Browsing by Author "Orr, Galya"

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    Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis
    (Springer Nature, 2024-02-21) Sarkar, Soumyadeep; Deiter, Cailin; Kyle, Jennifer E.; Guney, Michelle A.; Sarbaugh, Dylan; Yin, Ruichuan; Li, Xiangtang; Cui, Yi; Ramos‑Rodriguez, Mireia; Nicora, Carrie D.; Syed, Farooq; Juan‑Mateu, Jonas; Muralidharan, Charanya; Pasquali, Lorenzo; Evans‑Molina, Carmella; Eizirik, Decio L.; Webb‑Robertson, Bobbie‑Jo M.; Burnum‑Johnson, Kristin; Orr, Galya; Laskin, Julia; Metz, Thomas O.; Mirmira, Raghavendra G.; Sussel, Lori; Ansong, Charles; Nakayasu, Ernesto S.; Pediatrics, School of Medicine
    Background: Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. Methods: We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. Results: Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis. Conclusions: Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids.
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    Three human cell types respond to multi-walled carbon nanotubes and titanium dioxide nanobelts with cell-specific transcriptomic and proteomic expression patterns
    (Taylor & Francis, 2014-08) Tilton, Susan C.; Karin, Norman J.; Tolic, Ana; Xie, Yumei; Lai, Xianyin; Hamilton Jr., Raymond F.; Waters, Katrina M.; Holian, Andrij; Witzmann, Frank A.; Orr, Galya; Cellular & Integrative Physiology, School of Medicine
    The growing use of engineered nanoparticles (NPs) in commercial and medical applications raises the urgent need for tools that can predict NP toxicity. We conducted global transcriptome and proteome analyses of three human cell types, exposed to two high aspect ratio NP types, to identify patterns of expression that might indicate high vs. low NP toxicity. Three cell types representing the most common routes of human exposure to NPs, including macrophage like (THP-1), small airway epithelial (SAE), and intestinal (Caco-2/HT29-MTX) cells, were exposed to TiO2 nanobelts (TiO2-NB; high toxicity) and multi-walled carbon nanotubes (MWCNT; low toxicity) at low (10 μg/ml) and high (100 μg/ml) concentrations for 1 and 24 h. Unique patterns of gene and protein expressions were identified for each cell type, with no differentially expressed (p<0.05, 1.5-fold change) genes or proteins overlapping across all three cell types. While unique to each cell-type, the early response was primarily independent of NP type, showing similar expression patterns in response to both TiO2-NB and MWCNT. The early response might therefore indicate a general response to insult. In contrast, the 24 h response was unique to each NP type. The most significantly (p<0.05) enriched biological processes in THP-1 cells indicated TiO2-NB regulation of pathways associated with inflammation, apoptosis, cell cycle arrest, DNA replication stress and genomic instability, while MWCNT regulated pathways indicating increased cell proliferation, DNA repair and anti-apoptosis. These two distinct sets of biological pathways might therefore underlie cellular responses to high and low NP toxicity, respectively.