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niemann-pick type c

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https://www.readbyqxmd.com/read/29904147/dpubchem-a-web-tool-for-qsar-modeling-and-high-throughput-virtual-screening
#1
Othman Soufan, Wail Ba-Alawi, Arturo Magana-Mora, Magbubah Essack, Vladimir B Bajic
High-throughput screening (HTS) performs the experimental testing of a large number of chemical compounds aiming to identify those active in the considered assay. Alternatively, faster and cheaper methods of large-scale virtual screening are performed computationally through quantitative structure-activity relationship (QSAR) models. However, the vast amount of available HTS heterogeneous data and the imbalanced ratio of active to inactive compounds in an assay make this a challenging problem. Although different QSAR models have been proposed, they have certain limitations, e...
June 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29900534/absence-of-infiltrating-peripheral-myeloid-cells-in-the-brains-of-mouse-models-of-lysosomal-storage-disorders
#2
REVIEW
Soo Min Cho, Ayelet Vardi, Nicolas Platt, Anthony H Futerman
Approximately 70 lysosomal storage diseases are currently known, resulting from mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in lysosomal enzymes that hydrolyze sphingolipids have been relatively well studied. Gaucher disease is caused by the loss of activity of glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease exhibits a number of subtypes, with types 2 and 3 showing significant neuropathology. Sandhoff disease results from the defective activity of β-hexosaminidase, leading to accumulation of ganglioside GM2...
June 14, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29897878/model-construction-of-niemann-pick-type-c-disease-in-zebrafish
#3
Yusheng Lin, Xiaolian Caia, Guiping Wang, Gang Ouyang, Hong Cao
Niemann-Pick Type C disease (NPC) is a rare human disease, with limited effective treatment options. Most cases of NPC disease are associated with inactivating mutations of the NPC1 gene. However, cellular and molecular mechanisms responsible for the NPC1 pathogenesis remain poorly defined. This is partly due to the lack of a suitable animal model to monitor the disease progression. In this study, we used CRISPR to construct an NPC1-/- zebrafish model, which faithfully reproduced the cardinal pathological features of this disease...
June 1, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29878115/aav9-intracerebroventricular-gene-therapy-improves-lifespan-locomotor-function-and-pathology-in-a-mouse-model-of-niemann-pick-type-c1-disease
#4
Michael P Hughes, Dave A Smith, Lauren Morris, Claire Fletcher, Alexandria Colaco, Mylene Huebecker, Julie Tordo, Nuria Palomar, Giulia Massaro, Els Henckaerts, Simon N Waddington, Frances M Platt, Ahad A Rahim
Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative lysosomal storage disorder. It is caused in 95% of cases by a mutation in the NPC1 gene that encodes NPC1, an integral transmembrane protein localised to the limiting membrane of the lysosome. There is no cure for NP-C but there is a disease-modifying drug (miglustat) that slows disease progression but with associated side effects. Here, we demonstrate in a well-characterised mouse model of NP-C that a single administration of AAV-mediated gene therapy to the brain can significantly extend lifespan, improve quality of life, prevent or ameliorate neurodegeneration, reduce biochemical pathology and normalize or improve various indices of motor function...
June 5, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29874879/niemann-pick-type-c2-protein-regulates-free-cholesterol-accumulation-and-influences-hepatic-stellate-cell-proliferation-and-mitochondrial-respiration-function
#5
Yuan-Hsi Wang, Yuh-Ching Twu, Chung-Kwe Wang, Fu-Zhen Lin, Chun-Ya Lee, Yi-Jen Liao
Liver fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. A high-cholesterol diet is associated with liver fibrosis via the accumulation of free cholesterol in hepatic stellate cells (HSCs). Niemann-Pick type C2 (NPC2) plays an important role in the regulation of intracellular free cholesterol homeostasis via direct binding with free cholesterol. Previously, we reported that NPC2 was downregulated in liver cirrhosis tissues. Loss of NPC2 enhanced the accumulation of free cholesterol in HSCs and made them more susceptible to transforming growth factor (TGF)-β1...
