scholarly journals Inhibition of neutral sphingomyelinase 2 promotes remyelination

2020 ◽  
Vol 6 (40) ◽  
pp. eaba5210
Author(s):  
Seung-Wan Yoo ◽  
Amit Agarwal ◽  
Matthew D. Smith ◽  
Saja S. Khuder ◽  
Emily G. Baxi ◽  
...  
Keyword(s):  
Oligodendrocyte Progenitor Cells ◽  
Neutral Sphingomyelinase ◽  
Myelin Sheaths ◽  
Lipid Species ◽  
Ceramide Content ◽  
Secondary Demyelination ◽  
Genetic Deletion ◽  
Factor Α ◽  
Necrosis Factor

Myelination requires a highly organized synthesis of multiple lipid species that regulate myelin curvature and compaction. For reasons that are not understood, central nervous system remyelinated axons often have thin myelin sheaths with a disorganized structure susceptible to secondary demyelination. We found that expression of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) during the differentiation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes changes their response to inflammatory cytokines. OPCs do not express nSMase2 and exhibit a protective/regenerative response to tumor necrosis factor–α and interleukin-1β. Oligodendrocytes express nSMase2 and exhibit a stress response to cytokine challenge that includes an overproduction of ceramide, a sphingolipid that forms negative curvatures in membranes. Pharmacological inhibition or genetic deletion of nSMase2 in myelinating oligodendrocytes normalized the ceramide content of remyelinated fibers and increased thickness and compaction. These results suggest that inhibition of nSMase2 could improve the quality of myelin and stabilize structure.

scholarly journals Inhibition of neutral sphingomyelinase-2 facilitates remyelination

2019 ◽  
Author(s):  
Seung-Wan Yoo ◽  
Amit Agarwal ◽  
Matthew D. Smith ◽  
Saja S. Khuder ◽  
Emily G. Baxi ◽  
...  
Keyword(s):  
Oligodendrocyte Progenitor Cells ◽  
Pharmacological Inhibition ◽  
Myelin Sheaths ◽  
Sphingosine 1 Phosphate ◽  
Secondary Demyelination ◽  
Myelin Thickness ◽  
Genetic Deletion ◽  
Active Caspase

AbstractFor reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2in vivoincreased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

scholarly journals Quality of Dabai Pulp Oil Extracted by Supercritical Carbon Dioxide and Supplementation in Hypercholesterolemic Rat—A New Alternative Fat

Foods ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 262
Author(s):  
Noor Atiqah Aizan Abdul Kadir ◽  
Azrina Azlan ◽  
Faridah Abas ◽  
Intan Safinar Ismail
Keyword(s):  
Fatty Acid Content ◽  
Total Antioxidant Status ◽  
High Cholesterol Diet ◽  
Reactive Protein ◽  
Total Antioxidant ◽  
Canarium Odontophyllum ◽  
Coa Reductase ◽  
Factor Α ◽  
Necrosis Factor

Dabai pulp oil (DPO) is new oil extracted from the pulp of Canarium odontophyllum. The quality and efficacy of DPO are needed to promote its potential as a new alternative fat. Therefore, we investigate the quality of DPO, which includes moisture and volatile content (MVC), free fatty acid content (FFA), iodine value (IV), and peroxide value (PV). Furthermore, we evaluate the efficacy of DPO against hypercholesterolemia elicited by a high-cholesterol diet in rats. The MVC of DPO was <0.001 ± 0.00%. Next, the FFA in DPO was 2.57 ± 0.03%, and the IV of DPO was 53.74 ± 0.08 g iodine/100 g oil. Meanwhile, the PV of DPO was 4.97 ± 0.00 mEq/kg. Supplementation of DPO in hypercholesterolemic rats for 30 days revealed the hypocholesterolemic effect (significant reduction of total cholesterol, triglyceride, and 3-hydroxy-3-methylglutaryl-CoA reductase) accompanied by a significant reduction of inflammatory markers (C-reactive protein, interleukin-6 and tumour necrosis factor-α), and lipid peroxidation (MDA). We also observed a significant improvement of lipoprotein lipase (LPL) and antioxidant capacities (total antioxidant status, superoxide dismutase, glutathione peroxidase, and catalase) of the rats. The results on the quality and efficacy of locally made DPO suggest its potential use as a healthy alternative fat in the future.

scholarly journals A neutral sphingomyelinase resides in sphingolipid-enriched microdomains and is inhibited by the caveolin-scaffolding domain: potential implications in tumour necrosis factor signalling

2001 ◽  
Vol 355 (3) ◽  
pp. 859-868 ◽  
Author(s):  
Robert J. VELDMAN ◽  
Nicolas MAESTRE ◽  
Osama M. ADUIB ◽  
Jeffrey A. MEDIN ◽  
Robert SALVAYRE ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Membrane Microdomains ◽  
Cell Fractionation ◽  
Minute Amount ◽  
Neutral Sphingomyelinase ◽  
Signalling Molecules ◽  
Niemann Pick ◽  
Factor Α ◽  
Necrosis Factor

