Sphingomyelinase dependent apoptosis following treatment of pancreatic beta-cells with amyloid peptides Aß1-42 or IAPP

Zhang, Ying; Ranta, Felicia; Tang, Chengying; Shumilina, Ekaterina; Mahmud, Hasan; Föller, Michael; Ullrich, Susanne; Häring, Hans‐Ulrich; Läng, Florian

doi:10.1007/s10495-009-0364-4

Cited by 17 publications

(11 citation statements)

References 85 publications

(99 reference statements)

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“…These patches are only present on the surface of ␤ cells, making them suitable for ligand binding. We believe that our fi ndings have implications for identifying future ligands for the proposed antigen for in vivo imaging purposes as well as for potential therapy, as SM-derived ceramide has been shown to have a role in the regulation of insulin synthesis ( 13,14 ) and contributes to ␤ -cell apoptosis (15)(16)(17)(18).…”

Section: Antigen Extraction and Purifi Cation By Tlcmentioning

confidence: 88%

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Kavishwar

Medarova

Moore

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org this restoration noninvasively ( 1 ). Recent years have seen exponential progress in applying various imaging modalities (MRI, positron emission tomography, optical) for noninvasive detection and monitoring of pancreatic ␤ -cell mass ( 2-6 ). A crucial prerequisite for clinical application of these techniques is the availability of a contrast agent with high affi nity and high specifi city toward ␤ -cell surface markers.Antibodies or their fragments, owing to their high specifi city, biocompatibility and ability to carry payload to the target site, could serve as an ideal molecule for imaging applications. A number of different antibodies have been suggested for noninvasive determination of ␤ -cell mass ( 7-9 ). However, most of them suffer from lack of specifi city for islet ␤ cells. Part of this problem emanates from the fact that ␤ cells share the same lineage as other cells in the pancreas, making it diffi cult to elucidate unique targets on the ␤ -cell surface. In addition, there is a challenging requirement for imaging agents to be retained by ␤ cells at least 1,000-fold more strongly than by exocrine cells ( 10 ). No antibodies/antibody fragments have yet been described that fulfi ll all the requirements, necessitating a further search for ␤ -cell biomarkers. The single-chain antibody SCA B5 has shown promise in the past ( 11 ). However, its target and its utility for ␤ -cell imaging are unknown.In a previous study, we showed that the 125 I-labeled ␤ -cell-specifi c IC2 antibody accumulates in the pancreas of streptozotocin-induced mice in direct proportion to ␤ -cell mass ( 2 ). However, further progress toward the development of an antibody-based in vivo imaging probe was impeded due to lack of information about the nature and identity of the ␤ -cell surface antigen. IC2 is a rat monoclonal antibody of the IgM isotype, obtained by fusing lymphocytes from diabetes-prone BB rats with a rat myeloma partner and selected by screening hybridoma supernatants against Rin5F insulinoma cells ( 12 ). In this study, we present Abstract To devise successful imaging and therapeutic strategies, the identifi cation of ␤ -cell surface markers is one of the challenges in diabetes research that has to be resolved. We previously showed that IC2, a rat monoclonal IgM antibody, can be used for ex vivo determination of Increased blood glucose levels mostly accompanied by a decrease in functional ␤ -cell mass are a key characteristic of human diabetes. While type 1 diabetes results from autoimmune destruction of insulin-producing ␤ cells, type 2 diabetes is characterized by insulin resistance and relative insulin defi ciency. In both cases, pancreatic ␤ -cell mass is affected by the disease. Patients suffering from these conditions would benefi t from clinical interventions aimed at restoring functional ␤ -cell mass and methods to monitor Award JDRF 37-2009-30 (A.M.). This work was supported in part by Juvenile Diabetes Research Foundation

