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Neutral sphingomyelinase 2

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https://www.readbyqxmd.com/read/29348617/neuronal-lysosomal-dysfunction-releases-exosomes-harboring-app-c-terminal-fragments-and-unique-lipid-signatures
#1
André M Miranda, Zofia M Lasiecka, Yimeng Xu, Jessi Neufeld, Sanjid Shahriar, Sabrina Simoes, Robin B Chan, Tiago Gil Oliveira, Scott A Small, Gilbert Di Paolo
Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes...
January 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29337691/the-neutral-sphingomyelinase-2-in-t-cell-receptor-signaling-and-polarity
#2
Lena Collenburg, Sibylle Schneider-Schaulies, Elita Avota
Hydrolyzing its substrate sphingomyelin at the cytosolic leaflet of cellular membranes, the neutral sphingomyelinase 2 (NSM2) generates microdomains which serve as docking sites for signaling proteins and thereby, functions to regulate signal relay. This has been particularly studied in cellular stress responses while the regulatory role of this enzyme in the immune cell compartment has only recently emerged. In T cells, phenotypic polarization by co-ordinated cytoskeletal remodeling is central to motility and interaction with endothelial or antigenpresenting cells during tissue recruitment or immune synapse formation, respectively...
June 27, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/29329781/dopamine-transporter-trafficking-is-regulated-by-neutral-sphingomyelinase-2-ceramide-kinase
#3
Jong Hoon Won, Seok Kyun Kim, In Chul Shin, Hae Chan Ha, Ji Min Jang, Moon Jung Back, Dae Kyong Kim
Dopamine (DA) reuptake is the primary mechanism to terminate dopaminergic transmission in the synaptic cleft. The dopamine transporter (DAT) has an important role in the regulation of DA reuptake. This study provides anatomical and physiological evidence that DAT recycling is regulated by ceramide kinase via the sphingomyelin pathway. First, the results show that DAT and neutral sphingomyelinase 2 (nSMase2) were successfully co-precipitated from striatal samples and were colocalized in the mouse striatum or PC12 cells...
January 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29321137/novel-function-of-ceramide-for-regulation-of-mitochondrial-atp-release-in-astrocytes
#4
Ji-Na Kong, Zhihui Zhu, Yutaka Itokazu, Guanghu Wang, Michael B Dinkins, Liansheng Zhong, Hsuan-Pei Lin, Ahmed Elsherbini, Silvia Leanhart, Xue Jiang, Haiyan Qin, Wenbo Zhi, Stefka D Spassieva, Erhard Bieberich
We reported that amyloid beta peptide (Abeta42) activated neutral sphingomyelinase 2 (nSMase2) thereby increasing the concentration of the sphingolipid ceramide in astrocytes. Here, we show that Abeta42 induced mitochondrial fragmentation in wild type astrocytes, but not in nSMase2-deficient cells or astrocytes treated with Fumonisin B1 (FB1), an inhibitor of ceramide synthases. Unexpectedly, ceramide depletion was concurrent with rapid movements of mitochondria, indicating an unknown function of ceramide for mitochondria...
January 10, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29158006/vdr-independent-induction-of-acid-sphingomyelinase-by-1-23-oh-2-d3-in-gastric-cancer-cells-impact-on-apoptosis-and-cell-morphology
#5
Elisabetta Albi, Samuela Cataldi, Ivana Ferri, Angelo Sidoni, Giovanna Traina, Katia Fettucciari, Francesco Saverio Ambesi-Impiombato, Andrea Lazzarini, Francesco Curcio, Maria Rachele Ceccarini, Tommaso Beccari, Michela Codini
1 alpha,25-dihydroxyvitamin D3 (1,23(OH)2 D3) is known to play a dual role in cancer, by promoting or inhibiting carcinogenesis via 1,23(OH)2 D3 receptor (VDR) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Fok I polymorphism of VDR may indirectly influence the receptor levels through autoregulation. The involvement of neutral sphingomyelinase in the non-classic VDR-mediated genomic pathway response to 1,23(OH)2 D3 treatment has been reported. Until now no information were reported about Fok I polymorphism of VDR in NCI-N87 human gastric cancer cells and the relation between acid sphingomyelinase and 1,23(OH)2 D3...
