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https://www.readbyqxmd.com/read/28230986/design-synthesis-and-evaluation-of-a-novel-series-of-oxadiazine-gamma-secretase-modulators-for-familial-alzheimer-s-disease
#1
Matthew G Bursavich, Bryce A Harrison, Raksha Acharya, Donald E Costa, Emily A Freeman, Hilliary E Hodgdon, Lori A Hrdlicka, Hong Jin, Sudarshan Kapadnis, Jeffrey S Moffit, Deirdre A Murphy, Scott Nolan, Holger Patzke, Cuyue Tang, Melody Wen, Gerhard Koenig, Jean-François Blain, Duane A Burnett
Herein we describe the design, synthesis and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conforma-tional restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aβ42 reductions and subsequent Aβ37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28230857/protein-phosphatase-4-coordinates-glial-membrane-recruitment-and-phagocytic-clearance-of-degenerating-axons-in-drosophila
#2
Lilly M Winfree, Sean D Speese, Mary A Logan
Neuronal damage induced by injury, stroke, or neurodegenerative disease elicits swift immune responses from glial cells, including altered gene expression, directed migration to injury sites, and glial clearance of damaged neurons through phagocytic engulfment. Collectively, these responses hinder further cellular damage, but the mechanisms that underlie these important protective glial reactions are still unclear. Here, we show that the evolutionarily conserved trimeric protein phosphatase 4 (PP4) serine/threonine phosphatase complex is a novel set of factors required for proper glial responses to nerve injury in the adult Drosophila brain...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28229904/regulation-of-g-protein-coupled-receptor-signalling-underpinning-neurobiology-of-mood-disorders-and-depression
#3
Dimitris K Grammatopoulos
G-protein coupled receptors (GPCRs) have long been at the centre of investigations of the neurobiology of depression and mood disorders. Different facets of GPCR signalling pathways, including those controlling monoaminergic and neuropeptidergic hormonal systems are believed to be dysregulated in major depressive and bipolar disorders. Although these receptors are key molecular targets for a variety of therapeutic agents and continue to be the focus of intense pharmaceutical development, the molecular mechanisms activated by these GPCRs and underpin the pathological basis of mood disorders remain poorly understood...
February 13, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28229303/phospholipase-d1-expression-analysis-in-relapsing-remitting-multiple-sclerosis-patients
#4
Mohammad Mahdi Eftekharian, Tahereh Azimi, Soudeh Ghafouri-Fard, Arezou Sayad, Mir Davood Omrani, Shaghayegh Sarrafzadeh, Roghayeh Abbasalipourkabir, Mehrdokht Mazdeh, Mohammad Taheri
Multiple sclerosis (MS) is a chronic disorder resulting from destruction of the myelin or insulating covers of neurons in the central nervous system (CNS). Several lines of evidence suggest a role for immune response in the occurrence and progression of this disorder. Several disease-modifying agents (DMA) including β-interferons (IFNβ) are being used in MS patients in order to stop the disease at the early inflammatory stage, postpone disease progression and diminish future disability. Phospholipase D1 (PLD1) is a critical enzyme responsible for the making lipid second messenger phosphatidic acid...
February 22, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28229085/folate-receptor-alpha-is-more-than-just-a-folate-transporter
#5
Vineet Mohanty, M Rizwan Siddiqui, Tadanori Tomita, Chandra Shekhar Mayanil
Until recently folate receptor alpha (FRα) has only been considered as a folate transporter. However, a novel role of FRα as a transcription factor was reported by our lab. More recently our lab showed a novel pleiotropic role of FRα: (a) direct transcriptional activation of Oct4, Sox2, and Klf4 genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules. These observations beg a question: "Can a simple molecule such as folate be used to manipulate the production and/or differentiation of endogenous neural stem cells (NSCs), which may hold promise for future therapies?" Conditions such as spinal cord injury, motor neuron diseases, Alzheimer's disease and multiple sclerosis may benefit from increasing stem cell pool and promoting specific pathways of differentiation...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28228718/current-concepts-on-the-physiopathological-relevance-of-dopaminergic-receptors
#6
REVIEW
Ada Ledonne, Nicola B Mercuri
Dopamine (DA) is a key neurotransmitter modulating essential functions of the central nervous system (CNS), like voluntary movement, reward, several cognitive functions and goal-oriented behaviors. The factual relevance of DAergic transmission can be well appreciated by considering that its dysfunction is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD) and associated movement disorders, as well as, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28228281/dysregulation-of-the-cytokine-gm-csf-induces-spontaneous-phagocyte-invasion-and-immunopathology-in-the-central-nervous-system
#7
Sabine Spath, Juliana Komuczki, Mario Hermann, Pawel Pelczar, Florian Mair, Bettina Schreiner, Burkhard Becher
Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits...
