A5023194202- Sphingolipid Metabolism and Signaling
- Pancreatic function and diabetes
- Immune cells in cancer
- Regulation of Appetite and Obesity
- Diet and metabolism studies
- Lipid Membrane Structure and Behavior
- Liver Disease and Transplantation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cellular transport and secretion
- Drug Transport and Resistance Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Liver Disease Diagnosis and Treatment
- Carbohydrate Chemistry and Synthesis
- Liver physiology and pathology
- Adipose Tissue and Metabolism
- Animal Genetics and Reproduction
- Digestive system and related health
- Cancer Cells and Metastasis
- Protein Kinase Regulation and GTPase Signaling
- Biomedical Research and Pathophysiology
- Sleep and Wakefulness Research
- Protein Hydrolysis and Bioactive Peptides
- Lipid metabolism and disorders
- Ferroptosis and cancer prognosis
- NF-κB Signaling Pathways
Stony Brook School
2022-2024
Stony Brook University
2014-2024
Université Paris Cité
2006-2024
Unit of Functional and Adaptive Biology
2011-2024
Centre National de la Recherche Scientifique
2011-2024
Institut Cochin
2017
Stony Brook Medicine
2016
Délégation Paris 7
2006-2014
Weatherford College
2013
Inserm
2006-2011
AbstractThe homeostatic self-renewal of the colonic epithelium requires coordinated regulation canonical Wnt/β-catenin and Notch signaling pathways to control proliferation lineage commitment multipotent stem cells. However, molecular mechanisms by which Notch1 interplay in controlling cell fate colon are poorly understood. Here we show that NADPH oxidase 1 (NOX1), a reactive oxygen species (ROS)-producing is highly expressed epithelial cells, pivotal determinant integrates signals....
Myeloid-derived suppressor cells (MDSCs) are immune suppressive that massively accumulate under pathological conditions to suppress T cell response. Dysregulated death contributes MDSC accumulation, but the molecular mechanism underlying this dysregulation is not fully understood. In study, we report neutral ceramidase (N-acylsphingosine amidohydrolase [ASAH2]) highly expressed in tumor-infiltrating MDSCs colon carcinoma and acts as an survival factor. To target ASAH2, performed docking...
Pancreatic β-cell apoptosis induced by palmitate requires high glucose concentrations. Ceramides have been suggested to be important mediators of glucolipotoxicity-induced apoptosis. In INS-1 β-cells, 0.4 mM with 5 increased the levels dihydrosphingosine and dihydroceramides, two lipid intermediates in de novo biosynthesis ceramides, without inducing Increasing concentrations 30 amplified palmitate-induced accumulation formation (dihydro)ceramides. Of note, glucolipotoxicity specifically...
Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of metabolism may emerge as novel regulators targets cancer. Neutral ceramidase (nCDase), a key enzyme hydrolyzes into sphingosine, is highly expressed the intestine; however, its role cancer has not defined. Here we show molecular pharmacological inhibition nCDase cells increases ceramide, this accompanied by decreased cell survival increased...
Hypothalamic lipotoxicity has been shown to induce central insulin resistance and dysregulation of glucose homeostasis; nevertheless, elucidation the regulatory mechanisms remains incomplete. Here, we aimed determine role de novo ceramide synthesis in hypothalamus on onset homeostasis induced by obesity. GT1-7 neuronal cells were treated with palmitate. De was inhibited either pharmacological (myriocin) or molecular (si-Serine Palmitoyl Transferase 2, siSPT2) approaches. Obese Zucker rats...
Brain lipid sensing is necessary to regulate energy balance. Lipoprotein lipase (LPL) may play a role in this process. We tested if hippocampal LPL regulated homeostasis rodents by specifically attenuating activity the hippocampus of rats and mice, either infusing pharmacological inhibitor (tyloxapol), or using genetic approach (adeno-associated virus expressing Cre-GFP injected into Lpl (lox/lox) mice). Decreased method led increased body weight gain due decreased locomotor expenditure,...
High-density lipoproteins (HDL) are known to neutralize lipopolysaccharide (LPS). Because patients with cirrhosis have lower HDL levels, this may contribute LPS-induced ex vivo monocyte overproduction of proinflammatory cytokines. However, the effects on cytokine production by monocytes from never been studied. The aim study was determine in whole blood and isolated severe controls. Plasma levels cytokines were determined. reconstituted (rHDL) assessed array tumor necrosis factor alpha...
Accumulating evidence suggests that glucolipotoxicity, arising from the combined actions of elevated glucose and free fatty acid levels, acts as a key pathogenic component in type II diabetes, contributing to β-cell dysfunction death. Endoplasmic reticulum (ER) stress is among molecular pathways regulators involved these negative effects, ceramide accumulation due glucolipotoxicity can be associated with induction ER stress. Increased levels may enhanced biosynthesis and/or decreased...
Activation of hepatic stellate cells (HSCs) in response to injury is a key step fibrosis, and characterized by trans-differentiation quiescent HSCs HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies directly inhibit fibrosis. We developed small molecule screen identify compounds that inactivate human myofibroblasts through quantification lipid droplets. screened 1600 identified 21 molecules induce inactivation....
Sphingosine kinase 1 (SK1), one of two SK enzymes, is highly regulated and has been shown to act as a focal point for the action many growth factors cytokines. SK1 leads generation sphingosine-1-phosphate (S1P) potentially activation S1P receptors mediate biologic effects. Our previous studies implicated SK1/S1P in regulation inflammatory processes, specifically bowel disease (IBD). These were conducted using total body knockout mouse unable determine source (hematopoietic or...
Bioactive sphingolipids are modulators of immune processes and their metabolism is often dysregulated in ulcerative colitis, a major category inflammatory bowel disease (IBD). While multiple axes sphingolipid have been investigated to delineate mechanisms regulating the role acid ceramidase (AC) intestinal inflammation yet be characterized. Here we demonstrate that AC expression elevated selectively infiltrate human murine colitis. To probe for mechanistic insight into how up-regulation can...
Ceramidases hydrolyze ceramides into sphingosine and fatty acids, with being further metabolized sphingosine-1-phosphate (S1P); thus, ceramidases control the levels of these bioactive sphingolipids in cells tissues. Neutral ceramidase (nCDase) is highly expressed colorectal tissues, a recent report showed that nCDase activity involved Wnt/β-catenin signaling. In addition, inhibition decreases development progression tumor growth. Here, to determine action cancer cells, we focused on...
There is interest in developing inhibitors of human neutral ceramidase (nCDase) because this enzyme plays a critical role colon cancer. are currently no potent or clinically effective for nCDase reported to date, so we adapted fluorescence-based activity method high-throughput screening format. We opted use an assay whereby hydrolyzes the substrate RBM 14-16, and addition NaIO4 acts as oxidant that releases umbelliferone, resulting fluorescent signal. As designed, test compounds act will...