A5090669842- Amino Acid Enzymes and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Endoplasmic Reticulum Stress and Disease
- Glutathione Transferases and Polymorphisms
- Cancer Research and Treatments
- Redox biology and oxidative stress
- Cancer, Hypoxia, and Metabolism
- Adipose Tissue and Metabolism
- Muscle metabolism and nutrition
- Mitochondrial Function and Pathology
- Asthma and respiratory diseases
- Sulfur Compounds in Biology
- Metabolism and Genetic Disorders
- Immune cells in cancer
- Genomics, phytochemicals, and oxidative stress
- Cancer, Lipids, and Metabolism
- Autophagy in Disease and Therapy
- Neonatal Respiratory Health Research
- Neuroendocrine Tumor Research Advances
- Advanced Proteomics Techniques and Applications
- Metabolism, Diabetes, and Cancer
- HER2/EGFR in Cancer Research
- Adipokines, Inflammation, and Metabolic Diseases
- Bacteriophages and microbial interactions
- Advanced Breast Cancer Therapies
University of Utah
2023-2025
Orano (United States)
2024
University of Pittsburgh
2022-2023
University of Vermont
2018-2023
University of South Carolina
2013-2023
Eli Lilly (United States)
2022
Emory University Hospital
2021
Bacteria can repurpose their own bacteriophage viruses (phage) to kill competing bacteria. Phage-derived elements are frequently strain specific in killing activity, although there is limited evidence that this specificity drives bacterial population dynamics. Here, we identified intact phage and derived a metapopulation of wild plant-associated Pseudomonas genomes. We discovered the most abundant viral cluster encodes remnant resembling tail called tailocin, which bacteria have co-opted...
4020 Background: 212 Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide (PRRT) beta-emitters like 177 Lu-DOTATATE, currently considered standard of care GEP-NETs. Methods: ALPHAMEDIX 02 Phase II, open-label, multicenter evaluating safety, tolerability...
Elevated fumarate concentrations as a result of Krebs cycle inhibition lead to increases in protein succination, an irreversible post-translational modification that occurs when reacts with cysteine residues generate S-(2-succino)cysteine (2SC). Metabolic events reduce NADH re-oxidation can block activity; therefore we hypothesized oxidative phosphorylation deficiencies, such those observed some mitochondrial diseases, would also increased succination. Using the Ndufs4 knockout (Ndufs4 KO)...
The fumarate ester dimethyl (DMF) has been introduced recently as a treatment for relapsing remitting multiple sclerosis (RRMS), chronic inflammatory condition that results in neuronal demyelination and axonal loss. DMF is known to act by depleting intracellular glutathione modifying thiols on Keap1 protein, resulting the stabilization of transcription factor Nrf2, which turn induces expression antioxidant response element genes. We have previously shown reacts with wide range protein...
Protein succination is a stable post-translational modification that occurs when fumarate reacts with cysteine residues to generate 2SC [S-(2-succino)cysteine]. We demonstrate both α- and β-tubulin are increasingly modified by in 3T3-L1 adipocytes the adipose tissue of db/db mice. Incubation purified tubulin from porcine brain (50 mM) or pharmacological compound DMF (dimethylfumarate, 500 μM) inhibited polymerization up 35% 59% respectively. Using MS we identified Cys347α, Cys376α, Cys12β...
Glutathione is a major redox buffer, reaching millimolar concentrations within cells and high micromolar in airways. While glutathione has been traditionally known as an antioxidant defense mechanism that protects the lung tissue from oxidative stress, more recently become recognized for its ability to covalently conjugated reactive cysteines proteins, modification S-glutathionylation (or S-glutathiolation or protein mixed disulfide). potential change structure function of target protein,...
Abstract Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1–induced glycolytic reprogramming contributes to allergic disease using murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well nasal epithelial cells from asthmatics compared with healthy controls. Although the tetramer form PKM2 converts phosphoenolpyruvate pyruvate, dimeric...
Interleukin-1-dependent increases in glycolysis promote allergic airways disease mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated asthma pathogenesis regulates the oxidation state proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes by promoting glycolytic reprogramming it involves PKM2.
