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https://www.readbyqxmd.com/read/27902765/loss-of-cathepsin-b-and-l-leads-to-lysosomal-dysfunction-npc-like-cholesterol-sequestration-and-accumulation-of-the-key-alzheimer-s-proteins
#1
Stjepko Cermak, Marko Kosicek, Aleksandra Mladenovic-Djordjevic, Kosara Smiljanic, Selma Kanazir, Silva Hecimovic
Proper function of lysosomes is particularly important in neurons, as they cannot dilute accumulated toxic molecules and aggregates by cell division. Thus, impairment of lysosomal function plays an important role in neuronal degeneration and in the pathogenesis of numerous neurodegenerative diseases. In this work we analyzed how inhibition and/or loss of the major lysosomal proteases, the cysteine cathepsins B and L (CtsB/L), affects lysosomal function, cholesterol metabolism and degradation of the key Alzheimer's disease (AD) proteins...
2016: PloS One
https://www.readbyqxmd.com/read/27900365/genome-sequencing-in-a-case-of-niemann-pick-type-c
#2
Max Dougherty, John Lazar, Jason C Klein, Karina Diaz, Theodore Gobillot, Eli Grunblatt, Nicholas Hasle, Daniel Lawrence, Megan Maurano, Maria Nelson, Gregory Olson, Sanjay Srivatsan, Jay Shendure, C Dirk Keene, Thomas Bird, Marshall S Horwitz, Desiree A Marshall
Adult-onset Niemann-Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical ("variant" level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27900236/identification-of-two-sulfated-cholesterol-metabolites-found-in-the-urine-of-a-patient-with-niemann-pick-disease-type-c-as-novel-candidate-diagnostic-markers
#3
Masamitsu Maekawa, Kaoru Omura, Shoutaro Sekiguchi, Takashi Iida, Daisuke Saigusa, Hiroaki Yamaguchi, Nariyasu Mano
In the urine of a Niemann-Pick disease type C (NPC) patient, we have identified three characteristic intense peaks that have not been observed in the urine of a 3β-hydroxysteroid-Δ(5)-C27-steroid dehydrogenase deficiency patient or a healthy infant and adult. Based on accurate masses of the protonated molecules, we focused on two of them as candidate NPC diagnostic markers. Two synthesized authentic preparations agreed with the two compounds found in NPC patient urine in regard to both chromatographic behavior and accurate masses of the deprotonated molecules...
2016: Mass Spectrometry
https://www.readbyqxmd.com/read/27895719/drabal-novel-method-to-mine-large-high-throughput-screening-assays-using-bayesian-active-learning
#4
Othman Soufan, Wail Ba-Alawi, Moataz Afeef, Magbubah Essack, Panos Kalnis, Vladimir B Bajic
BACKGROUND: Mining high-throughput screening (HTS) assays is key for enhancing decisions in the area of drug repositioning and drug discovery. However, many challenges are encountered in the process of developing suitable and accurate methods for extracting useful information from these assays. Virtual screening and a wide variety of databases, methods and solutions proposed to-date, did not completely overcome these challenges. This study is based on a multi-label classification (MLC) technique for modeling correlations between several HTS assays, meaning that a single prediction represents a subset of assigned correlated labels instead of one label...
2016: Journal of Cheminformatics
https://www.readbyqxmd.com/read/27890675/synergistic-drug-combination-effectively-blocks-ebola-virus-infection
#5
Wei Sun, Shihua He, Carles Martínez-Romero, Jennifer Kouznetsova, Gregory Tawa, Miao Xu, Paul Shinn, Ethan Fisher, Yan Long, Omid Motabar, Shu Yang, Philip E Sanderson, Peter R Williamson, Adolfo García-Sastre, Xiangguo Qiu, Wei Zheng
Although a group of FDA-approved drugs were previously identified with activity against Ebola virus, most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection...
