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https://www.readbyqxmd.com/read/27796320/orexin-signaling-regulates-both-the-hippocampal-clock-and-the-circadian-oscillation-of-alzheimer-s-disease-risk-genes
#1
Zhixiong Ma, Weiliang Jiang, Eric Erquan Zhang
Alzheimer's disease (AD) is a circadian clock-related disease. However, it is not very clear whether pre-symptomatic AD leads to circadian disruption or whether malfunction of circadian rhythms exerts influence on development of AD. Here, we report a functional clock that exists in the hippocampus. This oscillator both receives input signals and maintains the cycling of the hippocampal Per2 gene. One of the potential inputs to the oscillator is orexin signaling, which can shorten the hippocampal clock period and thereby regulate the expression of clock-controlled-genes (CCGs)...
October 31, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27639619/asp32-and-asp228-determine-the-selective-inhibition-of-bace1-as-shown-by-docking-and-molecular-dynamics-simulations
#2
Maricarmen Hernández-Rodríguez, José Correa-Basurto, Antonia Gutiérrez, Javier Vitorica, Martha C Rosales-Hernández
Inhibition of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases...
August 16, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27334786/genes-involved-in-interleukin-1-receptor-type-ii-activities-are-associated-with-asthmatic-phenotypes
#3
Anne Marie Madore, Vanessa T Vaillancourt, Emmanuelle Bouzigon, Chloé Sarnowski, Florent Monier, Marie Hélène Dizier, Florence Demenais, Catherine Laprise
PURPOSE: Interleukin-1 (IL-1) plays a key role in inflammation and immunity and its decoy receptor, IL-1R2, has been implicated in transcriptomic and genetic studies of asthma. METHODS: Two large asthma family collections, the French-Canadian Saguenay-Lac-St-Jean (SLSJ) study and the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA), were used to investigate the association of SNPs in 10 genes that modulate IL-1R2 activities with asthma, allergic asthma, and atopy...
September 2016: Allergy, Asthma & Immunology Research
https://www.readbyqxmd.com/read/26912421/pharmacological-bace1-and-bace2-inhibition-induces-hair-depigmentation-by-inhibiting-pmel17-processing-in-mice
#4
Derya R Shimshek, Laura H Jacobson, Carine Kolly, Natasa Zamurovic, Kamal Kumar Balavenkatraman, Laurent Morawiec, Robert Kreutzer, Juliane Schelle, Mathias Jucker, Barbara Bertschi, Diethilde Theil, Annabelle Heier, Karine Bigot, Karen Beltz, Rainer Machauer, Irena Brzak, Ludovic Perrot, Ulf Neumann
Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD)...
2016: Scientific Reports
https://www.readbyqxmd.com/read/26880803/deletion-of-interstitial-genes-between-tmprss2-and-erg-promotes-prostate-cancer-progression
#5
Douglas E Linn, Kathryn L Penney, Roderick T Bronson, Lorelei A Mucci, Zhe Li
TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency...
April 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/26858770/germinated-brown-rice-alters-a%C3%AE-1-42-aggregation-and-modulates-alzheimer-s-disease-related-genes-in-differentiated-human-sh-sy5y-cells
#6
Nur Hanisah Azmi, Maznah Ismail, Norsharina Ismail, Mustapha Umar Imam, Noorjahan Banu Mohammed Alitheen, Maizaton Atmadini Abdullah
The pathogenesis of Alzheimer's disease involves complex etiological factors, of which the deposition of beta-amyloid (Aβ) protein and oxidative stress have been strongly implicated. We explored the effects of H2O2, which is a precursor for highly reactive hydroxyl radicals, on neurotoxicity and genes related to AD on neuronal cells. Candidate bioactive compounds responsible for the effects were quantified using HPLC-DAD. Additionally, the effects of germinated brown rice (GBR) on the morphology of Aβ(1-42) were assessed by Transmission Electron Microscopy and its regulatory effects on gene expressions were explored...
2015: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/26840340/identification-of-human-islet-amyloid-polypeptide-as-a-bace2-substrate
#7
Ingrid C Rulifson, Ping Cao, Li Miao, David Kopecky, Linda Huang, Ryan D White, Kim Samayoa, Jonitha Gardner, Xiaosu Wu, Kui Chen, Trace Tsuruda, Oliver Homann, Helene Baribault, Harvey Yamane, Tim Carlson, Jed Wiltzius, Yang Li
Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets...
2016: PloS One
https://www.readbyqxmd.com/read/26833257/bace1-physiological-functions-may-limit-its-use-as-therapeutic-target-for-alzheimer-s-disease
#8
REVIEW
Soraia Barão, Diederik Moechars, Stefan F Lichtenthaler, Bart De Strooper
The protease β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is required for the production of the amyloid-β (Aβ) peptide, which is central to the pathogenesis of Alzheimer's disease (AD). Chronic inhibition of this protease may temper amyloid production and cure or prevent AD. However, while BACE1 inhibitors are being pushed forward as drug candidates, a remarkable gap in knowledge on the physiological functions of BACE1 and its close homolog BACE2 becomes apparent. Here we discuss the major discoveries of the past 3 years concerning BACE1 biology and to what extent these could limit the use of BACE1 inhibitors in the clinic...
