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• W3120602695 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. 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. SummaryPreclinical studies suggest a role for oxidative molecules in the pathophysiology of colitis-associated cancer. This review analyzes evidence for DNA oxidation as a precipitating event in gastrointestinal cancers and synthesizes an argument for the use of antioxidants as a viable therapeutic treatment to prevent colitis-associated colon cancers. Preclinical studies suggest a role for oxidative molecules in the pathophysiology of colitis-associated cancer. This review analyzes evidence for DNA oxidation as a precipitating event in gastrointestinal cancers and synthesizes an argument for the use of antioxidants as a viable therapeutic treatment to prevent colitis-associated colon cancers. Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disorder associated with dysregulation in the interaction between the host’s immune system and the environment within the gastrointestinal tract. Chronic inflammation of the intestinal epithelium is positively associated with cancer development, and although there are several mechanisms by which inflammation could induce epithelial damage, only a few of those point to a direct source of the DNA lesions necessary for cellular transformation and cancer initiation. The oxidant environment created by activated inflammatory cells in the intestinal epithelium has been associated with carcinogenesis.1Frick A. Khare V. Paul G. Lang M. Ferk F. Knasmuller S. Beer A. Oberhuber G. Gasche C. Overt increase of oxidative stress and DNA damage in murine and human colitis and colitis-associated neoplasia.Mol Cancer Res. 2018; 16: 634-642Crossref PubMed Scopus (14) Google Scholar, 2Nair J. Gansauge F. Beger H. Dolara P. Winde G. Bartsch H. Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis.Antioxidants & Redox Signaling. 2006; 8: 1003-1010Crossref PubMed Scopus (0) Google Scholar, 3Irrazabal T. Thakur B.K. Kang M. Malaise Y. Streutker C. Wong E.O.Y. Copeland J. Gryfe R. Guttman D.S. Navarre W.W. Martin A. Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer.Nat Commun. 2020; 11: 1802Crossref PubMed Scopus (4) Google Scholar, 4Westbrook A.M. Wei B. Braun J. Schiestl R.H. Intestinal mucosal inflammation leads to systemic genotoxicity in mice.Cancer Res. 2009; 69: 4827-4834Crossref PubMed Scopus (0) Google Scholar Although linked to cancer initiation, reactive oxygen species (ROS) also act as signalling molecules that regulate multiple signaling pathways associated with mitogenesis, immune and stress response, and autophagy and are therefore required to maintain homeostasis.5Zhou D. Shao L. Spitz D.R. Reactive oxygen species in normal and tumor stem cells.Adv Cancer Res. 2014; 122: 1-67Crossref PubMed Scopus (155) Google Scholar In this review, we will discuss the evidence that supports the notion that chronic intestinal oxidation is one of the main factors leading to DNA lesions that promote carcinogenesis in IBD patients (Figure 1). This review will also discuss how antioxidants could be used to suppress tumor development within the inflamed intestinal tissue. There are several sources of oxidative molecules in the intestinal epithelium. Classically activated macrophages, infiltrating neutrophils, and intestinal epithelial cells are all equipped with enzymes that produce ROS and reactive nitrogen intermediaries (RNI) in response to the gut microbiota, specific gut pathogens, or other stimuli. ROS and RNI are normally produced to keep microbes in line and maintain homeostasis within the intestine. For example, the nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2, which produces superoxide (O2•-), is expressed in macrophages, dendritic cells, and neutrophils that infiltrate the lamina propria.6Panday A. Sahoo M.K. Osorio D. Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies.Cellular & Molecular Immunology. 2015; 12: 5-23Crossref PubMed Scopus (0) Google Scholar Intestinal epithelial cells express the O2•- producing enzyme NOX1 and the hydrogen peroxide (H2O2) producing enzyme dual oxidase 2 (DUOX2). Usually O2•- is further converted into the more stable molecule H2O2 by the enzyme superoxide dismutase (SOD). In phagocytes, H2O2 is further transformed into hypochlorous acid, which has antimicrobial properties. In addition, macrophages, epithelial cells, and neutrophils also express the enzyme inducible nitric oxide synthase, which produces the highly diffusible molecule NO•.6Panday A. Sahoo M.K. Osorio D. Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies.Cellular & Molecular Immunology. 2015; 12: 5-23Crossref PubMed Scopus (0) Google Scholar,7Mittal M. Siddiqui M.R. Tran K. Reddy S.P. Malik A.B. Reactive oxygen species in inflammation and tissue injury.Antioxidants & Redox Signaling. 2014; 20: 1126-1167Crossref PubMed Scopus (324) Google Scholar Although ROS is necessary for various cellular functions,8Myant K.B. Cammareri P. McGhee E.J. Ridgway R.A. Huels D.J. Cordero J.B. Schwitalla S. Kalna G. Ogg E.L. Athineos D. Timpson P. Vidal M. Murray G.I. Greten F.R. Anderson K.I. Sansom O.J. ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.Cell Stem Cell. 2013; 12: 761-773Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 9Coant N. Ben Mkaddem S. Pedruzzi E. Guichard C. Treton X. Ducroc R. Freund J.N. Cazals-Hatem D. Bouhnik Y. Woerther P.L. Skurnik D. Grodet A. Fay M. Biard D. Lesuffleur T. Deffert C. Moreau R. Groyer A. Krause K.H. Daniel F. Ogier-Denis E. NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon.Mol Cell Biol. 2010; 30: 2636-2650Crossref PubMed Scopus (131) Google Scholar, 10Knaus U.G. Hertzberger R. Pircalabioru G.G. Yousefi S.P. Branco Dos Santos F. Pathogen control at the intestinal mucosa: H2O2 to the rescue.Gut Microbes. 2017; 8: 67-74Crossref PubMed Scopus (14) Google Scholar, 11Singh A.K. Hertzberger R.Y. Knaus U.G. Hydrogen peroxide production by lactobacilli promotes epithelial restitution during colitis.Redox Biology. 2018; 16: 11-20Crossref PubMed Scopus (19) Google Scholar, 12Matthews J.D. Reedy A.R. Wu H. Hinrichs B.H. Darby T.M. Addis C. Robinson B.S. Go Y.M. Jones D.P. Jones R.M. Neish A.S. Proteomic analysis of microbial induced redox-dependent intestinal signaling.Redox Biology. 2019; 20: 526-532Crossref PubMed Scopus (0) Google Scholar excessive accumulation causes damage to biological molecules. Consequently, tissues are armed with several defense mechanisms including an intricate antioxidant defense system. The antioxidant defense system primarily functions through (1) limiting the excessive production of ROS/RNI, (2) scavenging free radicals, and (3) converting toxic free radicals into less toxic molecules.13Pisoschi A.M. Pop A. The role of antioxidants in the chemistry of oxidative stress: a review.Eur J Med Chem. 2015; 97: 55-74Crossref PubMed Scopus (854) Google Scholar An incompetent or dysregulated antioxidant system is associated with inflammatory diseases. Accordingly, mice deficient in nuclear factor erythroid-2–related factor 2, a master regulator of antioxidant responses in tissue through transcriptional regulation of antioxidant genes, develop colitis and colitis-associated cancer (CAC).14Osburn W.O. Karim B. Dolan P.M. Liu G. Yamamoto M. Huso D.L. Kensler T.W. Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment.Int J Cancer. 