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https://www.readbyqxmd.com/read/29458036/plasma-amyloid-levels-within-the-alzheimer-s-process-and-correlations-with-central-biomarkers
#1
Olivier Hanon, Jean-Sébastien Vidal, Sylvain Lehmann, Stéphanie Bombois, Bernadette Allinquant, Jean-Marc Tréluyer, Patrick Gelé, Christine Delmaire, Fredéric Blanc, Jean-François Mangin, Luc Buée, Jacques Touchon, Jacques Hugon, Bruno Vellas, Evelyne Galbrun, Athanase Benetos, Gilles Berrut, Elèna Paillaud, David Wallon, Giovanni Castelnovo, Lisette Volpe-Gillot, Marc Paccalin, Philippe-Henri Robert, Olivier Godefroy, Thierry Dantoine, Vincent Camus, Joël Belmin, Pierre Vandel, Jean-Luc Novella, Emmanuelle Duron, Anne-Sophie Rigaud, Suzanna Schraen-Maschke, Audrey Gabelle
BACKGROUNDS: Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. OBJECTIVES: To assess plasma levels of Aβ42 and Aβ40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. METHODS: One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included...
February 16, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/29456508/the-molecular-determinants-of-small-molecule-ligand-binding-at-p2x-receptors
#2
Gaia Pasqualetto, Andrea Brancale, Mark T Young
P2X receptors are trimeric eukaryotic ATP-gated cation channels. Extracellular ATP-their physiological ligand-is released as a neurotransmitter and in conditions of cell damage such as inflammation, and substantial evidence implicates P2X receptors in diseases including neuropathic pain, cancer, and arthritis. In 2009, the first P2X crystal structure, Danio rerio P2X4 in the apo - state, was published, and this was followed in 2012 by the ATP-bound structure. These structures transformed our understanding of the conformational changes induced by ATP binding and the mechanism of ligand specificity, and enabled homology modeling of mammalian P2X receptors for ligand docking and rational design of receptor modulators...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29456458/proteomic-identification-and-characterization-of-hepatic-glyoxalase-1-dysregulation-in-non-alcoholic-fatty-liver-disease
#3
Christos Spanos, Elaina M Maldonado, Ciarán P Fisher, Petchpailin Leenutaphong, Ernesto Oviedo-Orta, David Windridge, Francisco J Salguero, Alexandra Bermúdez-Fajardo, Mark E Weeks, Caroline Evans, Bernard M Corfe, Naila Rabbani, Paul J Thornalley, Michael H Miller, Huan Wang, John F Dillon, Alberto Quaglia, Anil Dhawan, Emer Fitzpatrick, J Bernadette Moore
Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE-/- ) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS)...
2018: Proteome Science
https://www.readbyqxmd.com/read/29456185/human-ips-derived-astroglia-from-a-stable-neural-precursor-state-show-improved-functionality-compared-with-conventional-astrocytic-models
#4
Anders Lundin, Louise Delsing, Maryam Clausen, Piero Ricchiuto, José Sanchez, Alan Sabirsh, Mei Ding, Jane Synnergren, Henrik Zetterberg, Gabriella Brolén, Ryan Hicks, Anna Herland, Anna Falk
In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells...
February 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29455526/structure-based-optimization-strategies-for-g-protein-coupled-receptor-gpcr-allosteric-modulators-a-case-study-from-analyses-of-new-metabotropic-glutamate-receptor-5-mglu-5-x-ray-structures
#5
John Christopher, Zoltán Orgován, Miles Congreve, Andrew S Dore, James C Errey, Fiona H Marshall, Jonathan S Mason, Krzysztof Okrasa, Prakash Rucktooa, Maria J Serrano-Vega, György G Ferenczy, Gyorgy M Keseru
Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu5 receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180º compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water mediated receptor interactions of a new chemotype represented by fenobam...
