A5072799468- Lysosomal Storage Disorders Research
- Sphingolipid Metabolism and Signaling
- Carbohydrate Chemistry and Synthesis
- Lipid Membrane Structure and Behavior
- Erythrocyte Function and Pathophysiology
- Biomedical Research and Pathophysiology
- Cellular transport and secretion
- Calcium signaling and nucleotide metabolism
- Trypanosoma species research and implications
- Glycosylation and Glycoproteins Research
- Pancreatic function and diabetes
- Caveolin-1 and cellular processes
- Neonatal Health and Biochemistry
- Phagocytosis and Immune Regulation
- Marriage and Sexual Relationships
- Ion Transport and Channel Regulation
- Retinal Diseases and Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Pancreatitis Pathology and Treatment
- Protein Kinase Regulation and GTPase Signaling
- Renal Diseases and Glomerulopathies
- Complement system in diseases
- Sleep and Wakefulness Research
- Genetic and Kidney Cyst Diseases
University of Michigan
2015-2025
Michigan Medicine
1992-2024
Michigan United
2009-2023
Alexian Brothers Health System
2012-2016
Northwestern University
2009-2013
Indiana University – Purdue University Indianapolis
2011-2013
Indiana University School of Medicine
2011-2013
New York Blood Center
2011-2013
Cornell University
1994-2013
Case Western Reserve University
2010-2013
We have recently demonstrated enhanced alpha-adrenergic responsiveness assessed electrophysiologically in ischemic and reperfused myocardium. This study was performed to determine whether ischemia alters alpha 1-adrenergic receptor number (Bmax) of affinity (KD) based on [3H]prazosin binding. Within 30 min after occlusion, Bmax increased regions 207% control 27 +/- 2 fmol/mg protein, with the increase persisting (+ 141% control) during early reperfusion (2 min), before returning base-line...
Previous work has led to the identification of inhibitors glucosylceramide synthase, enzyme catalyzing first glycosylation step in synthesis glucosylceramide-based glycosphingolipids. These have two identified sites action: inhibition resulting depletion cellular glycosphingolipids, and 1-O-acylceramide elevation cell ceramide levels. A new series synthase based on substitutions phenyl ring a parent compound, 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), was made. For single...
Noroviruses are the major cause of nonbacterial gastroenteritis in humans. However, little is known regarding norovirus life cycle, including cell binding and entry. In contrast to human noroviruses, recently discovered murine 1 (MNV-1) readily infects macrophages dendritic cells culture. Many viruses, related feline calicivirus, use terminal sialic acids (SA) as receptors for infection. Therefore, we tested whether SA moieties play a role during MNV-1 infection macrophages. Competition with...
Inhibitors of sphingolipid synthesis protect mice from diet induced-insulin resistance, and sphingolipids such as ceramides glucosylated-ceramides (<i>e.g.</i>, GM3) are putative nutritional intermediates linking obesity to diabetes risk. Herein we investigated the role each these in muscle adipose tissue conclude that they independent separable antagonists insulin signaling. Of particular note, antagonize signaling both myotubes adipocytes, whereas glucosyceramides only efficacious...
In an attempt to define the basis for sphingolipid regulation of cell proliferation, we studied effects glucosylceramide (GlcCer) synthase inhibition by threo1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) on NIH 3T3 cells overexpressing insulin-like growth factor-1 (IGF-1) receptors. PDMP treatment resulted in a time-dependent decrease GlcCer levels and increase cellular ceramide levels. abolished serum IGF-1-stimulated as measured reduction [3H]thymidine incorporation, protein, DNA...
We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in alpha-galactosidase A (alpha-gal A) knockout mice, model Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidi no-propanol (D-t-EtDO-P4) showed concentration-dependent decrement kidney, liver, and spleen. single intraperitoneal injection D-t-EtDO-P4 resulted 55% reduction renal...