2007; 121: 1883-1891Crossref PubMed Scopus (147) Google Scholar During chronic inflammation, ROS and RNI surpass the physiological antioxidant detoxifying capacity of cells, leading to the generation of high amounts of oxidant molecules. H2O2 can react with transition metals via Fenton reaction and produce the highly reactive hydroxyl radical (HO•).7Mittal M. Siddiqui M.R. Tran K. Reddy S.P. Malik A.B. Reactive oxygen species in inflammation and tissue injury.Antioxidants & Redox Signaling. 2014; 20: 1126-1167Crossref PubMed Scopus (324) Google Scholar On the other hand, •NO can react with O2•- to generate the highly reactive molecule peroxynitrite (ONOO-).15Niles J.C. Wishnok J.S. Tannenbaum S.R. Peroxynitrite-induced oxidation and nitration products of guanine and 8-oxoguanine: structures and mechanisms of product formation.Nitric Oxide. 2006; 14: 109-121Crossref PubMed Scopus (0) Google Scholar When these oxidant molecules are not neutralized by intracellular antioxidants, these agents induce cell membrane damage and cancer-causing DNA lesions.1Frick A. Khare V. Paul G. Lang M. Ferk F. Knasmuller S. Beer A. Oberhuber G. Gasche C. Overt increase of oxidative stress and DNA damage in murine and human colitis and colitis-associated neoplasia.Mol Cancer Res. 2018; 16: 634-642Crossref PubMed Scopus (14) Google Scholar,3Irrazabal T. Thakur B.K. Kang M. Malaise Y. Streutker C. Wong E.O.Y. Copeland J. Gryfe R. Guttman D.S. Navarre W.W. Martin A. Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer.Nat Commun. 2020; 11: 1802Crossref PubMed Scopus (4) Google Scholar,16Ö Canli Nicolas A.M. Gupta J. Finkelmeier F. Goncharova O. Pesic M. Neumann T. Horst D. Löwer M. Sahin U. Greten F.R. Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis.Cancer Cell. 2017; 32: 869-883.e5Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar In addition, inflamed colons in IBD patients and mice with colitis have decreased expression of antioxidant enzymes such as glutathione-S-transferase theta 1 (GSTT1). GSTT1 is not only necessary for the detoxification of oxidative free radicals, but it is also necessary to induce goblet cell differentiation and mucin production in response to triggers such as interleukin 22 and H2O2.17Kim J.H. Ahn J.B. Kim D.H. Kim S. Ma H.W. Che X. Seo D.H. Kim T.I. Kim W.H. Cheon J.H. Kim S.W. Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22.FASEB J. 2020; 34: 3289-3304Crossref PubMed Scopus (0) Google Scholar Because mucus produced by goblet cells is the first barrier that protects intestinal cells from the microbiome, this study suggests that GSTT1 deficiency would disrupt the epithelial barrier, generating a positive loop for oxidative epithelial damage.17Kim J.H. Ahn J.B. Kim D.H. Kim S. Ma H.W. Che X. Seo D.H. Kim T.I. Kim W.H. Cheon J.H. Kim S.W. Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22.FASEB J. 2020; 34: 3289-3304Crossref PubMed Scopus (0) Google Scholar Several innate immune cells produce O2•-, H2O2, and NO as a defense mechanism. However, some studies suggest that an increase in oxidative molecules can precede inflammation. For example, an inhibitor of the DNA repair enzyme OGG1 (8-oxoguanine DNA glycosylase 1) has been shown to prevent proinflammatory gene expression and cell recruitment in mouse lungs,18Visnes T. Cazares-Korner A. Hao W. Wallner O. Masuyer G. Loseva O. Mortusewicz O. Wiita E. Sarno A. Manoilov A. Astorga-Wells J. Jemth A.S. Pan L. Sanjiv K. Karsten S. Gokturk C. Grube M. Homan E.J. Hanna B.M.F. Paulin C.B.J. Pham T. Rasti A. Berglund U.W. von Nicolai C. Benitez-Buelga C. Koolmeister T. Ivanic D. Iliev P. Scobie M. Krokan H.E. Baranczewski P. Artursson P. Altun M. Jensen A.J. Kalderen C. Ba X. Zubarev R.A. Stenmark P. Boldogh I. Helleday T. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation.Science. 