November 17, 2017: Biochimie
https://www.readbyqxmd.com/read/29141446/myocardial-reparative-functions-of-exosomes-from-mesenchymal-stem-cells-are-enhanced-by-hypoxia-treatment-of-the-cells-via-transferring-microrna-210-in-an-nsmase2-dependent-way
#6
Jinyun Zhu, Kai Lu, Ning Zhang, Yun Zhao, Qunchao Ma, Jian Shen, Yinuo Lin, Pingping Xiang, Yaoliang Tang, Xinyang Hu, Jinghai Chen, Wei Zhu, Keith A Webster, Jian'an Wang, Hong Yu
Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (Exo(H)) are superior to those from normoxia-treated MSCs (Exo(N)) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. Exo(H) resulted in significantly higher survival, smaller scar size and better cardiac functions recovery...
November 16, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/29070689/both-sphingomyelin-and-cholesterol-in-the-host-cell-membrane-are-essential-for-rubella-virus-entry
#7
Noriyuki Otsuki, Masafumi Sakata, Kyoko Saito, Kiyoko Okamoto, Yoshio Mori, Kentaro Hanada, Makoto Takeda
Rubella virus (RuV) causes a systemic infection and transplacental fetal infection causes congenital rubella syndrome. In this study, we showed that treatment of cells with sphingomyelinase inhibited RuV infection. Assays using inhibitors of serine palmitoyl transferase and ceramide transport protein demonstrated the contribution of sphingomyelin (SM) to RuV infection. Compelling evidence for direct binding of RuV to lipid membranes at neutral pH was obtained using liposome co-flotation assays. The absence of either SM or cholesterol (Chol) abrogated the RuV--liposome interaction...
October 25, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29043558/enriched-expression-of-neutral-sphingomyelinase-2-in-the-striatum-is-essential-for-regulation-of-lipid-raft-content-and-motor-coordination
#8
Laura Hui-Ru Tan, Angela Jin-Rong Tan, Yu-Ying Ng, John Jia-En Chua, Wee-Siong Chew, Sneha Muralidharan, Federico Torta, Bamaprasad Dutta, Siu Kwan Sze, Deron R Herr, Wei-Yi Ong
Sphingomyelinases are a family of enzymes that hydrolyze sphingomyelin to generate phosphocholine and ceramide. The brain distribution and function of neutral sphingomyelinase 2 (nSMase2) were elucidated in this study. nSMase2 mRNA expression was greatest in the striatum, followed by the prefrontal cortex, hippocampus, cerebellum, thalamus, brainstem, and olfactory bulb. The striatum had the highest level of nSMase2 protein expression, followed by the prefrontal cortex, thalamus, hippocampus, brainstem, and cerebellum...
October 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29030399/robust-lysosomal-calcium-signaling-through-channel-trpml1-is-impaired-by-lysosomal-lipid-accumulation
#9
Néstor Más Gómez, Wennan Lu, Jason C Lim, Kirill Kiselyov, Keith E Campagno, Yulia Grishchuk, Susan A Slaugenhaupt, Bruce A Pfeffer, Steven J Fliesler, Claire H Mitchell
The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations...
