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https://www.readbyqxmd.com/read/28933295/applications-of-multi-target-computer-aided-methodologies-in-molecular-design-of-cns-drugs
#1
Oleg A Raevsky, Azat Mukhametov, Veniamin Y Grigorev, Alexey Ustyugov, Shwu-Chen Tsay, Reuben Jih-Ru Hwu, Nagendra Sastry Yarla, George E Barreto, Gjumrakch Aliev, Sergey O Bachurin
: Discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bio-informatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL...
September 20, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28715006/substitution-reactions-of-iron-ii-carbamoyl-thioether-complexes-related-to-mono-iron-hydrogenase
#2
Zhu-Lin Xie, Gummadi Durgaprasad, Azim K Ali, Michael J Rose
A C,N,S pincer complex has been synthesized for structural modeling of the organometallic active site of mono-[Fe] hydrogenase (HMD). The C,N,S chelate allows for systematic investigation of the substitution reactions of CO and other exogenous X/L-type ligands, as well as examination of the exact roles of the Fe-carbamoyl and {Fe(CO)2}(2+) units in stabilizing the low-spin Fe(ii) center. Reaction of the 'apo-ligand' 6-(2-(methylthio)phenyl)pyridin-2-amine ((H2N)N(py)S(Me)) with [Fe(CO)4(Br)2] affords the organometallic complex [((O[double bond, length as m-dash])C(NH)N(py)S(Me))Fe(CO)2(Br)] (1)...
August 22, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28378140/management-of-non-hodgkin-lymphoma-icmr-consensus-document
#3
Nirav Thacker, Sameer Bakhshi, Girish Chinnaswamy, Tushar Vora, Maya Prasad, Deepak Bansal, Sandeep Agarwala, Gauri Kapoor, Venkatraman Radhakrishnan, Siddharth Laskar, Tanvir Kaur, G K Rath, Rupinder Singh Dhaliwal, Brijesh Arora
Hitherto poor outcomes, paucity of data and heterogeneity in International approach to Pediatric NHL (Non-Hodgkin Lymphoma) prompted the need for guidelines for Indian population with vast variability in access, affordability and infrastructure across the country. These guidelines are based on consensus among the experts and best available evidence applicable to Indian setting. Evaluation of NHL should consist of easily doable and rapid tissue diagnosis (biopsy or flow cytometry of peripheral blood/malignant effusions), St Jude/IPNHLSS (International Pediatric Non-Hodgkin Lymphoma Staging System) and risk grouping with CSF (Cerebro-spinal fluid), bone marrow, whole body imaging [CECT (Contrast enhanced computerized tomography) ± MRI (Magnetic resonance imaging)] and blood investigations for LDH (Lactate dehydrogenase), TLS (Tumor lysis syndrome) and organ functions...
May 2017: Indian Journal of Pediatrics
https://www.readbyqxmd.com/read/28298292/cellular-cholesterol-homeostasis-in-alzheimer-s-disease
#4
Ta Yuan Chang, Yoshio Yamauchi, Mazahir T Hasan, Catherine Cy Chang
Alzheimer's disease [AD] is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid beta peptides [Abeta; especially Abeta1-42], and neurofibrillary tangles, composed of hyper-phosphorylated tau, accompanied with chronic neuroinflammation. Abeta are derived from the amyloid precursor protein APP. The oligomeric form of Abeta is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques...
March 15, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28292942/the-apoe-receptors-vldlr-and-apoer2-in-central-nervous-system-function-and-disease
#5
REVIEW
Courtney Lane-Donovan, Joachim Herz
The LDL receptor (LDLR) family has long been studied for its role in cholesterol transport and metabolism; however, the identification of ApoE4, an LDLR ligand, as a genetic risk factor for late-onset Alzheimer's disease has focused attention on the role this receptor family plays in the CNS. Surprisingly, it was discovered that two LDLR family members, ApoE receptor 2 (Apoer2) and VLDL receptor (Vldlr), play key roles in brain development and adult synaptic plasticity, primarily by mediating Reelin signaling...
June 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28118087/identification-of-a-peptide-for-systemic-brain-delivery-of-a-morpholino-oligonucleotide-in-mouse-models-of-spinal-muscular-atrophy
#6
Fazel Shabanpoor, Suzan M Hammond, Frank Abendroth, Gareth Hazell, Matthew J A Wood, Michael J Gait
Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood-brain barrier (BBB) to reach targets in the central nervous system (CNS)...
