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https://www.readbyqxmd.com/read/29193080/neuroprotection-mediated-post-ischemically-by-a-non-peptidic-%C3%AE-opioid-receptor-agonist-tan-67-in-ischemic-stroke-mice-is-associated-with-altered-amyloid-precursor-protein-expression-maturation-and-processing
#1
Jia-Wei Min, Yanying Liu, David Wang, Fangfang Qiao, Hongmin Wang
Tan-67 is a selective non-peptidic δ-opioid receptor (DOR) agonist that confers neuroprotection against cerebral ischemia/reperfusion (I/R)-caused neuronal injury in pre-treated animals. In this study, we examined whether post-ischemic administration of Tan-67 in stroke mice is also neuroprotective and whether the treatment affects expression, maturation and processing of the amyloid precursor protein (APP). A focal cerebral I/R model in mice was induced by middle cerebral artery occlusion for 1 hour (h) and Tan-67 (1...
November 29, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29141208/crispr-transcriptional-activation-analysis-unmasks-an-occult-%C3%AE-secretase-processivity-defect-in-familial-alzheimer-s-disease-skin-fibroblasts
#2
Keiichi Inoue, Luis M A Oliveira, Asa Abeliovich
Mutations in presenilin (PSEN) 1 and 2, which encode components of the γ-secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29128320/exercise-decreases-bace-and-app-levels-in-the-hippocampus-of-a-rat-model-of-alzheimer-s-disease
#3
Karim A Alkadhi, An T Dao
We investigated the effect of treadmill exercise training on the levels of Alzheimer's disease (AD)-related protein molecules in the DG and CA1 areas of a rat model of AD, i.c.v. infusion of Aβ1-42 peptide, 2weeks (250pmol/day). Aβ infusion markedly increased protein levels of amyloid precursor protein (APP), the secretase beta-site APP cleaving enzyme-1 (BACE-1) and Aβ in the CA1 and DG areas. The results also revealed that 4weeks of treadmill exercise prevented the increase in the levels of APP, BACE-1 and Aβ proteins in both hippocampal areas...
November 9, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29106038/the-physical-approximation-of-app-and-bace-1-a-key-event-in-alzheimer-s-disease-pathogenesis
#4
REVIEW
Jichao Sun, Subhojit Roy
Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of Amyloid β (Aβ) in brains. Aβ is derived by sequential cleavage of the amyloid precursor protein (APP) by β-site secretase enzyme (BACE-1) and γ-secretase. Proteolytic processing of APP by BACE-1 is the rate-limiting step in Aβ production, and this pathway is a prime target for AD drug development. Both APP and BACE-1 are membrane-spanning proteins, transported via secretory and endocytic pathways; and the physical interaction of APP and BACE-1 during trafficking is a key cell biological event initiating the amyloidogenic pathway...
November 6, 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/29096057/spiropiperidine-sultam-and-lactam-templates-diastereoselective-overman-rearrangement-and-metathesis-followed-by-nh-arylation
#5
Luis A Martinez-Alsina, John C Murray, Leanne M Buzon, Mark W Bundesmann, Joseph Michael Young, Brian T O'Neill
We report the diastereoselective synthesis of novel spiropiperidine templates for use in SAR studies of β-secretase (BACE) inhibitors and also as versatile ligands for other receptor types. The overall synthetic approach stems from chiral starting material benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and employs an Overman rearrangement to control the stereochemistry at the quaternary center. This process is followed by a Grubbs metathesis to close a 5-membered "top" ring to form an α,β-unsaturated lactam or an α,β-unsaturated sultam...
November 2, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29094110/enhanced-sleep-reverses-memory-deficits-and-underlying-pathology-in-drosophila-models-of-alzheimer-s-disease
#6
Stephane Dissel, Markus Klose, Jeff Donlea, Lijuan Cao, Denis English, Raphaelle Winsky-Sommerer, Bruno van Swinderen, Paul J Shaw
To test the hypothesis that sleep can reverse cognitive impairment during Alzheimer's disease, we enhanced sleep in flies either co-expressing human amyloid precursor protein and Beta-secretase (APP:BACE), or in flies expressing human tau. The ubiquitous expression of APP:BACE or human tau disrupted sleep. The sleep deficits could be reversed and sleep could be enhanced when flies were administered the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Expressing APP:BACE disrupted both Short-term memory (STM) and Long-term memory (LTM) as assessed using Aversive Phototaxic Suppression (APS) and courtship conditioning...
January 2017: Neurobiology of Sleep and Circadian Rhythms
https://www.readbyqxmd.com/read/29078760/in-silico-repurposing-of-antipsychotic-drugs-for-alzheimer-s-disease
#7
Shivani Kumar, Suman Chowdhury, Suresh Kumar
BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace...