October 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28652336/structure-of-human-nsmase2-reveals-an-interdomain-allosteric-activation-mechanism-for-ceramide-generation
#10
Michael V Airola, Prajna Shanbhogue, Achraf A Shamseddine, Kip E Guja, Can E Senkal, Rohan Maini, Nana Bartke, Bill X Wu, Lina M Obeid, Miguel Garcia-Diaz, Yusuf A Hannun
Neutral sphingomyelinase 2 (nSMase2, product of the SMPD3 gene) is a key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication. nSMase2 is activated by diverse stimuli, including the anionic phospholipid phosphatidylserine. Phosphatidylserine binds to an integral-membrane N-terminal domain (NTD); however, how the NTD activates the C-terminal catalytic domain is unclear. Here, we identify the complete catalytic domain of nSMase2, which was misannotated because of a large insertion...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28479957/4-hydroxynonenal-contributes-to-angiogenesis-through-a-redox-dependent-sphingolipid-pathway-prevention-by-hydralazine-derivatives
#11
Caroline Camaré, Corinne Vanucci-Bacqué, Nathalie Augé, Mélanie Pucelle, Corinne Bernis, Audrey Swiader, Michel Baltas, Florence Bedos-Belval, Robert Salvayre, Anne Nègre-Salvayre
The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs) contribute to the formation of tubes via the generation of sphingosine 1-phosphate (S1P), a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28374513/identification-and-characterization-of-laodelphax-striatellus-insecta-hemiptera-delphacidae-neutral-sphingomyelinase
#12
Y Zhou, X-W Lin, M-A Begum, C-H Zhang, X-X Shi, W-J Jiao, Y-R Zhang, J-Q Yuan, H-Y Li, Q Yang, C Mao, Z-R Zhu
The neutral sphingomyelinase (nSMase) 1 homologue gene LsSMase was cloned from Laodelphax striatellus, a direct sap-sucker and virus vector of gramineous plants, and expressed via a Bac to Bac baculovirus expression system. The LsSMase-enhanced green fluorescent protein fusion protein was located in the endoplasmic reticulum in a similar manner to mammalian nSMase 1. The biochemical properties of LsSMase were determined in detail. The optimal pH and temperature for recombinant LsSMase were 8 and 37 °C, respectively...
August 2017: Insect Molecular Biology
https://www.readbyqxmd.com/read/28322796/modulation-of-the-sphingolipid-rheostat-is-involved-in-paclitaxel-resistance-of-the-human-prostate-cancer-cell-line-pc3-pr
#13
Yuka Aoyama, Sayaka Sobue, Naoki Mizutani, Chisato Inoue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Mamoru Kyogashima, Motoshi Suzuki, Yoshinoti Nozawa, Takashi Murate
Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PC3, but not PC3-PR, cells. PC3-PR contained higher S1P levels than did PC3, regardless of PTX treatment...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28221099/sphingomyelin-phosphodiesterase-3-enhances-cytodifferentiation-of-periodontal-ligament-cells
#14
S Miyauchi, J Kitagaki, R Masumoto, A Imai, K Kobayashi, A Nakaya, S Kawai, C Fujihara, Y Asano, M Yamashita, M Yanagita, S Yamada, M Kitamura, S Murakami
Sphingomyelin phosphodiesterase 3 ( Smpd3), which encodes neutral sphingomyelinase 2 (nSMase2), is a key molecule for skeletal development as well as for the cytodifferentiation of odontoblasts and alveolar bone. However, the effects of nSMase2 on the cytodifferentiation of periodontal ligament (PDL) cells are still unclear. In this study, the authors analyzed the effects of Smpd3 on the cytodifferentiation of human PDL (HPDL) cells. The authors found that Smpd3 increases the mRNA expression of calcification-related genes, such as alkaline phosphatase (ALPase), type I collagen, osteopontin, Osterix (Osx), and runt-related transcription factor (Runx)-2 in HPDL cells...
March 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/27826102/the-trka-receptor-mediates-experimental-thermal-hyperalgesia-produced-by-nerve-growth-factor-modulation-by-the-p75-neurotrophin-receptor
#15
Alla Khodorova, Grant D Nicol, Gary Strichartz
The p75 neurotrophin receptor (p75(NTR)) and its activation of the sphingomyelin signaling cascade are essential for mechanical hypersensitivity resulting from locally injected nerve growth factor (NGF). Here the roles of the same effectors, and of the tropomyosin receptor kinase A (TrkA) receptor, are evaluated for thermal hyperalgesia from NGF. Sensitivity of rat hind paw plantar skin to thermal stimulation after local sub-cutaneous injection of NGF (500ng) was measured by the latency for paw withdrawal (PWL) from a radiant heat source...
