen, A; Torres, G E; Galli, A

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA. PMID:27187231

  11. Biomimetic peptide nanosensors.

    Science.gov (United States)

    Cui, Yue; Kim, Sang N; Naik, Rajesh R; McAlpine, Michael C

    2012-05-15

    The development of a miniaturized sensing platform tailored for sensitive and selective detection of a variety of biochemical analytes could offer transformative fundamental and technological opportunities. Due to their high surface-to-volume ratios, nanoscale materials are extremely sensitive sensors. Likewise, peptides represent robust substrates for selective recognition due to the potential for broad chemical diversity within their relatively compact size. Here we explore the possibilities of linking peptides to nanosensors for the selective detection of biochemical targets. Such systems raise a number of interesting fundamental challenges: What are the peptide sequences, and how can rational design be used to derive selective binders? What nanomaterials should be used, and what are some strategies for assembling hybrid nanosensors? What role does molecular modeling play in elucidating response mechanisms? What is the resulting performance of these sensors, in terms of sensitivity, selectivity, and response time? What are some potential applications? This Account will highlight our early attempts to address these research challenges. Specifically, we use natural peptide sequences or sequences identified from phage display as capture elements. The sensors are based on a variety of nanomaterials including nanowires, graphene, and carbon nanotubes. We couple peptides to the nanomaterial surfaces via traditional surface functionalization methods or self-assembly. Molecular modeling provides detailed insights into the hybrid nanostructure, as well as the sensor detection mechanisms. The peptide nanosensors can distinguish chemically camouflaged mixtures of vapors and detect chemical warfare agents with sensitivities as low as parts-per-billion levels. Finally, we anticipate future uses of this technology in biomedicine: for example, devices based on these sensors could detect disease from the molecular components in human breath. Overall, these results provide a

  12. Does Serum N-Terminal pro-Brain Natriuretic Peptide Level Predict the Severity of Angiographic Lesions in Patients with Acute Coronary Syndrome?

    Directory of Open Access Journals (Sweden)

    Afsaneh Rajabiani

    2015-10-01

    Full Text Available Background: Serum N-terminal pro-brain natriuretic peptide (NT-proBNP, a polypeptide secreted by ventricular myocytes in response to stretch, was suggested as a predictor of adverse prognosis of the acute coronary syndrome (ACS. We examined the association between NT-proBNP level and angiographic findings in ACS patients to determine whether it could be used as a predictor of the severity of angiographic lesions.Methods: This cross-sectional study was performed on 126 patients with chest pain or other ischemic heart symptoms suggestive  of ACS.  Venous  blood  samples  were  drawn  to  measure  serum  levels  of  NT-proBNP. Afterward,  coronary angiography was performed and the patients were categorized into four groups according to the number of coronary vessels with significant stenosis. The severity of angiographic lesions was assessed with the Gensini scoring system.Results: According to angiographic diagnosis, 11 (8.7% patients had normal coronary arteries (no coronary artery disease [CAD] and 115 (91.3% had CAD, of whom 108 (85.7% had obstructive CAD and 7 (5.6% had minimal CAD. The serum NT-proBNP concentration was higher in the CAD group than in the non-CAD group (p value <0.01. A progressive significant increase in the NT-proBNP concentration according to the Gensini score and the number of involved vessels was reported after adjustment for sex and age. Furthermore, the Receiver Operating Characteristic Curve (ROC analysis indicated that an NT-proBNP cut-point of 400 pg/ml could predict obstructive CAD with a sensitivity of 65% and a specificity of 78%.Conclusion: Higher levels of NT-proBNP among our ACS patients were associated with the severity of angiographic lesions in terms of both the Gensini score and the number of involved vessels. This finding underscores the potential role of NT-proBNP in predicting the severity of CAD before performing angiography.

  13. Plasma Levels of Monocyte Chemoattractant Protein-1, n-Terminal Fragment of Brain Natriuretic Peptide and Calcidiol Are Independently Associated with the Complexity of Coronary Artery Disease.

    Directory of Open Access Journals (Sweden)

    Roberto Martín-Reyes

    Full Text Available We investigated the relationship of the Syntax Score (SS and coronary artery calcification (CAC, with plasma levels of biomarkers related to cardiovascular damage and mineral metabolism, as there is sparse information in this field.We studied 270 patients with coronary disease that had an acute coronary syndrome (ACS six months before. Calcidiol, fibroblast growth factor-23, parathormone, phosphate and monocyte chemoattractant protein-1 [MCP-1], high-sensitivity C-reactive protein, galectin-3, and N-terminal pro-brain natriuretic peptide [NT-proBNP] levels, among other biomarkers, were determined. CAC was assessed by coronary angiogram as low-grade (0-1 and high-grade (2-3 calcification, measured with a semiquantitative scale ranging from 0 (none to 3 (severe. For the SS study patients were divided in SS<14 and SS≥14. Multivariate linear and logistic regression analyses were performed.MCP-1 predicted independently the SS (RC = 1.73 [95%CI = 0.08-3.39]; p = 0.040, along with NT-proBNP (RC = 0.17 [95%CI = 0.05-0.28]; p = 0.004, male sex (RC = 4.15 [95%CI = 1.47-6.83]; p = 0.003, age (RC = 0.13 [95%CI = 0.02-0.24]; p = 0.020, hypertension (RC = 3.64, [95%CI = 0.77-6.50]; p = 0.013, hyperlipidemia (RC = 2.78, [95%CI = 0.28-5.29]; p = 0.030, and statins (RC = 6.12 [95%CI = 1.28-10.96]; p = 0.013. Low calcidiol predicted high-grade calcification independently (OR = 0.57 [95% CI = 0.36-0.90]; p = 0.013 along with ST-elevation myocardial infarction (OR = 0.38 [95%CI = 0.19-0.78]; p = 0.006, diabetes (OR = 2.35 [95%CI = 1.11-4.98]; p = 0.028 and age (OR = 1.37 [95%CI = 1.18-1.59]; p<0.001. During follow-up (1.79 [0.94-2.86] years, 27 patients developed ACS, stroke, or transient ischemic attack. A combined score using SS and CAC predicted independently the development of the outcome.MCP-1 and NT-proBNP are independent predictors of SS, while low calcidiol plasma levels are associated with CAC. More studies are needed to confirm these data.

  14. Plasma Levels of Monocyte Chemoattractant Protein-1, n-Terminal Fragment of Brain Natriuretic Peptide and Calcidiol Are Independently Associated with the Complexity of Coronary Artery Disease

    Science.gov (United States)

    Martín-Reyes, Roberto; Franco-Peláez, Juan Antonio; Lorenzo, Óscar; González-Casaus, María Luisa; Pello, Ana María; Aceña, Álvaro; Carda, Rocío; Martín-Ventura, José Luis; Blanco-Colio, Luis; Martín-Mariscal, María Luisa; Martínez-Milla, Juan; Villa-Bellosta, Ricardo; Piñero, Antonio; Navarro, Felipe; Egido, Jesús; Tuñón, José

    2016-01-01

    Background and Objectives We investigated the relationship of the Syntax Score (SS) and coronary artery calcification (CAC), with plasma levels of biomarkers related to cardiovascular damage and mineral metabolism, as there is sparse information in this field. Methods We studied 270 patients with coronary disease that had an acute coronary syndrome (ACS) six months before. Calcidiol, fibroblast growth factor-23, parathormone, phosphate and monocyte chemoattractant protein-1 [MCP-1], high-sensitivity C-reactive protein, galectin-3, and N-terminal pro-brain natriuretic peptide [NT-proBNP] levels, among other biomarkers, were determined. CAC was assessed by coronary angiogram as low-grade (0–1) and high-grade (2–3) calcification, measured with a semiquantitative scale ranging from 0 (none) to 3 (severe). For the SS study patients were divided in SS<14 and SS≥14. Multivariate linear and logistic regression analyses were performed. Results MCP-1 predicted independently the SS (RC = 1.73 [95%CI = 0.08–3.39]; p = 0.040), along with NT-proBNP (RC = 0.17 [95%CI = 0.05–0.28]; p = 0.004), male sex (RC = 4.15 [95%CI = 1.47–6.83]; p = 0.003), age (RC = 0.13 [95%CI = 0.02–0.24]; p = 0.020), hypertension (RC = 3.64, [95%CI = 0.77–6.50]; p = 0.013), hyperlipidemia (RC = 2.78, [95%CI = 0.28–5.29]; p = 0.030), and statins (RC = 6.12 [95%CI = 1.28–10.96]; p = 0.013). Low calcidiol predicted high-grade calcification independently (OR = 0.57 [95% CI = 0.36–0.90]; p = 0.013) along with ST-elevation myocardial infarction (OR = 0.38 [95%CI = 0.19–0.78]; p = 0.006), diabetes (OR = 2.35 [95%CI = 1.11–4.98]; p = 0.028) and age (OR = 1.37 [95%CI = 1.18–1.59]; p<0.001). During follow-up (1.79 [0.94–2.86] years), 27 patients developed ACS, stroke, or transient ischemic attack. A combined score using SS and CAC predicted independently the development of the outcome. Conclusions MCP-1 and NT-proBNP are independent predictors of SS, while low calcidiol plasma levels

  15. The Impact of Trimetazidine Treatment on Left Ventricular Functions and Plasma Brain Natriuretic Peptide Levels in Patients with Non-ST Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention

    OpenAIRE

    Demirelli, Selami; KARAKELLEOĞLU, Şule; Gündoğdu, Fuat; TAŞ, Muhammed Hakan; KAYA, Ahmet; Duman, Hakan; Değirmenci, Hüsnü; Hamur, Hikmet; Şimşek, Ziya

    2013-01-01

    Background and Objectives The aim of this study was to investigate the impact of treatment with oral trimetazidine (TMZ) applied before and after percutaneous coronary interventions (PCI) on short-term left ventricular functions and plasma brain natriuretic peptide (BNP) levels in patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing PCI. Subjects and Methods The study included 45 patients who were undergoing PCI with the diagnosis of NSTEMI. The patients were rando...

  16. Protective effect of amyloid-beta 42 protein and its subunit vaccines immunization on spatial learning and memory of APPSWE transgenic mice%淀粉样β蛋白42及其亚单位疫苗预防接种对APPSWE转基因小鼠学习记忆能力的保护作用

    Institute of Scientific and Technical Information of China (English)

    胡金家; 李国营; 汪华侨; 李少兵; 袁群芳; 谢瑶; 姚志彬

    2005-01-01

    照组、淀粉样β蛋白42组、淀粉样β蛋白1-15组和淀粉样β蛋白36-42组小鼠空间探索试验穿过平台次数分别为0.71±0.29,8.14±1.37,7.28±1.34和3.29±0.67,第一象限游泳距离百分率分别为(24.3±2.9)%,(50.6±11.6)%,(49.9±9.3)%和(35.4±7.0)%,20%边缘区游泳距离百分率分别为(46.4±7.3)%,(11.6±3.9)%,(14.4±2.6)%和(25.8±3.3)%,淀粉样β蛋白42组、淀粉样β蛋白1-15组和淀粉样β蛋白36-42组较对照组穿过平台次数显著增多、第一象限游泳距离百分率升高和20%边缘区游泳距离百分率降低,其中淀粉样β蛋白42组、淀粉样β蛋白1-15组和淀粉样β蛋白36-42组比较差异无显著性意义(P<0.05).结论:淀粉样β蛋白42及其亚单位疫苗预防接种可有效减轻APPSWE转基因小鼠学习记忆能力的损害.%BACKGROUND: It has been demonstrated that amyloid-beta 42 protein (Aβ42) immunization in transgenic mouse models of Alzheimer disease(AD)can induce specific Aβ42 antibody, clear Aβ from the brain, and thereby improve spatial learning and memory. It has been a promising treatment strategy for AD.OBJECTIVE: To explore the effect of Aβ42 and its subunit vaccines immunization on spatial learning and memory of APPSWE transgenic mice.DESIGN: A randomized controlled experiment with mice as subjects.SETTING: The brain research laboratory of the anatomy department in a the medical college of a univeristy.MATERIALS: The experiment was conducted in the Experimental Animal Center and the Anatomy Department of Sun Yat-sen University from April 2003 to February 2004. Thirty-two APPSWE transgenic mice of 5 months old were bought from Taconic Company, USA. The second generation of mice were successfully reproduced in the Anatomy Department. These mice were randomly assigned into four groups: control group, Aβ42 group, Aβ1-15group, and Aβ36-42 group. Each group contained 8 in each group.INTERVENTIONS: Aβ42 and its subunits combined with MF59 adjuvant were subcutaneously injected for

  17. Galanin-like peptide (GALP) neurone-specific phosphoinositide 3-kinase signalling regulates GALP mRNA levels in the hypothalamus of males and luteinising hormone levels in both sexes.

    Science.gov (United States)

    Aziz, R; Beymer, M; Negrón, A L; Newshan, A; Yu, G; Rosati, B; McKinnon, D; Fukuda, M; Lin, R Z; Mayer, C; Boehm, U; Acosta-Martínez, M

    2014-07-01

    Galanin-like peptide (GALP) neurones participate in the metabolic control of reproduction and are targets of insulin and leptin regulation. Phosphoinositide 3-kinase (PI3K) is common to the signalling pathways utilised by both insulin and leptin. Therefore, we investigated whether PI3K signalling in neurones expressing GALP plays a role in the transcriptional regulation of the GALP gene and in the metabolic control of luteinising hormone (LH) release. Accordingly, we deleted PI3K catalytic subunits p110α and p110β via conditional gene targeting (cKO) in mice (GALP-p110α/β cKO). To monitor PI3K signalling in GALP neurones, these animals were also crossed with Cre-dependent FoxO1GFP reporter mice. Compared to insulin-infused control animals, the PI3K-Akt-dependent FoxO1GFP nuclear exclusion in GALP neurones was abolished in GALP-p110α/β cKO mice. We next used food deprivation to investigate whether the GALP-neurone specific ablation of PI3K activity affected the susceptibility of the gonadotrophic axis to negative energy balance. Treatment did not affect LH levels in either sex. However, a significant genotype effect on LH levels was observed in females. By contrast, no genotype effect on LH levels was observed in males. A sex-specific genotype effect on hypothalamic GALP mRNA was observed, with fed and fasted GALP-p110α/β cKO males having lower GALP mRNA expression compared to wild-type fed males. Finally, the effects of gonadectomy and steroid hormone replacement on GALP mRNA levels were investigated. Compared to vehicle-treated mice, steroid hormone replacement reduced mediobasal hypothalamus GALP expression in wild-type and GALP-p110α/β cKO animals. In addition, within the castrated and vehicle-treated group and compared to wild-type mice, LH levels were lower in GALP-p110α/β cKO males. Double immunofluorescence using GALP-Cre/R26-YFP mice showed androgen and oestrogen receptor co-localisation within GALP neurones. Our data demonstrate that GALP

  18. The Equine PeptideAtlas

    DEFF Research Database (Denmark)

    Bundgaard, Louise; Jacobsen, Stine; Sorensen, Mette A.;

    2014-01-01

    Progress in MS-based methods for veterinary research and diagnostics is lagging behind compared to the human research, and proteome data of domestic animals is still not well represented in open source data repositories. This is particularly true for the equine species. Here we present a first...... current release comprises 24 131 distinct peptides representing 2636 canonical proteins observed at false discovery rates of 0.2% at the peptide level and 1.4% at the protein level. Data from the Equine PeptideAtlas are available for experimental planning, validation of new datasets, and as a proteomic...... data mining resource. The advantages of the Equine PeptideAtlas are demonstrated by examples of mining the contents for information on potential and well-known equine acute phase proteins, which have extensive general interest in the veterinary clinic. The extracted information will support further...

  19. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults

    DEFF Research Database (Denmark)

    Kistorp, Caroline; Raymond, Ilan; Pedersen, Frants;

    2005-01-01

    B-type natriuretic peptides have been shown to predict cardiovascular disease in apparently healthy individuals but their predictive ability for mortality and future cardiovascular events compared with C-reactive protein (CRP) and urinary albumin/creatinine ratio is unknown....

  20. Random Insertion of a TetR-Inducing Peptide Tag into Escherichia coli Proteins Allows Analysis of Protein Levels by Induction of Reporter Gene Expression

    OpenAIRE

    Schlicht, Maximilian; Berens, Christian; Daam, Janko; Hillen, Wolfgang

    2006-01-01

    The insertion element InsTipα was constructed to generate protein expression data. It randomly fuses the TetR-inducing peptide Tip to the affected reading frame. Fusion protein expression is quantified by Tet-regulated reporter gene expression. The expression patterns of tagged Escherichia coli genes fully agree with published data from transcriptional fusions or microarrays, validating the Tip tag approach.

  1. Exercise alleviates hypoalgesia and increases the level of calcitonin gene-related peptide in the dorsal horn of the spinal cord of diabetic rats

    Directory of Open Access Journals (Sweden)

    Patrícia Severo do Nascimento

    2012-09-01

    Full Text Available OBJECTIVE: The aim of this study was to evaluate the effects of treadmill training on nociceptive sensitivity and immunoreactivity to calcitonin gene-related peptide in the dorsal horn of the spinal cord of diabetic rats. METHODS: Male Wistar rats were divided into three groups: control, diabetic and trained diabetic. Treadmill training was performed for 8 weeks. The blood glucose concentrations and body weight were evaluated 48 h after diabetes induction and every 30 days thereafter. The nociceptive sensitivity was evaluated using the tail-flick apparatus. The animals were then transcardially perfused, and the spinal cords were post-fixed, cryoprotected and sectioned in a cryostat. Immunohistochemistry for calcitonin gene-related peptide analysis was performed on the dorsal horn of the spinal cord. RESULTS: The nociceptive sensitivity analysis revealed that, compared with the control and trained diabetic animals, the latency to tail deflection on the apparatus was longer for the diabetic animals. Optical densitometry demonstrated decreased calcitonin gene-related peptide immunoreactivity in the dorsal horn of the spinal cord in diabetic animals, which was reversed by treadmill training. CONCLUSION: We concluded that treadmill training can alleviate nociceptive hypoalgesia and reverse decreased calcitonin gene-related peptide immunoreactivity in the dorsal horn of the spinal cord of diabetic animals without pharmacological treatment.

  2. Effect of a Single Session of Aerobic and Circuit-Resistance Exercise on Plasma Ghrelin and Agouti-Related Peptide (AgRP Levels in Well-Trained Females

    Directory of Open Access Journals (Sweden)

    Mahdiyeh Ebrahimnia

    2014-06-01

    Full Text Available Background: Ghrelin and agouti-related protein (AgRP are orexigenic peptides secreted from stomach mucosa and the arcuate nucleus of the hypothalamus, respectively. Both peptides affect feeding behavior and play a role in energy balance, glucose homeostasis, and adiposity. The purpose of the present study was to investigate the effect of two types of exercises, aerobic and single circuit resistance exercise on plasma ghrelin and AgRP levels. Materials and Methods: The current study is semi-experimental. Twenty two athletes young females randomly selected and assigned into two experimental groups and one control group. Blood samples were collected before and after the enforced protocol. Plasma AgRP and ghrelin levels were measured using the enzyme-linked immunosorbent assay (ELISA method. Results: Results showed a significant increase in plasma AgRP (p=0.001 and ghrelin concentration in control and aerobic (p=0.001 and circulate-resistance (p=0.001 groups. Conclusion: In healthy females a single session of aerobic and circuit-resistance exercise could be associated with the increase of these peptides in response to the negative balance of energy produced by exercising for increasing appetite to compensate energy resources body subjects.

  3. Radioiodination of monoclonal antibodies, proteins and peptides for diagnosis and therapy. A review of standardized, reliable and safe procedures for clinical grade levels kBq to GBq in the Goettingen/Marburg experience

    Energy Technology Data Exchange (ETDEWEB)

    Behr, Th.M.; Gotthardt, M.; Behe, M. [Marburg Univ. (Germany). Dept. of Nuclear Medicine; Becker, W. [Goettingen Univ. (Germany). Dept. of Nuclear Medicine

    2002-04-01

    Simple and reliable methodologies for radioiodination of proteins and peptides are described. The labeling systems are easy to assemble, capable of radioiodinating any protein or, with slight modifications, also peptide (molecular mass 1000-300,000) from kBq to GBq levels of activity for use in diagnosis and/or therapy. Furthermore, the procedures are feasible in any nuclear medicine department. Gigabecquerel amounts of activity can be handled safely. The most favored iodination methodology relies on the lodogen system, a mild oxidating agent without reducing agents. Thus, protein degradation is minimized. Labeling yields are between 60 and 90%, and immunoreactivities remain {>=}85%. Other radioiodination methods (chloramine-T, Bolton-Hunter) are described and briefly discussed. (orig.)

  4. Radioiodination of monoclonal antibodies, proteins and peptides for diagnosis and therapy. A review of standardized, reliable and safe procedures for clinical grade levels kBq to GBq in the Goettingen/Marburg experience

    International Nuclear Information System (INIS)

    Simple and reliable methodologies for radioiodination of proteins and peptides are described. The labeling systems are easy to assemble, capable of radioiodinating any protein or, with slight modifications, also peptide (molecular mass 1000-300,000) from kBq to GBq levels of activity for use in diagnosis and/or therapy. Furthermore, the procedures are feasible in any nuclear medicine department. Gigabecquerel amounts of activity can be handled safely. The most favored iodination methodology relies on the lodogen system, a mild oxidating agent without reducing agents. Thus, protein degradation is minimized. Labeling yields are between 60 and 90%, and immunoreactivities remain ≥85%. Other radioiodination methods (chloramine-T, Bolton-Hunter) are described and briefly discussed. (orig.)

  5. δ-Aminolevulinic Acid Dehydratase Single Nucleotide Polymorphism 2 (ALAD2) and Peptide Transporter 2*2 Haplotype (hPEPT2*2) Differently Influence Neurobehavior in Low-Level Lead Exposed Children

    OpenAIRE

    Sobin, Christina; Gisel Flores-Montoya, Mayra; Gutierrez, Marisela; Parisi, Natali; Schaub, Tanner

    2014-01-01

    Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and ne...

