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https://www.readbyqxmd.com/read/28737179/total-synthesis-of-the-dictyodendrins-as-an-arena-to-highlight-emerging-synthetic-technologies
#1
REVIEW
Wenhan Zhang, Joseph M Ready
Covering: 1993-2017This review discusses the isolation, biological activity, and syntheses of the dictyodendrin class of natural products, covering the years 1993-2017. The dictyodendrins are a family of alkaloids isolated from marine sponges, Dictyodendrilla verongiformis and Ianthella sp., which possess a highly substituted pyrrolo[2,3-c]carbazole core at the phenol or quinone oxidation states. Dictyodendrins exhibit a wide range of biological activities, such as telomerase inhibition, BACE1 enzyme inhibition, and cytotoxicity against several cancer cell lines...
July 24, 2017: Natural Product Reports
https://www.readbyqxmd.com/read/28733667/rtn1-and-rtn3-protein-are-differentially-associated-with-senile-plaques-in-alzheimer-s-brains
#2
Qi Shi, Yingying Ge, Wanxia He, Xiangyou Hu, Riqiang Yan
Reticulon proteins (RTNs), consisting of RTN1 to RTN4, were previously shown to interact with BACE1 by negatively modulating its secretase activity. In RTN3-null mice, RTN1 expression was slightly elevated. To understand the in vivo role of RTN1, we generated RTN1-null mice and compared the effects of RTN1 and RTN3 on BACE1 modulation. We show that RTN1 is mostly expressed by neurons and not by glial cells under normal conditions, similar to the expression of RTN3. However, RTN1 is more localized in dendrites and is an excellent marker for dendrites of Purkinje cells, while RTN3 expression is less evident in dendrites...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28728105/discovery-of-imidazopyridines-containing-isoindoline-1-3-dione-framework-as-a-new-class-of-bace1-inhibitors-design-synthesis-and-sar-analysis
#3
Sara Azimi, Afsaneh Zonouzi, Omidreza Firuzi, Aida Iraji, Mina Saeedi, Mohammad Mahdavi, Najmeh Edraki
Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-β. Inhibiting BACE1 is a well-studied approach to lower the burden of amyloid-β aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The compounds 8a-o were synthesized by the Groebke-Blackburn-Bienaymé three-component reaction of heteroaromatic amidines, aldehydes and isocyanides...
June 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28728041/multi-structure-docking-analysis-of-bace1-crystal-structures-and-non-peptidic-ligands
#4
Zahra Haghighijoo, Bahram Hemmateenejad, Najmeh Edraki, Ramin Miri, Saeed Emami
In order to design novel non-peptidic inhibitors of BACE1, many research groups have attempted using computational studies including docking analyses. Since there are too many 3D structures for BACE1 in the protein database, the selection of suitable crystal structures is a key prerequisite for the successful application of molecular docking. We employed a multi-structure docking protocol. In which 615 ligands' structures were docked into 150 BACE1 structures. The large number of the resultant docking scores were post-processed by different data analysis methods including exploratory data analysis, regression analysis and discriminant analysis...
June 28, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28711506/sodium-selenate-activated-wnt-%C3%AE-catenin-signaling-and-repressed-amyloid-%C3%AE-formation-in-a-triple-transgenic-mouse-model-of-alzheimer-s-disease
#5
Na Jin, Huazhang Zhu, Xiao Liang, Wei Huang, Qingguo Xie, Peng Xiao, Jiazuan Ni, Qiong Liu
Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease (AD). Sodium selenate has been reported to reduce neurofibrillary tangles (NFT) in the tauopathic mouse models, but its effects on the Wnt/β-catenin signaling pathway and APP processing remain unknown during AD formation. In this paper, triple transgenic AD mice (3×Tg-AD) had been treated with sodium selenate in drinking water for 10month before the detection of hippocampal pathology...
July 12, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28710924/identification-of-new-bace1-inhibitors-using-pharmacophore-and-molecular-dynamics-simulations-approach
#6
Anantha Krishnan Dhanabalan, Manish Kesherwani, Devadasan Velmurugan, Krishnasamy Gunasekaran
Inhibition of β-Secretase (BACE1) is crucial for the treatment of Alzheimer's disease (AD). Availability of BACE1 crystal structures in both apo and complexed forms enables to find structure-based BACE1 inhibitors for controlling AD. There are two catalytic aspartates (ASP32 and ASP228) presents in the active domain of BACE1. In order to understand the binding mechanism and structure-activity relationship of amidine-containing BACE1 inhibitors, molecular docking, and pharmacophore and 3D-QSAR studies have been carried out with 34 amidine derivatives to develop a pharmacophore model...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28707894/vitamin-d-receptor-regulates-amyloid-beta-1-42-production-with-protein-disulfide-isomerase-a3
#7
Duygu Gezen-Ak, Irem L Atasoy, Esin Candas, Merve Alaylioglu, Selma Yilmazer, Erdinc Dursun
The challenge of understanding the biology of neuronal amyloid processing could provide a basis for understanding the amyloid pathology in Alzheimer's disease (AD). Based on our previous studies we have suggested that AD might be the consequence of a hormonal imbalance in which the critical hormone is vitamin D. The present study primarily focused on the creation of a condition that prevents the genomic or non-genomic action of vitamin D by disrupting vitamin D receptors (VDR or PDIA3/1,25MARRS); the effects of these disruptions on the series of proteins involved in secretases that play a crucial role in amyloid pathology and on amyloid beta (Aβ) production in primary cortical neurons were observed...
