An Enzymatic Assay for Quantifying Sphingomyelin in Tissues and Plasma from Humans and Mice with Niemann–Pick Disease

He, Xingxing; Chen, Fei; Gátt, Shimon; Schuchman, Edward H.

doi:10.1006/abio.2001.5108

Cited by 18 publications

(16 citation statements)

References 29 publications

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“…Plasma from normal, MPS VI, and Remicadetreated MPS VI rats was collected at the end of the 8-and 24-week treatment periods, respectively. Plasma ceramide was quantified using the diacylglycerol kinase method (40). S1P was quantified using HPLC methods after napthalene-2,3-dicarboxaldehyde derivatization (41).…”

Section: Methodsmentioning

confidence: 99%

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Simonaro¹,

Ge²,

Eliyahu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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170

175

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Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-α drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4 (lps−/−) ) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-α were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-α, receptor activator of NF-κB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-monthold animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-α may have positive therapeutic effects.bone and joint disease | inflammation | glycosaminoglycans | growth plate

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Section: Methodsmentioning

confidence: 99%

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Simonaro¹,

Ge²,

Eliyahu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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170

175

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“…Ceramide levels (A) were verified using the DAG kinase method (He et al, 2001). Caspase 3 activity (B) was measured using EnzCheck Caspase-3 assay kit.…”

Section: Fig 6 the Effect Of Aβ On Ceramide Levels And Apoptosis Inmentioning

confidence: 99%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

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450

468

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Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pretreatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis.

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“…Ceramide was quantified from the lipid extracts using the diacylglycerol kinase method. 21 The combined data from triplicate experiments were subjected to a t-test analysis, and the results were considered significant at P Ͻ 0.01.…”

Section: Ceramide and Sphingosine-1-phosphate Quantificationmentioning

confidence: 99%

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

Simonaro

D’Angelo

et al. 2008

The American Journal of Pathology

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188

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We have previously shown that glycosaminoglycan (GAG) storage in animal models of the mucopolysaccharidoses (MPS) leads to inflammation and apoptosis within cartilage. We have now extended these findings to synovial tissue and further explored the mechanism underlying GAG-mediated disease. Analysis of MPS rats, cats, and/or dogs revealed that MPS synovial fibroblasts and fluid displayed elevated expression of numerous inflammatory molecules, including several proteins important for lipopolysaccharide signaling (eg, Toll-like receptor 4 and lipoprotein-binding protein). The expression of tumor necrosis factor, in particular, was elevated up to 50-fold, leading to up-regulation of the osteoclast survival factor, receptor activator of nuclear factor-B ligand, and the appearance of multinucleated osteoclast-like cells in the MPS bone marrow. Treatment of normal synovial fibroblasts with GAGs also led to production of the prosurvival lipid sphingosine-1-phosphate, resulting in enhanced cell proliferation, consistent with the hyperplastic synovial tissue observed in MPS patients. In contrast, GAG treatment of normal chondrocytes led to production of the proapoptotic lipid ceramide, confirming the enhanced cell death we had previously observed in MPS cartilage. These findings have important implications for the pathogenesis and treatment of MPS and have further defined the mechanism of GAG-stimulated disease. (Am J Pathol

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An Enzymatic Assay for Quantifying Sphingomyelin in Tissues and Plasma from Humans and Mice with Niemann–Pick Disease

Cited by 18 publications

References 29 publications

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Deregulation of sphingolipid metabolism in Alzheimer's disease

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

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