  6. In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function

    DEFF Research Database (Denmark)

    Follin, Elna; Karlsson, Maria; Lundegaard, Claus; Nielsen, Morten; Wallin, Stefan; Paulsson, Kajsa Maria; Westerdahl, Helena

    2013-01-01

    The major histocompatibility complex (MHC) genes are the most polymorphic genes found in the vertebrate genome, and they encode proteins that play an essential role in the adaptive immune response. Many songbirds (passerines) have been shown to have a large number of transcribed MHC class I genes...... compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (α1–α3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide-binding predictions to investigate their...... functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably...

  7. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease.

    Science.gov (United States)

    Rovelet-Lecrux, A; Charbonnier, C; Wallon, D; Nicolas, G; Seaman, M N J; Pottier, C; Breusegem, S Y; Mathur, P P; Jenardhanan, P; Le Guennec, K; Mukadam, A S; Quenez, O; Coutant, S; Rousseau, S; Richard, A-C; Boland, A; Deleuze, J-F; Frebourg, T; Hannequin, D; Campion, D

    2015-09-01

    We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD. PMID:26194182

  8. Influence of the amount of co-infused amino acids on post-therapeutic potassium levels in peptide receptor radionuclide therapy

    OpenAIRE

    Werner, Rudolf A; Lapa, Constantin; Bluemel, Christina; Lückerath, Katharina; Schirbel, Andreas; Strate, Alexander; Buck, Andreas K.; Herrmann, Ken

    2014-01-01

    Background Peptide receptor radionuclide therapy (PRRT) is routinely used for advanced or metastasized neuroendocrine tumours (NET). To prevent nephrotoxicity, positively charged amino acids (AA) are co-infused. The aim of this study was to correlate the risk for therapy-related hyperkalaemia with the total amount of AA infused. Methods Twenty-two patients undergoing PRRT with standard activities of 177Lu-DOTATATE/-TOC were monitored during two following treatment cycles with co-i...

  9. Changes in liraglutide-induced body composition are related to modifications in plasma cardiac natriuretic peptides levels in obese type 2 diabetic patients

    OpenAIRE

    Li, Chun-Jun; Yu, Qian; Yu, Pei; Yu, Tie-Lian; Zhang, Qiu-mei; Lu, Shan; Yu, De-Min

    2014-01-01

    Background and aims Liraglutide treatment can improve glycemic control with a concomitant weight loss, but the underlying mechanism on weight loss is not completely understood. Cardiac natriuretic peptides (NPs) can resist body fat accumulation through increasing adipocytes lypolysis. In this study, we tested the hypothesis that liraglutide-induced weight loss was associated with increased plasma NPs concentrations. Methods Thirty-one outpatients with type 2 diabetes (T2D) treated with metfor...

  10. Utility of indices using C‐peptide levels for indication of insulin therapy to achieve good glycemic control in Japanese patients with type 2 diabetes

    OpenAIRE

    Funakoshi, Shogo; Fujimoto, Shimpei; Hamasaki, Akihiro; Fujiwara, Hideya; Fujita, Yoshihito; Ikeda, Kaori; Takahara, Shiho; Nagashima, Kazuaki; Hosokawa, Masaya; Seino, Yutaka; Inagaki, Nobuya

    2011-01-01

    Abstract Aims/Introduction:  Type 2 diabetes is progressive in that therapy must be altered over time, which is partly as a result of the progressive loss of pancreatic β‐cell function. To elucidate the relationship between residual endogenous insulin secretion and the necessity of insulin therapy to achieve good glycemic control, indices using serum C‐peptide immunoreactivity (CPR) were analyzed in patients with type 2 diabetes. Materials and Methods:  The data of 201 Japanese patients with ...

  11. Membrane Perturbation Induced by Interfacially Adsorbed Peptides

    OpenAIRE

    Zemel, Assaf; Ben-Shaul, Avinoam; May, Sylvio

    2004-01-01

    The structural and energetic characteristics of the interaction between interfacially adsorbed (partially inserted) α-helical, amphipathic peptides and the lipid bilayer substrate are studied using a molecular level theory of lipid chain packing in membranes. The peptides are modeled as “amphipathic cylinders” characterized by a well-defined polar angle. Assuming two-dimensional nematic order of the adsorbed peptides, the membrane perturbation free energy is evaluated using a cell-like model;...

  12. [Brain natriuretic peptide].

    Science.gov (United States)

    La Villa, G; Lazzeri, C; Fronzaroli, C; Franchi, F; Gentilini, P

    1995-01-01

    Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis. PMID:8718658

  13. Human peptide transporters

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Brodin, Birger; Jørgensen, Flemming Steen;

    2002-01-01

    Peptide transporters are epithelial solute carriers. Their functional role has been characterised in the small intestine and proximal tubules, where they are involved in absorption of dietary peptides and peptide reabsorption, respectively. Currently, two peptide transporters, PepT1 and PepT2, wh...

  14. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels

    DEFF Research Database (Denmark)

    Reddy, I A; Pino, J A; Weikop, P;

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine...... actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the...... ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the...

  15. Exogenous glucagon-like peptide-2 (GLP-2) augments GLP-2 receptor mRNA and maintains proglucagon mRNA levels in resected rats

    DEFF Research Database (Denmark)

    Koopmann, Matthew C; Nelson, David W; Murali, Sangita G;

    2008-01-01

    BACKGROUND: Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon-derived hormone that stimulates intestinal adaptive growth. Our aim was to determine whether exogenous GLP-2 increases resection-induced adaptation without diminishing endogenous proglucagon and GLP-2 receptor...... expression. METHODS: Rats underwent transection or 70% jejunoileal resection +/- GLP-2 infusion (100 microg/kg body weight/d) and were fed a semipurified diet with continuous infusion of GLP-2 or saline by means of jugular catheter. After 7 days, body weight, mucosal cellularity (dry mass, protein and DNA......), crypt-villus height, and crypt cell proliferation (by bromodeoxyuridine staining) were determined. Plasma bioactive GLP-2 (by radioimmunoassay), proglucagon and GLP-2 receptor mRNA expression (by Northern blot and real-time reverse transcriptase quantitative polymerase chain reaction) were measured. GLP...

  16. Peptide-Carrier Conjugation

    DEFF Research Database (Denmark)

    Hansen, Paul Robert

    To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined.......To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined....

  17. Reversible peptide oligomerization over nanoscale gold surfaces

    Directory of Open Access Journals (Sweden)

    Kazushige Yokoyama

    2015-11-01

    Full Text Available A selective oligomeric formation of amyloid beta 1-40 (Ab1-40 monomers over a nanogold colloidal surface was investigated. An unfolded Ab1-40 monomer is considered to construct a dimer or trimer based oligomeric form with its hydrophobic segment placing outward under an acidic condition. Under a basic condition, a conformation of Ab is expected to take a folded monomeric form with its hydrophilic segment folded inward, avoiding the networking with residual colloidal particles. The most probable oligomeric form constructed over a 20 nm gold colloidal surface within a 25 ℃ to 65 ℃ temperature range is a dimer based unit and that over 30 or 40 nm gold colloidal surface below 15 ℃ is concluded to be a trimer based unit. However, selective oligomerization was not successfully reproduced under the rest of the conditions. A dipole-induced dipole interaction must cause a flexible structural change between folded and unfolded forms.

  18. The immunotherapy of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Weksler Marc E

    2004-11-01

    Full Text Available Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.

  19. PeptideAtlas

    Data.gov (United States)

    U.S. Department of Health & Human Services — PeptideAtlas is a multi-organism, publicly accessible compendium of peptides identified in a large set of tandem mass spectrometry proteomics experiments. Mass...

  20. Peptider holder krabben rask

    DEFF Research Database (Denmark)

    Buchmann, Kurt

    Antimikrobielle Peptider har hos mere primitive dyr en vigtig funktion i organismernes immunforsvar Udgivelsesdato: 1. februar......Antimikrobielle Peptider har hos mere primitive dyr en vigtig funktion i organismernes immunforsvar Udgivelsesdato: 1. februar...

  1. Peptide Nucleic Acid Synthons

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  2. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2003-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  3. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    1998-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  4. Peptide Nucleic Acids (PNA)

    DEFF Research Database (Denmark)

    2002-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  5. Antimicrobial Peptides in 2014

    Directory of Open Access Journals (Sweden)

    Guangshun Wang

    2015-03-01

    Full Text Available This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.

  6. PH dependent adhesive peptides

    Science.gov (United States)

    Tomich, John; Iwamoto, Takeo; Shen, Xinchun; Sun, Xiuzhi Susan

    2010-06-29

    A novel peptide adhesive motif is described that requires no receptor or cross-links to achieve maximal adhesive strength. Several peptides with different degrees of adhesive strength have been designed and synthesized using solid phase chemistries. All peptides contain a common hydrophobic core sequence flanked by positively or negatively charged amino acids sequences.

  7. Natriuretic peptides and their therapeutic potential.

    Science.gov (United States)

    Cho, Y; Somer, B G; Amatya, A

    1999-01-01

    Natriuretic peptides are a group of naturally occurring substances that act in the body to oppose the activity of the renin-angiotensin system. There are three major natriuretic peptides: atrial natriuretic peptide (ANP), which is synthesized in the atria; brain natriuretic peptide (BNP), which is synthesized in the ventricles; and C-type natriuretic peptide (CNP), which is synthesized in the brain. Both ANP and BNP are released in response to atrial and ventricular stretch, respectively, and will cause vasorelaxation, inhibition of aldosterone secretion in the adrenal cortex, and inhibition of renin secretion in the kidney. Both ANP and BNP will cause natriuresis and a reduction in intravascular volume, effects amplified by antagonism of antidiuretic hormone (ADH). The physiologic effects of CNP are different from those of ANP and BNP. CNP has a hypotensive effect, but no significant diuretic or natriuretic actions. Three natriuretic peptide receptors (NPRs) have been described that have different binding capacities for ANP, BNP, and CNP. Removal of the natriuretic peptides from the circulation is affected mainly by binding to clearance receptors and enzymatic degradation in the circulation. Increased blood levels of natriuretic peptides have been found in certain disease states, suggesting a role in the pathophysiology of those diseases, including congestive heart failure (CHF), systemic hypertension, and acute myocardial infarction. The natriuretic peptides also serve as disease markers and indicators of prognosis in various cardiovascular conditions. The natriuretic peptides have been used in the treatment of disease, with the most experience with intravenous BNP in the treatment of CHF. Another pharmacologic approach being used is the inhibition of natriuretic peptide metabolism by neutral endopeptidase (NEP) inhibitor drugs. The NEP inhibitors are currently being investigated as treatments for CHF and systemic hypertension. PMID:11720638

  8. Membrane poration by antimicrobial peptides combining atomistic and coarse-grained descriptions

    NARCIS (Netherlands)

    Rzepiela, Andrzej J.; Sengupta, Durba; Goga, Nicolae; Marrink, Siewert J.

    2010-01-01

    Antimicrobial peptides (AMPs) comprise a large family of peptides that include small cationic peptides, such as magainins, which permeabilize lipid membranes. Previous atomistic level simulations of magainin-H2 peptides show that they act by forming toroidal transmembrane pores. However, due to the

  9. [Plant signaling peptides. Cysteine-rich peptides].

    Science.gov (United States)

    Ostrowski, Maciej; Kowalczyk, Stanisław

    2015-01-01

    Recent bioinformatic and genetic analyses of several model plant genomes have revealed the existence of a highly abundant group of signaling peptides that are defined as cysteine-rich peptides (CRPs). CRPs are usually in size between 50 and 90 amino acid residues, they are positively charged, and they contain 4-16 cysteine residues that are important for the correct conformational folding. Despite the structural differences among CRP classes, members from each class have striking similarities in their molecular properties and function. The present review presents the recent progress in research on signaling peptides from several families including: EPF/EPFL, SP11/SCR, PrsS, RALF, LURE, and some other peptides belonging to CRP group. There is convincing evidence indicating multiple roles for these CRPs as signaling molecules during the plant life cycle, ranging from stomata development and patterning, self-incompatibility, pollen tube growth and guidance, reproductive processes, and nodule formation. PMID:26281357

  10. A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus.

    Science.gov (United States)

    Mansur, Sity Aishah; Mieczkowska, Aleksandra; Flatt, Peter R; Bouvard, Beatrice; Chappard, Daniel; Irwin, Nigel; Mabilleau, Guillaume

    2016-06-01

    Obesity and type 2 diabetes mellitus (T2DM) progress worldwide with detrimental effects on several physiological systems including bone tissue mainly by affecting bone quality. Several gut hormones analogues have been proven potent in ameliorating bone quality. In the present study, we used the leptin receptor-deficient db/db mice as a model of obesity and severe T2DM to assess the extent of bone quality alterations at the organ and tissue levels. We also examined the beneficial effects of gut hormone therapy in this model by using a new triple agonist ([d-Ala(2)]GIP-Oxm) active at the GIP, GLP-1 and glucagon receptors. As expected, db/db mice presented with dramatic alterations of bone strength at the organ level associated with deterioration of trabecular and cortical microarchitectures and an augmentation in osteoclast numbers. At the tissue level, these animals presented also with alterations of bone strength (reduced hardness, indentation modulus and dissipated energy) with modifications of tissue mineral distribution, collagen glycation and collagen maturity. The use of [d-Ala(2)]GIP-Oxm considerably improved bone strength at the organ level with modest effects on trabecular microarchitecture. At the tissue level, [d-Ala(2)]GIP-Oxm ameliorated bone strength reductions with positive effects on collagen glycation and collagen maturity. This study provides support for including gut hormone analogues as possible new therapeutic strategies for improving bone quality in bone complications associated to T2DM. PMID:27062994

  11. Blood angiotensin II (AT-II), vascular endothelial growth factor (VEGF), endothelin (ET) and atrial natriuretic peptide (ANP) levels before and after treatment in patients with diabetic nephropathy

    International Nuclear Information System (INIS)

    Objective: To evaluate the treatment effect of chinese herb medicine by observing variations of blood AT-II, VEGF, ET and ANP levels in patients with diabetic nephropathy (DN). Methods: Seventy DN patients were divided into two groups: combined chinese herb with western medicine treated group (n=35) and western medicine only (group n=35). Blood was tested for levels of AT-II, ET, ANP (with RIA) and VEGF (with ELISA) in all the patients both before and 12 weeks after starting the treatment as well as in 35 controls. Results: AT-II, VEGF, ET and ANP levels were significantly higher in patients of the two DN groups than those in the controls (p<0.05-0.01) and decreased significantly after treatment in both groups (p<0.05-0.01). In the two DN groups, AT-II level was positively correlated to VEGF level (r=0.465, p<0.05) and ET was positively correlated to ANP (r=0.61, p<0.05). Result of treatment was slightly better in the herb combined group. Conclusion: Blood AT-II, VEGF, ET and ANP were substances that played important role in the pathogenesis of DN; measurement of which were ideal for evaluation of treatment effect. Result of treatment was more desirable with additional herb medicine

  12. Effect of a regimen of optimal medical therapy on brain natriuretic peptide (BNP) levels in heart failure in the Pakistani population

    International Nuclear Information System (INIS)

    Objective: To document the effect of optimal medical therapy (OMT) on BNP levels in heart failure in Pakistani population. Methodology: In this Quasi experimental study, 75 consecutive stage C heart failure patients that had not been on OMT were included. These patients had been referred to AFIC-NIHD Heart Transplantation Department for assessment regarding heart transplantation. Initial assessments were carried out in hospital. Patients who were on OMT already were excluded. The prescription (carvedilol, lisinopril, spironolactone) was introduced as in patient as per pre defined protocol after clinical, imaging and lab evaluation. The patients were followed up in clinic and the dose escalation was done at regular intervals in out patients department. Clinical and lab variables were collected included BNP levels before starting treatment and 4 weeks after treatment. Results : Males were 75% and females were 25%. Mean age was 38.69 +- 12.98 years (range 18-70 years). Mean Ejection fraction was 23.9% (range 15 - 34%). At one month clinical status of all patients improved except one. The patients had improved from NYHA class-III to NYHA class-II of dyspnoea. The mean baseline BNP level was 1331 pg/ mL, and the BNP level 4 weeks after the OMT trial was 951.9 pg/mL. This reduction was statistically significant (p=0.016). Conclusion: OMT improves the BNP levels within a span of one month in patients with advanced systolic heart failure. This also correlated with the clinical improvement in the patients, and it was observed that BNP levels helped to monitor patients objectively and adjust OMT. (author)

  13. Clinical value of N-terminal pro-brain natriuretic peptide and troponin I plasma levels in elderly patients with sepsis

    Institute of Scientific and Technical Information of China (English)

    苏琴

    2014-01-01

    Objective To evaluate the clinical significance for assessment and prognosis of elder patients with sepsis by way of detecting plasma NT-proBNP and cTnI levels.Methods It was a prospective trial conducted.A total of145 elderly patients with sepsis were admitted to the emergency observation center and the emergency ward from January 2011 through January 2013.Of them,there were 84 patients with mild sepsis,45 patients with severe sepsis,and 16 patients with septic shock.Plasma levels

  14. 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR attenuates the expression of LPS- and Aβ peptide-induced inflammatory mediators in astroglia

    Directory of Open Access Journals (Sweden)

    Giri Shailendra

    2005-09-01

    Full Text Available Abstract Background Alzheimer's disease (AD pathology shows characteristic 'plaques' rich in amyloid beta (Aβ peptide deposits. Inflammatory process-related proteins such as pro-inflammatory cytokines have been detected in AD brain suggesting that an inflammatory immune reaction also plays a role in the pathogenesis of AD. Glial cells in culture respond to LPS and Aβ stimuli by upregulating the expression of cytokines TNF-α, IL-1β, and IL-6, and also the expression of proinflammatory genes iNOS and COX-2. We have earlier reported that LPS/Aβ stimulation-induced ceramide and ROS generation leads to iNOS expression and nitric oxide production in glial cells. The present study was undertaken to investigate the neuroprotective function of AICAR (a potent activator of AMP-activated protein kinase in blocking the pro-oxidant/proinflammatory responses induced in primary glial cultures treated with LPS and Aβ peptide. Methods To test the anti-inflammatory/anti-oxidant functions of AICAR, we tested its inhibitory potential in blocking the expression of pro-inflammatory cytokines and iNOS, expression of COX-2, generation of ROS, and associated signaling following treatment of glial cells with LPS and Aβ peptide. We also investigated the neuroprotective effects of AICAR against the effects of cytokines and inflammatory mediators (released by the glia, in blocking neurite outgrowth inhibition, and in nerve growth factor-(NGF induced neurite extension by PC-12 cells. Results AICAR blocked LPS/Aβ-induced inflammatory processes by blocking the expression of proinflammatory cytokine, iNOS, COX-2 and MnSOD genes, and by inhibition of ROS generation and depletion of glutathione in astroglial cells. AICAR also inhibited down-stream signaling leading to the regulation of transcriptional factors such as NFκB and C/EBP which are critical for the expression of iNOS, COX-2, MnSOD and cytokines (TNF-α/IL-1β and IL-6. AICAR promoted NGF-induced neurite growth

  15. An optimized method for measuring hypocretin-1 peptide in the mouse brain reveals differential circadian regulation of hypocretin-1 levels rostral and caudal to the hypothalamus

    DEFF Research Database (Denmark)

    Justinussen, Jessica; Holm, A; Kornum, B R

    2015-01-01

    as does prepro-hypocretin mRNA in the hypothalamus. However, in midbrain and brainstem tissue caudal to the hypothalamus, there was less circadian fluctuation and a tendency for higher levels during the light phase. These data suggest that regulation of the hypocretin system differs between brain areas....

  16. Sleep deficits in mild cognitive impairment are related to increased levels of plasma amyloid-β and cortical thinning.

    Science.gov (United States)

    Sanchez-Espinosa, Mayely P; Atienza, Mercedes; Cantero, Jose L

    2014-09-01

    Evidence suggests that amyloid-beta (Aβ) depositions parallel sleep deficits in Alzheimer's disease (AD). However, it remains unknown whether impaired sleep and changes in plasma Aβ levels are related in amnestic mild cognitive impairment (aMCI) subjects, and whether both markers are further associated with cortical thinning in canonical AD regions. To jointly address this issue, we investigated relationships between changes in physiological sleep and plasma Aβ concentrations in 21 healthy old (HO) adults and 21 aMCI subjects, and further assessed whether these two factors were associated with cortical loss in each group. aMCI, but not HO subjects, showed significant relationships between disrupted slow-wave sleep (SWS) and increased plasma levels of Aβ42. We also found that shortened rapid-eye movement (REM) sleep in aMCI correlated with thinning of the posterior cingulate, precuneus, and postcentral gyrus; whereas higher levels of Aβ40 and Aβ42 accounted for grey matter (GM) loss of posterior cingulate and entorhinal cortex, respectively. These results support preliminary relationships between Aβ burden and altered sleep physiology observed in animal models of AD amyloidosis, and provide precise cortical correlates of these changes in older adults with aMCI. Taken together, these findings open new research avenues on the combined role of sleep, peripheral Aβ levels and cortical integrity in tracking the progression from normal aging to early neurodegeneration. PMID:24845621

  17. δ-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2*2 haplotype (hPEPT2*2) differently influence neurobehavior in low-level lead exposed children.

    Science.gov (United States)

    Sobin, Christina; Flores-Montoya, Mayra Gisel; Gutierrez, Marisela; Parisi, Natali; Schaub, Tanner

    2015-01-01

    Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1-11.8years. Ninety-six percent of children had BLLssex, age and mother's level of education) and sibling exclusion (N=252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior. PMID:25514583

  18. The plasma B-type natriuretic peptide levels are low in males with stable ischemic heart disease (IHD compared to those observed in patients with non-IHD: a retrospective study.