November 24, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27888692/mitochondrial-gsh-replenishment-as-a-potential-therapeutic-approach-for-niemann-pick-type-c-disease
#6
Sandra Torres, Nuria Matías, Anna Baulies, Susana Nuñez, Cristina Alarcon-Vila, Laura Martinez, Natalia Nuño, Anna Fernandez, Joan Caballeria, Thierry Levade, Alba Gonzalez-Franquesa, Pablo Garcia-Rovés, Elisa Balboa, Silvana Zanlungo, Gemma Fabrías, Josefina Casas, Carlos Enrich, Carmen Garcia-Ruiz, José C Fernández-Checa
Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease...
November 20, 2016: Redox Biology
https://www.readbyqxmd.com/read/27884455/-acid-sphingomyelinase-deficiency-niemann-pick-disease-type-b-in-adulthood-a-retrospective-multicentric-study-of-28%C3%A2-adult-cases
#7
O Lidove, N Belmatoug, R Froissart, C Lavigne, I Durieu, K Mazodier, C Serratrice, C Douillard, C Goizet, P Cathebras, G Besson, Z Amoura, A Tazi, M Gatfossé, S Rivière, T Sené, M T Vanier, J-M Ziza
INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease with a clinical spectrum ranging from a neurovisceral infantile form (Niemann-Pick disease type A) to a chronic visceral form also encountered in adults (Niemann-Pick disease type B, NP-B). METHODS: Retrospective multicentric analysis of French adult patients with ASMD over the period 1985-March 2015. Clinical, biological, and imaging data were analyzed. RESULTS: Twenty-eight patients (19 males, 9 females) were analyzed...
November 22, 2016: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/27877888/lysosomal-ph-inducible-supramolecular-dissociation-of-polyrotaxanes-possessing-acid-labile-n-triphenylmethyl-end-groups-and-their-therapeutic-potential-for-niemann-pick-type-c-disease
#8
Atsushi Tamura, Kei Nishida, Nobuhiko Yui
Niemann-Pick type C (NPC) disease is characterized by the accumulation of cholesterol in lysosomes. We have previously reported that biocleavable polyrotaxanes (PRXs) composed of β-cyclodextrins (β-CDs) threaded onto a linear polymer capped with bulky stopper molecules via intracellularly cleavable linkers show remarkable cholesterol reducing effects in NPC disease patient-derived fibroblasts owing to the stimuli-responsive intracellular dissociation of PRXs and subsequent β-CD release from the PRXs. Herein, we describe a series of novel acid-labile 2-(2-hydroxyethoxy)ethyl group-modified PRXs (HEE-PRXs) bearing terminal N-triphenylmethyl (N-Trt) groups as a cleavable component for the treatment of NPC disease...
2016: Science and Technology of Advanced Materials
https://www.readbyqxmd.com/read/27876313/lysosomal-acid-lipase-deficiency-expanding-differential-diagnosis
#9
Vassili Valayannopoulos, Eugen Mengel, Anais Brassier, Gregory Grabowski
The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal acid lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia...
November 10, 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27865842/decreasing-smpd1-activity-in-beas-2b-bronchial-airway-epithelial-cells-results-in-increased-nrf2-activity-cytokine-synthesis-and-neutrophil-recruitment
#10
Elyse MacFadden-Murphy, Lucie Roussel, Guy Martel, Julie Bérubé, Simon Rousseau
Niemann-Pick disease (NPD) type B is a rare autosomal recessive disease characterized by variable levels of impairment in sphingomyelin phosphodiesterase 1 (SMPD1) activity. Lung involvement is the most important prognostic factor in NPD-B, with recurrent respiratory infections starting in infancy being the major cause of morbidity and mortality. We hypothesized that decreased SMPD1 activity impaired airway epithelium host defense response. SMPD1 activity was reduced using inducible shRNA. Surprisingly, decreasing SMPD1 activity by 50%, resulted in increased neutrophil recruitment, both at baseline and in response to bacterial stimulation...