February 21, 2017: Immunity
https://www.readbyqxmd.com/read/28228272/commanding-cns-invasion-gm-csf
#8
Junjie Zhao, Lillian Sun, Xiaoxia Li
Granulocyte-macrophage colony-stimulating factor (GM-CSF or Csf-2) is a pro-inflammatory mediator implicated in the pathogenesis of various autoimmune diseases. In this issue of Immunity, Spath et al. (2017) show that the dysregulated production of GM-CSF rather than IL-17 induces spontaneous immunopathology in a mouse model of CNS inflammation.
February 21, 2017: Immunity
https://www.readbyqxmd.com/read/28226226/microglia-function-in-the-central-nervous-system-during-health-and-neurodegeneration
#9
Marco Colonna, Oleg Butovsky
Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses...
February 9, 2017: Annual Review of Immunology
https://www.readbyqxmd.com/read/28226077/superficial-siderosis-of-the-central-nervous-system-is-a-rare-and-possibly-underdiagnosed-disorder
#10
Yara Dadalti Fragoso, Tarso Adoni, Joseph Bruno Bidin Brooks, Sidney Gomes, Marcus Vinicius Magno Goncalves, Cassio Lemos Jovem, Andre Palma da Cunha Matta, Joao Filipe Oliveira, Fabio Siquinelli, Carlos Bernardo Tauil, Guilherme Navarro Troiani, Paulo Roberto Wille
Methods: Series of cases collected from Brazilian centers. Results: We studied 13 cases of patients presenting with progressive histories of neurological dysfunction caused by SS-CNS. The most frequent clinical findings in these patients were progressive gait ataxia, hearing loss, hyperreflexia and cognitive dysfunction. The diagnoses of SS-CNS were made seven months to 30 years after the disease onset. Conclusion: SS-CNS is a rare disease that may remain undiagnosed for long periods...
February 2017: Arquivos de Neuro-psiquiatria
https://www.readbyqxmd.com/read/28225293/rituximab-associated-progressive-multifocal-leukoencephalopathy
#11
Juraj Sokol, Lenka Lisá, Jana Zeleňáková, Tomáš Balhárek, Ivana Plameňová, Ján Staško, Peter Kubisz
The definition "Progressive Multifocal Leukoencephalopathy" (PML) was first used in 1958 to describe a fatal demyelinating central nervous system (CNS) disease in patients with lymphoproliferative disorders. In 1971, the virus responsible for the disease was isolated and named John Cunningham virus (JCV). We present a rare case of a 62-year-old male with chronic lymphocytic leukemia and PML. In our work, we discuss the diagnostic and therapeutic challenges and offer suggestions for preventing PML development...
2017: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/28224485/incidence-of-varicella-zoster-virus-infections-of-the-central-nervous-system-in-the-elderly-a-large-tertiary-hospital-based-series-2007-2014
#12
M Arruti, L D Piñeiro, Y Salicio, G Cilla, M A Goenaga, A López de Munain
The aim of the study was to describe the clinical and epidemiological characteristics of the central nervous system (CNS) infection by varicella zoster virus (VZV) in patients older than 65 years in a tertiary community hospital. We retrospectively analysed the results of cerebrospinal fluid (CSF) testing in patients older than 65 years between 2007 and 2014 with clinically suspected VZV infection with CNS involvement. Patients whose CSF samples were positive for VZV DNA were included, as were those with negative results who simultaneously presented herpes zoster and CSF or magnetic resonance imaging findings suggestive of CNS infection, and in whom other possible aetiologies had been ruled out...
February 21, 2017: Journal of Neurovirology
https://www.readbyqxmd.com/read/28224478/targeting-the-nf-e2-related-factor-2-pathway-a-novel-strategy-for-traumatic-brain-injury
#13
REVIEW
Li Zhang, Handong Wang
As an essential component of cellular defense against a variety of endogenous and exogenous stresses, nuclear factor erythroid 2-related factor 2 (Nrf2) has received increased attention in the past decades. Multiple studies indicate that Nrf2 acts not only as an important protective factor in injury models but also as a downstream target of therapeutic agents. Activation of Nrf2 has increasingly been linked to many human diseases, especially in central nervous system (CNS) injury such as traumatic brain injury (TBI)...
February 21, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28224343/amphotericin-b-increases-transglutaminase-2-expression-associated-with-upregulation-of-endocytotic-activity-in-mouse-microglial-cell-line-bv-2
#14
Kenji Kawabe, Katsura Takano, Mitsuaki Moriyama, Yoichi Nakamura
Amphotericin B (AmB), a polyene antibiotic, is reported to cause the microglial activation to induce nitric oxide (NO) production and proinflammatory cytokines expression, and change neurotrophic factors expression in cultured microglia (Motoyoshi et al. in Neurochem Int 52:1290-1296, 2008). On the other hand, tissue-type transglutaminase (TG2) is involved in connection to phagocytes with apoptotic cells. Engulfment of neurons by activated microglia is thought to cause neurodegenerative diseases but detail is unclear, and involvement of TG2 in phagocytosis has been reported in our previous study using lipopolysaccharide-stimulated BV-2 cells (Kawabe et al...
