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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
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
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
Esther Channah Broner, Claes G Tropé, Reuven Reich, Ben Davidson
The objective of this study was to analyze the expression and clinical role of molecules involved in exosome synthesis and secretion in high-grade serous carcinoma (HGSC), with focus on malignant effusions. The mRNA expression levels of ARF6, nSMase2, TSAP6, Rab27a and Rab27b by qRT-PCR were analyzed in 103 HGSC effusions and 65 solid specimens (35 ovarian, 30 abdominal metastases). Protein expression of ARF6, nSMase2, TSAP6 and Rab27a by Western blotting was analyzed in 150 specimens (94 effusions, 29 ovarian carcinomas, 27 solid metastases)...
November 4, 2016: Human Pathology
Jennifer K Lang, Rebeccah F Young, Hashmat Ashraf, John M Canty
Numerous studies have shown a beneficial effect of cardiosphere-derived cell (CDC) therapy on regeneration of injured myocardium. Paracrine signaling by CDC secreted exosomes may contribute to improved cardiac function. However, it has not yet been demonstrated by a genetic approach that exosome release contributes to the therapeutic effect of transplanted CDCs. By employing a lentiviral knockdown (KD) strategy against neutral spingomyelinase 2 (nSMase2), a crucial gene in exosome secretion, we have defined the role of physiologically secreted human CDC-derived exosomes on cardiac fibroblast, endothelial cell and primary cardiomyocyte proliferation, cell death, migration and angiogenesis using a series of in vitro coculture assays...
2016: PloS One
Ted Getz, Jingdong Qin, Igor L Medintz, James B Delehanty, Kimihiro Susumu, Philip E Dawson, Glyn Dawson
The use of RNAi to suppress protein synthesis offers a potential way of reducing the level of enzymes or the synthesis of mutant toxic proteins but there are few tools currently available for their delivery. To address this problem, bioconjugated quantum dots (QDs) containing a hydrophobic component (N-palmitate) and a sequence VKIKK designed to traverse across cell membranes and visualize drug delivery were developed and tested on cell lines of brain origin. We used the Zn outer shell of the QD to bind HIS6 in JB577 (W•G•Dap(N-Palmitoyl)•VKIKK•P9 •G2 •H6 ) and by a gel-shift assay showed that siRNAs would bind to the positively charged KIKK sequence...
December 2016: Journal of Neurochemistry
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
D A Houston, K Myers, V E MacRae, K A Staines, C Farquharson
Sustained exposure to high levels of parathyroid hormone (PTH), as observed in hyperparathyroidism, is catabolic to bone. The increase in the RANKL/OPG ratio in response to continuous PTH, resulting in increased osteoclastogenesis, is well established. However, the effects of prolonged PTH exposure on key regulators of skeletal mineralisation have yet to be investigated. This study sought to examine the temporal expression of PHOSPHO1, TNAP and nSMase2 in mineralising osteoblast-like cell cultures and to investigate the effects of continuous PTH exposure on the expression of these enzymes in vitro...
November 2016: Calcified Tissue International
Qiang Chen, Jun-Jie Bei, Chuan Liu, Shi-Bin Feng, Wei-Bo Zhao, Zhou Zhou, Zheng-Ping Yu, Xiao-Jun Du, Hou-Yuan Hu
Numerous clinical conditions have been linked to ectopic mineralization (EM). This process of pathological biomineralization is complex and not fully elucidated, but thought to be started within matrix vesicles (MVs). We hypothesized that high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions, induces EM via promoting MVs secretion from macrophages. In this study, we found that HMGB1 significantly promoted secretion of MVs from macrophages and subsequently led to mineral deposition in elevated Ca/Pi medium in vitro...
2016: PloS One
Juan Liao, Ran Liu, Ya-Juan Shi, Li-Hong Yin, Yue-Pu Pu
Recent evidence indicates that exosomes can mediate certain microRNAs (miRNAs) involved in a series of biological functions in tumor occurrence and development. Our previous studies showed that microRNA-21 (miR-21) was abundant in both esophageal cancer cells and their corresponding exosomes. The present study explored the function of exosome-shuttling miR-21 involved in esophageal cancer progression. We found that exosomes could be internalized from the extracellular space to the cytoplasm. The exosome-derived Cy3-labeled miR-21 mimics could be transported into recipient cells in a neutral sphingomyelinase 2 (nSMase2)-dependent manner...
June 2016: International Journal of Oncology
Christopher J Clarke, Achraf A Shamseddine, Joseph J Jacob, Gabrielle Khalife, Tara A Burns, Yusuf A Hannun
Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional level. Previously, we reported that nSMase2 is induced by all-trans retinoic acid (ATRA) in MCF7 cells and implicated nSMase2 in ATRA-induced growth arrest. Here, we further investigated how ATRA regulates nSMase2. We find that ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-α, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity...
May 2016: Journal of Lipid Research
Jingdong Qin, John Kilkus, Glyn Dawson
Increased synthesis of hyaluronic acid (HA) is often associated with increased metastatic potential and invasivity of tumor cells. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis, and has been studied as a potential anti-tumor drug to inhibit the growth of primary tumors and distant metastasis of tumor cells. Although several studies reported that the anticancer effects of MU are mediated by inhibition of HA signaling, the mechanism still needs to be clarified. In a previous study we demonstrated the regulation of HA synthesis by ceramide, and now show how MU activated neutral sphingomyelinase2 (NSMase2) generates ceramides and mediates MU induced inhibition of HA synthesis, cell migration and invasion, and apoptosis of tumor cells...