    Directory of Open Access Journals (Sweden)

    Kosuke Minai

    Full Text Available OBJECTIVE: Although the plasma B-type natriuretic peptide (BNP level is a marker of heart failure, it is unclear whether BNP per se plays a pivotal role for pathogenic mechanisms underlying the development of ischemic heart disease (IHD. In this study, we retrospectively examined the plasma BNP levels in stable patients with IHD and compared to stable patients with cardiovascular diseases other than IHD. METHODS: The study population was 2088 patients (1698 males and 390 females who were admitted to our hospital due to IHD (n = 1,661 and non-IHD (n = 427 and underwent cardiac catheterization. Measurements of the hemodynamic parameters and blood sampling were performed. RESULTS: The plasma BNP levels were significantly lower in the IHD group than in the non-IHD group (p<0.001. The multiple regression analysis examining the logBNP values showed that age, a male gender, low left ventricular ejection fraction, low body mass index, serum creatinine, atrial fibrillation and IHD per se were significant explanatory variables. When the total study population was divided according to gender, the plasma BNP levels were found to be significantly lower in the IHD group than in the non-IHD group among males (p<0.001, but not females (p = NS. Furthermore, a multiple logistic regression analysis of IHD showed the logBNP value to be a significant explanatory variable in males (regression coefficient: -0.669, p<0.001, but not females (p = NS. CONCLUSIONS: The plasma BNP levels were relatively low in stable patients with IHD compared with those observed in stable patients with non-IHD; this tendency was evident in males. Perhaps, the low reactivity of BNP is causally associated with IHD in males. We hope that this study will serve as a test of future prospective studies.

  19. Expression of human uncoupling protein-3 in insulin-producing cells increases insulin-like peptide (DILP) levels and shortens lifespan

    OpenAIRE

    Humphrey, Dickon M.; Toivonen, Janne M.; Giannakou, Maria; Partridge, Linda; Brand, Martin D.

    2009-01-01

    Abstract Uncoupling proteins (UCPs) can dissipate mitochondrial protonmotive force by increasing the proton conductance of the inner membrane and through this effect could decrease ROS production, ameliorate oxidative stress and extend lifespan. We investigated whether ubiquitous, pan-neuronal or neurosecretory cell-specific expression of human UCP3 (hUCP3) in adult Drosophila melanogaster affected lifespan. Low, ubiquitous expression of hUCP3 at levels found in rodent skeletal mus...

  20. Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

    OpenAIRE

    Manchini, Martha Trindade; Serra, Andrey Jorge; Feliciano, Regiane dos Santos; Santana, Eduardo Tadeu; Antônio, Ednei Luis; de Tarso Camillo de Carvalho, Paulo; Montemor, Jairo; Crajoinas, Renato Oliveira; Girardi, Adriana Castello Costa; Tucci, Paulo José Ferreira; Silva, José Antônio

    2014-01-01

    Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS...

  1. Computational detection of allergenic proteins attains a new level of accuracy with in silico variable-length peptide extraction and machine learning

    OpenAIRE

    Soeria-Atmadja, D.; Lundell, T.; Gustafsson, M. G.; Hammerling, U.

    2006-01-01

    The placing of novel or new-in-the-context proteins on the market, appearing in genetically modified foods, certain bio-pharmaceuticals and some household products leads to human exposure to proteins that may elicit allergic responses. Accurate methods to detect allergens are therefore necessary to ensure consumer/patient safety. We demonstrate that it is possible to reach a new level of accuracy in computational detection of allergenic proteins by presenting a novel detector, Detection based...

  2. Plant signalling peptides

    OpenAIRE

    Wiśniewska, Justyna; Trejgell, Alina; Tretyn, Andrzej

    2003-01-01

    Biochemical and genetic studies have identified peptides that play crucial roles in plant growth and development, including defence mechanisms in response to wounding by pests, the control of cell division and expansion, and pollen self-incompatibility. The first two signalling peptides to be described in plants were tomato systemin and phytosulfokine (PSK). There is also biochemical evidence that natriuretic peptide-like molecules, immunologically-relatedt o those found ...

  3. Quantitative single-vesicle analysis of antimicrobial peptide-induced leakage

    DEFF Research Database (Denmark)

    Kristensen, Kasper; Ehrlich, Nicky; Henriksen, Jonas Rosager;

    2013-01-01

    Although the research field of antimicrobial peptides has attracted considerable scientific attention in the past decades, the microbicidal mechanisms of antimicrobial peptides still remain elusive. One of the keys to a more profound comprehension of the function of these peptides is a deeper und...... three canonical antimicrobial peptides: melittin, magainin 2, and mastoparan X. The results demonstrate an unprecedented level of insight into the molecular processes governing antimicrobial peptide-induced permeabilization of phospholipid membranes....

  4. Polycyclic peptide therapeutics.

    Science.gov (United States)

    Baeriswyl, Vanessa; Heinis, Christian

    2013-03-01

    Owing to their excellent binding properties, high stability, and low off-target toxicity, polycyclic peptides are an attractive molecule format for the development of therapeutics. Currently, only a handful of polycyclic peptides are used in the clinic; examples include the antibiotic vancomycin, the anticancer drugs actinomycin D and romidepsin, and the analgesic agent ziconotide. All clinically used polycyclic peptide drugs are derived from natural sources, such as soil bacteria in the case of vancomycin, actinomycin D and romidepsin, or the venom of a fish-hunting coil snail in the case of ziconotide. Unfortunately, nature provides peptide macrocyclic ligands for only a small fraction of therapeutic targets. For the generation of ligands of targets of choice, researchers have inserted artificial binding sites into natural polycyclic peptide scaffolds, such as cystine knot proteins, using rational design or directed evolution approaches. More recently, large combinatorial libraries of genetically encoded bicyclic peptides have been generated de novo and screened by phage display. In this Minireview, the properties of existing polycyclic peptide drugs are discussed and related to their interesting molecular architectures. Furthermore, technologies that allow the development of unnatural polycyclic peptide ligands are discussed. Recent application of these technologies has generated promising results, suggesting that polycyclic peptide therapeutics could potentially be developed for a broad range of diseases. PMID:23355488

  5. Are Brain Natriuretic Peptide Levels, High-sensitivity Troponin T Assay and Certain Left Atrial Echocardiographic Parameters Useful in the Evaluation of Patients with Permanent Pacemakers?

    Directory of Open Access Journals (Sweden)

    Janusz Sielski

    2014-09-01

    Full Text Available Background: The present study was undertaken to evaluate the practical value of BNP measurements, high-sensitivity troponinT (TnT hs assay and echocardiographic left ventricular volume index (LAVI in patients with permanent pacemakers, as there are no such reports in the literature. Methods and Results: BNP measurements were performed on venous blood samples using the Triage meters. The “sandwich” test was used to assess TnT hs assay. The Simpson method and the ellipse method were used to assess the left atrium on echocardiography. In the group II BNP levels, TnT hs levels increased. LAVI decreased. The probability of survival was higher in patients with low BNP before implantation. Conclusions: 1. Measurements of BNP, TnT hs and LAVI provide new information regarding cardiovascular changes after pacemaker implantation and contribute to improvement of post-implant checkups. 2. Measurements of BNP, TnT hs and LAVI in patients with permanent pacemakers facilitate the assessment of survival and cardiovascular hospitalisation rate.

  6. The S100B/RAGE Axis in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Estelle Leclerc

    2010-01-01

    Full Text Available Increasing evidence suggests that the small EF-hand calcium-binding protein S100B plays an important role in Alzheimer's disease. Among other evidences are the increased levels of both S100B and its receptor, the Receptor for Advanced Glycation Endproducts (RAGEs in the AD diseased brain. The regulation of RAGE signaling by S100B is complex and probably involves other ligands including the amyloid beta peptide (A, the Advanced Glycation Endproducts (AGEs, or transtheyretin. In this paper we discuss the current literature regarding the role of S100B/RAGE activation in Alzheimer's disease.

  7. Relationship Between Prohormone Brain Natriuretic Peptide (NT-proBNP Level and Severity of Pulmonary Dysfunction in Patients With Chronic Congestive Heart Failure

    Directory of Open Access Journals (Sweden)

    Nazemiyeh Masoud

    2015-03-01

    Full Text Available Introduction: Congestive heart failure (CHF is a common disease and its prevalence is increasingin industrialized countries. NT-proBNP measurement is an established diagnostic test fordiagnosis of CHF in patients who present to emergency room with acute dyspnea. The primaryobject of this study was to determine the relationship between levels of brain natriuretic peptideprecursor and severity of lung function impairment in patients with chronic CHF.Methods: This cross-sectional and analytical study that performed in Tuberculosis andLung Disease Research Center of Tabriz University of Medical Sciences on 95 patients withchronic heart failure, and relation between NT-proBNP levels and pulmonary functionparameters were examined.Results: Sixty-four patients were male and 31 were female. The average age of male and femaleswas 62.90 ± 11.54 and 61.61 ± 11.98 years, respectively. A significant inverse linear correlationwas found between NT-proBNP and FEV1 (P<0.001, r = -0.367, FVC (P<0.001, r = -0.444,TLC (P=0.022, r = -0.238, maximal midexpiratory flow (MMEF (P=0.047, r = -0.207 andleft ventricular ejection fraction (LVEF (P<0.001, r = -0.461. A significant positive linearcorrelation was found between NT-proBNP and FEV1/FVC (P =0.013, r = 0.257, RV/TLC (P =0.003, r=0.303 and 5 Hz Raw (r = 0.231, P = 0.024.Conclusion: This study showed that, both restrictive and obstructive ventilator impairments canoccur in chronic CHF and as NT-proBNP increases appropriate to hemodynamic deterioration,pulmonary dysfunction increases.

  8. A peptide & peptide nucleic acid synthesis technology for transporter molecules and theranostics--the SPPS.

    Science.gov (United States)

    Pipkorn, Ruediger; Braun, Klaus; Wiessler, Manfred; Waldeck, Waldemar; Schrenk, Hans-Hermann; Koch, Mario; Semmler, Wolfhard; Komljenovic, Dorde

    2014-01-01

    Advances in imaging diagnostics using magnetic resonance tomography (MRT), positron emission tomography (PET) and fluorescence imaging including near infrared (NIR) imaging methods are facilitated by constant improvement of the concepts of peptide synthesis. Feasible patient-specific theranostic platforms in the personalized medicine are particularly dependent on efficient and clinically applicable peptide constructs. The role of peptides in the interrelations between the structure and function of proteins is widely investigated, especially by using computer-assisted methods. Nowadays the solid phase synthesis (SPPS) chemistry emerges as a key technology and is considered as a promising methodology to design peptides for the investigation of molecular pharmacological processes at the transcriptional level. SPPS syntheses could be carried out in core facilities producing peptides for large-scale scientific implementations as presented here. PMID:24843319

  9. A Peptide & Peptide Nucleic Acid Synthesis Technology for Transporter Molecules and Theranostics - The SPPS

    Science.gov (United States)

    Pipkorn, Ruediger; Braun, Klaus; Wiessler, Manfred; Waldeck, Waldemar; Schrenk, Hans-Hermann; Koch, Mario; Semmler, Wolfhard; Komljenovic, Dorde

    2014-01-01

    Advances in imaging diagnostics using magnetic resonance tomography (MRT), positron emission tomography (PET) and fluorescence imaging including near infrared (NIR) imaging methods are facilitated by constant improvement of the concepts of peptide synthesis. Feasible patient-specific theranostic platforms in the personalized medicine are particularly dependent on efficient and clinically applicable peptide constructs. The role of peptides in the interrelations between the structure and function of proteins is widely investigated, especially by using computer-assisted methods. Nowadays the solid phase synthesis (SPPS) chemistry emerges as a key technology and is considered as a promising methodology to design peptides for the investigation of molecular pharmacological processes at the transcriptional level. SPPS syntheses could be carried out in core facilities producing peptides for large-scale scientific implementations as presented here. PMID:24843319

  10. Insulin C-peptide test

    Science.gov (United States)

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  11. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds known as peptide nucleic acids, bind complementary DNA and RNA strands, and generally do so more strongly than the corresponding DNA or RNA strands while exhibiting increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from a...

  12. PNA Peptide chimerae

    DEFF Research Database (Denmark)

    Koch, T.; Næsby, M.; Wittung, P.; Jørgensen, M.; Larsson, C.; Buchardt, O.; Stanly, C.J.; Norden, B.; Nielsen, P.E.; Ørum, H.

    1995-01-01

    Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields.......Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields....

  13. Structural transition in peptide nanotubes.

    Science.gov (United States)

    Amdursky, Nadav; Beker, Peter; Koren, Itai; Bank-Srour, Becky; Mishina, Elena; Semin, Sergey; Rasing, Theo; Rosenberg, Yuri; Barkay, Zahava; Gazit, Ehud; Rosenman, Gil

    2011-04-11

    Phase transitions in organic and inorganic materials are well-studied classical phenomena, where a change in the crystal space group symmetry induces a wide variation of physical properties, permitted by the crystalline symmetry in each phase. Here we observe a conformational induced transition in bioinspired peptide nanotubes (PNTs). We found that the PNTs change their original molecular assembly from a linear peptide conformation to a cyclic one, followed by a change of the nanocrystalline structure from a noncentrosymmetric hexagonal space group to a centrosymmetric orthorhombic space group. The observed transition is irreversible and induces a profound variation in the PNTs properties, from the microscopic to the macroscopic level. In this context, we follow the unique changes in the molecular, morphological, piezoelectric, second harmonic generation, and wettability properties of the PNTs. PMID:21388228

  14. Immunological half-life of porcine proinsulin C-peptide

    International Nuclear Information System (INIS)

    Immunological half-lifes of injected porcine C-peptide and insulin with RIA were studied and calculated as 9.8 and 8.0 minutes. Higher circulating levels of C-peptide as compared to insulin in normal young swines lead to speculation about a longer half-life of C-peptide. This hypothesis was verified in this study. Immunological half-lifes of porcine proinsulin and insulin in the pig were 20 and 6 minutes, respectively. (GSE)

  15. Competitive binding of antagonistic peptides fine-tunes stomatal patterning

    OpenAIRE

    Lee, Jin Suk; Hnilova, Marketa; Maes, Michal; Lin, Ya-Chen Lisa; Putarjunan, Aarthi; Han, Soon-Ki; Avila, Julian; U.Torii, Keiko

    2015-01-01

    During development, cells interpret complex, often conflicting signals to make optimal decisions. Plant stomata, the cellular interface between a plant and the atmosphere, develop according to positional cues including a family of secreted peptides, EPIDERMAL PATTERNING FACTORS (EPFs). How these signaling peptides orchestrate pattern formation at a molecular level remains unclear. Here we report that Stomagen/EPF-LIKE9 peptide, which promotes stomatal development, requires ERECTA (ER)-family ...

  16. Protective effects of berberine against amyloid beta-induced toxicity in cultured rat cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Yanjun Zhang; Shuai Du; Mixia Zhang

    2011-01-01

    Berberine, a major constituent of Coptidis rhizoma, exhibits neural protective effects. The present study analyzed the potential protective effect of berberine against amyloid G-induced cytotoxicity in rat cerebral cortical neurons. Alzheimer's disease cell models were treated with 0.5 and 2 μmol/Lberberine for 36 hours to inhibit amyloid G-induced toxicity. Methyl thiazolyl tetrazolium assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining results showed that berberine significantly increased cell viability and reduced cell apoptosis in primary cultured rat cortical neurons. In addition, western blot analysis revealed a protective effect of berberine against amyloid β-induced toxicity in cultured cortical neurons, which coincided with significantly decreased abnormal up-regulation of activated caspase-3. These results showed that berberine exhibited a protective effect against amyloid 13-induced cytotoxicity in cultured rat cortical neurons.

  17. Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation

    NARCIS (Netherlands)

    A. Familian; R.S. Boshuizen; P. Eikelenboom; R. Veerhuis

    2006-01-01

    Minocycline, a derivative of the antibiotic tetracycline, displays neuroprotective properties in various models of neurodegenerative diseases and is now used in clinical trials, because of its relative safety and tolerability. Minocycline passes the blood-brain barrier and is presumed to inhibit mic

  18. Uncoupling of M1 muscarinic receptor/G-protein interaction by amyloid beta(1-42)

    Czech Academy of Sciences Publication Activity Database

    Janíčková, Helena; Rudajev, Vladimír; Zimčík, Pavel; Jakubík, Jan; Tanila, H.; El-Fakahany, E. E.; Doležal, Vladimír

    2013-01-01

    Roč. 67, April (2013), s. 272-283. ISSN 0028-3908 R&D Projects: GA ČR(CZ) GA305/09/0681; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) 7E10060 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : Alzheimer ´s Disease * muscarinic receptors * G-proteins Subject RIV: ED - Physiology Impact factor: 4.819, year: 2013

  19. Conformational stability of fibrillar amyloid-beta oligomers via protofilament pair formation - a systematic computational study.

    Directory of Open Access Journals (Sweden)

    Anna Kahler

    Full Text Available Amyloid-[Formula: see text] (A[Formula: see text] oligomers play a crucial role in Alzheimer's disease due to their neurotoxic aggregation properties. Fibrillar A[Formula: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respectively. Small fibrillar oligomers adopt the protofilament topology, whereas fibrils contain at least protofilament pairs. To date, the underlying growth mechanism from oligomers to the mature fibril still remains to be elucidated. Here, we performed all-atom molecular dynamics simulations in explicit solvent on single layer-like protofilaments and fibril-like protofilament pairs of different size ranging from the tetramer to the 48-mer. We found that the initial U-shaped topology per monomer is maintained over time in all oligomers. The observed deviations of protofilaments from the starting structure increase significantly with size due to the twisting of the in-register parallel [Formula: see text]-sheets. This twist causes long protofilaments to be unstable and leads to a breakage. Protofilament pairs, which are stabilized by a hydrophobic interface, exhibit more fibril-like properties such as the overall structure and the twist angle. Thus, they can act as stable conformational templates for further fibril growth. Key properties like the twist angle, shape complementarity, and energetics show a size-dependent behavior so that small oligomers favor the protofilament topology, whereas large oligomers favor the protofilament pair topology. The region for this conformational transition is at the size of approximately twelve A[Formula: see text] monomers. From that, we propose the following growth mechanism from A[Formula: see text] oligomers to fibrils: (1 elongation of short protofilaments; (2 breakage of large protofilaments; (3 formation of short protofilament pairs; and (4 elongation of protofilament pairs.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. The conjugation of amyloid beta protein on the gold colloidal nanoparticles' surfaces

    International Nuclear Information System (INIS)

    The conjugation of various sequences of amyloid β protein solution (Aβ); Aβ1-11, Aβ12-28, Aβ31-35, Aβ1-40, and Aβ1-42 with gold colloidal suspension of 20 nm size was examined. Absorption spectroscopy was utilized to identify changes in the optical properties of gold colloid for pHs, ranging from pH 2 to pH 10. Colour changes were seen for all tested proteins in this study at a higher pH than where bare gold colloid exhibits its colour change at pH = 3.09 ± 0.02. All tested Aβ sequences except for Aβ1-42 exhibited colour changes around pI values of Aβ1-40, about pH 5.2. The Aβ1-42 exhibited precipitants in all pH lower than pH 7 and showed the colour change around pH 3.96 ± 0.05. The colour change observed at a pH lower than 5 is attributed to the unfolded Aβ monomer units around the gold colloidal surface. Interestingly, only Aβ1-40-coated gold colloidal nanoparticles exhibited a reversible colour change as the pH was externally altered between pH 4 and 10. This reversibility is an important implication of the observation of a reversible step reported for the fibrillogenesis. It was interpreted that the reversible process takes place when hydrophilic Aβ possesses a three-dimensional network containing both β-sheet and α-helices

  2. High-level Expression and Purification of Human Zona Pellucida huZP3a22-176 and huZP3b177-348 Peptides in Escherichia coli

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective To try making huZP3a22-176 and huZP3b177-348 polypeptides (representing an intact huZP322-348 protein without its N-terminal signal peptide and C-terminal transmembrane domain ) express in E. coli at a higher levelMethods The cDNAs encoding huZP3a and huZP3b were obtained with PCR method.The pB V221 plasmid was used to construct thermo-inducible recombinant expression vector. Purification of two target expression products employed an improved method of preparative gel polyacrylamide gel electrophoresis.Results Two polypeptides of recombinant huZP3a (rhuZP3a) and recombinant huZP3b(rhuZP3b) were all expressed respectively in an E. coli BL21(DE3)pLysS strain at a higher level, which were recognized by two specific polyclonal antisera in Western blotting test which recognize a linear B cell epitope present in rhuZP3a or rhuZP3b respectively. Using the shake-flask method, approximately 5 mg of rhuZP3a and rhuZP3b with more than 95% relative homogeneity were harvested from 1 L culture respectively.Conclusion The availability of two rhuZP3 polypeptides will help in detecting the immunogenicities of rhuZP3a and rhuZP3b through animal experiments and confirming the function domain of non-glycosylated huZP3 to induce acrosome reaction in vitro.

  3. Cerebral level of vGlut1 is increased and level of glycine is decreased in TgSwDI mice

    NARCIS (Netherlands)

    Timmer, N.M.; Metaxas, A.; Stelt, I. van der; Kluijtmans, L.A.J.; Berckel, B.N. van; Verbeek, M.M.

    2014-01-01

    Amyloid-beta (Abeta) deposition, one of the main hallmarks of Alzheimer's disease (AD), has been linked to glutamatergic dysfunction, i.e., increased stimulation of synaptic glutamate receptors that may ultimately result in neuronal loss. It was our aim to study the effect of Abeta on multiple compo

  4. Descriptors for antimicrobial peptides

    DEFF Research Database (Denmark)

    Jenssen, Håvard

    2011-01-01

    Introduction: A frightening increase in the number of isolated multidrug resistant bacterial strains linked to the decline in novel antimicrobial drugs entering the market is a great cause for concern. Cationic antimicrobial peptides (AMPs) have lately been introduced as a potential new class of...... antimicrobial drugs, and computational methods utilizing molecular descriptors can significantly accelerate the development of new peptide drug candidates. Areas covered: This paper gives a broad overview of peptide and amino-acid scale descriptors available for AMP modeling and highlights which of these are...