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Section: Antigen Extraction and Purifi Cation By Tlcmentioning

confidence: 88%

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Kavishwar

Medarova

Moore

2011

Journal of Lipid Research

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“…Calpain biomarker activity was accomplished by measuring the relative amount of calpain-specific cleavage products of talin, vinculin, or αII-spectrin on immunoblots using the following antibodies: anti-talin (1:400; Abcam 9290), anti-vinculin (1:2000; Sigma V4505), and anti-αII-spectrin (1:5000, Enzo Life Sciences; Nath et al, 1996; McGinn et al, 2009; Zhang et al, 2009). Following over-night blocking, membranes were rinsed, probed with the primary antibodies followed by Horseradish Peroxidase (HRP)-linked anti-Biotin and goat anti-mouse IgG (Cell Signaling Technology, Beverly, MA, USA) secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…ImageJ densitometry software (Version 1.4, National Institute of Health, Bethesda, MD, USA) was used to measure density of immunoblot bands (Kobeissy et al, 2006; McGinn et al, 2009; Zhang et al, 2009). Optical density for each band was measured three times and values were averaged.…”

Section: Methodsmentioning

confidence: 99%

Chronic Administration of a Leupeptin-Derived Calpain Inhibitor Fails to Ameliorate Severe Muscle Pathology in a Canine Model of Duchenne Muscular Dystrophy

Childers¹,

Bogan²,

Bogan³

et al. 2012

Front. Pharmacol.

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Calpains likely play a role in the pathogenesis of Duchenne muscular dystrophy (DMD). Accordingly, calpain inhibition may provide therapeutic benefit to DMD patients. In the present study, we sought to measure benefit from administration of a novel calpain inhibitor, C101, in a canine muscular dystrophy model. Specifically, we tested the hypothesis that treatment with C101 mitigates progressive weakness and severe muscle pathology observed in young dogs with golden retriever muscular dystrophy (GRMD). Young (6-week-old) GRMD dogs were treated daily with either C101 (17 mg/kg twice daily oral dose, n = 9) or placebo (vehicle only, n = 7) for 8 weeks. A battery of functional tests, including tibiotarsal joint angle, muscle/fat composition, and pelvic limb muscle strength were performed at baseline and every 2 weeks during the 8-week study. Results indicate that C101-treated GRMD dogs maintained strength in their cranial pelvic limb muscles (tibiotarsal flexors) while placebo-treated dogs progressively lost strength. However, concomitant improvement was not observed in posterior pelvic limb muscles (tibiotarsal extensors). C101 treatment did not mitigate force drop following repeated eccentric contractions and no improvement was seen in the development of joint contractures, lean muscle mass, or muscle histopathology. Taken together, these data do not support the hypothesis that treatment with C101 mitigates progressive weakness or ameliorates severe muscle pathology observed in young dogs with GRMD.

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“…Incubation of β cells isolated from wild type mice in ceramide induced apoptosis [55]. Isolated murine β cells lacking caspase 8 – a crucial substance in death receptor-mediated apoptosis, incubated in ceramide, showed increased viability in comparison to the control β cells, suggesting that ceramide is importantly involved in β cell apoptosis [56].…”

Section: Reviewmentioning

confidence: 99%

Sphingolipids in cardiovascular diseases and metabolic disorders

et al. 2015

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Many investigations suggest the pivotal role of sphingolipids in the pathogenesis of lifestyle diseases such as myocardial infarction, hypertension, stroke, diabetes mellitus type 2 and obesity. Some studies suggest that sphingolipids are important factors in cellular signal transduction. They serve as biologically active components of cell membrane and are involved in many processes such as proliferation, maturation and apoptosis. Recently, ceramide and sphingosine-1-phosphate have become the target of many investigations. Ceramide is generated in three metabolic pathways and many factors induce its production as a cellular stress response. Ceramide has proapoptotic properties and acts as a precursor for many other sphingolipids. Sphingosine-1-phosphate is a ceramide derivative, acting antiapoptotically and mitogenically and it is importantly involved in cardioprotection. Further research on the involvement of sphingolipids in cellular pathophysiology may improve the prevention and therapy of lifestyle diseases.

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Sphingomyelinase dependent apoptosis following treatment of pancreatic beta-cells with amyloid peptides Aß1-42 or IAPP

Cited by 17 publications

References 85 publications

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Chronic Administration of a Leupeptin-Derived Calpain Inhibitor Fails to Ameliorate Severe Muscle Pathology in a Canine Model of Duchenne Muscular Dystrophy

Sphingolipids in cardiovascular diseases and metabolic disorders

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