February 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29455218/apoe-gene-polymorphism-among-jordanian-alzheimer-s-patients-with-relation-to-lipid-profile
#6
Yanal A Shafagoj, Randa G Naffa, Mohammed S El-Khateeb, Yazeed L Abdulla, Aseem A Al-Qaddoumi, Faisal A Khatib, Yousef F Al-Motassem, Eman M Al-Khateeb
OBJECTIVE: To investigate the frequencies of the apolipoprotein E (APOE) alleles and genotypes and study their relationship with the lipid profile in Jordanian patients with late-onset Alzheimer`s disease (AD). METHODS: This case-control study was carried out on 71 Jordanian individuals: 38 patients with late-onset AD (age >/=65 years) and 33 age-matched healthy controls. All participants were recruited from senior homes and Jordan University Hospital, Amman, Jordan between January 2010 and December 2013...
January 2018: Neurosciences: the Official Journal of the Pan Arab Union of Neurological Sciences
https://www.readbyqxmd.com/read/29454996/apo-10-lycopenoic-acid-inhibits-cancer-cell-migration-and-angiogenesis-and-induces-peroxisome-proliferator-activated-receptor-%C3%AE
#7
Junrui Cheng, Benchun Miao, Kang-Quan Hu, Xueyan Fu, Xiang-Dong Wang
SCOPE: We have previously shown that apo-10'-lycopenoic acid (ALA), a derivative of lycopene through cleavage by carotene-9',10'-oxygenase, inhibits tumor progression and metastasis in both liver and lung cancer animal models. The underlying mechanism remains unknown. We hypothesized that ALA inhibits cancer cell motility and angiogenesis by up-regulating peroxisome proliferator-activated receptor γ (PPARγ) which is involved in controlling angiogenesis, tumor progression and metastasis...
January 31, 2018: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/29454149/study-of-manganese-binding-to-the-ferroxidase-centre-of-human-h-type-ferritin
#8
Matteo Ardini, Barry D Howes, Annarita Fiorillo, Elisabetta Falvo, Silvia Sottini, Donella Rovai, Marco Lantieri, Andrea Ilari, Dante Gatteschi, Gabriele Spina, Emilia Chiancone, Simonetta Stefanini, Maria Fittipaldi
Ferritins are ubiquitous and conserved proteins endowed with enzymatic ferroxidase activity, that oxidize Fe(II) ions at the dimetal ferroxidase centre to form a mineralized Fe(III) oxide core deposited within the apo-protein shell. Herein, the in vitro formation of a heterodimetal cofactor constituted by Fe and Mn ions has been investigated in human H ferritin (hHFt). Namely, Mn and Fe binding at the hHFt ferroxidase centre and its effects on Fe(II) oxidation have been investigated by UV-Vis ferroxidation kinetics, fluorimetric titrations, multifrequency EPR, and preliminary Mössbauer spectroscopy...
February 9, 2018: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29453321/inhibition-of-cd95-cd95l-signaling-with-apg101-prevents-invasion-and-enhances-radiation-therapy-for-glioblastoma
#9
Jonas Blaes, Carina M Thomé, Philipp-Niclas Pfenning, Petra Rübmann, Felix Sahm, Antje Wick, Theresa Bunse, Torsten Schmenger, Jaromir Sykora, Andreas von Deimling, Benedikt Wiestler, Christian Merz, Manfred Jugold, Uwe Haberkorn, Amir Abdollahi, Jürgen Debus, Christian Gieffers, Claudia Kunz, Martin Bendszus, Michael Kluge, Michael Platten, Harald Fricke, Wolfgang Wick, Dieter Lemke
CD95 (Fas/APO-1), a death receptor family member, activity has been linked to tumorigenicity in multiple cancers, including glioblastoma multiforme (GBM). A phase II clinical trial on relapsed glioblastoma patients demonstrated that targeted inhibition of CD95 signaling via the CD95 ligand (CD95L) binding and neutralizing Fc-fusion protein APG101 (asunercept) prolonged patient survival. While CD95 signaling may be relevant for multiple aspects of tumor growth, the mechanism of action of APG101 in glioblastoma is not clear...
