8-hydroxy-2--deoxyguanosine and Colitis

Reactive oxygen species (ROS) attack guanine bases in DNA easily and form 8-hydroxydeoxyguanosine (8-OHdG), which can bind to thymidine rather than cytosine, based on which, the level of 8-OHdG is generally regarded as a biomarker of mutagenesis consequent to oxidative stress. For example, higher levels of 8-OHdG are noted in Helicobacter pylori-associated chronic atrophic gastritis as well as gastric cancer. However, we have found that exogenous 8-OHdG can paradoxically reduce ROS production, attenuate the nuclear factor-κB signaling pathway, and ameliorate the expression of proinflammatory mediators such as interleukin (IL)-1, IL-6, cyclo-oxygenase-2, and inducible nitric oxide synthase in addition to expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX)-1, NOX organizer-1 and NOX activator-1 in various conditions of inflammation-based gastrointestinal (GI) diseases including gastritis, inflammatory bowel disease, pancreatitis, and even colitis-associated carcinogenesis. Our recent finding that exogenous 8-OHdG was very effective in either inflammation-based or oxidative-stress-associated diseases of stress-related mucosal damage has inspired the hope that synthetic 8-OHdG can be a potential candidate for the treatment of inflammation-based GI diseases, as well as the prevention of inflammation-associated GI cancer. In this editorial review, the novel fact that exogenous 8-OHdG can be a functional molecule regulating oxidative-stress-induced gastritis through either antagonizing Rac-guanosine triphosphate binding or blocking the signals responsible for gastric inflammatory cascade is introduced.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Biomarkers; Colitis; Deoxyguanosine; Gastrointestinal Diseases; Humans; Inflammation; Oxidative Stress; Reactive Oxygen Species; Stomach Neoplasms

Aims of this study were to test whether sleep fragmentation (SF) increased carcinogenesis and to investigate the possible mechanisms of carcinogenesis in a chemical-induced colon cancer model. In this study, eight-week-old C57BL/6 mice were divided into Home cage (HC) and SF groups. After the azoxymethane (AOM) injection, the mice in the SF group were subjected to SF for 77 days. SF was accomplished in a sleep fragmentation chamber. In the second protocol, mice were divided into 2% dextran sodium sulfate (DSS)-treated, HC, and SF groups and were exposed to the HC or SF procedures. Immunohistochemical and immunofluorescent stainings were conducted to determine the level of 8-OHdG and reactive oxygen species (ROS), respectively. Quantitative real-time polymerase chain reaction was used to assess the relative expression of inflammatory and ROS-generating genes. The number of tumors and average tumor size were significantly higher in the SF group than in the HC group. The intensity (%) of the 8-OHdG stained area was significantly higher in the SF group than in the HC group. The fluorescence intensity of ROS was significantly higher in the SF group than the HC group. SF accelerated cancer development in a murine AOM/DSS-induced model of colon cancer, and the increased carcinogenesis was associated with ROS- and oxidative stress-induced DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Azoxymethane; Carcinogenesis; Colitis; Colon; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Mice; Mice, Inbred C57BL; Reactive Oxygen Species; Sleep Deprivation

Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Chemokine CCL2; Colitis; Cytochrome P-450 CYP2E1; Dioxoles; Endotoxins; Ethanol; Furans; Heme Oxygenase-1; Inflammation; Interleukin-6; Lignans; Malondialdehyde; Mice; Nitric Oxide Synthase Type II; Oxidative Stress; Tight Junction Proteins; Tumor Necrosis Factor-alpha

Excessive alcohol consumption is a risk factor associated with colorectal cancer; however, some studies have reported that moderate alcohol consumption may not contribute additional risk for developing colorectal cancer while others suggest that moderate alcohol consumption provides a protective effect that reduces colorectal cancer risk. The purpose of this study was to determine the effects of moderate voluntary alcohol (20% ethanol) intake on alternate days for 3 months in outbred Wistar rats on risk factors associated with colorectal cancer development. Colonic gene expression of cyclooxygenase-2, RelA, 8-oxoguanine DNA glycosylase 1, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase M1, and aldehyde dehydrogenase 2 were determined. Blood alcohol content, liver function enzyme activities, and 8-oxo-deoxyguanosine DNA adducts were also assessed. Alcohol-treated rats were found to have significantly lower 8-oxo-deoxyguanosine levels in blood, a marker of DNA damage. Alanine aminotransferase and lactate dehydrogenase were both significantly lower in the alcohol group. Moderate alcohol significantly decreased cyclooxygenase-2 gene expression, an inflammatory marker associated with colorectal cancer risk. The alcohol group had significantly increased glutathione-S-transferase M1 expression, an antioxidant enzyme that helps detoxify carcinogens, such as acetaldehyde, and significantly increased aldehyde dehydrogenase 2 expression, which allows for greater acetaldehyde clearance. Increased expression of glutathione-S-transferase M1 and aldehyde dehydrogenase 2 likely contributed to reduce mucosal damage that is caused by acetaldehyde accumulation. These results indicate that moderate alcohol may reduce the risk for colorectal cancer development, which was evidenced by reduced inflammation activity and lower DNA damage after alcohol exposure.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; Animals; Antioxidants; Colitis; Colorectal Neoplasms; Cyclooxygenase 2; Deoxyguanosine; DNA Damage; Ethanol; Gene Expression; Glutathione Transferase; Inflammation; Liver; Male; Rats; Rats, Wistar; Risk Factors

