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https://www.readbyqxmd.com/read/28091531/tnf-%C3%AE-regulates-the-proteolytic-degradation-of-st6gal-1-and-endothelial-cell-cell-junctions-through-upregulating-expression-of-bace1
#1
Xiao Deng, Jun Zhang, Yan Liu, Linmu Chen, Chao Yu
Endothelial dysfunction and monocyte adhesion to vascular endothelial cells are two critical steps in atherosclerosis development, and emerging evidence suggests that protein sialylation is involved in these processes. However, the mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that treatment with the proinflammatory cytokine TNF-α disrupted vascular endothelial cell-cell tight junctions and promoted monocyte endothelial cell adhesion. Western blotting and Sambucus nigra lectin (SNA) blotting analyses revealed that TNF-α treatment decreased α-2, 6-sialic acid transferase 1 (ST6Gal-I) levels and downregulated VE-Cadherin α-2, 6 sialylation...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28059793/resveratrol-intervenes-in-the-cholesterol-and-isoprenoid-mediated-amyloidogenic-processing-of-a%C3%AE-pp-in-familial-alzheimer-s-disease
#2
Mohan Sathya, Ponnusamy Moorthi, Palanisamy Premkumar, Mahesh Kandasamy, Kesavan Swaminathan Jayachandran, Muthuswamy Anusuyadevi
Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer's disease (AD). Though amyloid-β protein precursor (AβPP) primes the pathological cascade, changes in cholesterol levels and its intermediates, geranyl geranyl pyrophosphate and farnesyl pyrophosphate, is expected to have a different consequence on AβPP processing and amyloid-β (Aβ) generation. However, the use of statins (HMG-COA reductase inhibitor) has been widely implicated in slowing down the pathogenic progression of AD, while the epidemiological reports on its biological effect remains controversial...
December 3, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28055952/seizure-6-proteins-highlight-bace1-functions-in-neurobiology
#3
EDITORIAL
Martina Pigoni, Jenny M Gunnersen, Stefan F Lichtenthaler
No abstract text is available yet for this article.
December 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/28043778/neuritogenic-activity-of-bi-functional-bis-tryptoline-triazole
#4
Jutamas Jiaranaikulwanitch, Sarin Tadtong, Piyarat Govitrapong, Valery V Fokin, Opa Vajragupta
Alzheimer's disease (AD) is a common neurodegenerative disorder, one of the hallmarks of which is the deposition of aggregated β-amyloid peptides (Aβ40,42) as plaques in the brain. Oligomers of these peptides have been reported to be toxic and to inhibit neurite outgrowth, as evidenced by neurite dystrophy and significant loss of synaptic connectivity of neurons in the AD brain resulting in cognitive decline. These peptides also react with biological metal in the brain to generate free radicals, thereby aggravating neuronal cell injury and death...
December 23, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28043074/comparative-qsar-studies-using-hqsar-comfa-and-comsia-methods-on-cyclic-sulfone-hydroxyethylamines-as-bace1-inhibitors
#5
Shuqun Zhang, Zichun Lin, Yinglan Pu, Yunqin Zhang, Li Zhang, Zhili Zuo
The inhibition of β-secretase (BACE1) is currently the main pharmacological strategy available for Alzheimer's disease (AD). 2D QSAR and 3D QSAR analysis on some cyclic sulfone hydroxyethylamines inhibitors against β-secretase (IC50: 0.002-2.75μM) were carried out using hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) methods. The best model based on the training set was generated with a HQSAR q(2) value of 0.693 and r(2) value of 0...
December 23, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28042460/asperterpenes-a-and-b-two-unprecedented-meroterpenoids-from-aspergillus-terreus-with-bace1-inhibitory-activities
#6
Changxing Qi, Jian Bao, Jianping Wang, Hucheng Zhu, Yongbo Xue, Xiaochuan Wang, Hua Li, Weiguang Sun, Weixi Gao, Yongji Lai, Jian-Guo Chen, Yonghui Zhang
Asperterpenes A (1) and B (2), two 3,5-dimethylorsellinic acid-based meroterpenoids that contain a unique β-oriented Me-21 with an unprecedented 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety, were obtained from Aspergillus terreus in very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of 1 was determined using X-ray diffraction. Because of the low yield of 1, a comprehensive characterization of the BACE1 inhibitory activities of 1 was completed via molecular biological, cell and animal studies guided by in silico target confirmation (ISTC)...