February 16, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29451880/apolipoprotein-e-genotype-does-not-moderate-the-associations-of-depressive-symptoms-neuroticism-and-allostatic-load-with-cognitive-ability-and-cognitive-aging-in-the-lothian-birth-cohort-1936
#10
Zander Crook, Tom Booth, Simon R Cox, Janie Corley, Dominika Dykiert, Paul Redmond, Alison Pattie, Adele M Taylor, Sarah E Harris, John M Starr, Ian J Deary
OBJECTIVES: In this replication-and-extension study, we tested whether depressive symptoms, neuroticism, and allostatic load (multisystem physiological dysregulation) were related to lower baseline cognitive ability and greater subsequent cognitive decline in older adults, and whether these relationships were moderated by the E4 allele of the apolipoprotein E (APOE) gene. We also tested whether allostatic load mediated the relationships between neuroticism and cognitive outcomes. METHODS: We used data from the Lothian Birth Cohort 1936 (n at Waves 1-3: 1,028 [M age = 69...
2018: PloS One
https://www.readbyqxmd.com/read/29450841/differential-binding-of-human-apoe-isoforms-to-insulin-receptor-is-associated-with-aberrant-insulin-signaling-in-ad-brain-samples
#11
Elizabeth S Chan, Christopher Chen, Tuck Wah Soong, Boon-Seng Wong
Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), where inheritance of this isoform predisposes development of AD in a gene dose-dependent manner. Although the mode of action of ApoE4 on AD onset and progression remains unknown, we have previously shown that ApoE4, and not ApoE3 expression, resulted in insulin signaling deficits in the presence of amyloid beta (Aβ). However, these reports were not conducted with clinical samples that more accurately reflect human disease...
February 15, 2018: Neuromolecular Medicine
https://www.readbyqxmd.com/read/29449376/structural-basis-for-the-glycosyltransferase-activity-of-the-salmonella-effector-ssek3
#12
Diego Esposito, Regina A Günster, Luigi Martino, Kamel El Omari, Armin Wagner, Teresa L M Thurston, Katrin Rittinger
The Salmonella secreted effector SseK3 translocates into host cells, targeting innate immune responses including NF-κB activation. SseK3 is a glycosyltransferase that transfers an N-acetylglucosamine (GlcNAc) moiety onto the guanidino group of a target arginine, modulating host cell function. However, a lack of structural information has precluded elucidation of the molecular mechanisms in arginine and GlcNAc selection. We report here the crystal structure of SseK3 in its apo form and in complex with hydrolysed UDP-GlcNAc...
February 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29449334/rgc-32-response-gene-to-complement-32-protein-deficiency-protects-endothelial-cells-from-inflammation-and-attenuates-atherosclerosis
#13
Xiao-Bing Cui, Jun-Na Luan, Kun Dong, Sisi Chen, Yongyi Wang, Wendy T Watford, Shi-You Chen
OBJECTIVE: The objective of this study is to determine the role and underlying mechanisms of RGC-32 (response gene to complement 32 protein) in atherogenesis. APPROACH AND RESULTS: RGC-32 was mainly expressed in endothelial cells of atherosclerotic lesions in both ApoE -/- (apolipoprotein E deficient) mice and human patients. RGC-32 deficiency (Rgc32 -/- ) attenuated the high-fat diet-induced and spontaneously developed atherosclerotic lesions in ApoE -/- mice without affecting serum cholesterol concentration...
February 15, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29448104/aim2-regulates-vascular-smooth-muscle-cell-migration-in-atherosclerosis
#14
Jinyu Pan, Lu Lu, Xuyang Wang, Dian Liu, Jingjing Tian, Hui Liu, Mingjun Zhang, Fengqin Xu, Fengshuang An
BACKGROUND: Atherosclerosis (AS) is a common pathological basis of various cardiovascular and cerebrovascular diseases. Plaque formation is initiated and triggered by vascular smooth musclecells (VSMCs) migration in vascular wall, which gradually aggravates atherosclerosis progression. Absent in melanoma 2 (AIM2), a member of HIN-200 family, plays an important role in activating inflammasome. However, the role of AIM2 in atherosclerotic plaque progression outside of the inflammasome has not yet been reported...