2018; 362: 834-839Crossref PubMed Scopus (42) Google Scholar suggesting that repair of oxidative DNA damage induces inflammation. Other studies showed that mitochondrial ROS (mtROS), generated when electrons leak from Complex I and III during oxidative phosphorylation and react with oxygen to form O2•-, can act as a signal-transducing molecule that either activates the NLRP3 inflammasome inducing the production of proinflammatory cytokines19Naik E. Dixit V.M. Mitochondrial reactive oxygen species drive proinflammatory cytokine production.J Exp Med. 2011; 208: 417-420Crossref PubMed Scopus (397) Google Scholar,20Zhou R. Yazdi A.S. Menu P. Tschopp J. A role for mitochondria in NLRP3 inflammasome activation.Nature. 2011; 469: 221-225Crossref PubMed Scopus (2579) Google Scholar or mediates an increased mitogen-activated protein kinase signaling that induces inflammatory cytokine production after TLR4 activation.21Bulua A.C. Simon A. Maddipati R. Pelletier M. Park H. Kim K.Y. Sack M.N. Kastner D.L. Siegel R.M. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).J Exp Med. 2011; 208: 519-533Crossref PubMed Scopus (537) Google Scholar Furthermore, gene transfer of the mitochondrial antioxidant enzyme GSTT1 into the colon of mice confers protection against colitis,17Kim J.H. Ahn J.B. Kim D.H. Kim S. Ma H.W. Che X. Seo D.H. Kim T.I. Kim W.H. Cheon J.H. Kim S.W. Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22.FASEB J. 2020; 34: 3289-3304Crossref PubMed Scopus (0) Google Scholar suggesting that in some cases, an increase in mtROS could precede chronic intestinal inflammation. However, mtROS can have anti-inflammatory properties as well because it can protect the intestine from inflammation by inducing polarization of alternatively activated macrophages and a reduction in the production of proinflammatory cytokines.22Formentini L. Santacatterina F. Núñez de Arenas C. Stamatakis K. López-Martínez D. Logan A. Fresno M. Smits R. Murphy M.P. Cuezva J.M. Mitochondrial ROS production protects the intestine from inflammation through functional M2 macrophage polarization.Cell Rep. 2017; 19: 1202-1213Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Overall, these data suggest that mtROS must surpass a physiological threshold to lead to activation of inflammatory pathways in the intestine. Another factor that can induce an oxidative environment that results in intestinal permeability and inflammation are high-fat diets (HFDs).23Gulhane M. Murray L. Lourie R. Tong H. Sheng Y.H. Wang R. Kang A. Schreiber V. Wong K.Y. Magor G. Denman S. Begun J. Florin T.H. Perkins A. Cuív P. McGuckin M.A. Hasnain S.Z. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22.Sci Rep. 2016; 6: 28990Crossref PubMed Google Scholar,24Cremonini E. Daveri E. Mastaloudis A. Adamo A.M. Mills D. Kalanetra K. Hester S.N. Wood S.M. Fraga C.G. Oteiza P.I. Anthocyanins protect the gastrointestinal tract from high fat diet-induced alterations in redox signaling, barrier integrity and dysbiosis.Redox Biology. 2019; 26: 101269Crossref PubMed Scopus (20) Google Scholar Non-esterified long chain saturated fatty acids present in HFD can increase expression of Nos2 and endoplasmic reticulum stress in goblet cells, which in turn triggers a reduction in the production of the mucus barrier and creates a positive feedback loop for inflammation.23Gulhane M. Murray L. Lourie R. Tong H. Sheng Y.H. Wang R. Kang A. Schreiber V. Wong K.Y. Magor G. Denman S. Begun J. Florin T.H. Perkins A. Cuív P. McGuckin M.A. Hasnain S.Z. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22.Sci Rep. 2016; 6: 28990Crossref PubMed Google Scholar In addition, mice fed a HFD had decreased expression of tight junctions proteins and MUC2 and increased expression of the enzymes NOX1, NOX4, and NOS2, which produce O2•-, H2O2, and NO, respectively.24Cremonini E. Daveri E. Mastaloudis A. Adamo A.M. Mills D. Kalanetra K. Hester S.N. Wood S.M. Fraga C.G. Oteiza P.I. Anthocyanins protect the gastrointestinal tract from high fat diet-induced alterations in redox signaling, barrier integrity and dysbiosis.Redox Biology. 