A5037386752- Protein Kinase Regulation and GTPase Signaling
- Cytokine Signaling Pathways and Interactions
- Pain Mechanisms and Treatments
- Rheumatoid Arthritis Research and Therapies
- Inflammatory mediators and NSAID effects
- Pharmacological Effects of Natural Compounds
- Systemic Lupus Erythematosus Research
- T-cell and B-cell Immunology
- Autoimmune and Inflammatory Disorders Research
- Cellular transport and secretion
- NF-κB Signaling Pathways
- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- Protein Tyrosine Phosphatases
- Adenosine and Purinergic Signaling
- Immune Cell Function and Interaction
- Pain Management and Opioid Use
- Mast cells and histamine
- Psoriasis: Treatment and Pathogenesis
- Asthma and respiratory diseases
- Phosphodiesterase function and regulation
- Immune Response and Inflammation
- Pediatric Pain Management Techniques
- interferon and immune responses
- Pharmacogenetics and Drug Metabolism
VA Palo Alto Health Care System
2000-2025
Stanford University
2000-2025
Stanford Medicine
2025
Jackson Laboratory
2014-2023
Pfizer (United States)
2010-2021
Pfizer (United Kingdom)
2012
Inflammation Research Foundation
2003-2009
Mount Sinai Medical Center
1995-2008
Pearl River Community College
2006
Savannah River National Laboratory
2005
The major dithiothreitol-resistant phospholipase A2 activity present in the cytosol of U937 cells has been purified greater than 200,000-fold by sequential chromatography on phenyl-5PW, heparin-Sepharose CL-6B, high-performance hydroxylapatite, TSK-gel G3000-SW, and Mono Q columns. This 110-kDa cytosolic is distinct from relatively small (14-kDa) dithiothreitol-sensitive phospholipases that are secreted many cell types. additional selectively hydrolyzes fatty acid at sn-2 position glycerol...
<h2>Summary</h2> Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For global view IFN signatures regulatory pathways, we performed gene expression chromatin analyses the IFN-induced response across range immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, sensitivity tonic revealed underlying changes in configuration. We combined...
Abstract The role of sex in biomedical studies has often been overlooked, despite evidence sexually dimorphic effects some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, found a large proportion mammalian traits both mutants are influenced by sex. This result implications interpreting disease phenotypes animal models humans.
Cytosolic phospholipase A, (cPLAJ associates with natural membranes in response to physiological increases Ca2+, resulting the selective hydrolysis of arachidonyl phospholipids.The isolation and sequence analysis cPLA, cDNA clones from four different species revealed several highly conserved regions.The N H 2 - terminal region is homologous other Ca2+-dependent lipid-binding proteins.Here we report that first 178 residues c P w , containing (CaLB) motif, another recombinant protein...
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells level that could not be achieved previously without such potency selectivity. In vitro, inhibits Th1 Th17 cell differentiation function, vivo it reduces disease pathology rat adjuvant-induced arthritis as well mouse...
Janus kinases (JAKs) are intracellular tyrosine that mediate the signaling of numerous cytokines and growth factors involved in regulation immunity, inflammation, hematopoiesis. As JAK1 pairs with JAK2, JAK3, TYK2, a JAK1-selective inhibitor would be expected to inhibit many inflammation immune function while avoiding inhibition JAK2 homodimer regulating erythropoietin thrombopoietin signaling. Our efforts began tofacitinib, an oral JAK approved for treatment rheumatoid arthritis. Through...
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator transcription (STAT) pathway. JAK1 for γ-common chain cytokines, interleukin (IL)-6, type-I interferon (IFN) family, while TYK2 in addition to IFN also plays a role IL-23 IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or inhibitors has demonstrated efficacy Phase III psoriasis, psoriatic arthritis,...
<h3>Background</h3> Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. <h3>Objective</h3> We sought to elucidate the molecular mechanisms underlying clinical efficacy of tofacitinib in patients with <h3>Methods</h3> Twelve plaque psoriasis were randomized (3:1) receive 10 mg or placebo twice daily 12 weeks. Biopsy specimens taken from nonlesional (baseline) and lesional (baseline, days 1 3, weeks 1, 2, 4, 12) skin. examined psoriatic epidermal features...