Peroxiredoxins (PRDXs) catalyze the reduction of hydrogen peroxide (H2O2). PRDX4 is only peroxiredoxin located within endoplasmic reticulum (ER) and most highly expressed H2O2 scavenger in ER. has emerged as an important player numerous diseases, such fibrosis metabolic syndromes, its overoxidation a potential indicator ER redox stress. It unclear how governs oligomerization state interacting partners. Herein, we addressed these questions via nonreducing Western blots, mass spectrometry,...
Abstract Objective Glucagon‐like peptide‐1 receptor agonists (e.g., semaglutide) potently induce weight loss, thereby reducing obesity‐related complications. However, regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet‐mediated loss has been described, which may contribute to reduced systemic energy expenditure and regain. We set out determine the unknown effect of semaglutide on OXPHOS efficiency. Methods...
Protein succination by fumarate increases in the adipose tissue of diabetic mice and adipocytes matured high glucose as a result glucotoxicity-driven mitochondrial stress. The endoplasmic reticulum (ER) oxidoreductase protein disulfide isomerase (PDI) is succinated that are glucose, this study we investigated whether would alter PDI activity, directly linking stress ER stress.Protein marker C/EBP homologous (CHOP) were diminished after pharmaceutical targeting with chemical uncoupler...
Abstract Protein-S-glutathionylation is a post-translational modification involving the conjugation of glutathione to protein thiols, which can modulate activity and structure key cellular proteins. Glutaredoxins (GLRX) are oxidoreductases that regulate this process by performing deglutathionylation. However, GLRX has five cysteines potentially vulnerable oxidative modification, associated with aggregation loss activity. To date, oxidatively modified their relative susceptibilities remain...
Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 CDK6 approved for administration on continuous dosing schedule as monotherapy or combination therapy with an aromatase fulvestrant patients advanced metastatic breast cancer. This Phase 1b study evaluated the safety tolerability, pharmacokinetics, antitumor activity abemaciclib endocrine cancer (MBC), including inhibitors (letrozole,...
Glycolysis is a well-known process by which metabolically active cells, such as tumor or immune cells meet their high metabolic demands. Previously, our laboratory has demonstrated that in airway epithelial the pleiotropic cytokine, interleukin-1 beta (IL1B) induces glycolysis and this contributes to allergic inflammation remodeling. Activation of known increase NADPH reducing equivalents generated from pentose phosphate pathway, linking reprogramming with redox homeostasis. In addition,...
Abstract Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer depend a greater extent on stress signaling, require the integrated response (ISR), amino acid metabolism, efficient protein folding degradation pathways survive. To define how these interconnected wired challenged we investigated abundance influences cell survival Hsp70, master...
Obesity is a risk factor for the development of asthma and represents difficult-to-treat disease phenotype. Aerobic glycolysis emerging as key feature asthma, changes in glucose metabolism are linked to leukocyte activation adaptation oxidative stress. Dysregulation PKM2 (pyruvate kinase M2), enzyme that catalyzes last step glycolysis, contributes house dust mite (HDM)–induced airway inflammation remodeling lean mice. It remains unclear whether glycolytic reprogramming dysregulation also...
Abstract Bacteriophages, the viruses of bacteria, are proposed to drive bacterial population dynamics, yet direct evidence their impact on natural populations is limited. Here we identified viral sequences in a metapopulation wild plant-associated Pseudomonas spp. genomes. We discovered that most abundant cluster does not encode an intact phage but instead encodes tailocin - phage-derived element bacteria use kill competitors for interbacterial warfare. Each pathogenic sp. strain carries one...
The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. irreversible succination of protein thiols by fumarate is increased in select regions KO brain affected neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component α-ketoglutarate dehydrogenase complex (KGDHC) tricarboxylic acid (TCA) cycle, succinated brain. Succination DLST reduced KGDHC activity brainstem (BS) and olfactory bulb (OB) mice. defective...
Extracellular vesicles (EV) have long been recognized as an important means of cell to communication, but current metrics delineate various subpopulations EV are limited. Recently, a distinctive subpopulation embedded within the extracellular matrix soft tissues, termed matrix-bound nanovesicles (MBV), has described. Although lipid membrane composition and intravesicular cargo MBV clearly differ from liquid phase (i.e. exosomes), more comprehensive characterization physical biologic...
<p>S1. Amino acid modulation orchestrates apoptosis when proteostasis is compromised.</p>