February 2016: Biochimica et Biophysica Acta
A A Shamseddine, C J Clarke, B Carroll, M V Airola, S Mohammed, A Rella, L M Obeid, Y A Hannun
Neutral sphingomyelinase-2 (nSMase2) is a ceramide-generating enzyme that has been implicated in growth arrest, apoptosis and exosome secretion. Although previous studies have reported transcriptional upregulation of nSMase2 in response to daunorubicin, through Sp1 and Sp3 transcription factors, the role of the DNA damage pathway in regulating nSMase2 remains unclear. In this study, we show that doxorubicin induces a dose-dependent induction of nSMase2 mRNA and protein with concomitant increases in nSMase activity and ceramide levels...
October 29, 2015: Cell Death & Disease
Gerald S Supinski, Alexander P Alimov, Lin Wang, Xiao-Hong Song, Leigh A Callahan
Calpain contributes to infection-induced diaphragm dysfunction but the upstream mechanism(s) responsible for calpain activation are poorly understood. It is known, however, that cytokines activate neutral sphingomyelinase (nSMase) and nSMase has downstream effects with the potential to increase calpain activity. We tested the hypothesis that infection-induced skeletal muscle calpain activation is a consequence of nSMase activation. We administered cytomix (20 ng/ml TNF-α, 50 U/ml IL-1β, 100 U/ml IFN-γ, 10 μg/ml LPS) to C2C12 muscle cells to simulate the effects of infection in vitro and studied mice undergoing cecal ligation puncture (CLP) as an in vivo model of infection...
September 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Mariana Figuera-Losada, Marigo Stathis, Joelle M Dorskind, Ajit G Thomas, Veera Venkata Ratnam Bandaru, Seung-Wan Yoo, Nicholas J Westwood, Graeme W Rogers, Justin C McArthur, Norman J Haughey, Barbara S Slusher, Camilo Rojas
Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression...
2015: PloS One
Ji Na Kong, Qian He, Guanghu Wang, Somsankar Dasgupta, Michael B Dinkins, Gu Zhu, Austin Kim, Stefka Spassieva, Erhard Bieberich
Many breast cancer cells acquire multidrug resistance (MDR) mediated by ABC transporters such as breast cancer resistance protein (BCRP/ABCG2). Here we show that incubation of human breast cancer MDA-MB-231 cells with farnesoid X receptor antagonist guggulsterone (gug) and retinoid X receptor agonist bexarotene (bex) elevated ceramide, a sphingolipid known to induce exosome secretion. The gug+bex combination reduced cellular levels of BCRP to 20% of control cells by inducing its association and secretion with exosomes...
October 1, 2015: International Journal of Cancer. Journal International du Cancer
Suzanne E Barbour, Phuong T Nguyen, Margaret Park, Bhargavi Emani, Xiaoyong Lei, Mamatha Kambalapalli, Jacqueline C Shultz, Dayanjan Wijesinghe, Charles E Chalfant, Sasanka Ramanadham
Diabetes is a consequence of reduced β-cell function and mass, due to β-cell apoptosis. Endoplasmic reticulum (ER) stress is induced during β-cell apoptosis due to various stimuli, and our work indicates that group VIA phospholipase A2β (iPLA2β) participates in this process. Delineation of underlying mechanism(s) reveals that ER stress reduces the anti-apoptotic Bcl-x(L) protein in INS-1 cells. The Bcl-x pre-mRNA undergoes alternative pre-mRNA splicing to generate Bcl-x(L) or Bcl-x(S) mature mRNA. We show that both thapsigargin-induced and spontaneous ER stress are associated with reductions in the ratio of Bcl-x(L)/Bcl-x(S) mRNA in INS-1 and islet β-cells...
April 24, 2015: Journal of Biological Chemistry
Christel Cinq-Frais, Christelle Coatrieux, Aude Savary, Romina D'Angelo, Corinne Bernis, Robert Salvayre, Anne Nègre-Salvayre, Nathalie Augé
Actin remodeling is a dynamic process associated with cell shape modification occurring during cell cycle and proliferation. Oxidative stress plays a role in actin reorganization via various systems including p38MAPK. Beside, the mitogenic response evoked by hydrogen peroxide (H2O2) in fibroblasts and smooth muscle cells (SMC) involves the metalloproteinase (MMPs)/sphingomyelinase 2 (nSMase2) signaling pathway. The aim of this work was to investigate whether this system plays a role in actin remodeling induced by H2O2...
2015: Redox Biology
Sandra Garoby-Salom, Myriam Rouahi, Elodie Mucher, Nathalie Auge, Robert Salvayre, Anne Negre-Salvayre
The neutral type 2 sphingomyelinase (nSMase2) hydrolyzes sphingomyelin and generates ceramide, a major bioactive sphingolipid mediator, involved in growth arrest and apoptosis. The role of nSMase2 in apoptosis is debated, and apparently contradictory results have been observed on fibroblasts isolated from nSMase2-deficient fragilitas ossium (homozygous fro/fro) mice. These mice exhibit a severe neonatal dysplasia, a lack of long bone mineralization and delayed apoptosis patterns of hypertrophic chondrocytes in the growth plate...
2015: Redox Biology
Belinda B Guo, Shayne A Bellingham, Andrew F Hill
Prion diseases are a group of transmissible, fatal neurodegenerative disorders associated with the misfolding of the host-encoded prion protein, PrP(C), into a disease-associated form, PrP(Sc). The transmissible prion agent is principally formed of PrP(Sc) itself and is associated with extracellular vesicles known as exosomes. Exosomes are released from cells both in vitro and in vivo, and have been proposed as a mechanism by which prions spread intercellularly. The biogenesis of exosomes occurs within the endosomal system, through formation of intraluminal vesicles (ILVs), which are subsequently released from cells as exosomes...
February 6, 2015: Journal of Biological Chemistry
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