2019; 26: 101269Crossref PubMed Scopus (20) Google Scholar However, none of these molecules or their oxidative effects were directly measured. Although the mechanism by which HFD induces the expression of these ROS-producing enzymes is not clear, it is possible that intestinal permeability associated with deficiencies in tight junctions and/or reduced mucus layer lead to the penetration of molecules such as lipopolysaccharide through the epithelial layer of the gastrointestinal tract. This in turn can lead to the induction of ROS-producing enzymes in immune cells. Interestingly, flavonoid anthocyanins could revert HFD-induced intestinal permeabilization and endotoxemia in part by modulating NOX expression and preventing the production of RNI.24Cremonini E. Daveri E. Mastaloudis A. Adamo A.M. Mills D. Kalanetra K. Hester S.N. Wood S.M. Fraga C.G. Oteiza P.I. Anthocyanins protect the gastrointestinal tract from high fat diet-induced alterations in redox signaling, barrier integrity and dysbiosis.Redox Biology. 2019; 26: 101269Crossref PubMed Scopus (20) Google Scholar This finding supports the idea that HFD-induced oxidative environment can lead to a positive feedback loop for intestinal permeability and intestinal oxidation. Anthocyanins also showed a promising anti-inflammatory potential in a small trial in ulcerative colitis (UC) patients,21Bulua A.C. Simon A. Maddipati R. Pelletier M. Park H. Kim K.Y. Sack M.N. Kastner D.L. Siegel R.M. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).J Exp Med. 2011; 208: 519-533Crossref PubMed Scopus (537) Google Scholar,25Biedermann L. Mwinyi J. Scharl M. Frei P. Zeitz J. Kullak-Ublick G.A. Vavricka S.R. Fried M. Weber A. Humpf H.U. Peschke S. Jetter A. Krammer G. Rogler G. Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis: an open pilot study.J Crohns Colitis. 2013; 7: 271-279Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and because HFD is a risk factor for IBD,26Hou J.K. Abraham B. El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature.Am J Gastroenterol. 2011; 106: 563-573Crossref PubMed Scopus (468) Google Scholar it is possible that anthocyanins could counteract the initial ROS-related processes that precede chronic intestinal inflammation. Overall, it seems that the source of oxidative damage in the intestine could be dependent or independent of inflammatory cells. Mitochondrial dysfunction and certain diets can mediate an increase in the production of O2•- and NO in the intestinal epithelium,20Zhou R. Yazdi A.S. Menu P. Tschopp J. A role for mitochondria in NLRP3 inflammasome activation.Nature. 2011; 469: 221-225Crossref PubMed Scopus (2579) Google Scholar,21Bulua A.C. Simon A. Maddipati R. Pelletier M. Park H. Kim K.Y. Sack M.N. Kastner D.L. Siegel R.M. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).J Exp Med. 2011; 208: 519-533Crossref PubMed Scopus (537) Google Scholar,23Gulhane M. Murray L. Lourie R. Tong H. Sheng Y.H. Wang R. Kang A. Schreiber V. Wong K.Y. Magor G. Denman S. Begun J. Florin T.H. Perkins A. Cuív P. McGuckin M.A. Hasnain S.Z. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22.Sci Rep. 2016; 6: 28990Crossref PubMed Google Scholar, 24Cremonini E. Daveri E. Mastaloudis A. Adamo A.M. Mills D. Kalanetra K. Hester S.N. Wood S.M. Fraga C.G. Oteiza P.I. Anthocyanins protect the gastrointestinal tract from high fat diet-induced alterations in redox signaling, barrier integrity and dysbiosis.Redox Biology. 2019; 26: 101269Crossref PubMed Scopus (20) Google Scholar, 25Biedermann L. Mwinyi J. Scharl M. Frei P. Zeitz J. Kullak-Ublick G.A. Vavricka S.R. Fried M. Weber A. Humpf H.U. Peschke S. Jetter A. Krammer G. Rogler G. Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis: an open pilot study.J Crohns Colitis. 2013; 7: 271-279Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,27Zhong Z. Umemura A. Sanchez-Lopez E. Liang S. Shalapour S. Wong J. He F. Boassa D. Perkins G. Ali S.R. McGeough M.D. Ellisman M.H. Seki E. Gustafsson A.B. Hoffman H.M. Diaz-Meco M.T. Moscat J. Karin M. NF-κB restricts inflammasome activation via elimination of damaged mitochondria.Cell. 2016; 164: 896-910Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar which in turn can activate inflammatory pathways and may lead to mutations that perpetuate inflammation and/or initiate cancer. However, in the majority of cases, it is likely that inflammation is itself caused by a response to microbial stimuli that causes an oxidative environment that can precipitate cancer. HO• and ONOO- directly damage DNA via strand breakage or nucleotide oxidation. Guanine is the nucleotide with the highest oxidation potential,15Niles J.C. Wishnok J.S. Tannenbaum S.R. Peroxynitrite-induced oxidation and nitration products of guanine and 8-oxoguanine: structures and mechanisms of product formation.Nitric Oxide. 2006; 14: 109-121Crossref PubMed Scopus (0) Google Scholar and oxidized guanine is commonly used to detect oxidative DNA damage. Elevated levels of oxidized guanine indicate that the oxidized environment has superseded the capacity of the cell to repair lesions caused by oxidation and therefore indicates potential oxidative damage. Guanine oxidation leads to the formation of 8-hydroxy-2′-deoyguanosine or 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxoG), which can lead to mutations if not repaired (Figure 2). If 8-oxoG is not removed from the DNA before replication and because 8-oxoG preferentially pairs with an adenine, unrepaired 8-oxoG will ultimately lead to G → T and C → A transversion mutations (Figure 2). Multiple DNA repair systems repair oxidative DNA lesions at different stages of the cell cycle.28Brown K.D. Rathi A. Kamath R. Beardsley D.I. Zhan Q. Mannino J.L. Baskaran R. The mismatch repair system is required for S-phase checkpoint activation.Nat Genet. 2003; 33: 80-84Crossref PubMed Scopus (163) Google Scholar, 29Markkanen E. Not breathing is not an option: how to deal with oxidative DNA damage.DNA Repair. 2017; 59: 82-105Crossref PubMed Scopus (0) Google Scholar, 30Colussi C. Parlanti E. Degan P. Aquilina G. Barnes D. Macpherson P. Karran P. Crescenzi M. Dogliotti E. Bignami M. The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool.Curr Biol. 2002; 12: 912-918Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 31Russo M.T. De Luca G. Degan P. Bignami M. Different DNA repair strategies to combat the threat from 8-oxoguanine.Mutat Res. 2007; 614: 69-76Crossref PubMed Scopus (72) Google Scholar C:8-oxoG pairs in DNA are recognized and repaired by the base excision repair and the nucleotide excision repair systems.29Markkanen E. Not breathing is not an option: how to deal with oxidative DNA damage.DNA Repair. 2017; 59: 82-105Crossref PubMed Scopus (0) Google Scholar,31Russo M.T. De Luca G. Degan P. Bignami M. Different DNA repair strategies to combat the threat from 8-oxoguanine.Mutat Res. 2007; 614: 69-76Crossref PubMed Scopus (72) Google Scholar In addition, 8-oxoG nucleotides from the dNTP pool are usually removed by MTH1, and failure to do so can lead to incorporation of this oxidized base into the nascent DNA strand during DNA replication (Figure 2D).29Markkanen E. Not breathing is not an option: how to deal with oxidative DNA damage.DNA Repair. 