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https://www.readbyqxmd.com/read/29686301/endocannabinoids-in-caenorhabditis-elegans-are-essential-for-the-mobilization-of-cholesterol-from-internal-reserves
#1
Celina Galles, Gastón M Prez, Sider Penkov, Sebastian Boland, Exequiel O J Porta, Silvia G Altabe, Guillermo R Labadie, Ulrike Schmidt, Hans-Joachim Knölker, Teymuras V Kurzchalia, Diego de Mendoza
Proper cholesterol transport is crucial for the functionality of cells. In C. elegans, certain cholesterol derivatives called dafachronic acids (DAs) govern the entry into diapause. In their absence, worms form a developmentally arrested dauer larva. Thus, cholesterol transport to appropriate places for DA biosynthesis warrants the reproductive growth. Recently, we discovered a novel class of glycosphingolipids, PEGCs, required for cholesterol mobilization/transport from internal storage pools. Here, we identify other components involved in this process...
April 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29676235/current-and-promising-therapies-in-autosomal-recessive-ataxias
#2
Vincent Picher-Martel, Nicolas Dupre
BACKGROUND & OBJECTIVE: Ataxia is clinically characterized by unsteady gait and imbalance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant, X-linked and autosomal recessive ataxias. Many years have passed since the description of Friedreich's ataxia, the most common autosomal recessive ataxia, and mutations in many other genes have now been described...
April 18, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29659804/high-content-screen-for-modifiers-of-niemann-pick-type-c-disease-in-patient-cells
#3
Emily K Pugach, McKenna Feltes, Randal J Kaufman, Daniel S Ory, Anne G Bang
Niemann-Pick type C disease (NPC) 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...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29655638/attenuation-of-the-niemann-pick-type-c2-disease-phenotype-by-intracisternal-administration-of-an-aavrh-10-vector-expressing-npc2
#4
Sandra Markmann, Jasmine Reid, Jonathan B Rosenberg, Bishnu P De, Stephen M Kaminsky, Ronald G Crystal, Dolan Sondhi
Niemann-Pick type C2 (NPC2) disease is a rare, neurodegenerative disorder caused by mutations in the NPC2 gene, leading to lysosomal accumulation of unesterified cholesterol and other lipids. It is characterized by hepatosplenomegaly, liver dysfunction and severe neurological manifestations, resulting in early death. There is no effective therapy for NPC2 disease. Here, we evaluated the effectiveness of an adeno-associated virus (AAV), serotype rh.10 gene transfer vector expressing the mouse Npc2 gene (AAVrh...
April 12, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29653265/proteomic-analysis-of-chemosensory-organs-in-the-honey-bee-parasite-varroa-destructor-a-comprehensive-examination-of-the-potential-carriers-for-semiochemicals
#5
Immacolata Iovinella, Alison McAfee, Guido Mastrobuoni, Stefan Kempa, Leonard J Foster, Paolo Pelosi, Francesca Romana Dani
We have performed a proteomic analysis on chemosensory organs of Varroa destructor, the honey bee mite, in order to identify putative soluble carriers for pheromones and other olfactory cues emitted by the host. In particular, we have analysed forelegs, mouthparts (palps, chelicera and hypostome) and the second pair of legs (as control tissue) in reproductive and phoretic stages of the Varroa life cycle. We identified 958 Varroa proteins, most of them common to the different organs and stages. Sequence analysis shows that four proteins can be assigned to the odorant-binding protein (OBP)-like class, which bear some similarity to insect OBPs, but so far have only been reported in some Chelicerata...
April 10, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/29649482/phylogeny-and-evolution-of-the-cholesterol-transporter-npc1-in-insects
#6
Jin-Cheng Zheng, Shao-Lei Sun, Xiao-Rong Yue, Tong-Xian Liu, Xiangfeng Jing
Sterols are essential nutrients for eukaryotes. Insects are obligate sterol auxotrophs and must acquire this key nutrient from their diets. The digestive tract is the organ for absorbing nutrients as well as sterols from food. In mice, the Niemann-Pick type C1 Like 1 (NPC1L1) gene is highly expressed in the intestine and is critical for cholesterol absorption. In contrast, the molecular mechanisms for the absorption of dietary sterols in insects have not been well studied. We annotated NPC1 genes in 39 insects from 10 orders using available genomic and transcriptomic information and inferred phylogenetic relationships...
April 9, 2018: Journal of Insect Physiology
https://www.readbyqxmd.com/read/29629999/cholesterol-transfer-at-endosomal-organelle-membrane-contact-sites
#7
Neale D Ridgway, Kexin Zhao
PURPOSE OF REVIEW: Cholesterol is delivered to the limiting membrane of late endosomes by Niemann-Pick Type C1 and C2 proteins. This review summarizes recent evidence that cholesterol transfer from endosomes to the endoplasmic reticulum and other organelles is mediated by lipid-binding proteins that localize to membrane contact sites (MCS). RECENT FINDINGS: LDL-cholesterol in the late endosomal/lysosomes is exported to the plasma membrane, where most cholesterol resides, and the endoplasmic reticulum, which harbors the regulatory complexes and enzymes that control the synthesis and esterification of cholesterol...