March 2016: Trends in Neurosciences
https://www.readbyqxmd.com/read/26804314/a-comparative-molecular-dynamics-study-on-bace1-and-bace2-flap-flexibility
#9
H M Kumalo, Mahmoud E Soliman
Beta-amyloid precursor protein cleavage enzyme1 (BACE1) and beta-amyloid precursor protein cleavage enzyme2 (BACE2), members of aspartyl protease family, are close homologs and have high similarity in their protein crystal structures. However, their enzymatic properties are different, which leads to different clinical outcomes. In this study, we performed sequence analysis and all-atom molecular dynamic (MD) simulations for both enzymes in their ligand-free states in order to compare their dynamical flap behaviors...
October 2016: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/26803651/genetics-of-gestational-diabetes-mellitus-and-maternal-metabolism
#10
REVIEW
William L Lowe, Denise M Scholtens, Victoria Sandler, M Geoffrey Hayes
Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance with onset or first recognition during pregnancy. Women with a history of GDM are at long-term risk for developing type 2 diabetes (T2DM), raising the question to what extent GDM and T2DM share a common genetic architecture. Meta-analysis of candidate gene studies and genome-wide association analysis (GWAS) have identified a number of genes which are reproducibly associated with GDM, including TCF7L2, GCK, KCNJ11, KCNQ1, CDKAL1, IGF2BP2, MTNR1B, and IRS1...
February 2016: Current Diabetes Reports
https://www.readbyqxmd.com/read/26788404/association-of-a-bace1-gene-polymorphism-with-parkinson-s-disease-in-a-norwegian-population
#11
Johannes Lange, Kristin Aaser Lunde, Camilla Sletten, Simon Geir Møller, Ole-Bjørn Tysnes, Guido Alves, Jan Petter Larsen, Jodi Maple-Grødem
Background. Parkinson's disease (PD) and Alzheimer's disease (AD) share pathological features, including amyloid-beta pathology. Amyloid-beta peptide is generated by sequential proteolysis of amyloid precursor protein (APP), and genetic variations in the processing pathway genes have been found to increase the risk of AD; however, the contribution in PD is unknown. Methods. The aim of this study was to investigate whether candidate polymorphisms in five genes (ADAM10, BACE1, BACE2, PSEN2, and CLU) involved in the APP processing pathway affect PD risk in a population-based cohort of patients with incident PD and control subjects from the Norwegian ParkWest study...
2015: Parkinson's Disease
https://www.readbyqxmd.com/read/26608551/synthesis-of-3s-4s-4-aminopyrrolidine-3-ol-derivatives-and-biological-evaluation-for-their-bace1-inhibitory-activities
#12
Quang De Tran, Sukumar Bepary, Ge Hyeong Lee, Heeyeong Cho, Woo Kyu Park, Hee-Jong Lim
Synthesis, SAR study and BACE1 inhibitory activity of (3S,4S)-4-aminopyrrolidine-3-ol derivatives (2) were described. The compound 7c exhibited more inhibition activity than 11a (IC50: 0.05μM vs 0.12μM, respectively), but the latter was more effective in cell-based assay (IC50: 1.7μM vs 40% inhibition by 7c @ 10μM) due to the relatively higher cell permeability. Most of the compounds showed high selectivity over BACE2 and cathepsin D. This work will provide useful information for further structural modifications to develop potent BACE1 inhibitors in cell...
January 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26194182/de-novo-deleterious-genetic-variations-target-a-biological-network-centered-on-a%C3%AE-peptide-in-early-onset-alzheimer-disease
#13
A Rovelet-Lecrux, C Charbonnier, D Wallon, G Nicolas, M N J Seaman, C Pottier, S Y Breusegem, P P Mathur, P Jenardhanan, K Le Guennec, A S Mukadam, O Quenez, S Coutant, S Rousseau, A-C Richard, A Boland, J-F Deleuze, T Frebourg, D Hannequin, D Campion
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...
September 2015: Molecular Psychiatry
https://www.readbyqxmd.com/read/25961820/loss-of-bace1-in-mice-does-not-alter-the-severity-of-caerulein-induced-pancreatitis
#14
Mario Heindl, Jan Tuennemann, Ines Sommerer, Joachim Mössner, Albrecht Hoffmeister
CONTEXT: Beta-site alpha-amyloid protein cleaving enzyme1 (BACE1) plays a key role in the pathogenesis of Alzheimer's disease. Additional to its moderate expression in the brain, high levels of BACE1 mRNA were found in the pancreas. Murine Bace1 has been immunohistochemicaly detected at the apical pole of acinar cells within the exocrine pancreas of mice and Bace1 activity was observed in pancreatic juice. In vitro experiments revealed enteropeptidase as a putative substrate for Bace1 suggesting a role in acute pancreatitis...