February 12, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29447225/low-apolipoprotein-a-i-levels-in-friedreich-s-ataxia-and-in-frataxin-deficient-cells-implications-for-therapy
#15
QingQing Wang, Lili Guo, Cassandra J Strawser, Lauren A Hauser, Wei-Ting Hwang, Nathaniel W Snyder, David R Lynch, Clementina Mesaros, Ian A Blair
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure...
2018: PloS One
https://www.readbyqxmd.com/read/29447078/effects-of-peutz-jeghers-syndrome-pjs-causing-missense-mutations-l67p-l182p-g242v-and-r297s-on-the-structural-dynamics-of-lkb1-liver-kinase-b1-protein
#16
Ikrormi Rungsung, Amutha Ramaswamy
The Liver kinase B1 (LKB1) is encoded by LKB1 gene. Several pathogenic mutations of LKB1 causing Peutz-Jeghers syndrome (PJS) and also cancers in breast, gastric, pancreas and colon have been reported. The present study is focused to analyze the effects on the structural dynamics of LKB1 caused by the 4 pathogenic missense mutations (L67P, L182P, G242V and R297S), which are reported to reduce the catalytic activity. In this study, the structural changes of LKB1 in apo- and in heterotrimeric complex (LKB1-STRADα-MO25α) form with wild and mutated LKB1 are investigated using all atomistic molecular dynamic simulation...
February 15, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29445990/time-dependent-lxr-rxr-pathway-modulation-characterizes-capillary-remodeling-in-inflammatory-corneal-neovascularization
#17
Anthony Mukwaya, Anton Lennikov, Maria Xeroudaki, Pierfrancesco Mirabelli, Mieszko Lachota, Lasse Jensen, Beatrice Peebo, Neil Lagali
Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency...
February 14, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29444387/the-structure-of-the-apo-camp-binding-domain-of-hcn4-a-stepping-stone-towards-understanding-the-camp-dependent-modulation-of-the-hyperpolarization-activated-cyclic-nucleotide-gated-hcn-ion-channels
#18
REVIEW
Madoka Akimoto, Bryan VanSchouwen, Giuseppe Melacini
The hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels control nerve impulse transmission and cardiac pacemaker activity. The modulation by cAMP is critical for the regulatory function of HCN in both neurons and cardiomyocytes, but the underlying mechanism is not fully understood. Here, we show how the structure of the apo cAMP-binding domain of the HCN4 isoform has contributed to a model for the cAMP-dependent modulation of the HCN ion-channel. This model recapitulates the structural and dynamical changes that occur along the thermodynamic cycle arising from the coupling of cAMP-binding and HCN self-association equilibria...
February 14, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29439314/effects-of-malat1-on-proliferation-and-apo-ptosis-of-human-non-small-cell-lung-cancer-a549-cells-in-vitro-and-tumor-xenograft-growth-in-vivo-by-modulating-autophagy
#19
Jun Ma, Kaiming Wu, Kuanzhi Liu, Rong Miao
OBJECTIVE: To explore the ability of MALAT1 to influence non-small cell lung cancer (NSCLC) A549 cells in vitro and tumor xenograft growth in vivo by modulating autophagy. METHODS: LncRNA MALAT-1 in normal HBE cells and human NSCLC cells was measured. A549 cells were treated with si-MALAT-1, negative control and si-MALAT-1 + rapamycin. The mRNA levels of MALAT-1, P62 and LC3 was determined by the qRT-PCR and the protein levels of autophagy-related proteins by the western blotting...
January 29, 2018: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/29438441/development-of-vaccine-for-dyslipidemia-targeted-to-a-proprotein-convertase-subtilisin-kexin-type-9-pcsk9-epitope-in-mice
#20
Ryo Kawakami, Yoichi Nozato, Hironori Nakagami, Yuka Ikeda, Munehisa Shimamura, Shota Yoshida, Jiao Sun, Tomohiro Kawano, Yoichi Takami, Takahisa Noma, Hiromi Rakugi, Tetsuo Minamino, Ryuichi Morishita
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates expression of low-density lipoprotein (LDL) receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti-hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH) as a carrier protein...
2018: PloS One
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