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Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes. / Dalia Saidely

Swansea University Author: Dalia, Saidely

Abstract

Long term gastric inflammation (chronic gastritis) and its coupled tumourigenic inflammatory milieu (Reactive Oxygen/ Nitrogen Species (RO/NS), cytokines, etc.) is seen to impact cells at several levels, and as such is seen to be a major driving force of gastric carcinogenesis. The goal of this inve...

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Published: 2008
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42638
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first_indexed 2018-08-02T18:55:11Z
last_indexed 2019-10-21T16:48:11Z
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spelling 2018-09-03T10:06:39.5206393 v2 42638 2018-08-02 Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes. cbff45b9e24af7e05c478b3523cccecf NULL Dalia Saidely Dalia Saidely true true 2018-08-02 Long term gastric inflammation (chronic gastritis) and its coupled tumourigenic inflammatory milieu (Reactive Oxygen/ Nitrogen Species (RO/NS), cytokines, etc.) is seen to impact cells at several levels, and as such is seen to be a major driving force of gastric carcinogenesis. The goal of this investigation was to examine the impact of inflammation, with a special focus on the oxidative stress component, on signal transduction and gene expression changes in gastric epithelial cells at the levels of Mitogen Activated Protein Kinase (MAPK) and Nuclear Factor Kappa-B (NFkappaB) pathways and downstream gene expression targets. Both in vitro and in vivo studies were performed, and a combination of microarray, real-time PCR, and western blot methodologies were employed to evaluate signalling and gene expression changes. Two in vitro models were utilised, comprising an initial chemically induced oxidative stress model, in which cells were exposed to hydrogen peroxide (H2O2), and a more elaborate inflammatory model whereby cells were exposed to leukocytes optimised to undergo an oxidative burst response. In both cases, MAPK and NFkB signal transduction pathways were seen to be affected, at the levels of the pathways themselves, and downstream gene expression targets, with over-expression of c-fos and interleukin-8 (IL-8) being the most consistently observed changes. Analysis of pre-malignant gastric biopsy specimens brought to light the potential importance of aberrant MAPK signalling and c-fos over-expression in the earliest stages of disease pathogenesis, the changes being observed most commonly in chronic inflammation/ gastritis tissues, so translating in vitro findings to a more clinically relevant setting. Overall, the findings provide strength to the notion that oxidative stress is a key player in gastric carcinogenesis, seen here at the levels of signalling and gene expression changes. Oxidative stress and the MAPK and NFkappaB pathways emerge as potential therapeutic targets for the management of gastric cancer. E-Thesis Molecular biology.;Cellular biology. 31 12 2008 2008-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-09-03T10:06:39.5206393 2018-08-02T16:24:29.9306015 Swansea University Medical School Swansea University Medical School Dalia Saidely NULL 1 0042638-02082018162510.pdf 10805414.pdf 2018-08-02T16:25:10.2270000 Output 27736223 application/pdf E-Thesis true 2018-08-02T16:25:10.2270000 false
title Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
spellingShingle Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
Dalia, Saidely
title_short Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
title_full Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
title_fullStr Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
title_full_unstemmed Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
title_sort Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes.
author_id_str_mv cbff45b9e24af7e05c478b3523cccecf
author_id_fullname_str_mv cbff45b9e24af7e05c478b3523cccecf_***_Dalia, Saidely
author Dalia, Saidely
author2 Dalia Saidely
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description Long term gastric inflammation (chronic gastritis) and its coupled tumourigenic inflammatory milieu (Reactive Oxygen/ Nitrogen Species (RO/NS), cytokines, etc.) is seen to impact cells at several levels, and as such is seen to be a major driving force of gastric carcinogenesis. The goal of this investigation was to examine the impact of inflammation, with a special focus on the oxidative stress component, on signal transduction and gene expression changes in gastric epithelial cells at the levels of Mitogen Activated Protein Kinase (MAPK) and Nuclear Factor Kappa-B (NFkappaB) pathways and downstream gene expression targets. Both in vitro and in vivo studies were performed, and a combination of microarray, real-time PCR, and western blot methodologies were employed to evaluate signalling and gene expression changes. Two in vitro models were utilised, comprising an initial chemically induced oxidative stress model, in which cells were exposed to hydrogen peroxide (H2O2), and a more elaborate inflammatory model whereby cells were exposed to leukocytes optimised to undergo an oxidative burst response. In both cases, MAPK and NFkB signal transduction pathways were seen to be affected, at the levels of the pathways themselves, and downstream gene expression targets, with over-expression of c-fos and interleukin-8 (IL-8) being the most consistently observed changes. Analysis of pre-malignant gastric biopsy specimens brought to light the potential importance of aberrant MAPK signalling and c-fos over-expression in the earliest stages of disease pathogenesis, the changes being observed most commonly in chronic inflammation/ gastritis tissues, so translating in vitro findings to a more clinically relevant setting. Overall, the findings provide strength to the notion that oxidative stress is a key player in gastric carcinogenesis, seen here at the levels of signalling and gene expression changes. Oxidative stress and the MAPK and NFkappaB pathways emerge as potential therapeutic targets for the management of gastric cancer.
published_date 2008-12-31T03:57:47Z
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