November 16, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27860245/telocytes-a-potential-defender-in-the-spleen-of-npc1-mutant-mice
#11
Bichao Zhang, Ciqing Yang, Liang Qiao, Qiuling Li, Congrui Wang, Xin Yan, Juntang Lin
Niemann-Pick disease, type C1 (Npc1), is an atypical lysosomal storage disorder caused by autosomal recessive inheritance of mutations in Npc1 gene. In the Npc1 mutant mice (Npc1(-/-) ), the initial manifestation is enlarged spleen, concomitant with free cholesterol accumulation. Telocytes (TCs), a novel type of interstitial cell, exist in a variety of tissues including spleen, presumably thought to be involved in many biological processes such as nursing stem cells and recruiting inflammatory cells. In this study, we found that the spleen is significantly enlarged in Npc1(-/-) mice, and the results from transmission electron microscopy examination and immunostaining using three different TCs markers, c-Kit, CD34 and Vimentin revealed significantly increased splenic TCs in Npc1(-/-) mice...
November 18, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27834854/pharmacologic-treatment-assigned-for-niemann-pick-type-c1-disease-partly-changes-behavioral-traits-in-wild-type-mice
#12
Victoria Schlegel, Markus Thieme, Carsten Holzmann, Martin Witt, Ulrike Grittner, Arndt Rolfs, Andreas Wree
Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1(nih)Npc1(-/-) mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1(-/-) animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones...
November 9, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27818935/intestinal-crebh-overexpression-prevents-high-cholesterol-diet-induced-hypercholesterolemia-by-reducing-npc1l1-expression
#13
Takuya Kikuchi, Kana Orihara, Fusaka Oikawa, Song-Iee Han, Motoko Kuba, Kanako Okuda, Aoi Satoh, Yoshinori Osaki, Yoshinori Takeuchi, Yuichi Aita, Takashi Matsuzaka, Hitoshi Iwasaki, Shigeru Yatoh, Motohiro Sekiya, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Yoshimi Nakagawa, Nobuhiro Yamada, Hitoshi Shimano
OBJECTIVE: The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown. METHODS: To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions...
November 2016: Molecular Metabolism
https://www.readbyqxmd.com/read/27816810/prevention-of-oxldl-uptake-leads-to-decreased-atherosclerosis-in-hematopoietic-npc1-deficient-ldlr-mice
#14
Mike L J Jeurissen, Sofie M A Walenbergh, Tom Houben, Marion J J Gijbels, Jieyi Li, Tim Hendrikx, Yvonne Oligschlaeger, Patrick J van Gorp, Christoph J Binder, Marjo M P C Donners, Ronit Shiri-Sverdlov
BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory disease of medium and large vessels and is typically characterized by the predominant accumulation of low-density lipoprotein (LDL)-cholesterol inside macrophages that reside in the vessel walls. Previous studies clearly demonstrated an association specifically between the oxidized type of LDL (oxLDL) and atherosclerotic lesion formation. Further observations revealed that these atherosclerotic lesions displayed enlarged, lipid-loaded lysosomes...
October 20, 2016: Atherosclerosis
https://www.readbyqxmd.com/read/27814975/smpd1-variants-in-chinese-han-patients-with-sporadic-parkinson-s-disease
#15
Cheng-Yuan Mao, Jing Yang, Hui Wang, Shu-Yu Zhang, Zhi-Hua Yang, Hai-Yang Luo, Fang Li, Mengmeng Shi, Yu-Tao Liu, Zheng-Ping Zhuang, Pan Du, Yao-He Wang, Chang-He Shi, Yu-Ming Xu
INTRODUCTION: A founder mutation, p.L302P, in sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1), causing Niemann-Pick disease, a recessive lysosomal storage disorder, was reported to be associated with increased risk of Parkinson's disease (PD) in Ashkenazi Jewish population. Several other studies about the association between SMPD1 variants and PD were performed afterward in other populations. However, the results on the role of SMPD1 mutations for PD have been conflicting. This study aimed to investigate the role of mutations in SMPD1 in Chinese PD patients...
