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https://www.readbyqxmd.com/read/28631941/analytical-characterization-of-methyl-%C3%AE-cyclodextrin-for-pharmacological-activity-to-reduce-lysosomal-cholesterol-accumulation-in-niemann-pick-disease-type-c1-cells
#1
Rong Li, Jon Hao, Hideji Fujiwara, Miao Xu, Shu Yang, Sheng Dai, Yan Long, Manju Swaroop, Changhui Li, Mylinh Vu, Juan J Marugan, Daniel S Ory, Wei Zheng
Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MβCDs obtained from different batches and different sources...
May 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28628327/impact-of-the-niemann-pick-c1-gene-mutation-on-the-total-cellular-glycomics-of-cho-cells
#2
Jun-Ichi Furukawa, Minami Soga, Kazue Okada, Ikuko Yokota, Jinhua Piao, Tetsumi Irie, Takumi Era, Yasuro Shinohara
Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, and the majority of cases are caused by mutations in the NPC1 gene. In this study, we clarified how a single gene mutation in the NPC1 gene impacts the cellular glycome by analyzing the total glycomic expression profile of Chinese hamster ovary cell mutants defective in the Npc1 gene (Npc1 KO CHO cells). A number of glycomic alterations were identified, including increased expression of lactosylceramide, GM1, GM2, GD1, various neolacto-series glycosphingolipids, and sialyl-T (O-glycan), which was found to be the major sialylated protein-bound glycan, as well as various N-glycans, which were commonly both fucosylated and sialylated...
June 19, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28627641/osteopontin-deficiency-protects-mice-from-cholesterol-gallstone-formation-by-reducing-expression-of-intestinal-npc1l1
#3
Jing Lin, Wei-Qing Shao, Qing-Zhi Chen, Wen-Wei Zhu, Lu Lu, Hu-Liang Jia, Jin-Hong Chen
Homeostasis of cholesterol is regulated by absorption in the intestine and synthesis in the liver. The authors previously demonstrated that OPN (osteopontin) exhibits the ability to alter hepatic cholesterol metabolism, thus affecting cholesterol gallstone formation in mice. The present study investigated the role of OPN in cholesterol gallstone formation, focusing on its effect on intestinal absorption of cholesterol. OPN gene knockout (OPN‑/‑) mice and wild‑type mice were respectively fed with a chow or lithogenic diet (LD) for 8 weeks...
June 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28626941/binding-of-canonical-wnt-ligands-to-their-receptor-complexes-occurs-in-ordered-plasma-membrane-environments
#4
Erdinc Sezgin, Yagmur Azbazdar, Xue Wen Ng, Cathleen Teh, Kai Simons, Gilbert Weidinger, Thorsten Wohland, Christian Eggeling, Gunes Ozhan
While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to co-internalize with the Wnt-receptor complex...
June 19, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28613987/methyl-%C3%AE-cyclodextrin-restores-impaired-autophagy-flux-in-niemann-pick-c1-deficient-cells-through-activation-of-ampk
#5
Sheng Dai, Andrés E Dulcey, Xin Hu, Christopher A Wassif, Forbes D Porter, Christopher P Austin, Daniel S Ory, Juan Marugan, Wei Zheng
The drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease, type C (NPC) and has been advanced to human clinical trials. However, its mechanism of action for reducing cholesterol accumulation in NPC cells is uncertain and its molecular target is unknown. We found that methyl-β-cyclodextrin (MβCD), a potent analog of HPβCD, restored impaired macroautophagy/autophagy flux in Niemann-Pick disease, type C1 (NPC1) cells. This effect was mediated by a direct activation of AMP-activated protein kinase (AMPK), an upstream kinase in the autophagy pathway, through MβCD binding to its β-subunits...
June 14, 2017: Autophagy
https://www.readbyqxmd.com/read/28610891/n-butyl-deoxynojirimycin-delays-motor-deficits-cerebellar-microgliosis-and-purkinje-cell-loss-in-a-mouse-model-of-mucolipidosis-type-iv
#6
Lauren C Boudewyn, Jakub Sikora, Ladislav Kuchar, Jana Ledvinova, Yulia Grishchuk, Shirley L Wang, Kostantin Dobrenis, Steven U Walkley
Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss...
June 10, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28606376/enhanced-delivery-and-effects-of-acid-sphingomyelinase-by-icam-1-targeted-nanocarriers-in-type-b-niemann-pick-disease-mice
#7
Carmen Garnacho, Rajwinder Dhami, Melani Solomon, Edward H Schuchman, Silvia Muro
Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Here, using polystyrene and poly(lactic-co-glycolic acid) nanocarriers, we optimized lung delivery by varying enzyme dose and nanocarrier concentration, verified endocytosis and lysosomal trafficking in vivo, and evaluated delivered activity and effects...