  5. Peptide conversations in Gram-positive bacteria.

    Science.gov (United States)

    Monnet, Véronique; Juillard, Vincent; Gardan, Rozenn

    2016-05-01

    Within Gram-positive bacteria, the expression of target genes is controlled at the population level via signaling peptides, also known as pheromones. Pheromones control a wide range of functions, including competence, virulence, and others that remain unknown. Until now, their role in bacterial gene regulation has probably been underestimated; indeed, bacteria are able to produce, by ribosomal synthesis or surface protein degradation, an extraordinary variety of peptides which are released outside bacteria and among which, some are pheromones that mediate cell-to-cell communication. The review aims at giving an updated overview of these peptide-dependant communication pathways. More specifically, it follows the whole peptide circuit from the peptide production and secretion in the extracellular medium to its interaction with sensors at bacterial surface or re-import into the bacteria where it plays its regulation role. In recent years, as we have accumulated more knowledge about these systems, it has become apparent that they are more complex than they first appeared. For this reason, more research on peptide-dependant pathways is needed to develop new strategies for controlling functions of interest in Gram-positive bacteria. In particular, such research could lead to alternatives to the use of antibiotics against pathogenic bacteria. In perspective, the review identifies new research questions that emerge in this field and that have to be addressed. PMID:25198780

  6. PNA Peptide chimerae

    DEFF Research Database (Denmark)

    Koch, T.; Næsby, M.; Wittung, P.;

    1995-01-01

    Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields....

  7. Tumor penetrating peptides

    Directory of Open Access Journals (Sweden)

    ErkkiRuoslahti

    2013-08-01

    Full Text Available Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC, contains the integrin-binding RGD motif. RGD mediates tumor homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular “zip code” of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is

  8. Introduction to Peptide Synthesis

    OpenAIRE

    Stawikowski, Maciej; Fields, Gregg B.

    2002-01-01

    A number of synthetic peptides are significant commercial or pharmaceutical products, ranging from the dipeptide sugar-substitute aspartame to clinically used hormones, such as oxytocin, adrenocorticotropic hormone, and calcitonin. This unit provides an overview of the field of synthetic peptides and proteins. It discusses selecting the solid support and common coupling reagents. Additional information is provided regarding common side reactions and synthesizing modified residues.

  9. Proinflammatory Effects of C-Peptide in Different Tissues

    Directory of Open Access Journals (Sweden)

    Dusica Vasic

    2012-01-01

    Full Text Available Atherosclerosis is well known as an inflammatory disease that can lead to clinical complications such as heart attack or stroke. C-peptide as a cleavage product of proinsulin is in the last few decades known as an active peptide with a number of different effects on microvascular and macrovascular complications in type 2 diabetic patients. Patients with insulin resistance and early type 2 diabetes show elevated levels of C-peptide in blood. Several last findings demonstrated deposition of C-peptide in the vessel wall in ApoE-deficient mice and induction of local inflammation. Besides that, C-peptide has proliferative effects on human mesangial cells. This review discusses recently published proinflammatory effects of C-peptide in different tissues.

  10. Review: Formation of Peptide Radical Ions Through Dissociative Electron Transfer in Ternary Metal-Ligand-Peptide Complexes

    International Nuclear Information System (INIS)

    The formation and fragmentation of odd-electron ions of peptides and proteins is of interest to applications in biological mass spectrometry. Gas-phase redox chemistry occurring during collision-induced dissociation of ternary metal-ligand-peptide complexes enables the formation of a variety of peptide radicals including the canonical radical cations, M+#smbullet#, radical dications, (M+H)2+#smbullet#, radical anions, (M-2H)-#smbullet#. In addition, odd-electron peptide ions with well-defined initial location of the radical site are produced through side chain losses from the radical ions. Subsequent fragmentation of these species provides information on the role of charge and the location of the radical site on the competition between radical-induced and proton-driven fragmentation of odd-electron peptide ions. This account summarizes current understanding of the factors that control the efficiency of the intramolecular electron transfer (ET) in ternary metal-ligand-peptide complexes resulting in formation of odd-electron peptide ions. Specifically, we discuss the effect of the metal center, the ligand and the peptide structure on the competition between the ET, proton transfer (PT), and loss of neutral peptide and neutral peptide fragments from the complex. Fundamental studies of the structures, stabilities, and the energetics and dynamics of fragmentation of such complexes are also important for detailed molecular-level understanding of photosynthesis and respiration in biological systems.

  11. Prediction of Antibacterial Activity from Physicochemical Properties of Antimicrobial Peptides

    NARCIS (Netherlands)

    de Sousa Pereira Simoes de Melo, Manuel; Ferre, Rafael; Feliu, Lidia; Bardaji, Eduard; Planas, Marta; Castanho, Miguel A. R. B.

    2011-01-01

    Consensus is gathering that antimicrobial peptides that exert their antibacterial action at the membrane level must reach a local concentration threshold to become active. Studies of peptide interaction with model membranes do identify such disruptive thresholds but demonstrations of the possible co

  12. Ovarian expression of insulin-like peptide 3 (INSL3) and its receptor (RXFP2) during development of bovine antral follicles and corpora lutea and measurement of circulating INSL3 levels during synchronized estrous cycles.

    Science.gov (United States)

    Satchell, Leanne; Glister, Claire; Bleach, Emma C; Glencross, Richard G; Bicknell, Andrew B; Dai, Yanzhenzi; Anand-Ivell, Ravinder; Ivell, Richard; Knight, Philip G

    2013-05-01

    Insulin-like peptide 3 (INSL3), a major product of testicular Leydig cells, is also expressed by the ovary, but its functional role remains poorly understood. Here, we quantified expression of INSL3 and its receptor RXFP2 in theca interna cell (TIC) and granulosa cell compartments of developing bovine antral follicles and in corpora lutea (CL). INSL3 and RXFP2 mRNA levels were much higher in TIC than granulosa cell and increased progressively during follicle maturation with INSL3 peaking in large (11-18 mm) estrogen-active follicles and RXFP2 peaking in 9- to 10-mm follicles before declining in larger (11-18 mm) follicles. Expression of both INSL3 and RXFP2 in CL was much lower than in TIC. In situ hybridization and immunohistochemistry confirmed abundant expression of INSL3 mRNA and protein in TIC. These observations indicate follicular TIC rather than CL as the primary site of both INSL3 production and action, implying a predominantly autocrine/paracrine role in TIC. To corroborate the above findings, we showed that in vitro exposure of TIC to a luteinizing concentration of LH greatly attenuated expression of both INSL3 and its receptor while increasing progesterone secretion and expression of STAR and CYP11A1. Moreover, in vivo, a significant cyclic variation in plasma INSL3 was observed during synchronized estrous cycles. INSL3 and estradiol-17β followed a similar pattern, both increasing after luteolysis, before falling sharply after the LH surge. Thus, theca-derived INSL3, likely from the dominant preovulatory follicle, is detectable in peripheral blood of cattle, and expression is down-regulated during luteinization induced by the preovulatory LH surge. Collectively, these findings underscore the likely role of INSL3 as an important intrafollicular modulator of TIC function/steroidogenesis, while raising doubts about its potential contribution to CL function. PMID:23546605

  13. Development of a renal collecting duct homing peptide using phage display

    DEFF Research Database (Denmark)

    Svenningsen, Per; Peti-Peterdi, Janos

    in a collecting duct cell line. Moreover, the phage was internalized in the collecting duct cells after i.v. injection in mice. To test if the peptide could be used for nonviral gene transfer, we synthesized the identified peptide fused to a protamine fragment. The fusion peptide was able to bind plasmid GFP c......DNA and when the peptide/cDNA complex was injected i.p. in mice, GFP expression was detected in the collecting duct cells. However, GFP expression level was very low. In order to track the fate of the peptide in vivo, we synthesized a FITC labeled version of the identified peptide. Using in vivo multiphoton...

  14. Relationship between placental glucagon like peptide-1,glucagon like peptide-1 receptor levels and birth weight of neonates%胎盘胰高血糖素样肽-1、胰高血糖素样肽-1受体水平与新生儿出生体重的关系

    Institute of Scientific and Technical Information of China (English)

    刘鑫; 王晶; 尚丽新; 李萍; 张文晶

    2011-01-01

    目的:探讨胎盘胰高血糖素样肽-1(GLP-1)、胰高血糖素样肽-1受体(GLP-1R)水平与新生儿出生体重的关系.方法:采用免疫组织化学SABC法检测30例分娩正常出生体重儿组(AGA组)、28例高出生体重儿组(LGA组)及28例低出生体重儿组(SGA组)胎盘组织中GLP-1、GLP-1R的表达水平.结果:①LGA组胎盘组织中GLP-1、GLP-IR的表达水平低于AGA组,差异有统计学意义(P<0.05).SGA组胎盘组织中GLP-1、GLP-IR的表达水平高于AGA组,差异有统计学意义(P<0.05).②胎盘组织中GLP-1、GLP-1R的表达水平与新生儿出生体重呈负相关(r=0.454,P<0.05;r=-0.512,P<0.05).结论:胎盘组织中GLP-1、GLP-1R表达水平的变化可能在新生儿出生体重的调节中起重要作用.%Objective: To explore the relationship between placental glucagon like peptide - 1 { GLP - 1) , glucagon like peplide - 1 receptor ( GLP - 1R) levels and birth weight of neonates. Methods: Immunohistochemjcal SABC method was used to detect the expression levels of GLP - 1 and GLP - 1R in appropriate for gestational age group ( AGA group, 30 neonates) , large for gestational age group ( LGA group, 28 neonates ) and small for gestational age group ( SGA group, 28 neonates) . Results: The expression levels of GLP - 1 and GLP - 1R in placental tissue in LGA group were significantly lower than those in AGA group ( P < 0. 05 ) . The expression levels of GLPI and GLP - IR in placental tissue in SGA group were significantly higher than those in AGA group ( P < 0. 05 ) . There was negative correlation between the expression levels of GLP - 1 and GLP - 1R in placental tissue and birth weight of neonates (y = - 0. 454, P < 0. 05 ; y = -0. 512, P <0. 05) . Conclusion: The changes of GLP - 1 and GLP- 1R expression levels in placental tissue may play important roles in regulation of neonatal birth weight.

  15. Calcitonin gene-related peptide (CGRP), peptide YY (PYY) gastrin releasing peptide (GRP) and others in hamster lung and plasma

    International Nuclear Information System (INIS)

    Rabbit antisera to CGRP, PYY, neuropeptide Y (NPY) and GRP were used for immunocytochemical localization of these peptides in lungs of neonate hamsters at birth and 6 d of age and young (70 gm) and adult (107 gm) hamsters. The peroxidase-antiperoxidase method was applied to paraffin sections of tissue fixed in Bouin's or Zamboni's solution. Furthermore, radioimmunoassay (RIA) was used to quantify these peptides in lung tissue and plasma from the young hamsters (n=13). Distinct CGRP-like immunoreactivity (IR) was noted in grouped (NEB) and individual (NEC) neuroendocrine cells at all ages including all airways from trachea (NECs only) to alveoli. In some NEBs this IR coexisted with 5-HT-like IR. PYY- and NPY-like Ir was mainly noted in NEBs and NECs at the level of bronchioles and alveoli, and weak GRP-like IR was present in neuroendocrine-like cells of small airways. Measurable quantities of all peptides were recorded by RIA. Females had higher lung and plasma levels of CGRP and plasma levels of PYY than males and tended to have higher lung levels of GRP. The neuropeptides CGRP, PYY and the analog NPY are putative regulators of local pulmonary blood flow by vasodilation (CGRP) and constriction (PYY, NPY), and GRP is known to regulate peptide release

  16. Peptide Vaccines for Hypertension and Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Hironori Nakagami

    2014-11-01

    Full Text Available Vaccines are commonly used as a preventive medicine for infectious diseases worldwide; however, the trial for an amyloid beta vaccine against Alzheimer’s disease will open a new concept in vaccination. In case of therapeutic vaccines for cancer, their targets are usually specific antigens in cancer cells, allowing activated cytotoxic T cells (CTLs to attach and remove the antigen-presenting cancer cells. In our therapeutic vaccines against hypertension, the target is angiotensin II (Ang II and induced anti-Ang II antibodies could efficiently ameliorate high blood pressure. Similarly, we developed the therapeutic vaccine against DPP4 for diabetes mellitus. However, because Ang II or DPP4 is an endogenous hormone, we must avoid autoimmune disease induced by these vaccines. Therefore, our system was used to design a therapeutic vaccine that elicits anti-Ang II or DPP4 antibodies without CTL activation against Ang II or DPP4. In this review, we will describe our concept of therapeutic vaccines for hypertension and diabetes mellitus.

  17. Ginkgo biloba extract and its flavonol and terpenelactone fractions do not affect beta-secretase mRNA and enzyme activity levels in cultured neurons and in mice.

    Science.gov (United States)

    Augustin, Sabine; Huebbe, Patricia; Matzner, Nicole; Augustin, Kay; Schliebs, Reinhard; Cermak, Rainer; Wolffram, Siegfried; Rimbach, Gerald

    2008-01-01

    Numerous clinical trials have reported beneficial effects of the Ginkgo biloba extract EGb761 in the prevention and therapy of cognitive disorders including Alzheimer's disease (AD). Although neuroprotective properties of EGb761 have been consistently reported, the molecular mechanisms of EGb761 and the specific role of its major constituents, the flavonols and terpenlactones, are largely unknown. One major hallmark of AD is the deposition of amyloid-beta (A beta) as amyloid plaques in the brain. A beta is a cleavage product of amyloid precursor protein (APP). Certain proteases, called beta-secretases (BACE), are crucial in the formation of A beta. The purpose of the present study was to investigate the efficacy of EGb761 and its flavonol and terpenelactone fraction to modulate BACE-1 enzyme activity and mRNA levels in vitro and in vivo. Neither EGb761 nor its fractions affected BACE-1 activity in vitro. Furthermore, also in Neuro-2a cells and wild-type as well as transgenic (Tg2576) laboratory mice, no significant effect of EGb761 on BACE-1 enzyme activity and mRNA levels were observed. Current findings suggest that BACE-1 may not be a major molecular target of EGb761 and its flavonol and terpenelactone fraction. PMID:18186016

  18. Antimicrobial Peptides from Plants

    Science.gov (United States)

    Tam, James P.; Wang, Shujing; Wong, Ka H.; Tan, Wei Liang

    2015-01-01

    Plant antimicrobial peptides (AMPs) have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs) of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic), lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms. PMID:26580629

  19. Antimicrobial Peptides from Plants

    Directory of Open Access Journals (Sweden)

    James P. Tam

    2015-11-01

    Full Text Available Plant antimicrobial peptides (AMPs have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic, lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms.

  20. Electromembrane extraction of peptides.

    Science.gov (United States)

    Balchen, Marte; Reubsaet, Léon; Pedersen-Bjergaard, Stig

    2008-06-20

    Rapid extraction of eight different peptides using electromembrane extraction (EME) was demonstrated for the first time. During an extraction time of 5 min, the model peptides migrated from a 500 microL aqueous acidic sample solution, through a thin supported liquid membrane (SLM) of an organic liquid sustained in the pores in the wall of a porous hollow fiber, and into a 25 microL aqueous acidic acceptor solution present inside the lumen of the hollow fiber. The driving force of the extraction was a 50 V potential sustained across the SLM, with the positive electrode in the sample and the negative electrode in the acceptor solution. The nature and the composition of the SLM were highly important for the EME process, and a mixture of 1-octanol and 15% di(2-ethylhexyl) phosphate was found to work properly. Using 1mM HCl as background electrolyte in the sample and 100 mM HCl in the acceptor solution, and agitation at 1050 rpm, enrichment up to 11 times was achieved. Recoveries were found to be dependent on the structure of the peptide, indicating that the polarity and the number of ionized groups were important parameters affecting the extraction efficiency. The experimental findings suggested that electromembrane extraction of peptides is possible and may be a valuable tool for future extraction of peptides. PMID:18479691

  1. 双水平气道正压通气对急性左心衰竭患者血浆脑钠素水平的影响%Effects of Bi-level Positive Airway Pressure on the level of B-type natriuretic peptide in patients with acute left ventricular failure

    Institute of Scientific and Technical Information of China (English)

    秦熠; 王丽敏; 宋倩

    2013-01-01

    Objective To observation the effects of Bi-level Positive Airway Pressure (BiPAP) on the levels of plasma B-type natriuretic peptide (BNP) in patients with acute left ventricular failure. Methods 126 consecutive cases admitted with acute left ventricular failure in the ICU of our hospital were included in the study. These cases were randomly divided into BiPAP group (62 cases, conventional treatment + BiPAP) and control group (64 cases, conventional therapy). The changes of the two groups on plasma BNP levels were compared. Results 6h and 24 h after therapy, plasma BNP levels of BiPAP group were significantly lower than that of control group (P<0. 05, P<0. 01). Conclusion BiPAP could decrease the level of plasma BNP in patients with acute left ventricular failure and is an advantageous treatment for patients with acute left ventricular failure.%目的 观察双水平气道正压通气(BiPAP)对急性左心衰竭患者血浆脑钠素(BNP)水平的影响.方法 对入我院急诊ICU的急性左心衰竭患者126例,随机分为BiPAP组(常规治疗+BiPAP) 62例和对照组(常规治疗)64例,比较两组BNP的变化.结果 治疗6h、24h后BiPAP组BNP较对照组显著降低(P<0.05,P<0.01).结论 BiPAP可使急性左心衰竭患者的BNP下降,有利于急性左心衰竭的治疗.

  2. Synthetic antibiofilm peptides.

    Science.gov (United States)

    de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete; Franco, Octavio Luiz; Hancock, Robert E W

    2016-05-01

    Bacteria predominantly exist as multicellular aggregates known as biofilms that are associated with at least two thirds of all infections and exhibit increased adaptive resistance to conventional antibiotic therapies. Therefore, biofilms are major contributors to the global health problem of antibiotic resistance, and novel approaches to counter them are urgently needed. Small molecules of the innate immune system called host defense peptides (HDPs) have emerged as promising templates for the design of potent, broad-spectrum antibiofilm agents. Here, we review recent developments in the new field of synthetic antibiofilm peptides, including mechanistic insights, synergistic interactions with available antibiotics, and their potential as novel antimicrobials against persistent infections caused by biofilms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID:26724202

  3. Biosynthetic engineering of nonribosomal peptide synthetases.

    Science.gov (United States)

    Kries, Hajo

    2016-09-01

    From the evolutionary melting pot of natural product synthetase genes, microorganisms elicit antibiotics, communication tools, and iron scavengers. Chemical biologists manipulate these genes to recreate similarly diverse and potent biological activities not on evolutionary time scales but within months. Enzyme engineering has progressed considerably in recent years and offers new screening, modelling, and design tools for natural product designers. Here, recent advances in enzyme engineering and their application to nonribosomal peptide synthetases are reviewed. Among the nonribosomal peptides that have been subjected to biosynthetic engineering are the antibiotics daptomycin, calcium-dependent antibiotic, and gramicidin S. With these peptides, incorporation of unnatural building blocks and modulation of bioactivities via various structural modifications have been successfully demonstrated. Natural product engineering on the biosynthetic level is not a reliable method yet. However, progress in the understanding and manipulation of biosynthetic pathways may enable the routine production of optimized peptide drugs in the near future. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27465074

  4. Pulling peptides across nanochannels: resolving peptide binding and translocation through the hetero-oligomeric channel from Nocardia farcinica.

    Science.gov (United States)

    Singh, Pratik Raj; Bárcena-Uribarri, Iván; Modi, Niraj; Kleinekathöfer, Ulrich; Benz, Roland; Winterhalter, Mathias; Mahendran, Kozhinjampara R

    2012-12-21

    We investigated translocation of cationic peptides through nanochannels derived from the Gram-positive bacterium Nocardia farcinica at the single-molecule level. The two subunits NfpA and NfpB form a hetero-oligomeric cation selective channel. On the basis of amino acid comparison we performed homology modeling and obtained a channel structurally related to MspA of Mycobacterium smegmatis. The quantitative single-molecule measurements provide an insight into transport processes of solutes through nanochannels. High-resolution ion conductance measurements in the presence of peptides of different charge and length revealed the kinetics of peptide binding. The observed asymmetry in peptide binding kinetics indicated a unidirectional channel insertion in the lipid bilayer. In the case of cationic peptides, the external voltage acts as a driving force that promotes the interaction of the peptide with the channel surface. At low voltage, the peptide just binds to the channel, whereas at higher voltage, the force is strong enough to pull the peptide across the channel. This allows distinguishing quantitatively between peptide binding and translocation through the channel. PMID:23121560

  5. Therapeutic HIV Peptide Vaccine

    DEFF Research Database (Denmark)

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

  6. Cationic Antimicrobial Peptide Cytotoxicity

    OpenAIRE

    Laverty, Garry; Gilmore, Brendan

    2014-01-01

    Fluorescence microscopy serves as a valuable tool for assessing the structural integrity and viability of eukaryotic cells. Through the use of calcein AM and the DNA stain 4,6-diamidino-2 phenylindole (DAPI), cell viability and membrane integrity can be qualified. Our group has previously shown the ultra-short cationic antimicrobial peptide H-OOWW-NH2; the amphibian derived 27-mer peptide Maximin-4and the ultra-short lipopeptide C12-OOWW-NH2 to be effective against a range of bacterial biofil...

