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      Preventing Colitis-Associated Colon Cancer With Antioxidants: A Systematic Review

      review-article
      1 , a , 2 , a , 3 , 2 ,
      Cellular and Molecular Gastroenterology and Hepatology
      Elsevier
      Colitis, Inflammatory Bowel Disease, Colorectal Cancer, Antioxidants, DNA Damage, AOM, azoxymethane, AT1, angiotensin II type 1, CAC, colitis-associated colon cancer, CAT, catalase, CRC, colorectal cancer, DSS, dextran sodium sulfate, DUOX2, dual oxidase 2, Gpx, glutathione peroxidase, GST, glutathione-S-transferase, GSTTT1, glutathione-S-transferase theta 1, HFD, high-fat diet, H2O2, hydrogen peroxidase, IBD, inflammatory bowel disease, MMR, mismatch repair, mtROS, mitochondrial ROS, NAC, N-acetylcysteine, NOX, nicotinamide adenine dinucleotide phosphate oxidase, O2•-, superoxide, PRDX, peroxiredoxin, RNI, reactive nitrogen intermediaries, ROS, reactive oxygen species, SOD, superoxide dismutase, UC, ulcerative colitis, vitC, vitamin C, vitE, vitamin E, 8-oxoG, 8-oxo-7,8-dihydro-2′-deoxyguanosine

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          Abstract

          Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors such as an excess in oxidant molecules released during chronic inflammation, mitochondrial dysfunction, a failure in antioxidant capacity, or oxidant promoting diets. It has been suggested that chronic oxidative environment in the intestine leads to the DNA lesions that precipitate colon carcinogenesis in IBD patients. Indeed, several preclinical and clinical studies show that different endogenous and exogenous antioxidant molecules are effective at reducing oxidation in the intestine. However, most clinical studies have focused on the short-term effects of antioxidants in IBD patients but not in CAC. This review article examines the role of oxidative DNA damage as a possible precipitating event in CAC in the context of chronic intestinal inflammation and the potential role of exogenous antioxidants to prevent these cancers.

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          Most cited references158

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          The repertoire of mutational signatures in human cancer

          Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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            A role for mitochondria in NLRP3 inflammasome activation.

            An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
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              Reactive oxygen species in inflammation and tissue injury.

              Abstract Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.
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                Author and article information

                Contributors
                Journal
                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                Elsevier
                2352-345X
                05 January 2021
                2021
                05 January 2021
                : 11
                : 4
                : 1177-1197
                Affiliations
                [1 ]Department of Medicine, University of Toronto, Toronto, Ontario, Canada
                [2 ]Department of Immunology, University of Toronto, Toronto, Ontario, Canada
                [3 ]Department of Medicine, Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada
                Author notes
                [] Correspondence Address correspondence to: Alberto Martin, PhD, Department of Immunology, University of Toronto, Medical Sciences Building 7302, Toronto, Canada M5S1A. alberto.martin@ 123456utoronto.ca
                [a]

                Authors share co-first authorship.

                Article
                S2352-345X(20)30212-5
                10.1016/j.jcmgh.2020.12.013
                7907812
                33418102
                f507dcb5-c12a-4a8c-bf4a-b106ab821a60
                © 2021 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 August 2020
                : 30 December 2020
                Categories
                Review

                colitis,inflammatory bowel disease,colorectal cancer,antioxidants,dna damage,aom, azoxymethane,at1, angiotensin ii type 1,cac, colitis-associated colon cancer,cat, catalase,crc, colorectal cancer,dss, dextran sodium sulfate,duox2, dual oxidase 2,gpx, glutathione peroxidase,gst, glutathione-s-transferase,gsttt1, glutathione-s-transferase theta 1,hfd, high-fat diet,h2o2, hydrogen peroxidase,ibd, inflammatory bowel disease,mmr, mismatch repair,mtros, mitochondrial ros,nac, n-acetylcysteine, nox, nicotinamide adenine dinucleotide phosphate oxidase,o2•-, superoxide,prdx, peroxiredoxin, rni, reactive nitrogen intermediaries,ros, reactive oxygen species,sod, superoxide dismutase,uc, ulcerative colitis,vitc, vitamin c,vite, vitamin e,8-oxog, 8-oxo-7,8-dihydro-2′-deoxyguanosine

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