June 9, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28601876/interstitial-lung-disease-associated-with-adult-niemann-pick-disease-type-b
#8
Nader Chebib, Françoise Thivolet-Bejui, Vincent Cottin
No abstract text is available yet for this article.
June 10, 2017: Respiration; International Review of Thoracic Diseases
https://www.readbyqxmd.com/read/28600536/imipramine-inhibits-chikungunya-virus-replication-in-human-skin-fibroblasts-through-interference-with-intracellular-cholesterol-trafficking
#9
Sineewanlaya Wichit, Rodolphe Hamel, Eric Bernard, Loïc Talignani, Fodé Diop, Pauline Ferraris, Florian Liegeois, Peeraya Ekchariyawat, Natthanej Luplertlop, Pornapat Surasombatpattana, Frédéric Thomas, Andres Merits, Valérie Choumet, Pierre Roques, Hans Yssel, Laurence Briant, Dorothée Missé
Chikungunya virus (CHIKV) is an emerging arbovirus of the Togaviridae family that poses a present worldwide threat to human in the absence of any licensed vaccine or antiviral treatment to control viral infection. Here, we show that compounds interfering with intracellular cholesterol transport have the capacity to inhibit CHIKV replication in human skin fibroblasts, a major viral entry site in the human host. Pretreatment of these cells with the class II cationic amphiphilic compound U18666A, or treatment with the FDA-approved antidepressant drug imipramine resulted in a near total inhibition of viral replication and production at the highest concentration used without any cytotoxic effects...
June 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28592657/induced-pluripotent-stem-cell-models-of-lysosomal-storage-disorders
#10
REVIEW
Daniel K Borger, Benjamin McMahon, Tamanna Roshan Lal, Jenny Serra-Vinardell, Elma Aflaki, Ellen Sidransky
Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses...
June 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28590904/niemann-pick-type-c-proteins-promote-microautophagy-by-expanding-raft-like-membrane-domains-in-the-yeast-vacuole
#11
Takuma Tsuji, Megumi Fujimoto, Tsuyako Tatematsu, Jinglei Cheng, Minami Orii, Sho Takatori, Toyoshi Fujimoto
Niemann-Pick type C is a storage disease caused by dysfunction of NPC proteins, which transport cholesterol from the lumen of lysosomes to the limiting membrane of that compartment. Using freeze fracture electron microscopy, we show here that the yeast NPC orthologs, Ncr1p and Npc2p, are essential for formation and expansion of raft-like domains in the vacuolar (lysosome) membrane, both in stationary phase and in acute nitrogen starvation. Moreover, the expanded raft-like domains engulf lipid droplets by a microautophagic mechanism...
June 7, 2017: ELife
https://www.readbyqxmd.com/read/28587793/miglustat-therapy-in-a-case-of-early-infantile-niemann-pick-type-c
#12
Miho Usui, Akihiko Miyauchi, Yuko Nakano, Sachie Nakamura, Eriko Jimbo, Shinji Itamura, Kaori Adachi, Eiji Nanba, Aya Narita, Takanori Yamagata, Hitoshi Osaka
Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPC1 or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Some reports suggested that miglustat therapy delayed the onset or progression of NPC when treatment was initiated before the onset of neurological manifestation or at an early stage...
June 3, 2017: Brain & Development
https://www.readbyqxmd.com/read/28583322/ocular-findings-in-patients-with-cholestatic-disorders-of-infancy-a-single-centre-experience
#13
Hanaa El-Karaksy, Dalia Hamed, Hanan Fouad, Engy Mogahed, Heba Helmy, Fotouh Hasanain
BACKGROUND AND STUDY AIMS: Neonatal cholestasis can be associated with ocular findings that might aid in its diagnosis, e.g., Alagille syndrome (AGS) and Niemann Pick disease (NPD). We aimed to investigate the frequency of ocular manifestations in infants with cholestasis. PATIENTS AND METHODS: This cross-sectional study included cholestatic infants presenting to the Paediatric Hepatology Unit, Cairo University Paediatric Hospital, Cairo, Egypt. All infants underwent examination of lid, ocular motility, anterior and posterior segments and measurement of intraocular pressure, cycloplegic refraction, ocular ultrasonography and vision...
June 2, 2017: Arab Journal of Gastroenterology: the Official Publication of the Pan-Arab Association of Gastroenterology
https://www.readbyqxmd.com/read/28574146/niemann-pick-type-c-as-a-cause-of-progressive-intellectual-and-neurological-deterioration-in-childhood
#14
Anne Marie Winstone, Lesley Ann Stellitano, Christopher Michael Verity
AIM: To describe the cases of Niemann-Pick type C (NP-C) disease in a United Kingdom epidemiological study of progressive intellectual and neurological deterioration in childhood. METHOD: Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015. RESULTS: Fifty-three NP-C patients were identified: 29 females, 24 males. Fifteen cases had a systemic presentation (neonatal jaundice and/or hepatosplenomegaly)...