June 5, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29871644/distinguishing-neurocognitive-deficits-in-adult-patients-with-np-c-from-early-onset-alzheimer-s-dementia
#6
Andreas Johnen, Matthias Pawlowski, Thomas Duning
BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, progressive neurodegenerative disease caused by mutations in the NPC1 or the NPC2 gene. Neurocognitive deficits are common in NP-C, particularly in patients with the adolescent/adult-onset form. As a disease-specific therapy is available, it is important to distinguish clinically between the cognitive profiles in NP-C and primary dementia (e.g., early Alzheimer's disease; eAD). METHODS: In a prospective observational study, we directly compared the neurocognitive profiles of patients with confirmed NP-C (n = 7) and eAD (n = 15)...
June 5, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29862881/cholesterol-impairs-autophagy-mediated-clearance-of-amyloid-beta-while-promoting-its-secretion
#7
Elisabet Barbero-Camps, Vicente Roca-Agujetas, Isabel Bartolessis, Cristina de Dios, Jose C Fernández-Checa, Montserrat Marí, Albert Morales, Tobias Hartmann, Anna Colell
Macroautophagy/autophagy failure with the accumulation of autophagosomes is an early neuropathological feature of Alzheimer disease (AD) that directly affects amyloid beta (Aβ) metabolism. Although loss of presenilin 1 function has been reported to impair lysosomal function and prevent autophagy flux, the detailed mechanism leading to autophagy dysfunction in AD remains to be elucidated. The resemblance between pathological hallmarks of AD and Niemann-Pick Type C disease, including endosome-lysosome abnormalities and impaired autophagy, suggests cholesterol accumulation as a common link...
June 4, 2018: Autophagy
https://www.readbyqxmd.com/read/29852178/ezetimibe-a-npc1l1-inhibitor-attenuates-neuronal-apoptosis-through-ampk-dependent-autophagy-activation-after-mcao-in-rats
#8
Jing Yu, Xue Li, Nathanael Matei, Devin McBride, Jiping Tang, Min Yan, John H Zhang
Autophagy activation exerts neuroprotective effects in the ischemic stroke model. Ezetimibe (Eze), a Niemann-Pick disease type C1-Like 1 (NPC1L1) pharmacological inhibitor, has been reported to protect hepatocytes from apoptosis via autophagy activation. In this study, we explored whether Eze could attenuate neuronal apoptosis in the rat model of middle cerebral artery occlusion (MCAO), specifically via activation of the AMPK/ULK1/autophagy pathway. Two hundred and one male Sprague-Dawley rats were subjected to transient MCAO followed by reperfusion...
May 28, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29783784/cyclodextrins-assessing-the-impact-of-cavity-size-occupancy-and-substitutions-on-cytotoxicity-and-cholesterol-homeostasis
#9
Lajos Szente, Ashutosh Singhal, Andras Domokos, Byeongwoon Song
Cyclodextrins (CDs) are cyclic oligosaccharides; the most common CDs contain six, seven, or eight glucose units called α-CDs, β-CDs, and γ-CDs, respectively. The use of CDs in biomedical research is increasing due to their ability to interact with membrane lipids as well as a wide variety of poorly water-soluble molecules. We assessed the impact of CD cavity size, occupancy, and substitutions on cytotoxicity and cholesterol homeostasis. The potency of CD-mediated cytotoxicity was in the order of β-CDs, α-CDs, and γ-CDs...
