Browsing by Subject "chronic inflammation"

Now showing 1 - 6 of 6
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    The Emerging Role of Epigenetic Modifiers in Repair of DNA Damage Associated with Chronic Inflammatory Diseases
    (Elsevier, 2017) Ding, Ning; Maiuri, Ashley R.; O'Hagan, Heather M.; Medicine, School of Medicine
    At sites of chronic inflammation epithelial cells are exposed to high levels of reactive oxygen species (ROS), which can contribute to the initiation and development of many different human cancers. Aberrant epigenetic alterations that cause transcriptional silencing of tumor suppressor genes are also implicated in many diseases associated with inflammation, including cancer. However, it is not clear how altered epigenetic gene silencing is initiated during chronic inflammation. The high level of ROS at sites of inflammation is known to induce oxidative DNA damage in surrounding epithelial cells. Furthermore, DNA damage is known to trigger several responses, including recruitment of DNA repair proteins, transcriptional repression, chromatin modifications and other cell signaling events. Recruitment of epigenetic modifiers to chromatin in response to DNA damage results in transient covalent modifications to chromatin such as histone ubiquitination, acetylation and methylation and DNA methylation. DNA damage also alters non-coding RNA expression. All of these alterations have the potential to alter gene expression at sites of damage. Typically, these modifications and gene transcription are restored back to normal once the repair of the DNA damage is completed. However, chronic inflammation may induce sustained DNA damage and DNA damage responses that result in these transient covalent chromatin modifications becoming mitotically stable epigenetic alterations. Understanding how epigenetic alterations are initiated during chronic inflammation will allow us to develop pharmaceutical strategies to prevent or treat chronic inflammation-induced cancer. This review will focus on types of DNA damage and epigenetic alterations associated with chronic inflammatory diseases, the types of DNA damage and transient covalent chromatin modifications induced by inflammation and oxidative DNA damage and how these modifications may result in epigenetic alterations.
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    Functional characterization of a competitive peptide antagonist of p65 in human macrophage- like cells suggests therapeutic potential for chronic inflammation
    (2014-12) Srinivasan, Mythily; Blackburn, Corinne; Lahiri, Debomoy
    Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid responsive protein that links the nuclear factor-kappa B (NFκB) and the glucocorticoid signaling pathways. Functional and binding studies suggest that the proline-rich region at the carboxy terminus of GILZ binds the p65 subunit of NFκB and suppresses the immunoinflammatory response. A widely-used strategy in the discovery of peptide drugs involves exploitation of the complementary surfaces of naturally occurring binding partners. Previously, we observed that a synthetic peptide (GILZ-P) derived from the proline-rich region of GILZ bound activated p65 and ameliorated experimental encephalomyelitis. Here we characterize the secondary structure of GILZ-P by circular dichroic analysis. GILZ-P adopts an extended polyproline type II helical conformation consistent with the structural conformation commonly observed in interfaces of transient intermolecular interactions. To determine the potential application of GILZ-P in humans, we evaluated the toxicity and efficacy of the peptide drug in mature human macrophage-like THP-1 cells. Treatment with GILZ-P at a wide range of concentrations commonly used for peptide drugs was nontoxic as determined by cell viability and apoptosis assays. Functionally, GILZ-P suppressed proliferation and glutamate secretion by activated macrophages by inhibiting nuclear translocation of p65. Collectively, our data suggest that the GILZ-P has therapeutic potential in chronic CNS diseases where persistent inflammation leads to neurodegeneration such as multiple sclerosis and Alzheimer’s disease.
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    In Brief
    (Elsevier, 2021-03) Maatman, Thomas K.; Zyromski, Nicholas J.; Surgery, School of Medicine
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    Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort
    (Nature Publishing group, 2017-12-20) Wu, Lijun; Zhu, Xiangzhu; Fan, Lei; Kabagambe, Edmond K.; Song, Yiqing; Tao, Menghua; Zhong, Xiaosong; Hou, Lifang; Shrubsole, Martha J.; Liu, Jie; Dai, Qi; Epidemiology, School of Public Health
    People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.
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    Rapid changes in shape and number of MHC class II expressing cells in rat airways after Mycoplasma pulmonis infection
    (Elsevier, 2002-12) Umemoto, Eric Y.; Brokaw, James J.; Dupuis, Marc; McDonald, Donald M.; Anatomy & Cell Biology, School of Medicine
    Mycoplasma pulmonis infection in rodents causes a chronic inflammatory airway disease with a strong immunological component, leading to mucosal remodeling and angiogenesis. We sought to determine the effect of this infection on the shape and number of dendritic cells and other major histocompatibility complex (MHC) class II expressing cells in the airway mucosa of Wistar rats. Changes in the shape of subepithelial OX6 (anti-MHC class II)-immunoreactive cells were evident in the tracheal mucosa 2 days after intranasal inoculation with M. pulmonis. By 1 week, the shape of the cells had changed from stellate to rounded (mean shape index increased from 0.42 to 0.77). The number of OX6-positive cells was increased 6-fold at 1 week and 16-fold at 4 weeks. Coincident with these changes, many columnar epithelial cells developed OX6 immunoreactivity, which was still present at 4 weeks. We conclude that M. pulmonis infection creates a potent immunologic stimulus that augments and transforms the OX6-immunoreactive cell population in the airways by changing the functional state of airway dendritic cells, initiating an influx of MHC class II expressing cells, and activating expression of MHC class II molecules by airway epithelial cells.
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    Topical Application of a Platelet Activating Factor Receptor Agonist Suppresses Phorbol Ester-Induced Acute and Chronic Inflammation and Has Cancer Chemopreventive Activity in Mouse Skin
    (PLoS, 2014-11) Sahu, Ravi P.; Rezania, Samin; Ocana, Jesus A.; DaSilva-Arnold, Sonia C.; Bradish, Joshua R.; Richey, Justin D.; Warren, Simon J.; Rashid, Badri; Travers, Jeffrey B.; Konger, Raymond L.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.