Sphingomyelinases hydrolyse sphingomyelin to ceramide, a process involved in signal-transduction routes leading to apoptosis and various other cellular responses. In the present study, we investigated the sphingomyelinase content of caveolae, invaginated plasma-membrane microdomains that contain a variety of signalling molecules. These structures are highly enriched in sphingomyelin as well as in ceramide, which suggests that metabolism of these lipids might, to some extent, occur locally. By cell fractionation, we demonstrate that, in addition to a previously reported minute amount of acidic sphingomyelinase activity, a substantial amount of neutral sphingomyelinase activity resides in caveolae of human skin fibroblasts. This caveolar neutral sphingomyelinase activity was also detected in Niemann–Pick disease type A fibroblasts, which are completely devoid of functional acidic sphingomyelinase. Neutral (but not acidic) sphingomyelinase activity was specifically inhibited by a peptide that corresponds to the scaffolding domain of caveolin, which suggests a direct molecular interaction between the two proteins. In addition, this finding implies a cytosolic orientation of the caveolar neutral sphingomyelinase. Interestingly, stimulation of fibroblasts with tumour necrosis factor α (TNFα) resulted in a partial shift of its p55 receptor to caveolin-enriched membrane fractions and the appearance of caveolin-sensitive neutral sphingomyelinase activity in the non-caveolar fractions. These results suggest that (part of) the presently identified caveolar neutral sphingomyelinase activity is involved in TNFα signalling.

scholarly journals L-Selectin Shedding Regulates Leukocyte Recruitment

2001 ◽  
Vol 193 (7) ◽  
pp. 863-872 ◽  
Author(s):  
Ali Hafezi-Moghadam ◽  
Kennard L. Thomas ◽  
Alyson J. Prorock ◽  
Yuqing Huo ◽  
Klaus Ley
Keyword(s):  
Leukocyte Adhesion ◽  
Leukocyte Recruitment ◽  
Intercellular Adhesion Molecule ◽  
Leukocyte Rolling ◽  
Lymphocyte Function ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dependent Mechanism

The physiologic role of L-selectin shedding is unknown. Here, we investigate the effect of L-selectin shedding on firm adhesion and transmigration. In a tumor necrosis factor α–induced model of inflammation, inhibition of L-selectin shedding significantly increased firm adhesion and transmigration by a lymphocyte function–associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1–dependent mechanism. We examined the quality of leukocyte rolling and L-selectin–mediated signaling. Blockade of L-selectin shedding significantly reduced the “jerkiness” of leukocyte rolling, defined as the variability of velocity over time. A low level of jerkiness was also observed in the rolling of microbeads conjugated with L-selectin, a model system lacking the mechanism for L-selectin shedding. Inhibition of L-selectin shedding potentiated activation of LFA-1 and Mac-1 induced by L-selectin cross-linking as shown by activation epitope expression and binding of ICAM-1–conjugated beads. We conclude that inhibition of L-selectin shedding increases leukocyte adhesion and transmigration by (a) increasing leukocyte exposure to the inflamed endothelium by decreasing jerkiness and (b) promoting leukocyte activation by outside-in signaling. These observations help to resolve the apparent discrepancy between the minor contribution of L-selectin to rolling and the significant leukocyte recruitment defect in L-selectin knockout mice.

scholarly journals Neutral sphingomyelinase 2 (nSMase2) is the primary neutral sphingomyelinase isoform activated by tumour necrosis factor-α in MCF-7 cells

2011 ◽  
Vol 435 (2) ◽  
pp. 381-390 ◽  
Author(s):  
Christopher J. Clarke ◽  
Emily A. Cloessner ◽  
Patrick L. Roddy ◽  
Yusuf A. Hannun
Keyword(s):  
Tumour Necrosis Factor ◽  
Cell Lines ◽  
Tumour Necrosis ◽  
Tumour Necrosis Factor Α ◽  
Neutral Sphingomyelinase ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Mcf 7

Activation of N-SMase (neutral sphingomyelinase) is an established part of the response of cytokines such as TNF (tumour necrosis factor)-α. However, it remains unclear which of the currently cloned N-SMase isoforms (nSMase1, nSMase2 and nSMase3) are responsible for this activity. In MCF-7 cells, we found that TNF-α induces late, but not early, increases in N-SMase activity, and that nSMase2 is the primary isoform activated, most likely through post-transcriptional mechanisms. Surprisingly, overexpression of tagged or untagged nSMase3 in multiple cell lines had no significant effect on in vitro N-SMase activity. Moreover, only overexpression of nSMase2, but not nSMase1 or nSMase3, had significant effects on cellular sphingolipid levels, increasing ceramide and decreasing sphingomyelin. Additionally, only siRNA (small interfering RNA) knockdown of nSMase1 significantly decreased basal in vitro N-SMase activity of MCF-7 cells, whereas nSMase2 but not nSMase3 siRNA inhibited TNF-α-induced activity. Taken together, these results identify nSMase2 as the major TNF-α-responsive N-SMase in MCF-7 cells. Moreover, the results suggest that nSMase3 may not possess in vitro N-SMase activity and does not affect cellular sphingolipid levels in the cell lines evaluated. On the other hand, nSMase1 contributes to in vitro N-SMase activity, but does not affect cellular sphingolipids much.

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