  7. Biosynthesis of cardiac natriuretic peptides

    DEFF Research Database (Denmark)

    Goetze, Jens Peter

    2010-01-01

    Cardiac-derived peptide hormones were identified more than 25 years ago. An astonishing amount of clinical studies have established cardiac natriuretic peptides and their molecular precursors as useful markers of heart disease. In contrast to the clinical applications, the biogenesis of cardiac p...... competent endocrine cells. The structurally related atrial natriuretic peptide will be mentioned where appropriate, whereas C-type natriuretic peptide will not be considered as a cardiac peptide of relevance in mammalian physiology....... characterized. An ongoing characterization of the molecular heterogeneity will help appreciate the biosynthetic capacity of the endocrine heart and could introduce new diagnostic possibilities. Notably, different biosynthetic products may not be equal markers of the same pathophysiological processes. An...... inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly...

  8. Biosynthesis of cardiac natriuretic peptides

    DEFF Research Database (Denmark)

    Goetze, Jens Peter

    2010-01-01

    Cardiac-derived peptide hormones were identified more than 25 years ago. An astonishing amount of clinical studies have established cardiac natriuretic peptides and their molecular precursors as useful markers of heart disease. In contrast to the clinical applications, the biogenesis of cardiac...... inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly...... competent endocrine cells. The structurally related atrial natriuretic peptide will be mentioned where appropriate, whereas C-type natriuretic peptide will not be considered as a cardiac peptide of relevance in mammalian physiology....

  9. Value of serum brain natriuretic peptide levels in the prognosis of brain damage after cardiopulmonary resuscitation%血清脑钠肽水平对心肺复苏后脑损伤的预测价值研究

    Institute of Scientific and Technical Information of China (English)

    李钦浩; 巩晓娜; 周娆娆; 刘朋; 张磊; 亓雪梅; 蒋芳杰

    2013-01-01

    OBJECTIVE To evaluate the effect of serum brain natriuretic peptide levels on brain damage at the early stage after cardiopulmonary resuscitation (CPR). METHODS There were 34 patients with restoration of spontaneous circulation after successful CPR.After 2 months of successful cardiopulmonary resuscitation (CPR) , patients with GCS score ≥ 12 were mild brain damage (I group, male 6 cases, female 8 cases); GCS score 9 ≤ GCS ≤ 11 were moderate brain damage (II group, male 4 cases, female 6 cases); GCS score 3 ≤ GCS ≤ 8 were severe brain damage (Ⅲ group, male 5 cases, and female 5 cases) . Control group was consisted of 15 healthy volunteers. All of the patients' venous blood were respectively collected and BNP was detected by enzyme linked immunosorbent assay at 2, 8, 12, 24 and 48 h after restoring of independent circulation. RESULTS Compared the age, sex, start time of cardiac arrest to recovery in cardiopulmonary resuscitation (CPR) group and control group, differences were not statistically significant (P> 0.05); at 2, 8, 12, 24 and 48 h, serum BNP levels in I , II and Ⅲ groups were significantly higher than the control group (P < 0.05); And in the trail group, I group was significantly lower than the II group (P< 0.05); II group and was significantly lower than the HI group (P< 0.05). CONCLUSION Serum BNP levels can reflect cardiopulmonary resuscitation (CPR) early after HPC ischemia brain damage, and for the assessment of the recovery cardiopulmonary resuscitation (CPR) has an important value.%目的 探讨血清脑钠肽(BNP)对心肺复苏后脑损伤的预测的价值.方法 34例经心肺复苏后自主循环恢复的患者,以心肺复苏成功后2个月格拉斯哥昏迷评分(GCS)≥12为轻度脑损伤(Ⅰ组),男6例,女8例;9≤GCS≤11为中度脑损伤(Ⅱ组),男4例,女6例;3≤GCS≤8为重度脑损伤(Ⅲ组),男5例,女5例.另外选取14例健康者(女8例,男6例)作为对照组.所有患者均在自主循环恢复后2、8

  10. Intrapulmonary administration of natural honey solution, hyperosmolar dextrose or hypoosmolar distill water to normal individuals and to patients with type-2 diabetes mellitus or hypertension: their effects on blood glucose level, plasma insulin and C-peptide, blood pressure and peaked expiratory flow rate.

    Science.gov (United States)

    Al-Waili, N

    2003-07-31

    Safety and effect intrapulmonary administration (by inhalation) of 60 % honey solution, 10% dextrose or distill water on blood sugar, plasma insulin and C-peptide, blood pressure, heart rate, and peaked expiratory flow rate (PEFR) in normal or diabetic subjects were studied. - Twenty-four healthy subjects, 16 patients with type 11 diabetes mellitus and six patients with hypertension were entered for study. They were underwent complete physical examination and laboratory investigations. Twelve healthy subjects were subjected for distill water inhalation for 10 min, and after one week they received inhalation of honey solution (60% wt/v) for 10 min. Another 12 healthy subjects received inhalation of 10% dextrose for 10 min. Blood glucose level, plasma insulin and C-peptide, blood pressure, heart rate and PEFR were estimated before inhalation and during 2-3 hrs after inhalation, at 30 min intervals. Random blood glucose level was estimated in eight patients with poorly controlled diabetes mellitus, and repeated 30 min after honey inhalation. One week later, fasting blood glucose level was estimated in each patient and blood glucose level was re-estimated during three hrs after honey inhalation, at 30 min intervals. Glucose tolerance test was performed in another eight patients with type-2 diabetes mellitus, and after one week the procedure was repeated with inhalation of honey, which was started immediately after ingestion of glucose. Six hypertensive patients received honey inhalation for 10 min; supine blood pressure and heart rate were measured before and after inhalation. - Results showed that in normal subjects distill water caused mild elevation of blood glucose level, mild lowering of plasma insulin, and significant reduction of plasma C-peptide. 10% dextrose inhalation caused mild reduction of plasma insulin and C-peptide and unremarkable changes in blood glucose level. No significant changes were obtained in blood pressure, heart rate or PEFR after distill

  11. Biochemical functionalization of peptide nanotubes with phage displayed peptides

    Science.gov (United States)

    Swaminathan, Swathi; Cui, Yue

    2016-09-01

    The development of a general approach for the biochemical functionalization of peptide nanotubes (PNTs) could open up existing opportunities in both fundamental studies as well as a variety of applications. PNTs are spontaneously assembled organic nanostructures made from peptides. Phage display has emerged as a powerful approach for identifying selective peptide binding motifs. Here, we demonstrate for the first time the biochemical functionalization of PNTs via peptides identified from a phage display peptide library. The phage-displayed peptides are shown to recognize PNTs. These advances further allow for the development of bifunctional peptides for the capture of bacteria and the self-assembly of silver particles onto PNTs. We anticipate that these results could provide significant opportunities for using PNTs in both fundamental studies and practical applications, including sensors and biosensors nanoelectronics, energy storage devices, drug delivery, and tissue engineering.

  12. Effects of Peptide Adsorption on the Electronic Properties of Graphene

    Science.gov (United States)

    Akdim, Brahim; Kuang, Zhifeng; Kim, Sang; Naik, Rajesh; Farmer, Barry; Walsh, Tiffany; Pachter, Ruth

    2012-02-01

    In this work we aim to explain the increase in the electrical conductance in a single-layer graphene (SLG) field-effect transistor (FET) upon binding the peptide HSSYWYAFNNKT, which we previously demonstrated. The adsorption of the peptide onto the SLG has been carefully modeled by applying empirical molecular dynamics simulations with the AMOEBA force-field. The peptide adsorbed SLG structure demonstrates π-π stacking with aromatic amino acids, namely His,Tyr, Thr and Ph. Based on this large-scale peptide-SLG system, calculations on the electron transport using the nonequilibrium Green's function formalism at the extended Huckel level were carried out. Transmission eigenchannels and spectra, projected density of states, effects of modeling realistic leads (gold vs. graphene) and I-V characteristics will be discussed in detail. In this context, suppositions as to the mechanism of increased conductance for the peptide-SLG FET will be proposed.

  13. Identification of high levels of phytochelatins, glutathione and cadmium in the phloem sap of Brassica napus. A role for thiol-peptides in the long-distance transport of cadmium and the effect of cadmium on iron translocation

    OpenAIRE

    Mendoza-Cózatl, David G.; Butko, Emerald; Springer, Franziska; Torpey, Justin W.; Komives, Elizabeth A.; Kehr, Julia; Schroeder, Julian

    2008-01-01

    Phytochelatins (PCs) are glutathione-derived peptides that function in heavy metal detoxification in plants and certain fungi. Recent research in Arabidopsis has shown that PCs undergo long-distance transport between roots and shoots. However, it remains unknown which tissues or vascular systems, xylem or phloem, mediate PC translocation and whether PC transport contributes to physiologically relevant long-distance transport of cadmium (Cd) between shoots and roots. To address these questions...

  14. Peptide iodination on phenylalanine residues

    International Nuclear Information System (INIS)

    Peptide labelling with radioactive isotopes is always a compromise between peptide chemistry, labelling chemistry, and biological receptor tolerance. Therefore new ways for isotope introduction are always useful. The present contribution describes the introduction of iodine isotopes onto synthetic polypeptides by means of the Gattermann/ Sandmeyer reactions. Peptides containing the nitrophenylalanyl residue are reduced to the corresponding aminophenylalanyl, diazolized to the diazonium phenylalanyl peptide and converted to the iodophenylalanyl peptide in the presence of copper. Two examples are presented: angiotensin II and enkephalin. In both cases, the iodophenylalanyl residue is well accepted by the biological target. (author). 13 refs.; 4 figs

  15. Immature transformed rat islet beta-cells differentially express C-peptides derived from the genes coding for insulin I and II as well as a transfected human insulin gene

    DEFF Research Database (Denmark)

    Blume, N; Petersen, J S; Andersen, L C;

    1992-01-01

    Synthetic peptides representing unique sequences in rat proinsulin C-peptide I and II were used to generate highly specific antisera, which, when applied on sections of normal rat pancreas, confirm a homogeneous coexpression of the two C-peptides in all islet beta-cells. Insulin gene expression is...... insulin-producing cells showed highly differential expression at the cellular level of the three proinsulin C-peptide immunoreactivities, as follows: C-peptide I greater than human C-peptide greater than C-peptide II. The fractions of cells expressing human C-peptide and C-peptide II decreased in time and...... species of proinsulin-C-peptide immunoreactivity but still at high levels. However, rat C-peptide II and human C-peptide were often colocalized, even in later passages. In situ hybridization studies combined with the immunocytochemical data suggest that the differential expression occurs at the level of...

  16. Clinical utility of natriuretic peptides and troponins in hypertrophic cardiomyopathy.

    Science.gov (United States)

    Kehl, Devin W; Buttan, Anshu; Siegel, Robert J; Rader, Florian

    2016-09-01

    The diagnosis of hypertrophic cardiomyopathy (HCM) is based on clinical, echocardiographic and in some cases genetic findings. However, prognostication remains limited except in the subset of patients with high-risk indicators for sudden cardiac death. Additional methods are needed for risk stratification and to guide clinical management in HCM. We reviewed the available data regarding natriuretic peptides and troponins in HCM. Plasma levels of natriuretic peptides, and to a lesser extent serum levels of troponins, correlate with established disease markers, including left ventricular thickness, symptom status, and left ventricular hemodynamics by Doppler measurements. As a reflection of left ventricular filling pressure, natriuretic peptides may provide an objective measure of the efficacy of a specific therapy. Both natriuretic peptides and troponins predict clinical risk in HCM independently of established risk factors, and their prognostic power is additive. Routine measurement of biomarker levels therefore may be useful in the clinical evaluation and management of patients with HCM. PMID:27236124

  17. Information-driven modeling of protein-peptide complexes.

    Science.gov (United States)

    Trellet, Mikael; Melquiond, Adrien S J; Bonvin, Alexandre M J J

    2015-01-01

    Despite their biological importance in many regulatory processes, protein-peptide recognition mechanisms are difficult to study experimentally at the structural level because of the inherent flexibility of peptides and the often transient interactions on which they rely. Complementary methods like biomolecular docking are therefore required. The prediction of the three-dimensional structure of protein-peptide complexes raises unique challenges for computational algorithms, as exemplified by the recent introduction of protein-peptide targets in the blind international experiment CAPRI (Critical Assessment of PRedicted Interactions). Conventional protein-protein docking approaches are often struggling with the high flexibility of peptides whose short sizes impede protocols and scoring functions developed for larger interfaces. On the other side, protein-small ligand docking methods are unable to cope with the larger number of degrees of freedom in peptides compared to small molecules and the typically reduced available information to define the binding site. In this chapter, we describe a protocol to model protein-peptide complexes using the HADDOCK web server, working through a test case to illustrate every steps. The flexibility challenge that peptides represent is dealt with by combining elements of conformational selection and induced fit molecular recognition theories. PMID:25555727

  18. Radiolabelled peptides for oncological diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Laverman, Peter; Boerman, Otto C.; Oyen, Wim J.G. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands); Sosabowski, Jane K. [Queen Mary University of London, Centre for Molecular Oncology, Barts Cancer Institute, London (United Kingdom)

    2012-02-15

    Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The {sup 111}In-labelled somatostatin analogue octreotide (OctreoScan trademark) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours. (orig.)

  19. Antimicrobial Peptides (AMPs

    Directory of Open Access Journals (Sweden)

    Mehrzad Sadredinamin

    2016-04-01

    Full Text Available Antimicrobial peptides (AMPs are extensive group of molecules that produced by variety tissues of invertebrate, plants, and animal species which play an important role in their immunity response. AMPs have different classifications such as; biosynthetic machines, biological sources, biological functions, molecular properties, covalent bonding patterns, three dimensional structures, and molecular targets.These molecules have multidimensional properties including antimicrobial activity, antiviral activity, antifungal activity, anti-parasite activity, biofilm control, antitumor activity, mitogens activity and linking innate to adaptive immunity that making them promising agents for therapeutic drugs. In spite of this advantage of AMPs, their clinical developments have some limitation for commercial development. But some of AMPs are under clinical trials for the therapeutic purpose such as diabetic foot ulcers, different bacterial infections and tissue damage. In this review, we emphasized on the source, structure, multidimensional properties, limitation and therapeutic applications of various antimicrobial peptides.

  20. Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice.

    Science.gov (United States)

    Robert, Jérôme; Stukas, Sophie; Button, Emily; Cheng, Wai Hang; Lee, Michael; Fan, Jianjia; Wilkinson, Anna; Kulic, Iva; Wright, Samuel D; Wellington, Cheryl L

    2016-05-01

    Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aβ40 and Aβ42 levels were significantly reduced within 24h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aβ levels in animals assessed 7days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aβ levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aβ pool. That systemic administration of rHDL can acutely modify brain Aβ levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26454209

  1. Antimicrobial peptides in crustaceans

    OpenAIRE

    RD Rosa; MA Barracco

    2010-01-01

    Crustaceans are a large and diverse invertebrate animal group that mounts a complex and efficient innate immune response against a variety of microorganisms. The crustacean immune system is primarily related to cellular responses and the production and release of important immune effectors into the hemolymph. Antimicrobial proteins and/or peptides (AMPs) are key components of innate immunity and are widespread in nature, from bacteria to vertebrate animals. In crustaceans, 15 distinct AMP fam...

  2. Graphene Symmetry Amplified by Designed Peptide Self-Assembly.

    Science.gov (United States)

    Mustata, Gina-Mirela; Kim, Yong Ho; Zhang, Jian; DeGrado, William F; Grigoryan, Gevorg; Wanunu, Meni

    2016-06-01

    We present a strategy for designed self-assembly of peptides into two-dimensional monolayer crystals on the surface of graphene and graphite. As predicted by computation, designed peptides assemble on the surface of graphene to form very long, parallel, in-register β-sheets, which we call β-tapes. Peptides extend perpendicularly to the long axis of each β-tape, defining its width, with hydrogen bonds running along the axis. Tapes align on the surface to create highly regular microdomains containing 4-nm pitch striations. Moreover, in agreement with calculations, the atomic structure of the underlying graphene dictates the arrangement of the β-tapes, as they orient along one of six directions defined by graphene's sixfold symmetry. A cationic-assembled peptide surface is shown here to strongly adhere to DNA, preferentially orienting the double helix along β-tape axes. This orientational preference is well anticipated from calculations, given the underlying peptide layer structure. These studies illustrate how designed peptides can amplify the Ångstrom-level atomic symmetry of a surface onto the micrometer scale, further imparting long-range directional order onto the next level of assembly. The remarkably stable nature of these assemblies under various environmental conditions suggests applications in enzymelike catalysis, biological interfaces for cellular recognition, and two-dimensional platforms for studying DNA-peptide interactions. PMID:27276268

  3. Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides

    Directory of Open Access Journals (Sweden)

    D.J. Campbell

    2000-06-01

    Full Text Available The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikrein-kinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikrein-kinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE and neutral endopeptidase (NEP inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

  4. Reference range of plasma N-terminal pro-brain natriuretic peptide levels in early preterm infants%早期早产儿血浆N末端脑钠肽参考值范围

    Institute of Scientific and Technical Information of China (English)

    张茜; 罗成汉; 时赞扬; 卢洁; 程欣茹; 徐千雅; 郭宏湘; 王丽; 程秀永

    2013-01-01

    .358,t1d与7 d=14.743,t3d与7d =11.105,P均=0.000).出生后1d、3d、7d早产儿血浆NT-proBNP水平分别为(1875 ±686) ng/L、(1615±574) ng/L、(1118 ±380) ng/L;均数95%置信区间分别为530~3220 ng/L、490~2740 ng/L、373~ 1863 ng/L.结论 早产儿血浆NT-proBNP水平出生第1天达高峰,之后随日龄增加而下降,二者呈负相关;血浆NT-proBNP水平不受胎龄、性别、出生体质量、分娩方式及营养方式的影响.%Objective To establish the reference range of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in early preterm infants.Methods 1.Inclusion criteria of the subjects:(1) preterm infants admitted to Neonatal Ward of First Affiliated Hospital of Zhengzhou University between Oct.2009 and Aug.2012 within 24 hours after birth;(2) maternal health during pregnancy; (3) written informed consent obtained from parents;(4) normal laboratory examination results such as blood gas analysis,electrolyte,hepatorenal function,myocardial enzyme,routine blood count and infectious disease screening (hepatitis B,hepatitis C,syphilis and acquired immune deficiency syndrome) within 24 hours after birth.Plasma NT-proBNP levels were measured on day 1,day 3 and day 7 of life.Variable data was analyzed using the Shapiro-Wilk test for normality test.Difference in plasma NT-proBNP levels on different days of life was analyzed using repeated measure analysis of variance.A multiple regression analysis was performed to determine the influencing factors for plasma NT-proBNP level,reference value interval:reference range containing 95 % of the reference population,namely(x-1.96 s)-(x-+ 1.96 s),with inspection level α =0.05.Results 1.A total of 204 preterm infants (104 cases were male and 100 cases were female) were included in the present study,with gestational age ranging from 27 + 1 to 36 +6 weeks(median 33 weeks) and birth weight ranging from 700 to 3050 g (median 1590 g).Of these preterm infants,vaginal delivery were 78

  5. Accurate Peptide Fragment Mass Analysis: Multiplexed Peptide Identification and Quantification

    OpenAIRE

    Weisbrod, Chad R.; Eng, Jimmy K.; Hoopmann, Michael R.; Baker, Tahmina; Bruce, James E.

    2012-01-01

    FT All Reaction Monitoring (FT-ARM) is a novel approach for the identification and quantification of peptides that relies upon the selectivity of high mass accuracy data and the specificity of peptide fragmentation patterns. An FT-ARM experiment involves continuous, data-independent, high mass accuracy MS/MS acquisition spanning a defined m/z range. Custom software was developed to search peptides against the multiplexed fragmentation spectra by comparing theoretical or empirical fragment ion...

  6. Improved stability and selectivity of lytic peptides through self-assembly

    International Nuclear Information System (INIS)

    Widespread clinical applications of peptide drugs have been hindered by their low stability and selectivity. Peptides can be easily digested by various enzymes in the blood and thus show a short life-span. Meanwhile, peptide drugs can cause severe normal tissue damage due to their low selectivity. Therefore, for effective therapy, a high dosage of peptide is required which is usually in excess of the clinically and economically acceptable level. In this study, we have tried to design new lytic peptides which can self-assemble into peptide fibrils with defined nanostructures as observed under atomic force microscopy. Lytic peptides in self-assembled peptide fibrils will lose their cell lysis activity but become resistant to enzyme degradation. Such lytic peptide self-assembly has proven to be a reversible process which is controlled by surrounded environments. A concentration controlled sustained release of free and active lytic peptide from self-assembled peptide fibrils has been achieved. Self-assembled lytic peptides with enzyme resistance, sustained release, and prodrug feature may have great clinical application potentials

  7. NCAM Mimetic Peptides: An Update

    DEFF Research Database (Denmark)

    Berezin, Vladimir; Bock, Elisabeth

    2008-01-01

    pharmacological tools interfering with NCAM functions. Recent progress in our understanding of the structural basis of NCAM-mediated cell adhesion and signaling has allowed a structure-based design of NCAM mimetic peptides. Using this approach a number of peptides termed P2, P1-B, P-3-DE and P-3-G, whose...... sequences contain one or several NCAM homophilic binding sites involved in NCAM binding to itself, have been identified. By means of NMR titration analysis and molecular modeling a number of peptides derived from NCAM and targeting NCAM heterophilic ligands such as the fibroblast growth factor receptor and...... heparan sulfate proteoglycans (HSPG) have been identified. The FGL, dekaCAM, FRM/EncaminA, BCL, EncaminC and EncaminE peptides all target the FGF receptor whereas the heparin binding peptide HBP targets HSPG. Moreover, a number of NCAM binding peptides have been identified employing screening of...

  8. Immunological responses to fungal epitope peptides

    OpenAIRE

    Sheth-Ughade, Parita

    2012-01-01

    Introduction: Fungi are common aeroallergens responsible for at least 3% – 10% of allergic diseases worldwide, with the proportion hugely variable in different populations. Treatment is complicated by viable nature and disease causing ability of the allergen and is often only palliative. Thus, this study aimed to serve as a pilot investigation to design novel anti-allergy therapeutics to cure allergy at the molecular level. It investigates the effect of wild type fungal peptides and correspon...