2017; 59: 82-105Crossref PubMed Scopus (0) Google Scholar, 30Colussi C. Parlanti E. Degan P. Aquilina G. Barnes D. Macpherson P. Karran P. Crescenzi M. Dogliotti E. Bignami M. The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool.Curr Biol. 2002; 12: 912-918Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 31Russo M.T. De Luca G. Degan P. Bignami M. Different DNA repair strategies to combat the threat from 8-oxoguanine.Mutat Res. 2007; 614: 69-76Crossref PubMed Scopus (72) Google Scholar The mismatch repair (MMR) system has an especially important role in the repair of 8-oxoG lesions in highly proliferative tissues such as the intestinal epithelium because MMR-deficient human and mouse colonic tissue have exceptionally high levels of this DNA lesion.3Irrazabal T. Thakur B.K. Kang M. Malaise Y. Streutker C. Wong E.O.Y. Copeland J. Gryfe R. Guttman D.S. Navarre W.W. Martin A. Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer.Nat Commun. 2020; 11: 1802Crossref PubMed Scopus (4) Google Scholar In the next sections, we discuss the role of endogenous and exogenous antioxidants on IBD and how these agents might prevent cellular transformation in inflamed intestinal tissue. The endogenous antioxidant defense system comprises both enzymatic antioxidants such as SOD, glutathione peroxidase (GPx), catalase (CAT), peroxiredoxin (PRDX), and thioredoxin as well as nonenzymatic antioxidants such as glutathione, alpha-lipoic acid, uric acid, melatonin, bilirubin, and ferritin. Multiple studies have found altered expression and/or activities of these antioxidant proteins in IBD and CAC patients, which suggest a role in disease pathology. SOD is a metalloenzyme that catalyzes the reduction of O2•- to H2O2 and O2, whereas CAT catalyzes the detoxification of H2O2 to O2 and H2O. Patients with active Crohn’s disease have increased SOD activity, which returned to control levels at remission.32Beltran B. Nos P. Dasi F. Iborra M. Bastida G. Martinez M. O'Connor J.E. Saez G. Moret I. Ponce J. Mitochondrial dysfunction, persistent oxidative damage, and catalase inhibition in immune cells of naive and treated Crohn's disease.Inflamm Bowel Dis. 2010; 16: 76-86Crossref PubMed Scopus (0) Google Scholar However, CAT activity remained permanently inhibited and was independent of disease activity.32Beltran B. Nos P. Dasi F. Iborra M. Bastida G. Martinez M. O'Connor J.E. Saez G. Moret I. Ponce J. Mitochondrial dysfunction, persistent oxidative damage, and catalase inhibition in immune cells of naive and treated Crohn's disease.Inflamm Bowel Dis. 2010; 16: 76-86Crossref PubMed Scopus (0) Google Scholar In a different study, a reduction in CAT or total SOD activity was found to be associated with increased risk of colorectal cancer (CRC) and gastric adenocarcinoma, respectively.33Chang D. Hu Z.L. Zhang L. Zhao Y.S. Meng Q.H. Guan Q.B. Zhou J. Pan H.Z. Association of catalase genotype with oxidative stress in the predication of colorectal cancer: modification by epidemiological factors.Biomed Environ Sci. 2012; 25: 156-162PubMed Google Scholar GPx, PRDX, and thioredoxin, the thiol-dependent proteins that catalyze the reduction of H2O2, lipid peroxides, and peroxynitrite, are found to be up-regulated in colonic mucosa of IBD and CRC patients compared with healthy subjects.34Horie K. Mikami T. Yoshida T. Sato Y. Okayasu I. Peroxiredoxin 1 expression in active ulcerative colitis mucosa identified by proteome analysis and involvement of thioredoxin based on immunohistochemistry.Oncology Letters. 2018; 15: 2364-2372PubMed Google Scholar, 35Fischer J. Eglinton T.W. Frizelle F.A. Hampton M.B. Peroxiredoxins in colorectal cancer: predictive bioma" @default.
• W3120602695 created "2021-01-18" @default.
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• W3120602695 date "2021-01-01" @default.
• W3120602695 modified "2023-09-29" @default.
• W3120602695 title "Preventing Colitis-Associated Colon Cancer With Antioxidants: A Systematic Review" @default.
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