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Wake Forest, NC, United States

Cao Q.,Georgia State University | Cui X.,Georgia State University | Wu R.,Georgia State University | Zha L.,Georgia State University | And 4 more authors.
Diabetes | Year: 2016

Macrophage inflammation marks all stages of atherogenesis, and AMPK is a regulator of macrophage inflammation. We therefore generated myeloid α1AMPK knockout (MAKO) mice on the LDL receptor knockout (LDLRKO) background to investigate whether myeloid deletion of α1AMPK exacerbates atherosclerosis. When fed an atherogenic diet, MAKO/LDLRKO mice displayed exacerbated atherosclerosis compared with LDLRKO mice. To determine the underlying pathophysiological pathways, we characterized macrophage inflammation/chemotaxis and lipid/cholesterol metabolism in MAKO/LDLRKO mice. Myeloid deletion of a1AMPK increased macrophage inflammatory gene expression and enhanced macrophage migration and adhesion to endothelial cells. Remarkably, MAKO/LDLRKO mice also displayed higher composition of circulating chemotaxically active Ly-6Chigh monocytes, enhanced atherosclerotic plaque chemokine expression, and monocyte recruitment into plaques, leading to increased atherosclerotic plaque macrophage content and inflammation. MAKO/LDLRKO mice also exhibited higher plasma LDL and VLDL cholesterol content, increased circulating apolipoprotein B (apoB) levels, and higher liver apoB expression. We conclude that macrophage a1AMPK deficiency promotes atherogenesis in LDLRKO mice and is associated with enhanced macrophage inflammation and hypercholesterolemia and that macrophage α1AMPK may serve as a therapeutic target for prevention and treatment of atherosclerosis. © 2016 by the American Diabetes Association. Source

Furdui C.M.,Section on Molecular Medicine | Poole L.B.,Medical Center Boulevard
Mass Spectrometry Reviews | Year: 2014

Orchestration of many processes relying on intracellular signal transduction is recognized to require the generation of hydrogen peroxide as a second messenger, yet relatively few molecular details of how this oxidant acts to regulate protein function are currently understood. This review describes emerging chemical tools and approaches that can be applied to study protein oxidation in biological systems, with a particular emphasis on a key player in protein redox regulation, cysteine sulfenic acid. While sulfenic acids (within purified proteins or simple mixtures) are detectable by physical approaches like X-ray crystallography, nuclear magnetic resonance and mass spectrometry, the propensity of these moieties to undergo further modification in complex biological systems has necessitated the development of chemical probes, reporter groups and analytical approaches to allow for their selective detection and quantification. Provided is an overview of techniques that are currently available for the study of sulfenic acids, and some of the biologically meaningful data that have been collected using such approaches. © 2013 Wiley Periodicals, Inc. Source

Furdui C.M.,Section on Molecular Medicine
Antioxidants and Redox Signaling | Year: 2014

While chemotherapy and radiation therapy have been integral components of cancer management for decades, the issues of local recurrence, clinical resistance, and toxicities resulting from these treatment modalities have increased the interest in novel therapeutic approaches that could attenuate tumor progression and prevent recurrences. This Forum highlights current research focused on elucidation of the mechanisms of response to radiation treatment and the development of out-of-the-box therapeutic strategies for cancer treatment with radiation. Experts in the field of radiation research contribute with review articles describing the current knowledge on DNA damage response mechanisms, regulation of signaling involved in the DNA damage response by miRNA, the function of tumor hypoxia in tumor response to radiation, and the role of stem cells in protection of normal tissue against radiation damage. Antioxid. Redox Signal. 21, 218-220. © Mary Ann Liebert, Inc. 2014. Source

Reisz J.A.,Section on Molecular Medicine | Bechtold E.,Wake forest University | Bechtold E.,Tufts University | King S.B.,Wake forest University | Furdui C.M.,Section on Molecular Medicine
FEBS Journal | Year: 2013

Cellular exposure to reactive oxygen species induces rapid oxidation of DNA, proteins, lipids and other biomolecules. At the proteome level, cysteine thiol oxidation is a prominent post-translational process that is implicated in normal physiology and numerous pathologies. Methods for investigating protein oxidation include direct labeling with selective chemical probes and indirect tag-switch techniques. Common to both approaches is chemical blocking of free thiols using reactive electrophiles to prevent post-lysis oxidation or other thiol-mediated cross-reactions. These reagents are used in large excess, and their reactivity with cysteine sulfenic acid, a critical oxoform in numerous proteins, has not been investigated. Here we report the reactivity of three thiol-blocking electrophiles, iodoacetamide, N-ethylmaleimide and methyl methanethiosulfonate, with protein sulfenic acid and dimedone, the structural core of many sulfenic acid probes. We demonstrate that covalent cysteine -SOR (product) species are partially or fully susceptible to reduction by dithiothreitol, tris(2-carboxyethyl)phosphine and ascorbate, regenerating protein thiols, or, in the case of ascorbate, more highly oxidized species. The implications of this reactivity on detection methods for protein sulfenic acids and S-nitrosothiols are discussed. © 2013 FEBS. Source

McCall C.E.,Wake forest University | Yoza B.,Section on Molecular Medicine | Yoza B.,Wake forest University | Liu T.,Section on Molecular Medicine | El Gazzar M.,Section on Molecular Medicine
Journal of Innate Immunity | Year: 2010

Inflammation is a fundamental biologic process that is evolutionally conserved by a germ line code. The interplay between epigenetics and environment directs the code into temporally distinct inflammatory responses, which can be acute or chronic. Here, we discuss the epigenetic processes of innate immune cells during serious infections with systemic inflammation in four stages: homeostasis, incitement, evolution, and resolution. We describe feed-forward loops of serious infections with systemic inflammation that create gene-specific silent facultative heterochromatin and active euchromatin according to gene function, and speculate on the role of epigenetics in survival. © 2010 S. Karger AG, Basel. Source

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