October 19, 2016: Chemical Science
https://www.readbyqxmd.com/read/28035928/consecutive-analysis-of-bace1-function-on-developing-and-developed-neuronal-cells
#7
Yuji Kamikubo, Nobumasa Takasugi, Kazue Niisato, Yoshie Hashimoto, Takashi Sakurai
The amyloid-β protein precursor (AβPP) is cleaved by a transmembrane protease termed β-site AβPP cleavage enzyme (BACE1), which is being explored as a target for therapy and prevention of Alzheimer's disease (AD). Although genetic deletion of BACE1 results in abolished amyloid pathology in AD model mice, it also results in neurodevelopmental phenotypes such as hypomyelination and synaptic loss, observed in schizophrenia and autism-like phenotype. These lines of evidence indicate that the inhibition of BACE1 causes adverse side effects during the neurodevelopmental stage...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28031572/alzheimer-disease-bace1-inhibitor-reduces-%C3%AE-amyloid-production-in-humans
#8
Sarah Crunkhorn
No abstract text is available yet for this article.
December 29, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28028177/autophagy-mediated-regulation-of-bace1-trafficking-and-degradation
#9
Tuancheng Feng, Prasad Tammineni, Chanchal Agrawal, Yu Young Jeong, Qian Cai
Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal beta-secretase for amyloid-beta (Abeta) generation, and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation...
December 27, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28026009/transcriptomic-profiling-of-platelet-senescence-and-platelet-extracellular-vesicles
#10
Annika Pienimaeki-Roemer, Tatiana Konovalova, Melina M Musri, Alexander Sigruener, Alfred Boettcher, Gunter Meister, Gerd Schmitz
BACKGROUND: Platelets (PLTs) are derived from megakaryocytes during PLT shedding. Senescent or activated PLTs are expanded in vascular and neurological diseases and release PLT extracellular vesicles (PL-EVs). A systematic analysis of regular messenger RNA (mRNA) and small RNA composition in PLTs and PL-EVs during in vitro PLT senescence has not yet been published. STUDY DESIGN AND METHODS: We isolated PLTs, total PL-EVs, and PL-EV subsets on Days 0 and 5 from human stored donor platelet concentrates...
December 27, 2016: Transfusion
https://www.readbyqxmd.com/read/28025519/development-and-structural-modification-of-bace1-inhibitors
#11
REVIEW
Ting Gu, Wen-Yu Wu, Ze-Xi Dong, Shao-Peng Yu, Ying Sun, Yue Zhong, Yu-Ting Lu, Nian-Guang Li
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which usually occurs in the elderly. The accumulation of β-amyloid and the formation of neurofibrillary tangles are considered as the main pathogenies of AD. Research suggests that β-secretase 1 (BACE1) plays an important role in the formation of β-amyloid. Discovery of new BACE1 inhibitors has become a significant method to slow down the progression of AD or even cure this kind of disease. This review summarizes the different types and the structural modification of these new BACE1 inhibitors...
December 22, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28012171/mir-15b-mediates-oxaliplatin-induced-chronic-neuropathic-pain-through-bace1-downregulation
#12
Naomi Ito, Atsushi Sakai, Noriko Miyake, Motoyo Maruyama, Hirotoshi Iwasaki, Koichi Miyake, Takashi Okada, Atsuhiro Sakamoto, Hidenori Suzuki
BACKGROUND AND PURPOSE: Although oxaliplatin is an effective anti-cancer platinum compound, it can cause painful chronic neuropathy, and its molecular mechanisms remain poorly understood. MicroRNAs are small non-coding RNAs that negatively regulate gene expression in a sequence-specific manner. Although microRNAs have been increasingly recognised as important modulators in a variety of pain conditions, their involvement in chemotherapy-induced neuropathic pain is unknown. EXPERIMENTAL APPROACH: Oxaliplatin-induced chronic neuropathic pain was induced in rats by intraperitoneal oxaliplatin injections (2 mg kg(-1) ) for 5 consecutive days...
December 23, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28005987/metabolic-characterization-of-intact-cells-reveals-intracellular-amyloid-beta-but-not-its-precursor-protein-to-reduce-mitochondrial-respiration
#13
Patrick M Schaefer, Bjoern von Einem, Paul Walther, Enrico Calzia, Christine A F von Arnim
One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization...
2016: PloS One
https://www.readbyqxmd.com/read/28004339/bace1-deficient-mice-exhibit-alterations-in-immune-system-pathways
#14
L Stertz, V Contreras-Shannon, N Monroy-Jaramillo, J Sun, C Walss-Bass
BACE1 encodes for the beta-site amyloid precursor protein cleaving enzyme 1 or β-secretase. Genetic deletion of Bace1 leads to behavioral alterations and affects midbrain dopaminergic signaling and memory processes. In order to further understand the role of BACE1 in brain function and behavior, we performed microarray transcriptome profiling and gene pathway analysis in the hippocampus of BACE1-deficient mice compared to wild type. We identified a total of 91 differentially expressed genes (DEGs), mostly enriched in pathways related to the immune and inflammation systems, particularly IL-9 and NF-κB activation pathways...