  9. Cationic Antimicrobial Peptides Disrupt the Streptococcus pyogenes ExPortal

    OpenAIRE

    Vega, Luis Alberto; Caparon, Michael G.

    2012-01-01

    Although they possess a well-characterized ability to porate the bacterial membrane, emerging research suggests that cationic antimicrobial peptides (CAPs) can influence pathogen behavior at levels that are sub-lethal. In this study, we investigated the interaction of polymyxin B and human neutrophil peptide (HNP-1) with the human pathogen Streptococcus pyogenes. At sub-lethal concentrations, these CAPs preferentially targeted the ExPortal, a unique microdomain of the S. pyogenes membrane, sp...

  10. Correlation between B type natriuretic peptide and metabolic risk factors

    OpenAIRE

    Zhu, Wen-hua; Chen, Li-Ying; Dai, Hong-Lei; CHEN, JIAN-HUA; Yan CHEN; Fang, Li-Zheng

    2016-01-01

    Introduction It has been shown that B type natriuretic peptide (BNP) level can indicate cardiovascular disease. However, the association between BNP and metabolic risk factors is unknown. The aim of this study was to investigate the correlation between N-terminal pro-B type natriuretic peptide (NT-proBNP) and metabolic risk factors. Material and methods A total of 11,508 subjects were selected from those who underwent health examinations in our hospital. NT-proBNP, waist circumference, blood ...

  11. The PeptideAtlas Project

    OpenAIRE

    Deutsch, Eric W.

    2010-01-01

    PeptideAtlas is a multi-species compendium of peptides observed with tandem mass spectrometry methods. Raw mass spectrometer output files are collected from the community and reprocessed through a uniform analysis and validation pipeline that continues to advance. The results are loaded into a database and the information derived from the raw data is returned to the community via several web-based data exploration tools. The PeptideAtlas resource is useful for experiment planning, improving g...

  12. Human Antimicrobial Peptides and Proteins

    OpenAIRE

    Guangshun Wang

    2014-01-01

    As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified ...

  13. Improving Peptide Applications Using Nanotechnology.

    Science.gov (United States)

    Narayanaswamy, Radhika; Wang, Tao; Torchilin, Vladimir P

    2016-01-01

    Peptides are being successfully used in various fields including therapy and drug delivery. With advancement in nanotechnology and targeted delivery carrier systems, suitable modification of peptides has enabled achievement of many desirable goals over-riding some of the major disadvantages associated with the delivery of peptides in vivo. Conjugation or physical encapsulation of peptides to various nanocarriers, such as liposomes, micelles and solid-lipid nanoparticles, has improved their in vivo performance multi-fold. The amenability of peptides to modification in chemistry and functionalization with suitable nanocarriers are very relevant aspects in their use and have led to the use of 'smart' nanoparticles with suitable linker chemistries that favor peptide targeting or release at the desired sites, minimizing off-target effects. This review focuses on how nanotechnology has been used to improve the number of peptide applications. The paper also focuses on the chemistry behind peptide conjugation to nanocarriers, the commonly employed linker chemistries and the several improvements that have already been achieved in the areas of peptide use with the help of nanotechnology. PMID:26279082

  14. Peptides that influence membrane topology

    Science.gov (United States)

    Wong, Gerard C. L.

    2014-03-01

    We examine the mechanism of a range of polypeptides that influence membrane topology, including antimicrobial peptides, cell penetrating peptides, viral fusion peptides, and apoptosis proteins, and show how a combination of geometry, coordination chemistry, and soft matter physics can be used to approach a unified understanding. We will also show how such peptides can impact biomedical problems such as auto-immune diseases (psoriasis, lupus), infectious diseases (viral and bacterial infections), and mitochondrial pathologies (under-regulated apoptosis leads to neurodegenerative diseases whereas over-regulated apoptosis leads to cancer.)

  15. Peptidomics and processing of regulatory peptides in the fruit fly Drosophila

    Directory of Open Access Journals (Sweden)

    Dennis Pauls

    2014-06-01

    Full Text Available More than a decade has passed since the release of the Drosophila melanogaster genome and the first predictions of fruit fly regulatory peptides (neuropeptides and peptide hormones. Since then, mass spectrometry-based methods have fuelled the chemical characterisation of regulatory peptides, from 7 Drosophila peptides in the pre-genomic area to more than 60 today. We review the development of fruit fly peptidomics, and present a comprehensive list of the regulatory peptides that have been chemically characterised until today. We also summarise the knowledge on peptide processing in Drosophila, which has strongly profited from a combination of MS-based techniques and the genetic tools available for the fruit fly. This combination has a very high potential to study the functional biology of peptide signalling on all levels, especially with the ongoing developments in quantitative MS in Drosophila.

  16. Polyclonal Peptide Antisera.

    Science.gov (United States)

    Pihl, Tina H; Illigen, Kristin E; Houen, Gunnar

    2015-01-01

    Polyclonal antibodies are relatively easy to produce and may supplement monoclonal antibodies for some applications or even have some advantages. The choice of species for production of (peptide) antisera is based on practical considerations, including availability of immunogen (vaccine) and animals. Two major factors govern the production of antisera: the nature of adaptive immune responses, which take place over days/weeks and ethical guidelines for animal welfare. Here, simple procedures for immunization of mice, rabbits, sheep, goats, pigs, horses, and chickens are presented. PMID:26424267

  17. Injectable polymer microspheres enhance immunogenicity of a contraceptive peptide vaccine.

    Science.gov (United States)

    Cui, Chengji; Stevens, Vernon C; Schwendeman, Steven P

    2007-01-01

    Advanced contraceptive peptide vaccines suffer from the unavailability of adjuvants capable of enhancing the antibody response with acceptable safety. We sought to overcome this limitation by employing two novel poly(lactic-co-glycolic acid) (PLGA) microsphere formulations to deliver a synthetic human chorionic gonadotropin (hCG) peptide antigen co-synthesized with a T-cell epitope from tetanus toxoid (TT), C-TT2-CTP35: surface-conjugated immunogen to induce phagocytosis; and encapsulated peptide to provide a depot effect, with MgCO(3) co-encapsulated in the polymer to neutralize acidity from the biodegrading PLGA polyester. A single immunization of encapsulated peptide in rabbits elicited a stronger antibody response with equivalent duration relative to a positive control--three injections of the peptide administered in a squalene-based water-in-oil emulsion. Surface-conjugated peptide was less effective but enhanced antibody levels at 1/5 the dose, relative to soluble antigen. Most remarkable and unexpected was the finding that co-encapsulation of base was essential to attain the powerful adjuvant effect of the PLGA-MgCO(3) system, as the MgCO(3)-free microspheres were completely ineffective. A promising contraceptive hCG peptide vaccine with acceptable side effects (i.e., local tissue reactions) was achieved by minimizing PLGA and MgCO(3) doses, without significantly affecting antibody response. PMID:16996662

  18. Phytosulfokine peptide signalling.

    Science.gov (United States)

    Sauter, Margret

    2015-08-01

    Phytosulfokine (PSK) belongs to the group of plant peptide growth factors. It is a disulfated pentapeptide encoded by precursor genes that are ubiquitously present in higher plants, suggestive of universal functions. Processing of the preproprotein involves sulfonylation by a tyrosylprotein sulfotransferase in the trans-golgi and proteolytic cleavage in the apoplast. The secreted peptide is perceived at the cell surface by a membrane-bound receptor kinase of the leucine-rich repeat family. The PSK receptor PSKR1 from Arabidopsis thaliana is an active kinase and has guanylate cyclase activity resulting in dual-signal outputs. Receptor activity is regulated by calmodulin. While PSK may be an autocrine growth factor, it also acts non-cell autonomously by promoting growth of cells that are receptor-deficient. In planta, PSK has multiple functions. It promotes cell growth, acts in the quiescent centre cells of the root apical meristem, contributes to funicular pollen tube guidance, and differentially alters immune responses depending on the pathogen. It has been suggested that PSK integrates growth and defence signals to balance the competing metabolic costs of these responses. This review summarizes our current understanding of PSK synthesis, signalling, and activity. PMID:25754406

  19. The intestinal distribution pattern of appetite- and glucose regulatory peptides in mice, rats and pigs

    DEFF Research Database (Denmark)

    Albrechtsen, Nicolai Jacob Wewer; Kuhre, Rune Ehrenreich; Toräng, Signe;

    2016-01-01

    distribution analysis of the tissue content of the major appetite- and glucose regulatory peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 (GLP-2), oxyntomodulin/glicentin, neurotensin, and peptide YY (PYY) from the duodenum to distal colon...... mouse the highest level was found in the distal colon. In rats and pigs, neurotensin was predominantly detected in mid and lower part of the small intestine, while the mouse showed the highest levels in the distal small intestine. In contrast, the distribution of GIP was restricted to the proximal small...

  20. Peptide-LNA oligonucleotide conjugates

    DEFF Research Database (Denmark)

    Astakhova, I Kira; Hansen, Lykke Haastrup; Vester, Birte; Wengel, Jesper

    2013-01-01

    Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical...

  1. Solid-phase peptide synthesis

    DEFF Research Database (Denmark)

    Jensen, Knud Jørgen

    This chapter provides an introduction to and overview of peptide chemistry with a focus on solid-phase peptide synthesis. The background, the most common reagents, and some mechanisms are presented. This chapter also points to the different chapters and puts them into perspective....

  2. Radiolabelled peptides for oncological diagnosis.

    NARCIS (Netherlands)

    Laverman, P.; Sosabowski, J.K.; Boerman, O.C.; Oyen, W.J.G.

    2012-01-01

    Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of resea

  3. Calcitonin gene-related peptide and adrenomedullin release in humans

    DEFF Research Database (Denmark)

    Hasbak, Philip; Lundby, Carsten; Olsen, Niels Vidiendal;

    2002-01-01

    Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasorelaxant peptides. This study examined exercise-induced changes in CGRP and AM levels in 12 healthy sea level natives at sea level (SL) and subsequently after 24 h (HA1) and 5 days (HA5) in high altitude hypoxia (4559 m......). Plasma values of CGRP, AM, calcitonin, noradrenaline, adrenaline, lactate and heart rate were measured at rest and during maximal exercise (W(max)). On each study day, the dopamine D(2)-receptor antagonist, domperidone (30 mg; n=6), or no medication (n=6) was given 1 h before exercise. W(max) at SL, HA1...

  4. Biomedical exploitation of self assembled peptide based nanostructures.

    Science.gov (United States)

    Roy, Anupam; Franco, Octavio L; Mandal, Santi M

    2013-11-01

    Nowadays, peptide based disease prevention is an important topic in biomedical science, which may radically change the traditional use of biomaterials and improve the life quality. Self-assembled nanostructured peptides have been receiving extreme attention in the drug delivery field due their high biocompatibility levels, better loading capacity, extended circulation and localization in required target site. This article focuses on the composition and synthesis of different forms of self-assembled peptide nanostructures as nanotubes, nanofibers, nanoparticles, nanotapes and nanogels. The most important properties for their self assembled mechanism and their biomedical applications are also discussed. Various potential applications of nanostructures peptide could be developed designed for therapeutic agent's delivery, biosensors, anticancerous and antimicrobial activities. PMID:23968344

  5. Peptides for radiotherapy of neuroendocrine cancers

    International Nuclear Information System (INIS)

    During the last decade there has been a resurgence of interest in therapeutic nuclear medicine, due to the limitation of conventional or external beam radiotherapy in the treatment of secondary or metastatic cancer sites outside of the primary treatment area. Some of the human tumours that produce metastases express high levels of somatostatin receptors. In order to make possible the diagnostic and radiotherapeutic treatment of these kind of tumours, various somatostatin analogue peptides have been developed in recent years. Peptides have become an important class of radiopharmaceuticals,due to its unique ability to detect specific sites as receptors or enzymes. This paper describes the work with 99m Tc to establish the labelling and analytical conditions for a somatostatin analogue as a precursor, to undertake a therapeutic radiopharmaceutical labelled with 188 Re for treatment of somatostatin receptor positive tumours. (Author)

  6. Neuroactive peptides as putative mediators of antiepileptic ketogenic diets

    Directory of Open Access Journals (Sweden)

    GiuseppeBiagini

    2014-04-01

    Full Text Available Various ketogenic diet (KD therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs. In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the

  7. Conus venom peptide pharmacology.

    Science.gov (United States)

    Lewis, Richard J; Dutertre, Sébastien; Vetter, Irina; Christie, MacDonald J

    2012-04-01

    Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies. PMID:22407615

  8. Synergistic Epithelial Responses to Endotoxin and a Naturally Occurring Muramyl Peptide

    OpenAIRE

    Flak, Tod A.; Heiss, Linda N.; Engle, Jacquelyn T.; Goldman, William E

    2000-01-01

    We have investigated the synergistic interactions of a naturally occurring peptidoglycan fragment (muramyl peptide) and bacterial endotoxin in the induction of inflammatory processes within respiratory epithelial cells, at the levels of both signal transduction events and ultimate cellular metabolic effects. The source of the muramyl peptide is Bordetella pertussis, the causative agent of the respiratory disease pertussis. During log-phase growth, B. pertussis releases the muramyl peptide tra...

  9. Relaxin Peptide Hormones Are Protective During the Early Stages of Ischemic Stroke in Male Rats

    OpenAIRE

    Bergeron, Lindsay H.; Willcox, Jordan M.; Alibhai, Faisal J.; Barry J. Connell; Tarek M Saleh; Wilson, Brian C.; Alastair J S Summerlee

    2014-01-01

    The pregnancy hormone relaxin protects tissue from ischemic damage. The ability of relaxin-3, a relaxin paralog, to do so has not been explored. The cerebral expression levels of these peptides and their receptors make them logical targets for study in the ischemic brain. We assessed relaxin peptide-mediated protection, relative relaxin family peptide receptor (RXFP) involvement, and protective mechanisms. Sprague-Dawley rats receiving permanent (pMCAO) or transient middle cerebral artery occ...

  10. The Role of Food Peptides in Lipid Metabolism during Dyslipidemia and Associated Health Conditions

    OpenAIRE

    Udenigwe, Chibuike C.; Kirsti Rouvinen-Watt

    2015-01-01

    Animal and human clinical studies have demonstrated the ability of dietary food proteins to modulate endogenous lipid levels during abnormal lipid metabolism (dyslipidemia). Considering the susceptibility of proteins to gastric proteolytic activities, the hypolipidemic functions of proteins are possibly due, in part, to their peptide fragments. Food-derived peptides may directly modulate abnormal lipid metabolism in cell cultures and animal models of dyslipidemia. The peptides are thought to...

  11. Production of Biologically Active Cecropin A Peptide in Rice Seed Oil Bodies.

    OpenAIRE

    Laura Montesinos; Mireia Bundó; Esther Izquierdo; Sonia Campo; Esther Badosa; Michel Rossignol; Emilio Montesinos; Blanca San Segundo; María Coca

    2016-01-01

    Cecropin A is a natural antimicrobial peptide that exhibits fast and potent activity against a broad spectrum of pathogens and neoplastic cells, and that has important biotechnological applications. However, cecropin A exploitation, as for other antimicrobial peptides, is limited by their production and purification costs. Here, we report the efficient production of this bioactive peptide in rice bran using the rice oleosin 18 as a carrier protein. High cecropin A levels were reached in rice ...

  12. Radiopharmaceutical development of radiolabelled peptides

    Energy Technology Data Exchange (ETDEWEB)

    Fani, Melpomeni; Maecke, Helmut R. [University Hospital Freiburg, Department of Nuclear Medicine, Freiburg (Germany)

    2012-02-15

    Receptor targeting with radiolabelled peptides has become very important in nuclear medicine and oncology in the past few years. The overexpression of many peptide receptors in numerous cancers, compared to their relatively low density in physiological organs, represents the molecular basis for in vivo imaging and targeted radionuclide therapy with radiolabelled peptide-based probes. The prototypes are analogs of somatostatin which are routinely used in the clinic. More recent developments include somatostatin analogs with a broader receptor subtype profile or with antagonistic properties. Many other peptide families such as bombesin, cholecystokinin/gastrin, glucagon-like peptide-1 (GLP-1)/exendin, arginine-glycine-aspartic acid (RGD) etc. have been explored during the last few years and quite a number of potential radiolabelled probes have been derived from them. On the other hand, a variety of strategies and optimized protocols for efficient labelling of peptides with clinically relevant radionuclides such as {sup 99m}Tc, M{sup 3+} radiometals ({sup 111}In, {sup 86/90}Y, {sup 177}Lu, {sup 67/68}Ga), {sup 64/67}Cu, {sup 18}F or radioisotopes of iodine have been developed. The labelling approaches include direct labelling, the use of bifunctional chelators or prosthetic groups. The choice of the labelling approach is driven by the nature and the chemical properties of the radionuclide. Additionally, chemical strategies, including modification of the amino acid sequence and introduction of linkers/spacers with different characteristics, have been explored for the improvement of the overall performance of the radiopeptides, e.g. metabolic stability and pharmacokinetics. Herein, we discuss the development of peptides as radiopharmaceuticals starting from the choice of the labelling method and the conditions to the design and optimization of the peptide probe, as well as some recent developments, focusing on a selected list of peptide families, including somatostatin

  13. Urinary C-peptide tracks seasonal and individual variation in energy balance in wild chimpanzees.

    Science.gov (United States)

    Emery Thompson, Melissa; Muller, Martin N; Wrangham, Richard W; Lwanga, Jeremiah S; Potts, Kevin B

    2009-02-01

    C-peptide of insulin presents a promising new tool for behavioral ecologists that allows for regular, non-invasive assessment of energetic condition in wild animals. C-peptide is produced on an equimolar basis with insulin, thus is indicative of the body's response to available glucose and, with repeated measurement, provides a biomarker of energy balance. As yet, few studies have validated the efficacy of C-peptide for monitoring energy balance in wild animals. Here, we assess seasonal and interindividual variation in urinary C-peptide concentrations of East African chimpanzees (Pan troglodytes schweinfurthii). We assayed 519 urine samples from 13 adult male chimpanzees in the Kanyawara community of Kibale National Park, Uganda. C-peptide levels were significantly predicted by the total amount of fruit and the amount of preferred fruit in the diet. However, chimpanzees had very low C-peptide titers during an epidemic of severe respiratory illness, despite highly favorable feeding conditions. Kanyawara males had significantly lower C-peptide levels than males at Ngogo, a nearby chimpanzee community occupying a more productive habitat. Among Kanyawara males, low-ranking males had consistently higher C-peptide levels than dominant males. While counterintuitive, this result supports previous findings of costs associated with dominance in male chimpanzees. Our preliminary investigations demonstrate that C-peptide has wide applications in field research, providing an accessible tool for evaluating seasonal and individual variation in energetic condition, as well as the costs of processes such as immune function and reproduction. PMID:19084530

  14. Peptide primary messengers in plants

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The peptide primary messengers regulate embryonic development,cell growth and many other activities in animal cells. But recent evidence verified that peptide primary messengers are also involved in plant defense responses, the recognition between pollen and stigma and keep the balance between cell proliferation and differentiations in shoot apical meristems. Those results suggest that plants may actually make wide use of peptide primary messengers, both in embryonic development and late life when they rally their cells to defend against pathogens and insect pests. The recent advance in those aspects is reviewed.