June 2, 2017: Developmental Medicine and Child Neurology
https://www.readbyqxmd.com/read/28564600/oxysterol-binding-protein-related-protein-1l-regulates-cholesterol-egress-from-the-endo-lysosomal-system
#15
Kexin Zhao, Neale D Ridgway
Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L) is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER...
May 30, 2017: Cell Reports
https://www.readbyqxmd.com/read/28550066/rapid-whole-genome-sequencing-identifies-a-novel-homozygous-npc1-variant-associated-with-niemann-pick-type-c1-disease-in-a-7-week-old-male-with-cholestasis
#16
Amber Hildreth, Kristen Wigby, Shimul Chowdhury, Shareef Nahas, Jaime Barea, Paulina Ordonez, Serge Batalov, David M Dimmock, Rcigm Investigators, Stephen F Kingsmore
Niemann-Pick Type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. While characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction due to intrahepatocyte lipid accumulation. We report a 7 week old who was admitted with neonatal cholestasis, who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole genome sequencing (WGS)...
May 26, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28549128/atad3-gene-cluster-deletions-cause-cerebellar-dysfunction-associated-with-altered-mitochondrial-dna-and-cholesterol-metabolism
#17
Radha Desai, Ann E Frazier, Romina Durigon, Harshil Patel, Aleck W Jones, Ilaria Dalla Rosa, Nicole J Lake, Alison G Compton, Hayley S Mountford, Elena J Tucker, Alice L R Mitchell, Deborah Jackson, Abdul Sesay, Miriam Di Re, Lambert P van den Heuvel, Derek Burke, David Francis, Sebastian Lunke, George McGillivray, Simone Mandelstam, Fanny Mochel, Boris Keren, Claude Jardel, Anne M Turner, P Ian Andrews, Jan Smeitink, Johannes N Spelbrink, Simon J Heales, Masakazu Kohda, Akira Ohtake, Kei Murayama, Yasushi Okazaki, Anne Lombès, Ian J Holt, David R Thorburn, Antonella Spinazzola
Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28544363/expression-patterns-of-sterol-transporters-npc1-and-npc2-in-the-cnidarian-dinoflagellate-symbiosis
#18
Vincent Dani, Fabrice Priouzeau, Marjolijn Mertz, Magali Mondin, Sophie Pagnotta, Sandra Lacas-Gervais, Simon K Davy, Cécile Sabourault
The symbiotic interaction between cnidarians (e.g. corals and sea anemones) and photosynthetic dinoflagellates of the genus Symbiodinium is triggered by both host-symbiont recognition processes and metabolic exchange between the two partners. The molecular communication is crucial for homeostatic regulation of the symbiosis, both under normal conditions and during stresses that further lead to symbiosis collapse. It is therefore important to identify and fully characterize the key players of this intimate interaction at the symbiotic interface...
May 22, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28542405/exchange-of-polar-lipids-from-adults-to-neonates-in-daphnia-magna-perturbations-in-sphingomyelin-allocation-by-dietary-lipids-and-environmental-toxicants
#19
Namrata Sengupta, Delaney C Reardon, Patrick D Gerard, William S Baldwin
Because xenosensing nuclear receptors are also lipid sensors that regulate lipid allocation, we hypothesized that toxicant-induced modulation of HR96 activity would alter lipid profiles and the balance between adult survival and neonate production following exposure in Daphnia magna. Adult daphnids were exposed to unsaturated fatty acid- and toxicant- activators or inhibitors of HR96 and later starved to test whether chemical exposure altered allocation toward survival or reproduction. The HR96 activators, linoleic acid and atrazine, decreased reproduction as expected with concomitant changes in the expression of HR96 regulated genes such as magro...
2017: PloS One
https://www.readbyqxmd.com/read/28542381/quantitative-magnetic-resonance-imaging-of-brain-atrophy-in-a-mouse-model-of-niemann-pick-type-c-disease
#20
John W Totenhagen, Adam Bernstein, Eriko S Yoshimaru, Robert P Erickson, Theodore P Trouard
In vivo magnetic resonance imaging (MRI) was used to investigate regional and global brain atrophy in the neurodegenerative Niemann Pick Type C1 (NPC1) disease mouse model. Imaging experiments were conducted with the most commonly studied mouse model of NPC1 disease at early and late disease states. High-resolution in vivo images were acquired at early and late stages of the disease and analyzed with atlas-based registration to obtain measurements of twenty brain region volumes. A two-way ANOVA analysis indicated eighteen of these regions were different due to genotype and thirteen showed a significant interaction with age and genotype...
2017: PloS One
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