January 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/27679482/exosome-secretion-is-a-key-pathway-for-clearance-of-pathological-tdp-43
#16
Yohei Iguchi, Lara Eid, Martin Parent, Geneviève Soucy, Christine Bareil, Yuichi Riku, Kaori Kawai, Shinnosuke Takagi, Mari Yoshida, Masahisa Katsuno, Gen Sobue, Jean-Pierre Julien
Cytoplasmic TDP-43 aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here we investigated the role of exosomes in the secretion and propagation of TDP-43 aggregates. TDP-43 was detected in secreted exosomes from Neuro2a cells and primary neurons but not from astrocytes or microglia. Evidence is presented that protein aggregation and autophagy inhibition are factors that promote exosomal secretion of TDP-43. We also report that levels of exosomal TDP-43 full length and C-terminal fragment species are upregulated in human amyotrophic lateral sclerosis brains...
December 2016: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/27660431/neutral-sphingomyelinase-2-acid-sphingomyelinase-and-ceramide-levels-in-copd-patients-compared-to-controls
#17
Simon R Lea, Hannah J Metcalfe, Jonathan Plumb, Christian Beerli, Chris Poll, Dave Singh, Katharine H Abbott-Banner
BACKGROUND: Increased pulmonary ceramide levels are suggested to play a causative role in lung diseases including COPD. Neutral sphingomyelinase-2 (nSMase-2) and acid SMase (aSMase), which hydrolyze sphingomyelin to produce ceramide, are activated by a range of cellular stresses, including inflammatory cytokines and pathogens, but notably cigarette smoke appears to only activate nSMase-2. Our primary objective was to investigate nSMase-2 and aSMase protein localization and quantification in lung tissue from nonsmokers (NS), smokers (S), and COPD patients...
2016: International Journal of Chronic Obstructive Pulmonary Disease
https://www.readbyqxmd.com/read/27556861/inhibition-of-interleukin-1%C3%AE-induced-endothelial-tissue-factor-expression-by-the-synthetic-cannabinoid-win-55-212-2
#18
Antje Scholl, Igor Ivanov, Burkhard Hinz
The role of cannabinoids in thrombosis remains controversial. In view of the primary importance of tissue factor (TF) in blood coagulation and its involvement in the pathology of several cardiovascular, inflammatory and neoplastic diseases, a regulation of this initial procoagulant signal seems to be of particular interest. Using human umbilical vein endothelial cells (HUVEC) the present study investigated the impact of the synthetic cannabinoid WIN 55,212-2 on interleukin (IL)-1β-induced TF expression and activity...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27535912/neutral-sphingomyelinase-2-deficiency-ameliorates-alzheimer-s-disease-pathology-and-improves-cognition-in-the-5xfad-mouse
#19
Michael B Dinkins, John Enasko, Caterina Hernandez, Guanghu Wang, Jina Kong, Inas Helwa, Yutao Liu, Alvin V Terry, Erhard Bieberich
UNLABELLED: Recent evidence implicates exosomes in the aggregation of Aβ and spreading of tau in Alzheimer's disease. In neural cells, exosome formation can be blocked by inhibition or silencing of neutral sphingomyelinase-2 (nSMase2). We generated genetically nSMase2-deficient 5XFAD mice (fro;5XFAD) to assess AD-related pathology in a mouse model with consistently reduced ceramide generation. We conducted in vitro assays to assess Aβ42 aggregation and glial clearance with and without exosomes isolated by ultracentrifugation and determined exosome-induced amyloid aggregation by particle counting...
August 17, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27528614/differences-and-similarities-in-trail-and-tumor-necrosis-factor-mediated-necroptotic-signaling-in-cancer-cells
#20
COMPARATIVE STUDY
Justyna Sosna, Stephan Philipp, Johaiber Fuchslocher Chico, Carina Saggau, Jürgen Fritsch, Alexandra Föll, Johannes Plenge, Christoph Arenz, Thomas Pinkert, Holger Kalthoff, Anna Trauzold, Ingo Schmitz, Stefan Schütze, Dieter Adam
Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H(+)-ATPase...
October 15, 2016: Molecular and Cellular Biology
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