  15. Hierarchical organization of ferrocene-peptides.

    Science.gov (United States)

    Beheshti, Samaneh; Martić, Sanela; Kraatz, Heinz-Bernhard

    2012-07-16

    Hierarchical self-assembly of disubstituted ferrocene (Fc)-peptide conjugates that possess Gly-Val-Phe and Gly-Val-Phe-Phe peptide substituents leads to the formation of nano- and micro-sized assemblies. Hydrogen-bonding and hydrophobic interactions provide directionality to the assembly patterns. The self-assembling behavior of these compounds was studied in solution by using (1)H NMR and circular dichroism (CD) spectroscopies. In the solid state, attenuated total reflectance (ATR) FTIR spectroscopy, single-crystal X-ray diffraction (XRD), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) methods were used. Spontaneous self-assembly of Fc-peptides through intra- and intermolecular hydrogen-bonding interactions induces supramolecular assemblies, which further associate and give rise to fibers, large fibrous crystals, and twisted ropes. In the case of Fc[CO-Gly-Val-Phe-OMe](2) (1), molecules initially interact to form pleated sheets that undergo association into long fibers that form bundles and rectangular crystalline cuboids. Molecular offsets and defects, such as screw dislocations and solvent effects that occur during crystal growth, induce the formation of helical arrangements, ultimately leading to large twisted ropes. By contrast, the Fc-tetrapeptide conjugate Fc[CO-Gly-Val-Phe-Phe-OMe](2) (2) forms a network of nanofibers at the supramolecular level, presumably due to the additional hydrogen-bonding and hydrophobic interactions that stem from the additional Phe residues. PMID:22707407

  16. Peptides: Basic determinants of reproductive functions.

    Science.gov (United States)

    Celik, Onder; Aydin, Suleyman; Celik, Nilufer; Yilmaz, Musa

    2015-10-01

    Mammalian reproduction is a costly process in terms of energy consumption. The critical information regarding metabolic status is signaled to the hypothalamus mainly through peripheral peptides from the adipose tissue and gastrointestinal tract. Changes in energy stores produce fluctuations in leptin, insulin, ghrelin and glucose signals that feedback mainly to the hypothalamus to regulate metabolism and fertility. In near future, possible effects of the nutritional status on GnRH regulation can be evaluated by measuring serum or tissue levels of leptin and ghrelin in patiens suffering from infertility. The fact that leptin and ghrelin are antagonistic in their effects on GnRH neurons, their respective agonistic and antagonistic roles make them ideal candidates to use instead of GnRH agonist and antagonist. Similarly, kisspeptin expressing neurons are likely to mediate the well-established link between energy balance and reproductive functions. Exogenous kisspeptin can be used for physiological ovarian hyperstimulation for in-vitro fertilization. Moreover, kisspeptin antagonist therapy can be used for the treatment of postmenapousal women, precocious puberty, PCOS, endometriosis and uterine fibroids. In this review, we will analyze the central mechanisms involved in the integration of metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of leptin, kisspeptin, ghrelin, NPY, orexin, urocortin, VIP, insulin, galanin, galanin like peptide, oxytocin, agouti gene-related peptide, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction. PMID:26074346

  17. Radioimmunoassay for C-peptide in diabetic children

    International Nuclear Information System (INIS)

    Direct insulin radioimmunoassay (RIA) studies in a diabetic are no longer meaningful once insulin therapy has been instituted. For this reason, use is made of RIA for blood C-peptide, a proinsulin component reflecting endogenous insulin secretion independently of insulin therapy. The paper reports experience with C-peptide RIA studies carried out on blood from 273 diabetic children of normal body weight and 11.3 years average age, as well as 31 healthy children (control group). Diabetes duration ranged from 7 days to 14 years. The basic level of C-peptide in diabetic children is lower than that of healthy ones. Glucose stimulation produces C-peptide elevation in healthy but not in diabetic children. Glucagon stimulation produced a further rise of blood C-peptide in the healthy children. Diabetics showed very modest response to glucagon stimulation. C-peptide secretion in diabetic children proved to be inversely proportional to the duration of the diabetes. These findings in children with diabetes mellitus indicated their insulin secretion by beta cells of the pancreatic islets of Langerhans to be substantially decreased and unresponsive to glucose and glucagon stimulation. 3 figs, 1 tab

  18. Dysferlin-peptides reallocate mutated dysferlin thereby restoring function.

    Directory of Open Access Journals (Sweden)

    Verena Schoewel

    Full Text Available Mutations in the dysferlin gene cause the most frequent adult-onset limb girdle muscular dystrophy, LGMD2B. There is no therapy. Dysferlin is a membrane protein comprised of seven, beta-sheet enriched, C2 domains and is involved in Ca(2+dependent sarcolemmal repair after minute wounding. On the protein level, point mutations in DYSF lead to misfolding, aggregation within the endoplasmic reticulum, and amyloidogenesis. We aimed to restore functionality by relocating mutant dysferlin. Therefore, we designed short peptides derived from dysferlin itself and labeled them to the cell penetrating peptide TAT. By tracking fluorescently labeled short peptides we show that these dysferlin-peptides localize in the endoplasmic reticulum. There, they are capable of reducing unfolded protein response stress. We demonstrate that the mutant dysferlin regains function in membrane repair in primary human myotubes derived from patients' myoblasts by the laser wounding assay and a novel technique to investigate membrane repair: the interventional atomic force microscopy. Mutant dysferlin abuts to the sarcolemma after peptide treatment. The peptide-mediated approach has not been taken before in the field of muscular dystrophies. Our results could redirect treatment efforts for this condition.

  19. Dysferlin-peptides reallocate mutated dysferlin thereby restoring function.

    Science.gov (United States)

    Schoewel, Verena; Marg, Andreas; Kunz, Severine; Overkamp, Tim; Carrazedo, Romy Siegert; Zacharias, Ute; Daniel, Peter T; Spuler, Simone

    2012-01-01

    Mutations in the dysferlin gene cause the most frequent adult-onset limb girdle muscular dystrophy, LGMD2B. There is no therapy. Dysferlin is a membrane protein comprised of seven, beta-sheet enriched, C2 domains and is involved in Ca(2+)dependent sarcolemmal repair after minute wounding. On the protein level, point mutations in DYSF lead to misfolding, aggregation within the endoplasmic reticulum, and amyloidogenesis. We aimed to restore functionality by relocating mutant dysferlin. Therefore, we designed short peptides derived from dysferlin itself and labeled them to the cell penetrating peptide TAT. By tracking fluorescently labeled short peptides we show that these dysferlin-peptides localize in the endoplasmic reticulum. There, they are capable of reducing unfolded protein response stress. We demonstrate that the mutant dysferlin regains function in membrane repair in primary human myotubes derived from patients' myoblasts by the laser wounding assay and a novel technique to investigate membrane repair: the interventional atomic force microscopy. Mutant dysferlin abuts to the sarcolemma after peptide treatment. The peptide-mediated approach has not been taken before in the field of muscular dystrophies. Our results could redirect treatment efforts for this condition. PMID:23185377

  20. Formation and Dissociation of Phosphorylated Peptide Radical Cations

    Science.gov (United States)

    Kong, Ricky P. W.; Quan, Quan; Hao, Qiang; Lai, Cheuk-Kuen; Siu, Chi-Kit; Chu, Ivan K.

    2012-12-01

    In this study, we generated phosphoserine- and phosphothreonine-containing peptide radical cations through low-energy collision-induced dissociation (CID) of the ternary metal-ligand phosphorylated peptide complexes [CuII(terpy) p M]·2+ and [CoIII(salen) p M]·+ [ p M: phosphorylated angiotensin III derivative; terpy: 2,2':6',2''-terpyridine; salen: N, N '-ethylenebis(salicylideneiminato)]. Subsequent CID of the phosphorylated peptide radical cations ( p M·+) revealed fascinating gas-phase radical chemistry, yielding (1) charge-directed b- and y-type product ions, (2) radical-driven product ions through cleavages of peptide backbones and side chains, and (3) different degrees of formation of [M - H3PO4]·+ species through phosphate ester bond cleavage. The CID spectra of the p M·+ species and their non-phosphorylated analogues featured fragment ions of similar sequence, suggesting that the phosphoryl group did not play a significant role in the fragmentation of the peptide backbone or side chain. The extent of neutral H3PO4 loss was influenced by the peptide sequence and the initial sites of the charge and radical. A preliminary density functional theory study, at the B3LYP 6-311++G(d,p) level of theory, of the neutral loss of H3PO4 from a prototypical model— N-acetylphosphorylserine methylamide—revealed several factors governing the elimination of neutral phosphoryl groups through charge- and radical-induced mechanisms.

  1. Structural and Functional Studies of Peptide-Carbohydrate Mimicry

    Science.gov (United States)

    Johnson, Margaret A.; Pinto, B. Mario

    Certain peptides act as molecular mimics of carbohydrates in that they are specifically recognized by carbohydrate-binding proteins. Peptides that bind to anti-carbohydrate antibodies, carbohydrate-processing enzymes, and lectins have been identified. These peptides are potentially useful as vaccines and therapeutics; for example, immunologically functional peptide molecular mimics (mimotopes) can strengthen or modify immune responses induced by carbohydrate antigens. However, peptides that bind specifically to carbohydrate-binding proteins may not necessarily show the corresponding biological activity, and further selection based on biochemical studies is always required. The degree of structural mimicry required to generate the desired biological activity is therefore an interesting question. This review will discuss recent structural studies of peptide-carbohydrate mimicry employing NMR spectroscopy, X-ray crystallography, and molecular modeling, as well as relevant biochemical data. These studies provide insights into the basis of mimicry at the molecular level. Comparisons with other carbohydrate-mimetic compounds, namely proteins and glycopeptides, will be drawn. Finally, implications for the design of new therapeutic compounds will also be presented.

  2. Screening of TACE Peptide Inhibitors from Phage Display Peptide Library

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    To obtain the recombinant tumor necrosis factor-α converting enzyme (TACE) ectodomain and use it as a selective molecule for the screening of TACE peptide inhibitors, the cDNA coding catalytic domain (T800) and full-length ectodomain (T1300) of TACE were amplified by RTPCR, and the expression plasmids were constructed by inserting T800 and T1300 into plasmid pET28a and pET-28c respectively. The recombinant T800 and T1300 were induced by IPTG, and SDSPAGE and Western blotting analysis results revealed that T800 and T1300 were highly expressed in the form of inclusion body. After Ni2+-NTA resin affinity chromatography, the recombinant proteins were used in the screening of TACE-binding peptides from phage display peptide library respectively. After 4 rounds of biopanning, the positive phage clones were analyzed by ELISA, competitive inhibition assay and DNA sequencing. A common amino acid sequence (TRWLVYFSRPYLVAT) was found and synthesized. The synthetic peptide could inhibit the TNF-α release from LPS-stimulated human peripheral blood mononuclear cells (PBMC) up to 60.3 %. FACS analysis revealed that the peptide mediated the accumulation of TNF-α on the cell surface. These results demonstrate that the TACE-binding peptide is an effective antagonist of TACE.

  3. Probing the mechanism of material specific peptides for optical biosensors

    Science.gov (United States)

    Ramakrishnan, Sathish K.; Estephan, Elias; Martin, Marta; Cloitre, Thierry; Gergely, Csilla

    2013-05-01

    The possibility to engineer bio-nanomaterials with programmed synthesis and controlled immobilization of biomolecules through biomimetic molecular evolution approach has been demonstrated. Material specific peptides with exquisite molecular recognition function were used as a linker for the attachment of biomolecules. Exploring the origin of peptide material specificity not only opens up rational design approach with precise control over biomimetic bio-sensor design, but more importantly provides a new route of functionalizing for various material surfaces with enhanced sensitivity over classical grafting chemistry. To study the fine prints of experimentally obtained peptides, theoretical understanding of surface interactions may serve as important clues for further refinement. By taking advantage of classical molecular dynamics (MD) simulations and density functional theory (DFT), we investigated the origin of this smart recognition function through the strength of interaction of experimentally selected 12mer peptides revealing high binding affinity towards n+-Si(100). Here, we attempt for the very first time to model the interaction of the peptides (in buffer solution) with semiconductors and we calculate their binding energies at the atomic level, enabling thereby linking direct evidence to our experimental evidence. Several peptide conformations have been taken into account simultaneously upon the surface. Our studies demonstrate that the peptides possess certain recognition function and their high interaction energy with the surface makes them unique among the populations. Our work is a step towards the understanding of the interactions between peptides and semiconductor surfaces that is a highly relevant challenge in the development of novel devices with a high degree of biocompatibility as well.

  4. Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

    Science.gov (United States)

    Horner, Katy; Lee, SoJung

    2015-11-01

    During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents. PMID:26466085

  5. Peptide nanostructures in biomedical technology.

    Science.gov (United States)

    Feyzizarnagh, Hamid; Yoon, Do-Young; Goltz, Mark; Kim, Dong-Shik

    2016-09-01

    Nanostructures of peptides have been investigated for biomedical applications due to their unique mechanical and electrical properties in addition to their excellent biocompatibility. Peptides may form fibrils, spheres and tubes in nanoscale depending on the formation conditions. These peptide nanostructures can be used in electrical, medical, dental, and environmental applications. Applications of these nanostructures include, but are not limited to, electronic devices, biosensing, medical imaging and diagnosis, drug delivery, tissue engineering and stem cell research. This review offers a discussion of basic synthesis methods, properties and application of these nanomaterials. The review concludes with recommendations and future directions for peptide nanostructures. WIREs Nanomed Nanobiotechnol 2016, 8:730-743. doi: 10.1002/wnan.1393 For further resources related to this article, please visit the WIREs website. PMID:26846352

  6. Production and characterization of peptide antibodies

    DEFF Research Database (Denmark)

    Trier, Nicole Hartwig; Hansen, Paul Robert; Houen, Gunnar

    2012-01-01

    Proteins are effective immunogens for generation of antibodies. However, occasionally the native protein is known but not available for antibody production. In such cases synthetic peptides derived from the native protein are good alternatives for antibody production. These peptide antibodies are...... powerful tools in experimental biology and are easily produced to any peptide of choice. A widely used approach for production of peptide antibodies is to immunize animals with a synthetic peptide coupled to a carrier protein. Very important is the selection of the synthetic peptide, where factors such as......, including solid-phase peptide-carrier conjugation and peptide-carrier conjugation in solution. Upon immunization, adjuvants such as Al(OH)(3) are added together with the immunogenic peptide-carrier conjugate, which usually leads to high-titred antisera. Following immunization and peptide antibody...

  7. Cholecystokinin, glucose dependent insulinotropic peptide and glucagon-like peptide 1 secretion in children with anorexia nervosa and simple obesity.

    Science.gov (United States)

    Tomasik, Przemyslaw J; Sztefko, Krystyna; Starzyk, Jerzy

    2004-12-01

    Cholecystokinin (CCK), glucose dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1) regulate satiety as enterogastrons and incretins. They also directly affect the satiety centers. Therefore, these peptides may participate in the pathogenesis of eating disorders. CCK, GIP, and GLP-1 secretion were studied in 13 adolescent girls suffering from simple obesity, 13 girls with anorexia nervosa, and 10 healthy girls. Each girl was subjected to an oral glucose tolerance test (OGTT) and standard meal test. Blood was collected before stimulation and at 15, 30, 60, and 120 min. The concentrations of all peptides were determined by RIA commercial kits. Fasting and postprandial levels of these peptides as well as integrated outputs were measured. High postprandial levels of CCK observed in the girls with anorexia may aggravate the course of this disease by intensifying nausea and vomiting. Low postprandial level of GLP-1 in girls with simple obesity may be responsible for excessive ingestion of food and weaker inhibition of gastric emptying, which also leads to obesity. PMID:15645696

  8. Targeting cancer with peptide aptamers

    OpenAIRE

    Seigneuric, Renaud; Gobbo, Jessica; Colas, Pierre; Garrido, Carmen

    2011-01-01

    A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards succe...

  9. Quantitative single-vesicle analysis of antimicrobial peptide-induced leakage

    DEFF Research Database (Denmark)

    Kristensen, Kasper; Ehrlich, Nicky; Henriksen, Jonas Rosager; Andresen, Thomas Lars

    understanding of their interactions with phospholipid membranes. In this study, the membrane-permeabilizing effects of antimicrobial peptides were scrutinized by combining two biophysical techniques. Confocal fluorescence microscopy to visualize leakage from individual surface-immobilized lipid vesicles was......Although the research field of antimicrobial peptides has attracted considerable scientific attention in the past decades, the microbicidal mechanisms of antimicrobial peptides still remain elusive. One of the keys to a more profound comprehension of the function of these peptides is a deeper...... three canonical antimicrobial peptides: melittin, magainin 2, and mastoparan X. The results demonstrate an unprecedented level of insight into the molecular processes governing antimicrobial peptide-induced permeabilization of phospholipid membranes....

  10. Application of reaction type of C-peptide release test in diabetes mellitus

    International Nuclear Information System (INIS)

    The author is to confirm the effect of C-peptide release test and types of release reaction in appraisal of pancreas function of β-cell and selection of treatment for diabetes mellitus (DM) patients. The serum C-peptide release test of 67 normal controls and 217 DM patients were determined by RIA, and the results were analyzed and compared. C-peptide release test can reflect the pancreas function of β-cell better, the peak of C-peptide ≥ 0.6 nmol/L after lunch can be the limit of whether to reduce the level of blood glucose only by oral drug. The authors should adjust the treatment through analyzing the type of C-peptide release reaction. C-peptide release test is very important in evaluating the pancreas function of β-cell, classifying the type of DM and selecting the treatment

  11. Manufacturing of peptides exhibiting biological activity

    OpenAIRE

    Zambrowicz, Aleksandra; Timmer, Monika; Polanowski, Antoni; Lubec, Gert; Trziszka, Tadeusz

    2012-01-01

    Numerous studies have shown that food proteins may be a source of bioactive peptides. Those peptides are encrypted in the protein sequence. They stay inactive within the parental protein until release by proteolytic enzymes (Mine and Kovacs-Nolan in Worlds Poult Sci J 62(1):87–95, 2006; Hartman and Miesel in Curr Opin Biotechnol 18:163–169, 2007). Once released the bioactive peptides exhibit several biofunctionalities and may serve therapeutic roles in body systems. Opioid peptides, peptides ...

  12. Peptides and proteins

    Energy Technology Data Exchange (ETDEWEB)

    Bachovchin, W.W.; Unkefer, C.J.

    1994-12-01

    Advances in magnetic resonance and vibrational spectroscopy make it possible to derive detailed structural information about biomolecular structures in solution. These techniques are critically dependent on the availability of labeled compounds. For example, NMR techniques used today to derive peptide and protein structures require uniformity {sup 13}C-and {sup 15}N-labeled samples that are derived biosynthetically from (U-6-{sup 13}C) glucose. These experiments are possible now because, during the 1970s, the National Stable Isotope Resource developed algal methods for producing (U-6-{sup 13}C) glucose. If NMR techniques are to be used to study larger proteins, we will need sophisticated labelling patterns in amino acids that employ a combination of {sup 2}H, {sup 13}C, and {sup 15}N labeling. The availability of these specifically labeled amino acids requires a renewed investment in new methods for chemical synthesis of labeled amino acids. The development of new magnetic resonance or vibrational techniques to elucidate biomolecular structure will be seriously impeded if we do not see rapid progress in labeling technology. Investment in labeling chemistry is as important as investment in the development of advanced spectroscopic tools.

  13. Antimicrobial peptides in annelids

    Directory of Open Access Journals (Sweden)

    A Tasiemski

    2008-06-01

    Full Text Available Gene encoded antimicrobial peptides (AMPs are widely distributed among living organisms including plants, invertebrates and vertebrates. They constitute important effectors of the innate immune response by exerting multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cytokine release, cell proliferation, angiogenesis, wound healing, chemotaxis and immune induction. In invertebrates, most of the data describe the characterization and/or the function of AMPs in the numerically and economically most representative group which are arthropods. Annelids are among the first coelomates and are therefore of special phylogenetic interest. Compared to other invertebrate groups, data on annelid’s immunity reveal heavier emphasis on the cellular than on the humoral response suggesting that immune defense of annelids seems to be principally developed as cellular immunity.This paper gives an overview of the variety of AMPs identified in the three classes of annelids, i.e. polychaetes, oligochaetes and achaetes. Their functions, when they have been studied, in the humoral or cellular response of annelids are also mentioned.

  14. Kinins and peptide receptors.

    Science.gov (United States)

    Regoli, Domenico; Gobeil, Fernand

    2016-04-01

    This paper is divided into two sections: the first contains the essential elements of the opening lecture presented by Pr. Regoli to the 2015 International Kinin Symposium in S. Paulo, Brazil on June 28th and the second is the celebration of Dr. Regoli's 60 years of research on vasoactive peptides. The cardiovascular homeostasis derives from a balance of two systems, the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS). The biologically active effector entity of RAS is angiotensin receptor-1 (AT-1R), and that of KKS is bradykinin B2 receptor (B2R). The first mediates vasoconstriction, the second is the most potent and efficient vasodilator. Thanks to its complex and multi-functional mechanism of action, involving nitric oxide (NO), prostacyclin and endothelial hyperpolarizing factor (EDHF). B2R is instrumental for the supply of blood, oxygen and nutrition to tissues. KKS is present on the vascular endothelium and functions as an autacoid playing major roles in cardiovascular diseases (CVDs) and diabetes. KKS exerts a paramount role in the prevention of thrombosis and atherosclerosis. Such knowledge emphasizes the already prominent value of the ACE-inhibitors (ACEIs) for the treatment of CVDs and diabetes. Indeed, the ACEIs, thanks to their double action (block of the RAS and potentiation of the KKS) are the ideal agents for a rational treatment of these diseases. PMID:26408609

  15. Antimicrobial peptides in crustaceans

    Directory of Open Access Journals (Sweden)

    RD Rosa

    2010-11-01

    Full Text Available Crustaceans are a large and diverse invertebrate animal group that mounts a complex and efficient innate immune response against a variety of microorganisms. The crustacean immune system is primarily related to cellular responses and the production and release of important immune effectors into the hemolymph. Antimicrobial proteins and/or peptides (AMPs are key components of innate immunity and are widespread in nature, from bacteria to vertebrate animals. In crustaceans, 15 distinct AMP families are currently recognized, although the great majority (14 families comes from members of the order Decapoda. Crustacean AMPs are generally cationic, gene-encoded molecules that are mainly produced by circulating immune-competent cells (hemocytes or are derived from unrelated proteins primarily involved in other biological functions. In this review, we tentatively classified the crustacean AMPs into four main groups based on their amino acid composition, structural features and multi-functionality. We also attempted to summarize the current knowledge on their implication both in an efficient response to microbial infections and in crustacean survival.

  16. Material Binding Peptides for Nanotechnology

    Directory of Open Access Journals (Sweden)

    Urartu Ozgur Safak Seker

    2011-02-01

    Full Text Available Remarkable progress has been made to date in the discovery of material binding peptides and their utilization in nanotechnology, which has brought new challenges and opportunities. Nowadays phage display is a versatile tool, important for the selection of ligands for proteins and peptides. This combinatorial approach has also been adapted over the past decade to select material-specific peptides. Screening and selection of such phage displayed material binding peptides has attracted great interest, in particular because of their use in nanotechnology. Phage display selected peptides are either synthesized independently or expressed on phage coat protein. Selected phage particles are subsequently utilized in the synthesis of nanoparticles, in the assembly of nanostructures on inorganic surfaces, and oriented protein immobilization as fusion partners of proteins. In this paper, we present an overview on the research conducted on this area. In this review we not only focus on the selection process, but also on molecular binding characterization and utilization of peptides as molecular linkers, molecular assemblers and material synthesizers.