May 20, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29721961/early-endosome-morphology-in-health-and-disease
#10
Gulpreet Kaur, Aparna Lakkaraju
Early endosomes are organelles that receive macromolecules and solutes from the extracellular environment. The major function of early endosomes is to sort these cargos into recycling and degradative compartments of the cell. Degradation of the cargo involves maturation of early endosomes into late endosomes, which, after acquisition of hydrolytic enzymes, form lysosomes. Endosome maturation involves recruitment of specific proteins and lipids to the early endosomal membrane, which drives changes in endosome morphology...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29718288/the-pathogenesis-of-lysosomal-storage-disorders-beyond-the-engorgement-of-lysosomes-to-abnormal-development-and-neuroinflammation
#11
Maria Teresa Fiorenza, Enrico Moro, Robert P Erickson
There is growing evidence that the complex clinical manifestations of lysosomal storage diseases (LSDs) are not fully explained by the engorgement of the endosomal-autophagic-lysosomal system. In this review, we explore current knowledge of common pathogenetic mechanisms responsible for the early onset of tissue abnormalities of two LSDs, Mucopolysaccharidosis type II (MPSII) and Niemann-Pick type C (NPC) diseases. In particular, perturbations of the homeostasis of glycosaminoglycans (GAGs) and cholesterol (Chol) in MPSII and NPC diseases, respectively, affect key biological processes, including morphogen signaling...
April 28, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29704574/the-intersection-of-lysosomal-and-endoplasmic-reticulum-calcium-with-autophagy-defects-in-lysosomal-diseases
#12
REVIEW
Elaine A Liu, Andrew P Lieberman
The lysosomal storage disorders (LSDs) encompass a group of more than 50 inherited diseases characterized by the accumulation of lysosomal substrates. Two-thirds of patients experience significant neurological symptoms, but the mechanisms of neurodegeneration are not well understood. Interestingly, a wide range of LSDs show defects in both autophagy and Ca2+ homeostasis, which is notable as Ca2+ is a key regulator of autophagy. The crosstalk between these pathways in the context of LSD pathogenesis is not well characterized, but further understanding of this relationship could open up promising therapeutic targets...
April 25, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29659804/high-content-screen-for-modifiers-of-niemann-pick-type-c-disease-in-patient-cells
#13
Emily K Pugach, McKenna Feltes, Randal J Kaufman, Daniel S Ory, Anne G Bang
Niemann-Pick type C (NPC) disease is a rare lysosomal storage disease caused primarily by mutations in NPC1. NPC1 encodes the lysosomal cholesterol transport protein NPC1. The most common NPC1 mutation is a missense mutation (NPC1I1061T) that causes misfolding and rapid degradation of mutant protein in the endoplasmic reticulum. Cholesterol accumulates in enlarged lysosomes as a result of decreased levels of lysosomal NPC1I1061T protein in patient cells. There is currently no cure or FDA-approved treatment for patients...
June 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29626102/identification-of-unusual-oxysterols-and-bile-acids-with-7-oxo-or-3%C3%AE-5%C3%AE-6%C3%AE-trihydroxy-functions-in-human-plasma-by-charge-tagging-mass-spectrometry-with-multistage-fragmentation
#14
William J Griffiths, Ian Gilmore, Eylan Yutuc, Jonas Abdel-Khalik, Peter J Crick, Thomas Hearn, Alison Dickson, Brian W Bigger, Teresa Hoi-Yee Wu, Anu Goenka, Arunabha Ghosh, Simon A Jones, Yuqin Wang
7-Oxocholesterol (7-OC), 5,6-epoxycholesterol (5,6-EC), and its hydrolysis product cholestane-3β,5α,6β-triol (3β,5α,6β-triol) are normally minor oxysterols in human samples; however, in disease, their levels may be greatly elevated. This is the case in plasma from patients suffering from some lysosomal storage disorders, e.g., Niemann-Pick disease type C, or the inborn errors of sterol metabolism, e.g., Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis. A complication in the analysis of 7-OC and 5,6-EC is that they can also be formed ex vivo from cholesterol during sample handling in air, causing confusion with molecules formed in vivo...
June 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29625568/consensus-clinical-management-guidelines-for-niemann-pick-disease-type-c
#15
REVIEW
Tarekegn Geberhiwot, Alessandro Moro, Andrea Dardis, Uma Ramaswami, Sandra Sirrs, Mercedes Pineda Marfa, Marie T Vanier, Mark Walterfang, Shaun Bolton, Charlotte Dawson, Bénédicte Héron, Miriam Stampfer, Jackie Imrie, Christian Hendriksz, Paul Gissen, Ellen Crushell, Maria J Coll, Yann Nadjar, Hans Klünemann, Eugen Mengel, Martin Hrebicek, Simon A Jones, Daniel Ory, Bruno Bembi, Marc Patterson
Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy...