July 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#8
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28698023/inhibitory-effects-of-serratene-type-triterpenoids-from-lycopodium-complanatum-on-cholinesterases-and-%C3%AE-secretase-1
#9
Van Thu Nguyen, Bing Tian Zhao, Su Hui Seong, Jeong Ah Kim, Mi Hee Woo, Jae Sui Choi, Byung Sun Min
Phytochemical investigation of Lycopodium complanatum whole plants led to the isolation of two new serratene-type triterpenoids (1 and 2) along with eight known triterpenoids (3-10). Their structures were established using 1D and 2D NMR spectroscopic techniques and mass spectrometry. These compounds did not inhibit acetylcholinesterases (AChE) and butyrylcholinesterase (BChE), but did inhibit β-secretase 1 (BACE1). Compounds 1 and 6 showed potent BACE1 inhibition with IC50 values of 2.79 ± 0.28 and 2.49 ± 0...
July 8, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28687442/increased-bace1-activity-inhibits-peripheral-nerve-regeneration-after-injury
#10
Carolyn Tallon, Edward Rockenstein, Eliezer Masliah, Mohamed H Farah
Axons of the peripheral nervous system possess the capacity to regenerate following injury. Previously, we showed that genetically knocking out Beta-Site APP-Cleaving Enzyme 1 (BACE1) leads to increased nerve regeneration. Two cellular components, macrophages and neurons, contribute to enhanced nerve regeneration in BACE1 knockout mice. Here, we utilized a transgenic mouse model that overexpresses BACE1 in its neurons to investigate whether neuronal BACE1 has an inverse effect on regeneration following nerve injury...
July 5, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28683457/mir-9-regulates-the-expression-of-bace1-in-dementia-induced-by-chronic-brain-hypoperfusion-in-rats
#11
Hailong Xie, Ying Zhao, You Zhou, Lin Liu, Yueting Liu, Dongxue Wang, Shuang Zhang, Mingyan Yang
BACKGROUND/AIMS: MicroRNA-9 (miR-9) plays important roles in nervous system diseases such as glioblastoma and neurodegenerative disorders. However, how miR-9 contributes to dementia requires further study. In this study, we evaluated the role of miR-9 in dementia and the molecular mechanisms underlying its effects. METHODS: A rat model of dementia was created by occlusion of the bilateral common carotid artery (2VO) for 8 weeks. Learning and memory were assessed using the Morris Water Maze (MWM)...
July 3, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28671121/selenomethionine-attenuates-the-amyloid-%C3%AE-level-by-both-inhibiting-amyloid-%C3%AE-production-and-modulating-autophagy-in-neuron-2a-a%C3%AE-ppswe-cells
#12
Zhong-Hao Zhang, Qiu-Yan Wu, Chen Chen, Rui Zheng, Yao Chen, Qiong Liu, Jia-Zuan Ni, Guo-Li Song
Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD...
June 24, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28670853/the-pathological-roles-of-ndrg2-in-alzheimer-s-disease-a-study-using-animal-models-and-appwt-overexpressed-cells
#13
Xian-Fang Rong, Ying-Ni Sun, Dong-Mei Liu, Hua-Jing Yin, Ying Peng, Shao-Feng Xu, Ling Wang, Xiao-Liang Wang
AIMS: To investigate the roles of N-myc downstream-regulated gene 2 (NDRG2) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease (AD). RESULTS: In this study, we confirmed the upregulation of NDRG2 in the brains of aging and AD animal models. To explore the role of NDRG2 in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N-SH cells (SK-N-SH APPwt). By silencing and overexpressing gene of NDRG2, we demonstrated that NDRG2-mediated increase in Aβ1-42 was through the pathways of BACE1 and GGA3...
July 2, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28669600/bace1-deficiency-causes-abnormal-neuronal-clustering-in-the-dentate-gyrus
#14
Hailong Hou, Qingyuan Fan, Wanxia He, Hoonkyo Suh, Xiangyou Hu, Riqiang Yan
BACE1 is validated as Alzheimer's β-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin-positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ). Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development...