An inhibitor of glucosylceramide (GlcCer) synthase, l-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), has been reported to deplete cells and mice their glucosphingolipids. This proved useful for the elucidation many functions this lipid family [reviewed by Radin, N.S. & Inokuchi, J. (1991) Trends Glycosci Glycotechnol 3, 200–213]. In present study, we have synthesized homologs PDMP having different acyl chains (C6-C18) compared effectiveness inhibition GlcCer synthase in vitro GlcCer,...
Analogs and homologs of PDMP were synthesized, based on its structure (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol). This compound had previously been found to block the synthesis GlcCer (glucosylceramide). Increasing acyl chain length from 10 16 carbon atoms greatly enhanced efficacy enzyme inhibitor, as did use a less polar cyclic amine, especially pyrrolidine instead morpholine ring. Replacement phenyl ring by corresponding sphingosine also yielded strongly inhibitory...
A lysosomal phospholipase A2, LPLA2, was recently characterized and shown to have substrate specificity for phosphatidylcholine phosphatidylethanolamine. LPLA2 is ubiquitously expressed but most highly in alveolar macrophages. Double conditional gene targeting employed elucidate the function of LPLA2. LPLA2-deficient mice (Lpla2−/−) were generated by systemic deletion exon 5 Lpla2 gene, which encodes lipase motif essential A2 activity. The survival Lpla2−/− normal. mouse mating pairs yielded...
Eliglustat tartrate (Genz-112638) is a novel, orally administered agent currently in development for the treatment of lysosomal storage disorders, including type 1 Gaucher disease and Fabry disease. This glucosylceramide analogue acts as an inhibitor synthase, Golgi complex enzyme that catalyzes formation from ceramide UDP-glucose first step glucocerebroside-based glycosphingolipids. Pre-clinical pharmacological studies demonstrate has high therapeutic index, excellent oral bioavailability...
The endothelial dysfunction of Fabry disease results from α-galactosidase A deficiency leading to the accumulation globotriaosylceramide. Vasculopathy in null mouse is manifested as oxidant-induced thrombosis, accelerated atherogenesis, and impaired arterial reactivity. To better understand pathogenesis humans, we generated a human cell model by using RNA interference. Hybrid cells were transiently transfected with small interfering (siRNA) specifically directed against A. Knockdown was...
Lysosomal phospholipase A2 (LPLA2) and lecithin:cholesterol acyltransferase (LCAT) belong to a structurally uncharacterized family of key lipid-metabolizing enzymes responsible for lung surfactant catabolism reverse cholesterol transport, respectively. Whereas LPLA2 is predicted underlie the development drug-induced phospholipidosis, somatic mutations in LCAT cause fish eye disease familial deficiency. Here we describe several high-resolution crystal structures human low-resolution structure...
The lipid-rich stratum corneum functions as a barrier against pathogens and desiccation inter alia by an unbroken meshwork of extracellular lipid lamellae. These lamellae are composed cholesterol, fatty acids, ceramides (Cers) in equimolar ratio. huge class skin Cers consists three groups: group I, "classical" long very chain Cers; II, ultra-long III, ω-esterified Cers, which esterified either with linoleic acid or cornified envelope proteins required for the water permeability barrier....
Ceramide, a product of agonist-stimulated sphingomyelinase activation, is known to be generated during the phagocytosis antibody-coated erythrocytes by polymorphonuclear leukocytes. Agonist-stimulated formation ceramide-1-phosphate now shown occur in 32PO4-labeled neutrophils. Ceramide-1-phosphate formed calcium-dependent ceramide kinase, found predominately neutrophil plasma membrane. The kinase specific for because, contrast bacterial diglyceride not phosphorylated under conditions...
The opportunistic mycopathogen Aspergillus fumigatus expresses both glucosylceramide and galactosylceramide (GlcCer GalCer), but their functional significance in species is unknown. We here identified characterized a GlcCer from nidulans , non‐pathogenic model fungus. Involvement of fungal development was tested on using family compounds known to inhibit synthase mammals. Two analogs, D ‐ threo ‐1‐phenyl‐2‐palmitoyl‐3‐pyrrolidinopropanol (P4) ‐3′,4′‐ethylenedioxy‐P4, strongly inhibited...