June 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28106546/a-common-variant-of-il-6r-is-associated-with-elevated-il-6-pathway-activity-in-alzheimer-s-disease-brains
#7
Patrick C G Haddick, Jessica L Larson, Nisha Rathore, Tushar R Bhangale, Qui T Phung, Karpagam Srinivasan, David V Hansen, Jennie R Lill, Margaret A Pericak-Vance, Jonathan Haines, Lindsay A Farrer, John S Kauwe, Gerard D Schellenberg, Carlos Cruchaga, Alison M Goate, Timothy W Behrens, Ryan J Watts, Robert R Graham, Joshua S Kaminker, Marcel van der Brug
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28077724/trem2-promotes-microglial-survival-by-activating-wnt-%C3%AE-catenin-pathway
#8
Honghua Zheng, Lin Jia, Chia-Chen Liu, Zhouyi Rong, Li Zhong, Longyu Yang, Xiao-Fen Chen, John D Fryer, Xin Wang, Yun-Wu Zhang, Huaxi Xu, Guojun Bu
Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models...
February 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27931217/lrp1-modulates-the-microglial-immune-response-via-regulation-of-jnk-and-nf-%C3%AE%C2%BAb-signaling-pathways
#9
Longyu Yang, Chia-Chen Liu, Honghua Zheng, Takahisa Kanekiyo, Yuka Atagi, Lin Jia, Daxin Wang, Aurelie N'songo, Dan Can, Huaxi Xu, Xiao-Fen Chen, Guojun Bu
BACKGROUND: Neuroinflammation is characterized by microglial activation and the increased levels of cytokines and chemokines in the central nervous system (CNS). Recent evidence has implicated both beneficial and toxic roles of microglia when over-activated upon nerve injury or in neurodegenerative diseases, including Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for apolipoprotein E (apoE) and amyloid-β (Aβ), which play critical roles in AD pathogenesis...
December 8, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27904515/interaction-between-c-reactive-protein-and-cognitive-functions-according-to-apoe-gene-polymorphism-in-post-menopausal-women
#10
Iwona Bojar, Mariusz Gujski, Jarosław Pinkas, Dorota Raczkiewicz, Alfred Owoc, Ewa Humeniuk
INTRODUCTION: A potential factor increasing the risk of the development of cognitive impairment with age is apolipoprotein E (APOE) ε4 carrier status. A subsequent factor which may increase the risk of development of cognitive impairment at an older age is the concentration of C-reactive protein (CRP). The objective of the study was to examine the relationship between cognitive functions and the concentration of CRP in post-menopausal women who were carriers of particular apolipoprotein E gene (APOE) polymorphisms...
December 1, 2016: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/27793990/human-central-nervous-system-cns-apoe-isoforms-are-increased-by-age-differentially-altered-by-amyloidosis-and-relative-amounts-reversed-in-the-cns-compared-with-plasma
#11
COMPARATIVE STUDY
Alaina T Baker-Nigh, Kwasi G Mawuenyega, James G Bollinger, Vitaliy Ovod, Tom Kasten, Erin E Franklin, Fan Liao, Hong Jiang, David Holtzman, Nigel J Cairns, John C Morris, Randall J Bateman
The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes...
December 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27683909/genetic-restoration-of-plasma-apoe-improves-cognition-and-partially-restores-synaptic-defects-in-apoe-deficient-mice
#12
Courtney Lane-Donovan, Wen Mai Wong, Murat S Durakoglugil, Catherine R Wasser, Shan Jiang, Xunde Xian, Joachim Herz
UNLABELLED: Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27647307/the-complex-role-of-apolipoprotein-e-in-alzheimer-s-disease-an-overview-and-update
#13
REVIEW
Laura Mahoney-Sanchez, Abdel Ali Belaidi, Ashley I Bush, Scott Ayton
Apolipoprotein E (ApoE) plays a crucial role in the homeostatic control of lipids in both the periphery and the central nervous system (CNS). In humans, ApoE exists in three different isoforms: ε2, ε3 and ε4. ApoE ε3 is the most common isoform, while the ε4 isoform confers the greatest genetic risk for Alzheimer's disease (AD). However, the mechanisms underlying how ApoE contributes to the pathogenesis of AD are still debated. ApoE has been shown to impact amyloid β (Aβ) deposition and clearance in the brain...