April 7, 2018: Current Opinion in Lipidology
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
#8
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...
April 6, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29625568/consensus-clinical-management-guidelines-for-niemann-pick-disease-type-c
#9
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/29617956/microglia-activation-in-niemann-pick-disease-type-c1-is-amendableto-therapeutic-intervention
#10
Antony Cougnoux, Rebecca A Drummond, Amanda L Collar, James R Iben, Alexander Salman, Harrison Westgarth, Christopher A Wassif, Niamh X Cawley, Nicole Y Farhat, Keiko Ozato, Mihalis S Lionakis, Forbes D Porter
Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 is associated with neuroinflammation; however, attempts to therapeutically target neuroinflammation in NPC1 have had mixed success. We show here that NPC1 neuroinflammation is characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- microglia demonstrated altered morphology, reduced levels of lineage markers and a shift towards glycolytic metabolism. Treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a drug currently being studied in a phase 3 clinical trial, reversed all microglia-associated defects in Npc1-/- animals...
March 30, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29601818/hepatic-npc1l1-promotes-hyperlipidemia-in-ldl-receptor-deficient-mice
#11
Youlin Wang, Weiqing Tang, Pan Yang, Hyunsu Shin, Qingwang Li
BACKGROUND AND AIMS: Niemann-Pick C1-like1 (NPC1L1), a crucial cholesterol absorption receptor expressed in human intestine and liver. But in mouse it is only expressed in intestine. Previous studies elucidated that expression of human NPC1L1 in mouse liver led to increase of plasma cholesterol due to activation of absorption from bile. However, hepatic NPC1L1 function was not elucidated in LDL receptor deficient mouse (LDLR-/-) in which LDL was a main lipoprotein as in human. METHODS AND RESULTS: L1-Tg/LDLR-/- mouse was created by crossing liver-specific NPC1L1 transgenic mouse (L1-Tg) with LDLR-/-...
March 27, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29587349/evaluation-of-two-liver-treatment-strategies-in-a-mouse-model-of-niemann-pick-disease-type-c1
#12
Lynn Ebner, Anne Gläser, Anja Bräuer, Martin Witt, Andreas Wree, Arndt Rolfs, Marcus Frank, Brigitte Vollmar, Angela Kuhla
Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD...
March 24, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29580834/niemann-pick-c2-protein-regulates-sterol-transport-between-plasma-membrane-and-late-endosomes-in-human-fibroblasts
#13
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...
March 23, 2018: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/29574331/butyrate-from-pectin-fermentation-inhibits-intestinal-cholesterol-absorption-and-attenuates-atherosclerosis-in-apolipoprotein-e-deficient-mice
#14
Ying Chen, Chengfang Xu, Rong Huang, Jiayi Song, Di Li, Min Xia
Short-chain fatty acids (SCFAs), the major products of dietary fiber fermentation by intestinal microflora, exert beneficial effects on pathogenesis of multiple metabolic diseases. The aim of this study was to determine whether SCFAs from fermentation of pectin (PE), a soluble dietary fiber, prevent the development of atherosclerosis in apolipoprotein E-deficient (apoE-/- ) mice. Male apoE-/- mice (8-week-old) were fed a high-fat, high-cholesterol diet (HCD; 21% wt/wt fat, 0.15% wt/wt cholesterol) or HCD supplemented with 20% wt/wt PE (HCD+PE) alone or with antibiotics (HCD+PE + A) in drinking water for 12 weeks...
February 27, 2018: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/29569242/egg-yolk-sphingomyelin-and-phosphatidylcholine-attenuate-cholesterol-absorption-in-caco-2-cells
#15
Fang Yang, Guoxun Chen, Meihu Ma, Ning Qiu, Lingjiao Zhu, Jing Li
Phospholipids have been shown to modulate intestinal cholesterol absorption in cells and animals, a process that is regulated by several transporter proteins. Of these proteins, Niemann-Pick C1-Like 1 (NPC1L1) is a major contributor to this process. The mechanism by which phospholipids modulate cholesterol absorption remains unknown. Here, we evaluate the effects of egg-yolk phospholipids on cholesterol absorption and transport in human colon carcinoma cell line (Caco-2 cells) and on the expression of NPC1L1 and others proteins associated with cholesterol absorption (ABCG5, ABCG8, ABCA1, ACAT2, MTP, CAV-1, ANX-2)...
March 22, 2018: Lipids
https://www.readbyqxmd.com/read/29560273/large-scale-computational-drug-repositioning-to-find-treatments-for-rare-diseases
#16
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
#17
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...
March 19, 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
#18
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-hp%C3%AE-cd-to-cholesterol-by-means-of-the-md-simulation-and-the-3d-rism-kh-theory
#19
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 in order 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 (MD) simulation and a statistical mechanics theory of liquids, or the 3D reference interaction site model theory with Kovalenko-Hirata closure relation (3D-RISM-KH)...
March 13, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29522754/the-formation-of-giant-plasma-membrane-vesicles-enable-new-insights-into-the-regulation-of-cholesterol-efflux
#20
Alanna Sedgwick, M Olivia Balmert, Crislyn D'Souza-Schorey
Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4 . Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation...
March 6, 2018: Experimental Cell Research
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