A5073656125- Atherosclerosis and Cardiovascular Diseases
- Immune cells in cancer
- Cancer, Lipids, and Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Sphingolipid Metabolism and Signaling
- Eicosanoids and Hypertension Pharmacology
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Lipid metabolism and disorders
- Antioxidant Activity and Oxidative Stress
- Lipid Membrane Structure and Behavior
- Angiogenesis and VEGF in Cancer
- Heme Oxygenase-1 and Carbon Monoxide
- Genetics, Aging, and Longevity in Model Organisms
- Adipose Tissue and Metabolism
- Diet, Metabolism, and Disease
- Cholesterol and Lipid Metabolism
- Alzheimer's disease research and treatments
- Single-cell and spatial transcriptomics
- Peroxisome Proliferator-Activated Receptors
- Liver Disease Diagnosis and Treatment
- Nuclear Receptors and Signaling
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- Electron Spin Resonance Studies
- Medicinal Plants and Bioactive Compounds
University of Kentucky
2015-2024
University of California, Los Angeles
2006-2014
University of Chicago
2012
Bristol-Myers Squibb (United States)
2011
University of Virginia
2005-2007
The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses in mice expressing human APOE to systematically address role across age, neuroinflammation, AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes APOE4 glial...
Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper effector cells to be retained in secondary lymphoid tissue away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated kinase 2 (SPHK2) null mice demonstrate this responsible for FTY720 phosphorylation thereby its...
Envenomation by the brown recluse spider (Loxosceles reclusa) may cause local dermonecrosis and, rarely, coagulopathies, kidney failure and death. A venom phospholipase, SMaseD (sphingomyelinase D), is responsible for pathological manifestations of envenomation. Recently, recombinant from Loxosceles laeta was demonstrated to hydrolyse LPC (lysophosphatidylcholine) produce LPA (lysophosphatidic acid) choline. Therefore activation signalling pathways be involved in some To begin investigating...
Oxidized palmitoyl arachidonyl phosphatidylcholine (Ox-PAPC) accumulates in atherosclerotic lesions, is proatherogenic, and influences the expression of more than 1000 genes endothelial cells.To elucidate major pathways involved Ox-PAPC action, we conducted a systems analysis cell gene after exposure to Ox-PAPC.We used variable responses primary cells from 149 individuals exposed construct network that consisted 11 groups genes, or modules. Modules were enriched for broad range Gene Ontology...
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) is present in oxidative modified LDL and accumulates lesions of many chronic inflammatory diseases, such as atherosclerosis. In a microarray study, OxPAPC has been demonstrated to modulate the expression >700 genes human aortic endothelial cells. We found that levels mRNA for OKL38 [also named Bone marrow Derived Growth Factor (BDGI)], tumor growth inhibitor, were strongly increased by OxPAPC. Here, we report...
Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. We previously showed that TSP1 has an important role in obesity-associated metabolic complications, including inflammation, insulin resistance, cardiovascular, and renal disease. However, its contribution to non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD or NASH) remains largely unknown; thus, we aimed determine role.High-fat diet AMLN (amylin diet-induced obese insulin-resistant NAFLD/NASH mouse...
Chronic infection has long been postulated as a stimulus for atherogenesis. Pseudomonas aeruginosa associated with increased atherosclerosis in rats, and these bacteria produce quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical colonization virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL also protects against the effects of oxidized phospholipids thought to contribute atherosclerosis. We now report response human aortic endothelial cells (HAECs)...
Background and AimsRecent studies have implicated platelets, particularly α-granules, in the development of steatohepatitis (NASH). However, specific mechanisms involved yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component platelet α-granules released during activation. The role derived TSP1 NASH remains unknown was investigated this study.MethodsPlatelet-specific knockout mice (TSP1Δpf4) their wild type littermates (TSP1F/F) were used. induced by feeding with diet...
Introduction Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) differentially modulate endothelial cell (EC) barrier function in a dose-dependent fashion. Vascular growth factor receptor-2 (VEGFR2) is involved the OxPAPC-induced EC inflammatory activation. This study examined role VEGFR2 dysfunction caused by high concentrations OxPAPC and evaluated downstream signaling mechanisms resulting from effect pulmonary systemic circulation. Methods monolayer...
Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), referred to as OxPAPC, and an active component, 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphatidylcholine (PEIPC), accumulate in atherosclerotic lesions regulate over 1,000 genes human aortic endothelial cells (HAEC). We previously demonstrated that OxPNB, a biotinylated analog covalently binds number proteins HAEC. The goal these studies was gain insight into the binding mechanism...
GM2-activator protein (GM2AP) is a lysosomal lipid transfer with important biological roles in ganglioside catabolism, phospholipid metabolism, and T-cell activation. Previous studies of crystal structures GM2AP complexed the physiological ligand GM2 platelet activating factor (PAF) have shown binding at two specific locations within spacious apolar pocket an ordering effect endogenous resident lipids. To investigate structural basis further, was cocrystallized phosphatidylcholine (PC),...
Atherosclerosis is a chronic inflammatory disease initiated by monocyte recruitment and retention in the vessel wall. An important mediator of endothelial interaction chemokine interleukin (IL)-8. The oxidation products phospholipids, including oxidized 1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine (Ox-PAPC), accumulate atherosclerotic lesions strongly induce IL-8 human aortic cells (HAECs). goal this study was to identify proximal events leading induction Ox-PAPC vascular cells.In...
The goal of these studies was to determine the effect 5,6-epoxyisoprostane, EI, on human aortic endothelial cells (HAEC). EI can form as a phospholipase product 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine, PEIPC, proinflammatory molecule that accumulates in sites inflammation where phospholipases are also increased. To HAEC, we synthesized several stereoisomers using convergent approach from individual optically pure building blocks, epoxyaldehydes 5 and 6 bromoenones...
Summary Apolipoprotein E4 (APOE4) is the strongest risk allele associated with development of late onset Alzheimer’s disease (AD). Across CNS, astrocytes are predominant expressor APOE while also being critical mediators neuroinflammation and cerebral metabolism. APOE4 has been consistently linked dysfunctional inflammation metabolic processes, yet insights into molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized mice isogenic...
The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk cardiovascular disease. In this study, we tested effects HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on development aortic aneurysm a mouse model.Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks age) were injected control ASOs for 10 weeks. To induce aneurysm, fed high fat diet (22% fat, 0.2% cholesterol; w/w) at...
Summary The E4 allele of Apolipoprotein E ( APOE ) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses to systematically address role across age, neuroinflammation, AD pathology. RNAseq highlighted immunometabolic changes APOE4 glial transcriptome, specifically in...
As the elderly population increases, chronic, age-associated diseases are challenging healthcare systems around world. Nutrient limitation is well known to slow aging process and improve health. Regrettably, practicing nutrient restriction health unachievable for most people. Alternatively, pharmacological strategies being pursued including myriocin which increases lifespan in budding yeast. Myriocin impairs sphingolipid synthesis, resulting lowered amino acid pools promote entry into a...