November 2016: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/27445158/the-effect-of-%C3%AE-amyloid-positivity-on-cerebral-metabolism-in-cognitively-normal-seniors
#14
Andrea C Bozoki, Monica Zdanukiewicz, David C Zhu
INTRODUCTION: We evaluated the effect of cerebral amyloid-β (Aβ) deposition in cognitively normal (CN) seniors on regional metabolism of specific brain regions known to be affected by p-tau deposition. METHODS: Fluorodeoxyglucose positron emission tomography (FDG-PET), volumetric magnetic resonance imaging scans, and global amyloid standardized uptake value ratios (SUVr) were obtained for 210 CNs from the Alzheimer's Disease Neuroimaging Initiative-2 (ADNI2). Region of interest (ROI) extraction was used to obtain functional SUVr from six bilateral ROIs: amygdala (AM), entorhinal cortex (EC), hippocampus, lateral orbitofrontal, posterior cingulate (PC), and middle temporal gyrus...
December 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/27258849/low-density-lipoprotein-receptor-related-protein-1-is-a-novel-modulator-of-radial-glia-stem-cell-proliferation-survival-and-differentiation
#15
Dina Safina, Frederik Schlitt, Ramona Romeo, Thorsten Pflanzner, Claus U Pietrzik, Vasanthy Narayanaswami, Frank Edenhofer, Andreas Faissner
The LDL family of receptors and its member low-density lipoprotein receptor-related protein 1 (LRP1) have classically been associated with a modulation of lipoprotein metabolism. Current studies, however, indicate diverse functions for this receptor in various aspects of cellular activities, including cell proliferation, migration, differentiation, and survival. LRP1 is essential for normal neuronal function in the adult CNS, whereas the role of LRP1 in development remained unclear. Previously, we have observed an upregulation of LewisX (LeX) glycosylated LRP1 in the stem cells of the developing cortex and demonstrated its importance for oligodendrocyte differentiation...
August 2016: Glia
https://www.readbyqxmd.com/read/27248362/clusterin-levels-are-increased-in-alzheimer-s-disease-and-influence-the-regional-distribution-of-a%C3%AE
#16
J Scott Miners, Polly Clarke, Seth Love
Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM)...
May 2017: Brain Pathology
https://www.readbyqxmd.com/read/27174096/central-nervous-system-lipoproteins-apoe-and-regulation-of-cholesterol-metabolism
#17
REVIEW
Robert W Mahley
ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid...
July 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27114256/quercetin-stabilizes-apolipoprotein-e-and-reduces-brain-a%C3%AE-levels-in-amyloid-model-mice
#18
Xilin Zhang, Jin Hu, Li Zhong, Na Wang, Longyu Yang, Chia-Chen Liu, Huifang Li, Xin Wang, Ying Zhou, Yunwu Zhang, Huaxi Xu, Guojun Bu, Jiangxing Zhuang
Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-density lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide...
September 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27021072/apolipoprotein-e-%C3%AE%C2%B54-genotype-status-is-not-associated-with-neuroimaging-outcomes-in-a-large-cohort-of-hiv-individuals
#19
Sarah A Cooley, Robert H Paul, Christine Fennema-Notestine, Erin E Morgan, Florin Vaida, Qianqian Deng, Jie Ashley Chen, Scott Letendre, Ronald Ellis, David B Clifford, Christina M Marra, Ann C Collier, Benjamin B Gelman, Justin C McArthur, J Allen McCutchan, David M Simpson, Susan Morgello, Igor Grant, Beau M Ances
Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study...
October 2016: Journal of Neurovirology
https://www.readbyqxmd.com/read/26554939/the-effects-of-the-apoe4-genotype-on-the-developing-mouse-retina
#20
Idit Maharshak, Shiran Salomon-Zimri, Ran Antes, Ori Liraz, Yael Nisgav, Tami Livnat, Dov Weinberger, Carol A Colton, Arieh S Solomon, Daniel M Michaelson
Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. The retina, which is as an extension of the central nervous system (CNS), is a particularly suitable model for studying developmental and functional aspects of the neuronal and vascular systems. This study investigates the apoE4-dependent developmental effects on the retinal vasculature and neuronal systems and on the levels of apoE and the vascular endothelial growth factor (VEGF) in the retina...
April 2016: Experimental Eye Research
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