October 19, 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/27798705/defective-autophagy-mitochondrial-clearance-and-lipophagy-in-niemann-pick-type-b-lymphocytes
#16
Barbara Canonico, Erica Cesarini, Sara Salucci, Francesca Luchetti, Elisabetta Falcieri, Gianna Di Sario, Fulvio Palma, Stefano Papa
Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied...
2016: PloS One
https://www.readbyqxmd.com/read/27798114/systemic-aav9-gene-therapy-improves-the-lifespan-of-mice-with-niemann-pick-disease-type-c1
#17
Randy J Chandler, Ian M Williams, Alana L Gibson, Cristin D Davidson, Arturo A Incao, Brandon T Hubbard, Forbes D Porter, William J Pavan, Charles P Venditti
Niemann-Pick disease, type C1 (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of NPC1 disease (Npc1(-/-)) displays a rapidly progressing form of NPC1 disease which is characterized by weight loss, ataxia, increased cholesterol storage, loss of cerebellar Purkinje neurons and early lethality. To test the potential efficacy of gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (AAV9) vectors to deliver the NPC1 gene under the transcriptional control of the neuronal-specific (CamKII) or a ubiquitous (EF1a) promoter...
October 25, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27792009/role-of-niemann-pick-type-c-disease-mutations-in-dementia
#18
Chiara Cupidi, Francesca Frangipane, Maura Gallo, Alessandra Clodomiro, Rosanna Colao, Livia Bernardi, Maria Anfossi, Maria Elena Conidi, Franca Vasso, Sabrina Anna Maria Curcio, Maria Mirabelli, Nicoletta Smirne, Giusi Torchia, Maria Gabriella Muraca, Gianfranco Puccio, Raffaele Di Lorenzo, Stefania Zampieri, Milena Romanello, Andrea Dardis, Raffaele Giovanni Maletta, Amalia Cecilia Bruni
BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult...
October 24, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27783333/relative-efficacy-of-nicotinamide-treatment-of-a-mouse-model-of-infantile-niemann-pick-c1-disease
#19
Craig A Marshall, Ivan A Borbon, Robert P Erickson
Nicotinamide delivered in drinking water at about 2 g/kg/day significantly prolonged survival and showed a suggestive improvement on memory in the Npc1 (nih) / Npc1 (nih) mouse model of infantile NPC1 disease. It is likely that this role is due to its function as a histone deacetylase (HDAC) inhibitor although another HDAC inhibitor, valproic acid, was without effect. Nicotinamide could also work by preventing/reversing oxidative stress.
October 25, 2016: Journal of Applied Genetics
https://www.readbyqxmd.com/read/27761360/ezetimibe-reduced-hepatic-steatosis-induced-by-dietary-oxysterols-in-nonhuman-primates
#20
Michiyo Deushi, Mizuko Osaka, Kaku Nakano, Kyoichi Osada, Kensuke Egashira, Masayuki Yoshida
Oxidized cholesterol (oxysterols) plays an important and multifaceted role in lipid metabolism. Here we examined whether dietary oxysterols accelerate hepatic lipid accumulation and inflammation in nonhuman primates. We also examined the effect of the Niemann-Pick C1-like1 inhibitor, ezetimibe (Ez). Macaca fascicularis (5-year-old males) were fed either regular cholesterol + high-fat diet (control-HFD) or oxysterols + high-fat diet (ox-HFD; with 0.015% of oxysterols cholesterol) for 24 weeks. Compared with control-HFD, ox-HFD did not affect plasma lipid levels, but it did affect hepatic lipid levels [total cholesterol, 40...
October 2016: FEBS Open Bio
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