Patients with complex regional pain syndrome have increased tryptase in the skin of affected extremity indicating mast cell (MC) accumulation and degranulation, processes known to be mediated by substance P (SP). The dysregulation SP release from primary afferent neurons is characteristic syndrome. authors hypothesized that acting through neurokinin-1 receptor results accumulation, nociceptive sensitization a rat model syndrome.Groups 6-10 rats underwent tibia fracture hind limb casting for...
Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced (CIA). Cytosolic phospholipase A2α (cPLA2α) releases arachidonic acid from cell membranes initiate production prostaglandins and leukotrienes. These inflammatory mediators have been implicated development CIA. To test hypothesis that cPLA2α plays a key role CIA, we backcrossed cPLA2α-deficient mice on DBA/1LacJ background is susceptible The disease severity scores incidence were markedly...
Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is model human multiple sclerosis. Cytosolic phospholipase A2α (cPLA2α), which initiates production prostaglandins, leukotrienes, and platelet-activating factor, present in EAE lesions. Using myelin oligodendrocyte glycoprotein (MOG) immunization, as well an adoptive transfer model, we showed that cPLA2α−/− mice are resistant to EAE. Histologic examination CNS from...
Opioid-induced hyperalgesia (OIH) is a syndrome of increased sensitivity to noxious stimuli, seen after both the acute and chronic administration opioids, that has been observed in humans rodent models. This may reduce clinical utility opioids treating pain.
The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210).To report haematology data from trial, given importance JAK-dependent signalling haematopoiesis.Patients with moderate-to-severe chronic plaque were randomized to receive tofacitinib 2, 5 or 15 mg, placebo, twice daily over 12 weeks. Blood samples collected at screening, baseline, weeks 4, 8 and during treatment, 14 16 off-treatment follow-up.Baseline...
In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering amount of interleukin (IL)-1 produced. We further investigate role IL-1 incisional biology and its effect on vivo whether this mechanism be active human subjects.A well-characterized murine model wounding was used assess biology. The 7 different cytokines/chemokines produced an experimentally induced skin incision a mouse paw...
Tyrosine kinase 2 (TYK2) is a member of the JAK family that regulates signal transduction downstream receptors for IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On basis human genetic emerging clinical data, selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering potentially differentiated profile compared currently approved inhibitors. The discovery ATP-competitive pyrazolopyrazinyl series inhibitors was...
The Ca<sup>2+</sup>-dependent lipid binding domain of the 85-kDa cytosolic phospholipase A<sub>2</sub> (cPLA<sub>2</sub>) is a homolog C2 domains present in protein kinase C, synaptotagmin, and numerous other proteins involved signal transduction. NH<sub>2</sub>-terminal fragments cPLA<sub>2</sub> spanning were expressed as inclusion bodies <i>Escherichia coli</i>, extracted with solvent to remove phospholipids, refolded yield capable phospholipid vesicles manner. Unlike characterized date,...
Production of leukotriene B4 (LTB4) by human neutrophils (PMN) in response to different stimuli is increased after pretreatment with lipopolysaccharides (LPS). We have analyzed the steps arachidonic acid (AA) metabolism affected LPS examining release AA and its metabolites from [3H]AA prelabeled PMN. Pretreatment PMN for 60 min up 1 microgram/ml alone had no effect, but was stimulated fivefold during subsequent stimulation a second agent. In absence LPS-binding protein (LBP), priming maximal...
The optimization of a class indole cPLA 2 alpha inhibitors is described herein. importance the substituent at C3 and substitution pattern phenylmethane sulfonamide region are highlighted. Optimization these regions led to discovery 111 (efipladib) 121 (WAY-196025), which shown be potent, selective in variety isolated enzyme assays, cell based rat human whole blood assays. binding compounds has been further examined using isothermal titration calorimetry. Finally, have efficacy when dosed...