April 6, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29580834/niemann-pick-c2-protein-regulates-sterol-transport-between-plasma-membrane-and-late-endosomes-in-human-fibroblasts
#16
Zane Berzina, Lukasz M Solanko, Ahmed S Mehadi, Maria Louise V Jensen, Frederik W Lund, Maciej Modzel, Maria Szomek, Katarzyna A Solanko, Alice Dupont, Gitte Krogh Nielsen, Christian W Heegaard, Christer S Ejsing, Daniel Wüstner
Niemann-Pick disease type C2 is a lipid storage disorder in which mutations in the NPC2 protein cause accumulation of lipoprotein-derived cholesterol in late endosomes and lysosomes (LE/LYSs). Whether cholesterol delivered by other means to NPC2 deficient cells also accumulates in LE/LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous diffusion in disease cells (D ∼ 4...
July 2018: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/29560273/large-scale-computational-drug-repositioning-to-find-treatments-for-rare-diseases
#17
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning...
2018: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/29556840/contribution-of-tandem-mass-spectrometry-to-the-diagnosis-of-lysosomal-storage-disorders
#18
Monique Piraud, Magali Pettazzoni, Pamela Lavoie, Séverine Ruet, Cécile Pagan, David Cheillan, Philippe Latour, Christine Vianey-Saban, Christiane Auray-Blais, Roseline Froissart
Tandem mass spectrometry (MS/MS) is a highly sensitive and specific technique. Thanks to the development of triple quadrupole analyzers, it is becoming more widely used in laboratories working in the field of inborn errors of metabolism. We review here the state of the art of this technique applied to the diagnosis of lysosomal storage disorders (LSDs) and how MS/MS has changed the diagnostic rationale in recent years. This fine technology brings more sensitive, specific, and reliable methods than the previous biochemical ones for the analysis of urinary glycosaminoglycans, oligosaccharides, and sialic acid...
May 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29536386/long-term-therapy-with-miglustat-and-cognitive-decline-in-the-adult-form-of-niemann-pick-disease-type-c-a-case-report
#19
Stefano Tozza, Raffaele Dubbioso, Rosa Iodice, Antonietta Topa, Marcello Esposito, Lucia Ruggiero, Emanuele Spina, Anna De Rosa, Francesco Saccà, Lucio Santoro, Fiore Manganelli
Niemann-Pick disease type C (NPC) is a recessive lysosomal lipid storage disorder characterized by central nervous system involvement. Miglustat treatment might improve or stabilize neurological manifestations but there is still limited data on the long-term efficacy. The aim of our study was to report a four-year clinical, neuropsychological and electrophysiological follow-up of two sisters under treatment with miglustat. We report data at basal (T0) and after 4 years (T4) of treatment with miglustat from two sisters (P1 and P2) affected by NPC disease...
March 13, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29534570/predicting-the-binding-mode-of-2-hydroxypropyl-%C3%AE-cyclodextrin-to-cholesterol-by-means-of-the-md-simulation-and-the-3d-rism-kh-theory
#20
Yuji Hayashino, Masatake Sugita, Hidetoshi Arima, Tetsumi Irie, Takeshi Kikuchi, Fumio Hirata
It has been found that a cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin (HPβCD), has reasonable therapeutic effect on Niemann-Pick disease type C, which is caused by abnormal accumulation of unesterified cholesterol and glycolipids in the lysosomes and shortage of esterified cholesterol in other cellular compartments. We study the binding affinity and mode of HPβCD with cholesterol to elucidate the possible mechanism of HPβCD for removing cholesterol from the lysosomes. The dominant binding mode of HPβCD with cholesterol is found based on the molecular dynamics simulation and a statistical mechanics theory of liquids, or the three-dimensional reference interaction site model theory with Kovalenko-Hirata closure relation...
March 19, 2018: Journal of Physical Chemistry. B
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