July 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28668332/ethanol-induced-pge2-up-regulates-a%C3%AE-production-through-pka-creb-signaling-pathway
#15
Amr Ahmed Gabr, Hyun Jik Lee, Xaykham Onphachanh, Young Hyun Jung, Jun Sung Kim, Chang Woo Chae, Ho Jae Han
Ethanol abuse aggravates dementia-associated cognitive defects through the progression of Alzheimer's disease (AD) pathophysiology. Beta-site APP-cleaving enzyme 1 (BACE1) has been considered as a key regulator of AD pathogenesis by controlling amyloid beta peptide (Aβ) accumulation. In addition, previous studies reported that endoplasmic reticulum (ER) stress and neuroinflammation have been proposed in ethanol-induced neurodegeneration. Thus, we investigated the role of ER stress and PGE2, a neuroinflammation mediator, in the ethanol-stimulated BACE1 expression and Aβ production...
June 28, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28659580/palmitic-acid-bsa-enhances-amyloid-%C3%AE-production-through-gpr40-mediated-dual-pathways-in-neuronal-cells-involvement-of-the-akt-mtor-hif-1%C3%AE-and-akt-nf-%C3%AE%C2%BAb-pathways
#16
Jeong Yeon Kim, Hyun Jik Lee, Sei-Jung Lee, Young Hyun Jung, Dae Young Yoo, In Koo Hwang, Je Kyung Seong, Jung Min Ryu, Ho Jae Han
The pathophysiological actions of fatty acids (FAs) on Alzheimer's disease (AD), which are possibly mediated by genomic effects, are widely known; however, their non-genomic actions remain elusive. The aim of this study was to investigate the non-genomic mechanism of extra-cellular palmitic acid (PA) regulating beta-amyloid peptide (Aβ) production, which may provide a link between obesity and the occurrence of AD. In an obese mouse model, a high-fat diet (HFD) significantly increased the expression levels of APP and BACE1 as well as the AD pathology in the mouse brain...
June 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28656081/effect-of-rosiglitazone-on-amyloid-precursor-protein-processing-and-a%C3%AE-clearance-in-streptozotocin-induced-rat-model-of-alzheimer-s-disease
#17
Li Wang, Wei Liu, Ying Fan, Tingting Liu, Chunjiang Yu
OBJECTIVES: Increasing evidence suggests that Alzheimer's disease (AD) is associated with diabetes. Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist and anti-diabetic agent, may improve symptoms of AD. However, the underlying therapeutic potential of it has not been fully elucidated. MATERIALS AND METHODS: Rats were divided into four groups: control group, sham operated group, Streptozotocin (STZ) group, rosiglitazone (RGZ) group...
May 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28646794/dexibuprofen-prevents-neurodegeneration-and-cognitive-decline-in-appswe-ps1de9-through-multiple-signaling-pathways
#18
Miren Ettcheto, Elena Sánchez-López, Laura Pons, Oriol Busquets, Jordi Olloquequi, Carlos Beas-Zarate, Merce Pallas, Maria Luisa García, Carme Auladell, Jaume Folch, Antoni Camins
The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα...
June 15, 2017: Redox Biology
https://www.readbyqxmd.com/read/28637867/full-length-cellular-beta-secretase-has-a-trimeric-subunit-stoichiometry-and-its-sulfur-rich-transmembrane-interaction-site-modulates-cytosolic-copper-compartmentalization
#19
Filip Liebsch, Mark R P Aurousseau, Tobias Bethge, Hugo McGuire, Silvia Scolari, Andreas Herrmann, Rikard Blunck, Derek Bowie, Gerd Multhaup
The beta-secretase (BACE1) initiates processing of the amyloid precursor protein (APP) into Aβ peptides, which have been implicated as central players in the pathology of Alzheimer disease. BACE1 has been described as a copper-binding protein and its oligomeric state as being monomeric, dimeric, and/or multimeric, but the native cellular stoichiometry has remained elusive. Here, by using single-molecule fluorescence and in vitro cross-linking experiments with photo-activatable unnatural amino acids, we show that full-length BACE1, independently of its subcellular localization, exists as trimers in human cells...
June 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28626832/fragment-binding-to-%C3%AE-secretase-1-without-catalytic-aspartate-interactions-identified-via-orthogonal-screening-approaches
#20
Frederik J R Rombouts, Richard Alexander, Erna Cleiren, Alex De Groot, Michel Carpentier, Joyce Dijkmans, Katleen Fierens, Stefan Masure, Diederik Moechars, Martina Palomino-Schätzlein, Antonio Pineda-Lucena, Andrés A Trabanco, Daan Van Glabbeek, Ann Vos, Gary Tresadern
An approach to identify β-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2...
February 28, 2017: ACS Omega
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