October 27, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/29073110/m344-promotes-nonamyloidogenic-amyloid-precursor-protein-processing-while-normalizing-alzheimer-s-disease-genes-and-improving-memory
#8
Claude-Henry Volmar, Hasib Salah-Uddin, Karolina J Janczura, Paul Halley, Guerline Lambert, Andrew Wodrich, Sivan Manoah, Nidhi H Patel, Gregory C Sartor, Neil Mehta, Nancy T H Miles, Sachi Desse, David Dorcius, Michael D Cameron, Shaun P Brothers, Claes Wahlestedt
Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28982375/pkr-involvement-in-alzheimer-s-disease
#9
REVIEW
Jacques Hugon, François Mouton-Liger, Julien Dumurgier, Claire Paquet
BACKGROUND: Brain lesions in Alzheimer's disease (AD) are characterized by Aβ accumulation, neurofibrillary tangles, and synaptic and neuronal vanishing. According to the amyloid cascade hypothesis, Aβ1-42 oligomers could trigger a neurotoxic cascade with kinase activation that leads to tau phosphorylation and neurodegeneration. Detrimental pathways that are associated with kinase activation could also be linked to the triggering of direct neuronal death, the production of free radicals, and neuroinflammation...
October 5, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28956672/proxy-reported-quality-of-life-and-family-impact-for-children-followed-longitudinally-by-a-pediatric-palliative-care-team
#10
Meaghann Weaver, Christopher Wichman, Cheryl Darnall, Sue Bace, Catherine Vail, Andrew MacFadyen
BACKGROUND: One goal of pediatric palliative care is to maintain quality of life for children and their families. Quality-of-life investigations may be enhanced by considering clinically important metrics in addition to statistical significance. OBJECTIVE: The purpose of this study was to longitudinally evaluate the effect of time on quality of life and family impact for pediatric palliative care patients across all diagnoses and ages. DESIGN: This prospective quality-of-life study included administration of a 23-item PedsQL™ Measurement Model to evaluate for physical, emotional, social, and cognitive dimensions of the child's quality of life and a 36-item PedsQL Family Impact Module to assess for the familial impact at time of initial palliative care consultation, Month 6, and Month 12...
September 28, 2017: Journal of Palliative Medicine
https://www.readbyqxmd.com/read/28950235/a-physicochemical-descriptor-based-method-for-effective-and-rapid-screening-of-dual-inhibitors-against-bace-1-and-gsk-3%C3%AE-as-targets-for-alzheimer-s-disease
#11
Akhil Kumar, Gaurava Srivastava, Ashok Sharma
Due to multifactorial nature of Alzheimer's disease one target-one ligand hypothesis often looks insufficient. BACE-1 and GSK-3β are well established therapeutic drug targets and interaction between BACE-1 and GSK-3β pathways has also been established. Thus, designing of dual inhibitor for these two targets seems rational and may provide effective therapeutic strategies against AD. Recent studies revealed that only two scaffolds i.e. triazinone and curcumin act as a dual inhibitor against BACE-1 and GSK-3β...
September 8, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28944861/panax-notoginseng-saponins-attenuates-sevoflurane%C3%A2-induced-nerve-cell-injury-by-modulating-akt-signaling-pathway
#12
Xu Yang, Sun Yang, Chen Hong, Wang Yu, Wang Guonian
General anesthesia in patients with or at risk for neuronal injury remains challenging due to the neurotoxic effects of volatile anesthetics. One inhalation anesthetic, sevoflurane, induces neuronal damage, including neuroapoptosis, and learning and memory impairment. Panax Notoginseng Saponins (PNS) is the active ingredient of Sanqui and has been reported to exert neuroprotective effects. In the current study, the protective effect of PNS on sevoflurane‑induced nerve cell injury was explored. Cell proliferation was significantly reduced in a dose‑dependent manner following stimulation with sevoflurane...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28930140/identification-of-phlogacantholide-c-as-a-novel-adam10-enhancer-from-traditional-chinese-medicinal-plants
#13
Myriam Meineck, Florian Schuck, Sara Abdelfatah, Thomas Efferth, Kristina Endres
Background: Alzheimer's disease is one of the most prevalent dementias in the elderly population with increasing numbers of patients. One pivotal hallmark of this disorder is the deposition of protein aggregates stemming from neurotoxic amyloid-beta peptides. Synthesis of those peptides has been efficiently prevented in AD model mice by activation of an enzyme called alpha-secretase. Therefore, drugs with the capability to increase the expression of this enzyme, named ADAM10, have been suggested as a valuable therapeutic medication...
December 5, 2016: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/28923680/potent-and-selective-bace-1-peptide-inhibitors-lower-brain-a%C3%AE-levels-mediated-by-brain-shuttle-transport
#14
Nadine Ruderisch, Daniel Schlatter, Andreas Kuglstatter, Wolfgang Guba, Sylwia Huber, Carlo Cusulin, Jörg Benz, Arne Christian Rufer, Joerg Hoernschemeyer, Christophe Schweitzer, Tina Bülau, Achim Gärtner, Eike Hoffmann, Jens Niewoehner, Christoph Patsch, Karlheinz Baumann, Hansruedi Loetscher, Eric Kitas, Per-Ola Freskgård
Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties...