2015: PloS One
https://www.readbyqxmd.com/read/25818872/adam-protease-inhibitors-reduce-melanogenesis-by-regulating-pmel17-processing-in-human-melanocytes
#15
Masakazu Kawaguchi, Yutaka Hozumi, Tamio Suzuki
BACKGROUND: ADAMs (a disintegrin and metalloprotease) are a family of proteases involved in ectodomain shedding that play a role in various biological processes such as cell adhesion and migration. ADAM10 and ADAM17 are suggested to be involved in pigmentary disorders. OBJECTIVE: We examined the effect of ADAM protease inhibitors on the modulation of melanogenesis in normal human epidermal melanocytes (NHEM). METHODS: NHEMs and B16F10 treated with ADAM protease inhibitors were analyzed...
May 2015: Journal of Dermatological Science
https://www.readbyqxmd.com/read/25808939/cerebrospinal-fluid-a%C3%AE-42-levels-and-app-processing-pathway-genes-in-parkinson-s-disease
#16
Lynn M Bekris, Debby W Tsuang, Elaine R Peskind, Chang E Yu, Thomas J Montine, Jing Zhang, Cyrus P Zabetian, James B Leverenz
BACKGROUND: Of recent interest is the finding that certain cerebrospinal fluid (CSF) biomarkers traditionally linked to Alzheimer's disease (AD), specifically amyloid beta protein (Aβ), are abnormal in PD CSF. The aim of this exploratory investigation was to determine whether genetic variation within the amyloid precursor protein (APP) processing pathway genes correlates with CSF Aβ42 levels in Parkinson's disease (PD). METHODS: Parkinson's disease (n = 86) and control (n = 161) DNA were genotyped for 19 regulatory region tagging single-nucleotide polymorphisms (SNPs) within nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN, and APH1B) involved in the cleavage of APP...
June 2015: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/25580148/mulberry-extracts-alleviate-a%C3%AE-25-35-induced-injury-and-change-the-gene-expression-profile-in-pc12-cells
#17
Nan Song, Hongpeng Yang, Wei Pang, Zhiwei Qie, Hao Lu, Long Tan, Haiqiang Li, Shoudan Sun, Fuzhi Lian, Chuan Qin, Yugang Jiang
Mulberry, which contained high amounts of anthocyanins, has been used in traditional Chinese medicine. Mulberry fruit extracts (ME) have demonstrated the antioxidant activity and neuroprotection. The study was to investigate the neuroprotective efficacy of ME against β-amyloid 25-35- (Aβ 25-35-) induced PC12 cells injury. Cells preincubated with or without ME (200 μg/mL) for 24 h were treated with Aβ 25-35 (20 μmol/L) for another 24 h. Cell viability was assessed by MTT, gene expression profiles were examined by cDNA microarrays, and RT-PCR were used to confirm the results of microarray assays...
2014: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/25537272/structure-based-design-synthesis-and-biological-evaluation-of-novel-%C3%AE-secretase-inhibitors-containing-a-pyrazole-or-thiazole-moiety-as-the-p3-ligand
#18
Arun K Ghosh, Margherita Brindisi, Yu-Chen Yen, Xiaoming Xu, Xiangping Huang, Thippeswamy Devasamudram, Geoffrey Bilcer, Hui Lei, Gerald Koelsch, Andrew D Mesecar, Jordan Tang
We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki=0.25nM, cellular EC50 of 194nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site...
February 1, 2015: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/25460285/hif1a-and-mif-as-potential-predictive-mrna-biomarkers-of-pre-eclampsia-a-longitudinal-prospective-study-in-high-risk-population
#19
Silvia Galbiati, Annalisa Inversetti, Vincenza Causarano, Stefania Stenirri, Nadia Soriani, Alessandro Ambrosi, Luca Valsecchi, Massimo Candiani, Laura Cremonesi, Maurizio Ferrari, Maddalena Smid
BACKGROUND: Pre-eclampsia (PE) is a hypertensive multisystem disorder, causing significant fetal-maternal mortality and morbidity worldwide. This study aims to define possible longitudinal predictive mRNA markers involved in the main pathogenic pathways of PE: inflammation [macrophage migration inhibitory factor (MIF)], hypoxia and oxidative stress [hypoxia inducible factor 1-α subunit (HIF1A) and β-site APP-cleaving enzyme-2 (BACE2)] and endothelial dysfunction [endoglin (ENG), fms-related tyrosine kinase-1 (FLT1) and vascular endothelial growth factor (VEGF)]...
August 2015: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/25391870/-association-between-exon-polymorphisms-of-bace2-gene-with-alzheimer-disease
#20
Yueyi Yu, Jianping Jia
OBJECTIVE: To explore the association between β-site APP-cleaving enzyme 2 gene exon polymorphisms with sporadic Alzheimer disease (AD) in a north Chinese Han population. METHODS: The exon regions of β-site APP-cleaving enzyme 2 gene were sequenced randomly in 10 sporadic AD patients and 10 healthy controls from Beijing and Qinhuangdao, Hebei province during 2000-2008. Using SnaPshot or direct sequencing, we genotyped these polymorphisms of 348 sporadic AD patients and 294 healthy controls in a Chinese Han population...
August 5, 2014: Zhonghua Yi Xue za Zhi [Chinese medical journal]
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