  17. Collagen-like antimicrobial peptides.

    Science.gov (United States)

    Masuda, Ryo; Kudo, Masakazu; Dazai, Yui; Mima, Takehiko; Koide, Takaki

    2016-11-01

    Combinatorial library composed of rigid rod-like peptides with a triple-helical scaffold was constructed. The component peptides were designed to have various combinations of basic and neutral (or hydrophobic) amino acid residues based on collagen-like (Gly-Pro-Yaa)-repeating sequences, inspired from the basic and amphiphilic nature of naturally occurring antimicrobial peptides. Screening of the peptide pools resulted in identification of antimicrobial peptides. A structure-activity relationship study revealed that the position of Arg-cluster at N-terminus and cystine knots at C-terminus in the triple helix significantly contributed to the antimicrobial activity. The most potent peptide RO-A showed activity against Gram-negative Escherichia coli and Gram-positive Bacillus subtilis. In addition, Escherichia coli exposed to RO-A resulted in abnormal elongation of the cells. RO-A was also shown to have remarkable stability in human serum and low cytotoxicity to mammalian cells. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 453-459, 2016. PMID:27271210

  18. Expression profiles of seven channel catfish antimicrobial peptides in response to Edwardsiella ictaluri infection

    Science.gov (United States)

    Using quantitative PCR technique, the relative transcriptional levels of seven channel catfish antimicrobial peptide (AMP) genes [NK-lysin type 1, NK-lysin type 2, NK-lysin type 3, bactericidal permeability-increasing protein (BPI), cathepsin D, hepcidin, and liver-expressed antimicrobial peptide 2 ...

  19. Chronic pre-treatment with memantine prevents amyloid-beta protein-mediated long-term potentiation disruption

    Institute of Scientific and Technical Information of China (English)

    Fushun Li; Xiaowei Chen; Feiming Wang; Shujun Xu; Lan Chang; Roger Anwyl; Qinwen Wang

    2013-01-01

    Previous studies indicate that memantine, a low-affinity N-methyl-D-aspartate receptor antagonist, exerted acute protective effects against amyloid-β protein-induced neurotoxicity. In the present study, the chronic effects and mechanisms of memantine were investigated further using electrophysiological methods. The results showed that 7-day intraperitoneal application of memantine, at doses of 5 mg/kg or 20 mg/kg, did not alter hippocampal long-term potentiation induction in rats, while 40 mg/kg memantine presented potent long-term potentiation inhibition. Then further in vitro studys were carried out in 5 mg/kg and 20 mg/kg memantine treated rats. We found that 20 mg/kg memantine attenuated the potent long-term potentiation inhibition caused by exposure to amyloid-β protein in the dentate gyrus in vitro. These findings are the first to demonstrate the antagonizing effect of long-term systematic treatment of memantine against amyloid-β protein triggered long-term potentiation inhibition to improve synaptic plasticity.

  20. Glial and endothelial blood-retinal barrier responses to amyloid-&beta; in the neural retina of the rat

    OpenAIRE

    Anderson, Peter

    2008-01-01

    Peter JB Anderson1,a, HR Watts1,a, CJ Hille3, KL Philpott3, P Clark4, M Croucher, S Gentleman2, Ling-Sun Jen11Department of Cellular and Molecular Neuroscience; 2Department of Clinical Neuroscience, Division of Neuroscience and Mental Health, Imperial College London, Charing Cross Hospital Campus, London, UK; 3Neurosciences, Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK; 4Leukocyte Biology Section, National Heart and Lung Institute, Imperial Colle...

  1. Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus

    OpenAIRE

    Patel Sunil; Lee Edward B; Xie Sharon X; Law Anica; Jackson Eric M; Arnold Steven E; Clark Christopher M; Shaw Leslie M; Grady M Sean; Trojanowski John Q; Hamilton Roy H

    2012-01-01

    Abstract Background Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to i...

  2. Nanoscale size dependence in the conjugation of amyloid beta and ovalbumin proteins on the surface of gold colloidal particles

    International Nuclear Information System (INIS)

    Absorption spectroscopy was utilized to investigate the conjugation of amyloid β protein solution (Aβ1-40) and chicken egg albumin (ovalbumin) with various sizes of gold colloidal nanoparticles for various pHs, ranging from pH 2 to pH 10. The pH value that indicates the colour change, pHo, exhibited colloidal size dependence for both Aβ1-40 and ovalbumin coated particles. In particular, Aβ1-40 coated gold colloidal particles exhibited non-continuous size dependence peaking at 40 and 80 nm, implying that their corresponding cage-like structures provide efficient net charge cancellation at these core sizes. Remarkably, only the pHo value for ovalbumin coated 80 nm gold colloid was pH>7, and a specific cage-like structure is speculated to have a positive net charge facing outward when ovalbumin self-assembles over this particular gold colloid. The previously reported reversible colour change between pH 4 and 10 took place only with Aβ1-40 coated 20 nm gold colloids; this was also explored with ovalbumin coated gold colloids. Interestingly, gold colloidal nanoparticles showed a quasi-reversible colour change when they were coated with ovalbumin for all test sizes. The ovalbumin coated gold colloid was found to maintain reversible properties longer than Aβ1-40 coated gold colloid

  3. Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer's disease rats.

    Science.gov (United States)

    Lee, Jae-Min; Shin, Mal-Soon; Ji, Eun-Sang; Kim, Tae-Woon; Cho, Han-Sam; Kim, Chang-Ju; Jang, Myung-Soo; Kim, Tae-Wook; Kim, Bo-Kyun; Kim, Dong-Hee

    2014-10-01

    Alzheimer's disease (AD) is a most common age-related neurodegenerative disease. AD is characterized by a progressive loss of neurons causing cognitive dysfunction. The cerebellum is closely associated with integration of movement, including motor coordination, control, and equilibrium. In the present study, we evaluated the effect of tread-mill exercise on the survival of Purkinje neurons in relation with reactive astrocyte in the cerebellum using Aβ25-35-induced AD rats. AD was induced by a bilateral intracerebroventricular (ICV) injection of Aβ25-35. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks, starting 2 days after Aβ25-35 injection. In the present results, ICV injection of Aβ25-35 deteriorated motor coordination and balance. The number of calbindin-positive cells in the cerebellar vermis was decreased and glial fibrillary acidic protein (GFAP) expression in the cerebellar vermis was increased in the Aβ25-35-induced AD rats. Treadmill exercise improved motor coordination and balance. Treadmill exercise increased the number of Purkinje neurons and suppressed GFAP expression in the cerebellar vermis. The present study demonstrated that treadmill exercises alleviated dysfunction of motor coordination and balance by reduction of Purkinje cell loss through suppressing reactive astrocytes in the cerebellum of AD rats. The present study provides the possibility that treadmill exercise might be an important therapeutic strategy for the symptom improvement of AD patients. PMID:25426461

  4. Automated solid-phase peptide synthesis to obtain therapeutic peptides

    Directory of Open Access Journals (Sweden)

    Veronika Mäde

    2014-05-01

    Full Text Available The great versatility and the inherent high affinities of peptides for their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS offers a suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to essentially improved microwave-assisted instruments is discussed. In order to improve pharmacokinetic properties of peptides, lipidation and PEGylation are described as covalent conjugation methods, which can be applied by a combination of automated and manual synthesis approaches. The synthesis and application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies.

  5. Insulinotropic action of bombesin-like peptides mediated by gastrin-releasing peptide receptors in steers.

    Science.gov (United States)

    Zhao, H Q; Yao, G; Yannaing, S; ThanThan, S; Kuwayama, H

    2016-01-01

    The present study characterizes the receptor that mediates the insulinotropic action of bombesin-like peptides (BLP) in ruminants. Eight Holstein steers were randomly and intravenously injected with synthetic bovine gastrin-releasing peptide (GRP; 0.9 nmol/kg BW), neuromedin B (NMB; 0.9 nmol/kg BW), or neuromedin C (NMC; 0.9 nmol/kg BW), each alone or combined with the antagonist of GRP receptors N-acetyl-GRP-OCHCH (N-GRP-EE; 22.5 nmol/kg BW) or the antagonist of GH secretagogue receptor type 1a (GHS-R1a) [D-Lys]-GHRP-6 (21.5 nmol/kg BW). Blood samples were collected at -10, 0 (just before injection), 5, 10, 15, 20, 30, 45, 60, 75, and 90 min relative to injection time. Levels of injected peptides, insulin, and glucose in plasma were analyzed. Results showed that the peak of insulin levels was seen at 5 min after injection of NMC or GRP. Plasma glucose was observed in 2 phases; a significant rise followed a remarkable fall after NMC or GRP administration compared with injection of the vehicle ( 0.05). These results indicated that the insulinotropic action of BLP is mediated by GRP receptors but not through a ghrelin/GHS-R1a pathway and that BLP may be involved in the regulation of glucose homeostasis in ruminants. PMID:26812312

  6. Perspectives and Peptides of the Next Generation

    Science.gov (United States)

    Brogden, Kim A.

    Shortly after their discovery, antimicrobial peptides from prokaryotes and eukaryotes were recognized as the next potential generation of pharmaceuticals to treat antibiotic-resistant bacterial infections and septic shock, to preserve food, or to sanitize surfaces. Initial research focused on identifying the spectrum of antimicrobial agents, determining the range of antimicrobial activities against bacterial, fungal, and viral pathogens, and assessing the antimicrobial activity of synthetic peptides versus their natural counterparts. Subsequent research then focused on the mechanisms of antimicrobial peptide activity in model membrane systems not only to identify the mechanisms of antimicrobial peptide activity in microorganisms but also to discern differences in cytotoxicity for prokaryotic and eukaryotic cells. Recent, contemporary work now focuses on current and future efforts to construct hybrid peptides, peptide congeners, stabilized peptides, peptide conjugates, and immobilized peptides for unique and specific applications to control the growth of microorganisms in vitro and in vivo.

  7. Exploration of the Medicinal Peptide Space.

    Science.gov (United States)

    Gevaert, Bert; Stalmans, Sofie; Wynendaele, Evelien; Taevernier, Lien; Bracke, Nathalie; D'Hondt, Matthias; De Spiegeleer, Bart

    2016-01-01

    The chemical properties of peptide medicines, known as the 'medicinal peptide space' is considered a multi-dimensional subset of the global peptide space, where each dimension represents a chemical descriptor. These descriptors can be linked to biofunctional, medicinal properties to varying degrees. Knowledge of this space can increase the efficiency of the peptide-drug discovery and development process, as well as advance our understanding and classification of peptide medicines. For 245 peptide drugs, already available on the market or in clinical development, multivariate dataexploration was performed using peptide relevant physicochemical descriptors, their specific peptidedrug target and their clinical use. Our retrospective analysis indicates that clusters in the medicinal peptide space are located in a relatively narrow range of the physicochemical space: dense and empty regions were found, which can be explored for the discovery of novel peptide drugs. PMID:26876881

  8. Serum Levels of Anticyclic Citrullinated Peptide Antibodies, Interleukin-6, Tumor Necrosis Factor-α, and C-Reactive Protein Are Associated with Increased Carotid Intima-Media Thickness: A Cross-Sectional Analysis of a Cohort of Rheumatoid Arthritis Patients without Cardiovascular Risk Factors

    Directory of Open Access Journals (Sweden)

    Mónica Vázquez-Del Mercado

    2015-01-01

    Full Text Available The main cause of death in rheumatoid arthritis (RA is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP antibody levels with increased carotid intima-media thickness (cIMT in RA patients. Methods. Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC were studied. All groups were assessed for atherogenic index of plasma (AIP and cIMT. Anti-CCP, C-reactive protein (CRP, and levels of tumor necrosis factor alpha (TNFα and interleukin-6 (IL-6 were measured by enzyme-linked immunosorbent assay (ELISA. Results. The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P<0.001. Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFα and IL-6 (P<0.01, and lower levels of high density lipoprotein cholesterol (HDL-c (P=0.02. The cIMT correlated with levels of anti-CCP (r=0.513, P=0.001, CRP (r=0.799, P<0.001, TNFα (r=0.642, P=0.001, and IL-6 (r=0.751, P<0.001. In multiple regression analysis, cIMT was associated with CRP (P<0.001 and anti-CCP levels (P=0.03. Conclusions. Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events.

  9. Serum Levels of Anticyclic Citrullinated Peptide Antibodies, Interleukin-6, Tumor Necrosis Factor-α, and C-Reactive Protein Are Associated with Increased Carotid Intima-Media Thickness: A Cross-Sectional Analysis of a Cohort of Rheumatoid Arthritis Patients without Cardiovascular Risk Factors

    Science.gov (United States)

    Vázquez-Del Mercado, Mónica; Nuñez-Atahualpa, Lourdes; Figueroa-Sánchez, Mauricio; Gómez-Bañuelos, Eduardo; Rocha-Muñoz, Alberto Daniel; Martín-Márquez, Beatriz Teresita; Martínez-García, Erika Aurora; Macias-Reyes, Héctor; Gamez-Nava, Jorge Ivan; Navarro-Hernandez, Rosa Elena; Nuñez-Atahualpa, María Alejandra; Andrade-Garduño, Javier

    2015-01-01

    The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients. Methods. Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Results. The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P < 0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFα and IL-6 (P < 0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P = 0.02). The cIMT correlated with levels of anti-CCP (r = 0.513, P = 0.001), CRP (r = 0.799, P < 0.001), TNFα (r = 0.642, P = 0.001), and IL-6 (r = 0.751, P < 0.001). In multiple regression analysis, cIMT was associated with CRP (P < 0.001) and anti-CCP levels (P = 0.03). Conclusions. Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events. PMID:25821796

  10. Design and expression of a short peptide as an HIV detection probe

    Energy Technology Data Exchange (ETDEWEB)

    Lines, Jamie A.; Yu, Zhiqiang; Dedkova, Larisa M.; Chen, Shengxi, E-mail: shengxi.chen.1@asu.edu

    2014-01-03

    Highlights: •We designed a short fusion peptide (FP-50) for in vivo expression. •This peptide is a very promising component for detection of gp120 protein. •The detectable level is about 20–200 times lower than previously published methods. •It is a novel probe to detect HIV-1 gp120 during early stages of HIV infection. -- Abstract: To explore a low-cost novel probe for HIV detection, we designed and prepared a 50-amino acid-length short fusion peptide (FP-50) via Escherichia coli in vivo expression. It was employed as a novel probe to detect HIV-1 gp120 protein. The detectable level of gp120 protein using the FP-50 peptide was approximately 20–200 times lower than previously published methods that used a pair of monoclonal antibodies. Thus, this short peptide is a very promising component for detection of gp120 protein during early stages of HIV infection.

  11. [Measurement of natriuretic peptides in heart failure: the good laboratory and clinical practice].

    Science.gov (United States)

    Kovács, L Gábor; Nyolczas, Noémi; Habon, Tamás; Sepp, Róbert; Piroth, Zsolt; Hajas, Ágota; Boncz, Imre; Tomcsányi, János; Kappelmayer, János; Merkely, Béla

    2015-08-01

    Cardiac natriuretic peptides (BNP, NT-proBNP) play a pivotal role in cardiovascular homeostasis, mainly due to their roles in vasodilatation, natriuresis, diuresis and due to their antiproliferative properties. Proper measurement of the natriuretic peptide levels may help differentiate between respiratory and cardiac forms of dyspnea, diagnose early forms of heart failure, evaluate severity of heart failure (prognosis) and monitor the efficacy of therapy. In many countries natriuretic peptide levels are being used as one of the earliest diagnostics tools to evaluate the involvement of the heart. Current theoretical and clinical data confirm the importance of natriuretic peptides in routine healthcare. These roles are clearly described in international recommendations and guidelines. In the current review the authors discuss the problems of the measurement of natriuretic peptides in Hungary, including several aspects related to laboratory medicine, cardiology and health economy. PMID:26211747

  12. Peptide-enhanced oral delivery of therapeutic peptides and proteins

    DEFF Research Database (Denmark)

    Kristensen, Mie; Foged, Camilla; Berthelsen, Jens;

    2013-01-01

    such as the cell penetrating peptides (CPPs) and the tight junction modulating peptides (TJMPs), which are able to translocate across the cellular membranes in a non-disruptive way or reversibly modulate the integrity of intercellular tight junctions (TJs), respectively. However, because of the harsh...... believed that CPP-mediated translocation involves transcytosis and/or direct translocation through the epithelial cells; whereas TJMP-mediated translocation is dependent on interaction with transmembrane or peripheral TJ proteins. This review focuses on the CPPs and the TJMPs currently employed as...

  13. Double-Stranded Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2001-01-01

    A novel class of compounds, known as peptide nucleic acids, form double-stranded structures with one another and with ssDNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker.......A novel class of compounds, known as peptide nucleic acids, form double-stranded structures with one another and with ssDNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  14. Recent development of peptide self-assembly

    Institute of Scientific and Technical Information of China (English)

    Xiubo Zhao; Fang Pan; Jian R. Lu

    2008-01-01

    Amino acids are the building blocks to build peptides and proteins. Recent development in peptide synthesis has however enabled us to mimic this natural process by preparing various long and short peptides possessing different conformations and biological functions. The self-assembly of short designed peptides into molecular nanostructures is becoming a growing interest in nanobiotechnology. Self-assembled peptides exhibit several attractive features for applications in tissue regeneration, drug delivery, biological surface engineering as well as in food science, cosmetic industry and antibiotics. The aim of this review is to introduce the readers to a number of representative studies on peptide self-assembly.

  15. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes

    NARCIS (Netherlands)

    Lee, Jiyeon; Retamal, Claudio; Cuitino, Loreto; Caruano-Yzermans, Amy; Shin, Jung-Eun; van Kerkhof, Peter; Marzolo, Maria-Paz; Bu, Guojun

    2008-01-01

    Accumulation of extracellular amyloid beta peptide (A beta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of A beta from APP is greatly affected by the subcellular loca

  16. Alzheimer disease : presenilin springs a leak

    NARCIS (Netherlands)

    Gandy, S.; Doeven, M.K.; Poolman, B.

    2006-01-01

    Presenilins are thought to contribute to Alzheimer disease through a protein cleavage reaction that produces neurotoxic amyloid-beta peptides. A new function for presenilins now comes to light - controlling the leakage of calcium out of the endoplasmic reticulum. Is this a serious challenge to the '

  17. Alzheimer disease: presenilin springs a leak

    OpenAIRE

    Gandy, S; Doeven, M.K.; Poolman, B.

    2006-01-01

    Presenilins are thought to contribute to Alzheimer disease through a protein cleavage reaction that produces neurotoxic amyloid-beta peptides. A new function for presenilins now comes to light - controlling the leakage of calcium out of the endoplasmic reticulum. Is this a serious challenge to the 'amyloid hypothesis' of Alzheimer disease?

  18. Human Proinsulin C-peptide from a Precursor Overexpressed in Pichia pastoris

    Institute of Scientific and Technical Information of China (English)

    Yang-Bin HUANG; Jun REN; You-Shang ZHANG; Jiang LI; Xin GAO; Jiu-Ru SUN; Yi LU; Tao FENG; Jian FEI; Da-Fu CUI; Qi-Chang XIA

    2006-01-01

    In this article we report the production of human proinsulin C-peptide with 31 amino acid residues from a precursor overexpressed in Pichia pastoris. A C-peptide precursor expression plasmid containing nine C-peptide genes in tandem was constructed and used to transform P. pastoris. Transformants with a high copy number of the C-peptide precursor gene integrated into the chromosome of P. pastoris were selected. In high-density fermentation in a 300 liter fermentor using a simple culture medium composed mainly of salt and methanol, the C-peptide precursor was overexpressed to a level of 2.28 g per liter. A simple procedure was established to purify the expression product from the culture medium. The purified C-peptide precursor was converted into C-peptide by trypsin and carboxypeptidase B joint digestion. The yield of C-peptide with a purity of 96% was 730 mg per liter of culture. The purified C-peptide was characterized by mass spectrometry, N- and C-terminal amino acid sequencing, and sodium dodecylsulfate-polyacrylamide gel electrophoresis.

  19. The SMART model: Soft Membranes Adapt and Respond, also Transiently, in the presence of antimicrobial peptides.

    Science.gov (United States)

    Bechinger, Burkhard

    2015-05-01

    Biophysical and structural studies of peptide-lipid interactions, peptide topology and dynamics have changed our view on how antimicrobial peptides insert and interact with membranes. Clearly, both the peptides and the lipids are highly dynamic, change and mutually adapt their conformation, membrane penetration and detailed morphology on a local and a global level. As a consequence, the peptides and lipids can form a wide variety of supramolecular assemblies in which the more hydrophobic sequences preferentially, but not exclusively, adopt transmembrane alignments and have the potential to form oligomeric structures similar to those suggested by the transmembrane helical bundle model. In contrast, charged amphipathic sequences tend to stay intercalated at the membrane interface where they cause pronounced disruptions of the phospholipid fatty acyl packing. At increasing local or global concentrations, the peptides result in transient membrane openings, rupture and ultimately lysis. Depending on peptide-to-lipid ratio, lipid composition and environmental factors (temperature, buffer composition, ionic strength, etc.), the same peptide sequence can result in a variety of those responses. Therefore, the SMART model has been introduced to cover the full range of possibilities. With such a view in mind, novel antimicrobial compounds have been designed from amphipathic polymers, peptide mimetics, combinations of ultra-short polypeptides with hydrophobic anchors or small designer molecules. PMID:25522713

  20. An effective conjugation strategy for designing short peptide-based HIV-1 fusion inhibitors.

    Science.gov (United States)

    Liang, Guodong; Wang, Huixin; Chong, Huihui; Cheng, Siqi; Jiang, Xifeng; He, Yuxian; Wang, Chao; Liu, Keliang

    2016-08-16

    Lengthy peptides corresponding to the C-terminal heptad repeat (C-peptides) of human immunodeficiency virus type 1 (HIV-1) gp41 are potent inhibitors against virus-cell fusion. Designing short C-peptide-based HIV-1 fusion inhibitors could potentially redress the physicochemical and technical liabilities of a long-peptide therapeutic. However, designing such inhibitors with high potency has been challenging. We generated a conjugated architecture by incorporating small-molecule inhibitors of gp41 into the N-terminus of a panel of truncated C-peptides. Among these small molecule-capped short peptides, the 26-residue peptide Indole-T26 inhibited HIV-1 Env-mediated cell-cell fusion and viral replication at low nanomolar levels, reaching the potency of the only clinically used 36-residue peptide T20 (enfuvirtide). Collectively, our work opens up a new avenue for developing short peptide-based HIV-1 fusion inhibitors, and may have broad applicability to the development of modulators of other class I fusion proteins. PMID:27454320