February 21, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28223512/glucosylceramide-synthase-inhibition-alleviates-aberrations-in-synucleinopathy-models
#15
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba(D409V/D409V) and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28223162/the-roles-of-histamine-and-its-receptor-ligands-in-central-nervous-system-disorders-an-update
#16
REVIEW
Weiwei Hu, Zhong Chen
The neurotransmitter histamine receives less attention compared with other biogenic amines, because of its moderate action in the central nervous system (CNS). However, recent evidence suggests that histamine plays an important role in multiple CNS disorders including insomnia, narcolepsy, Parkinson's diseases, schizophrenia, Alzheimer's disease, and cerebral ischemia. New insights are emerging into the potential roles of histamine receptors as targets for the treatment of these diseases. Although some histamine related agents have failed in clinical trials, current preclinical studies suggest that this neurotransmitter may still have extensive applications in treating CNS disorders, however, advanced studies are warranted...
February 18, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28222836/presumptive-spontaneous-lysosomal-storage-like-disease-in-a-crl-cd1-icr-mouse
#17
Krista M Hernon, Tiffany L Whitcomb, Lori Davis, Timothy K Cooper
A clinically unremarkable 4.5-mo-old female Crl:CD1(ICR) VAF/Elite mouse was euthanized for scheduled sentinel processing. Gross necropsy findings included significant hepatosplenomegaly and visceral lymphadenomegaly, resulting in a preliminary gross diagnosis of lymphoma. Histology revealed florid accumulations of large, 'foamy' macrophages present in the bone marrow, small intestines, and viscera including liver, spleen, lymph nodes, thymus, uterus, and ovaries. The cytoplasm of these cells was abundant, stained pale blue with Wright-Giemsa and was periodic acid-Schiff positive...
February 1, 2017: Comparative Medicine
https://www.readbyqxmd.com/read/28222655/a-cytologic-diagnosis-of-braf-v600e-erdheim-chester-disease-on-pericardial-fluid
#18
P Chasseur, M Kyriakopoulou, B Vokaer, I Beukinga, R Casado Arroyo, E Cogan, B Couturier
We report the case of a 74-year-old woman admitted to the emergency unit for resting dyspnea. Clinical presentation, cardiac MRI and echocardiography were consistent with cardiac tamponade requiring emergency pericardiocentesis. Cytologic examination of the pericardial fluid revealed the presence of CD68(pos) CD1a(neg) S100(neg) foamy histiocytes (Fig. 1). Additional investigations complied with the diagnosis of Erdheim-Chester histiocytosis. Treatment with αIFN was initiated but the patient developed severe neutropenia that contraindicated further administration...
February 22, 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/28221867/osimertinib-in-pretreated-t790m-positive-advanced-non-small-cell-lung-cancer-aura-study-phase-ii-extension-component
#19
James Chih-Hsin Yang, Myung-Ju Ahn, Dong-Wan Kim, Suresh S Ramalingam, Lecia V Sequist, Wu-Chou Su, Sang-We Kim, Joo-Hang Kim, David Planchard, Enriqueta Felip, Fiona Blackhall, Daniel Haggstrom, Kiyotaka Yoh, Silvia Novello, Kathryn Gold, Tomonori Hirashima, Chia-Chi Lin, Helen Mann, Mireille Cantarini, Serban Ghiorghiu, Pasi A Jänne
Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg...
February 21, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28219834/incidence-and-outcomes-of-central-nervous-system-hemophagocytic-lymphohistiocytosis-relapse-after-reduced-intensity-conditioning-hematopoietic-stem-cell-transplant
#20
Dana T Lounder, Pooja Khandelwal, Sharat Chandra, Michael B Jordan, Ashish R Kumar, Michael Grimley, Stella M Davies, Jack J Bleesing, Rebecca A Marsh
Hemophagocytic Lymphohistiocytosis (HLH) is an immune regulatory disorder that commonly presents with CNS involvement. The only cure for genetic HLH is hematopoietic stem cell transplantation (HSCT), typically treated with reduced intensity conditioning (RIC) regimens. We sought to estimate the incidence of CNS relapse after RIC HSCT, determine risk factors, and evaluate outcomes. We performed a retrospective chart review of 94 consecutive children and young adults with primary HLH who received RIC HSCT. CNS relapse within 1 year after transplant was diagnosed by review of clinical symptoms, cerebral spinal fluid (CSF), and radiologic findings...
February 17, 2017: Biology of Blood and Marrow Transplantation
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