October 2017: EBioMedicine
https://www.readbyqxmd.com/read/28923172/handgrip-strength-is-associated-with-but-poorly-predicts-disability-in-older-women-with-acute-low-back-pain-a-12-month-follow-up-study
#15
Diogo Carvalho Felício, Juliano Bergamaschine Mata Diz, Daniele Sirineu Pereira, Bárbara Zille de Queiroz, Juscélio Pereira de Silva, Bruno de Souza Moreira, Vinícius Cunha Oliveira, Leani Souza Máximo Pereira
BACKGROUND: Older women with low back pain (LBP) constitute a special subpopulation at risk of severe and permanent disability. It is important to identify factors limiting functionality in this population in order to reduce costs and improve both prevention and intervention. Handgrip strength (HGS) is a biomarker of aging associated with several adverse health outcomes, but long-term associations with disability in older patients with LBP are not known. OBJECTIVE: To examine whether HGS predicts disability in older women with acute low back pain (LBP)...
October 2017: Maturitas
https://www.readbyqxmd.com/read/28915693/the-application-of-is6110-baced-loop-mediated-isothermal-amplification-lamp-in-the-early-diagnosis-of-tuberculous-meningitis
#16
Wen-Wen Sun, Qin Sun, Li-Ping Yan, Qing Zhang
Here, we evaluated the potential activity of rapid Mycobacterium tuberculosis detection with loop-mediated isothermal amplification (LAMP), for the early diagnosis of tuberculous meningitis (TBM). Patients with suspected TBM from January 2014 to December 2015 were reviewed retrospectively. The cerebrospinalfluid(CSF) was collected. Acid-fast bacillus (AFB) staining, MGIT 960 culture, real-time fluorescent quantitative polymerase chain reaction (RTFQ PCR) and LAMP were performed. A total of 200 patients were included in the study...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901306/bronchial-artery-chemoembolization-combined-with-radioactive-iodine-125-seed-implantation-in-the-treatment-of-advanced-nonsmall-cell-lung-cancer
#17
Yaoyong Chen, Yuwei Li, Yuming Jia, Kaijian Lei, Xinfeng Zhang, Yueyong Cao, Jun Zhu
OBJECTIVE: The aim of this study was to investigate the short-term efficacy and safety of bronchial artery chemoembolization (BACE) combined with radioactive iodine-125 seed implantation in the treatment of nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty-two Stage III-IV NSCLC patients were divided into Groups A and B. Thirty cases were treated with BACE combined with radioactive iodine-125 seed implantation in the Group A and 32 cases were treated with BACE alone in the Group B until disease progression...
2017: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28877031/genetic-associations-with-gestational-duration-and-spontaneous-preterm-birth
#18
Ge Zhang, Bjarke Feenstra, Jonas Bacelis, Xueping Liu, Lisa M Muglia, Julius Juodakis, Daniel E Miller, Nadia Litterman, Pan-Pan Jiang, Laura Russell, David A Hinds, Youna Hu, Matthew T Weirauch, Xiaoting Chen, Arun R Chavan, Günter P Wagner, Mihaela Pavličev, Mauris C Nnamani, Jamie Maziarz, Minna K Karjalainen, Mika Rämet, Verena Sengpiel, Frank Geller, Heather A Boyd, Aarno Palotie, Allison Momany, Bruce Bedell, Kelli K Ryckman, Johanna M Huusko, Carmy R Forney, Leah C Kottyan, Mikko Hallman, Kari Teramo, Ellen A Nohr, George Davey Smith, Mads Melbye, Bo Jacobsson, Louis J Muglia
BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome...
September 21, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28872858/fast-and-reliable-thermodynamic-approach-for-determining-the-protonation-state-of-the-asp-dyad
#19
Jinfeng Huang, Bin Sun, Yuan Yao, Junjun Liu
The protonation state of the asp dyad is significantly important in revealing enzymatic mechanisms and developing drugs. However, it is hard to determine by calculating free energy changes between possible protonation states, because the free energy changes due to protein conformational flexibility are usually much larger than those originating from different locations of protons. Sophisticated and computationally expensive methods such as free energy perturbation, thermodynamic integration (TI), and quantum mechanics/molecular mechanics are therefore usually used for this purpose...
September 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28870602/the-brazilian-back-complaints-in-the-elders-brazilian-bace-study-characteristics-of-brazilian-older-adults-with-a-new-episode-of-low-back-pain
#20
Fabianna Resende De Jesus-Moraleida, Paulo Henrique Ferreira, Manuela Loureiro Ferreira, Juscelio Pereira Da Silva, Marcella Guimarães Assis, Leani Souza Máximo Pereira
OBJECTIVE: Low back pain (LBP) is little explored in the aging population especially when considering age-relevant and culturally dependent outcomes. We aimed to describe socio-demographic and clinical characteristics of Brazilian older people with a new episode of LBP presenting to primary care. METHODS: We sourced baseline information on socio-demographic, pain-related and clinical characteristics from 602 older adults from the Brazilian Back Complaints in the Elders (Brazilian BACE) study...
August 10, 2017: Brazilian Journal of Physical Therapy
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