December 21, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/28003341/chicoric-acid-supplementation-prevents-systemic-inflammation-induced-memory-impairment-and-amyloidogenesis-via-inhibition-of-nf-%C3%AE%C2%BAb
#15
Qian Liu, Yuwei Chen, Chun Shen, Yating Xiao, Yutang Wang, Zhigang Liu, Xuebo Liu
Chicoric acid (CA), a natural phenolic acid extracted from chicory and the echinacea (purple coneflower) plant (Echinacea purpurea), has been regarded as a nutraceutical that has powerful antioxidant and antiobesity activities. We investigated the inhibitory effects of CA on systemic inflammation-induced neuroinflammation, amyloidogenesis, and cognitive impairment. C57BL/6J mice were treated with 0.05% CA in the drinking water for 45 d. The mice were then treated by intraperitoneal injection of LPS (lipopolysaccharide)...
December 21, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28000893/hyperlipidemia-induced-apoptosis-of-hippocampal-neurons-in-apoe-mice-may-be-associated-with-increased-pcsk9-expression
#16
Xue-Shan Zhao, Qi Wu, Juan Peng, Li-Hong Pan, Zhong Ren, Hui-Ting Liu, Zhi-Sheng Jiang, Gui-Xue Wang, Zhi-Han Tang, Lu-Shan Liu
Hyperlipidemia is a risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a lipid regulatory gene involved in cell apoptosis. However, the function and mechanism of PCSK9 in neuronal apoptosis following hyperlipidemia remains to be elucidated. The present study established a hyperlipidemic mouse model by feeding a high‑fat diet (HFD) to 6‑week‑old apoE(‑/‑) mice. Plasma lipid levels, hippocampal lipid accumulation, hippocampal histology, and hippocampal neuronal apoptosis were all monitored for changes...
December 16, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28000370/amyloid-precursor-protein-traffics-from-the-golgi-directly-to-early-endosomes-in-an-arl5b-and-ap4-dependent-pathway
#17
Wei Hong Toh, Jing Zhi A Tan, Khalisah L Zulkefli, Fiona J Houghton, Paul A Gleeson
The intracellular trafficking and proteolytic processing of the membrane-bound amyloid precursor protein (APP) are co-ordinated events leading to the generation of pathogenic amyloid-beta (Aβ) peptides. The membrane transport of newly synthesised APP from the Golgi to the endolysosomal system is not well defined, yet is likely to be critical for regulating its processing by β-secretase (BACE1) and γ-secretase. Here we show that the majority of newly synthesised APP is transported from the trans-Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface...
December 20, 2016: Traffic
https://www.readbyqxmd.com/read/27997172/aminomethyl-derived-beta-secretase-bace1-inhibitors-engaging-gly230-without-an-anilide-functionality
#18
Christopher R Butler, Kevin Ogilvie, Luis Martinez-Alsina, Gabriela Barreiro, Elizabeth M Beck, Charles E Nolan, Kevin Atchison, Eric Benvenuti, Leanne Buzon, Shawn Doran, Cathleen Gonzales, Christopher J Helal, Xinjun Hou, Mei-Hui Hsu, Eric F Johnson, Kimberly Lapham, Lorraine Lanyon, Kevin Parris, Brian T O'Neill, David Riddell, Ashley Robshaw, Felix Vajdos, Michael A Brodney
A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety...
December 20, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27993242/hiv-protease-inhibitors-alter-amyloid-precursor-protein-processing-via-%C3%AE-site-amyloid-precursor-protein-cleaving-enzyme-1-translational-up-regulation
#19
Patrick J Gannon, Cagla Akay-Espinoza, Alan C Yee, Lisa A Briand, Michelle A Erickson, Benjamin B Gelman, Yan Gao, Norman J Haughey, M Christine Zink, Janice E Clements, Nicholas S Kim, Gabriel Van De Walle, Brigid K Jensen, Robert Vassar, R Christopher Pierce, Alexander J Gill, Dennis L Kolson, J Alan Diehl, Joseph L Mankowski, Kelly L Jordan-Sciutto
Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1)...
January 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/27991726/an-optimized-version-of-the-secretome-protein-enrichment-with-click-sugars-specs-method-leads-to-enhanced-coverage-of-the-secretome
#20
Alperen Serdaroglu, Stephan A Müller, Ute Schepers, Stefan Bräse, Stefan F Lichtenthaler, Peer-Hendrik Kuhn
The secretome, the entirety of all soluble proteins either being secreted or proteolytically released by a cell, plays a key role in intercellular communication of multicellular organisms. Pathological alterations contribute to diseases such as hypertension, cancer, autoimmune disorders or neurodegenerative diseases. Hence, studying disease related perturbations of the secretome and the secretome itself covers an important aspect of cellular physiology. We recently developed the Secretome Protein Enrichment with Click Sugars (SPECS) method which enables the analysis of secretomes of in vitro cell cultures even in the presence of fetal calf serum with mass spectrometry...
December 19, 2016: Proteomics
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