Xanthine oxidase (XO) is one of the major enzymes to generate superoxide anion (O2(-)), that is frequently associated with various diseases involving reactive oxygen species (ROS). 4-Amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) is a potent XO inhibitor showing therapeutic potential for oxidative inflammatory diseases. However its very poor aqueous solubility makes pharmaceutical application difficult. To overcome this drawback, we have successfully synthesized a water soluble polyethylene glycol (PEG) conjugate of AHPP (PEG-AHPP) that exhibited good water solubility, forming micelles in aqueous solution. In the present study, the in vivo pharmacokinetics of this PEG-AHPP was examined. Further its therapeutic potential was investigated in dextran sulfate sodium (DSS) induced mouse colitis model. Compared to parental AHPP, the plasma t1/2 of PEG-AHPP was increased remarkably from 3h to 14h, indicating macromolecular nature of AHPP in circulation. In the DSS induced colitis model, oral administration of 2% DSS in drinking water resulted in the progression of the colitis with diarrhea and hematochezia as well as shortening of the large bowel. Administration of PEG-AHPP intravenously (10mg/kg) or orally (20mg/kg) suppressed pathogenesis significantly; namely diarrhea was reduced markedly, and the length of large bowel returned to almost normal level. Pathological examination clearly revealed improvement of colonic ulcer or necrosis. Production of inflammatory cytokines, i.e., interleukin-6 and tumor necrosis factor (TNF)-α, was significantly increased in DSS-induced colitis mice. However, it was markedly suppressed by PEG-AHPP administration. Similar results were found when serum 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances (TBARS), that are the index of oxidative injury, were measured. PEG-AHPP thus may be a potential candidate drug for ROS-related diseases including inflammatory bowel disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Caco-2 Cells; Colitis; Colon; Cytokines; Deoxyguanosine; Dextran Sulfate; Female; Humans; Mice, Inbred ICR; Micelles; Oxypurinol; Polyethylene Glycols; Reactive Oxygen Species; Solubility; Thiobarbituric Acid Reactive Substances; Water; Xanthine Oxidase

Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Azoxymethane; Carcinogenesis; Colitis; Colonic Neoplasms; Deoxyguanosine; Dextran Sulfate; Diet; DNA Damage; Epidermal Growth Factor; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Selenium; Signal Transduction; Transforming Growth Factor beta; Weight Loss

Colitis-associated cancer (CAC) is one of clear examples of inflammation-carcinogenesis sequence, by which the strict control of colitis with potent anti-inflammatory or antioxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3, which are significantly upregulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-oxo-7,8-dihydrodeoxyguanosine or 8-OHdG) paradoxically can block Rac1 activation and subsequent NADPH oxidase (NOX) inactivation in various inflammation models, we hypothesized that attenuated Rac1-STAT3 and COX-NF-κB pathway by exogenous 8-OHdG administration may ameliorate inflammatory signaling in dextran sodium sulfate (DSS)-induced colitis and can prevent CAC. Before commencing carcinogenesis model, we checked whether exogenous 8-OHdG can alleviate IBD, for which interleukin (IL)-10 knockout mice were designed to ingest 5% DSS for 1 week, and 8-OHdG is given through intraperitoneal route daily. 8-OHdG treatment groups significantly reduced pathologic grade of DSS-induced colitis as well as various inflammatory mediators such as TNF-α, IL-6, COX-2, and iNOS in a dose-dependent manner. To document the cancer prevention effects of 8-OHdG, mice were injected azoxymethane followed by drinking 2.5% DSS for 1 week, after which 8-OHdG-containing diets were given for 20 weeks. As results, mice that consumed 8-OHdG-containing diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in the 8-OHdG-treated group. Significantly decreased levels of malondialdehyde, monocyte chemotactic protein-1, matrix metalloproteinasess, COX-2, NOX4, and β-catenin nuclear accumulation were responsible for cancer prevention effects of exogenous 8-OHdG. In conclusion, we clearly showed cancer-preventive effect of exogenous 8-OHdG against CAC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anticarcinogenic Agents; Azoxymethane; Colitis; Colorectal Neoplasms; Deoxyguanosine; Dextrans; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; STAT3 Transcription Factor; Sulfates

To evaluate whether combination therapy with anti-tumour necrosis factor α (TNFα) antibody and Zn acetate is beneficial in dextran sodium sulphate (DSS) colitis.. Colitis was induced in CD1-Swiss mice with 5% DSS for 7 d. The experimental mice were then randomised into the following subgroups: standard diet + DSS treated (induced colitis group); standard diet + DSS + subcutaneous 25 μg anti-TNFα treated group; Zn acetate treated group + DSS + subcutaneous 25 μg anti-TNFα; standard diet + DSS + subcutaneous 6.25 μg anti-TNFα treated group and Zn acetate treated group + DSS + subcutaneous 6.25 μg anti-TNFα. Each group of mice was matched with a similar group of sham control animals. Macroscopic and histological features were scored blindly. Homogenates of the colonic mucosa were assessed for myeloperoxidase activity as a biochemical marker of inflammation and DNA adducts (8OH-dG) as a measure of oxidative damage.. DSS produced submucosal erosions, ulcers, inflammatory cell infiltration and cryptic abscesses which were reduced in both groups of mice receiving either anti-TNFα alone or combined with zinc. The effect was more pronounced in the latter group (vs Zn diet, P < 0.02). Myeloperoxidase activity (vs controls, P < 0.02) and DNA adducts, greatly elevated in the DSS fed colitis group (vs controls, P < 0.05), were significantly reduced in the treated groups, with a more remarkable effect in the group receiving combined therapy (vs standard diet, P < 0.04).. DSS induces colonic inflammation which is modulated by the administration of anti-TNFα. Combining anti-TNFα with Zn acetate offers marginal benefit in colitis severity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antibodies; Antioxidants; Colitis; Deoxyguanosine; Dextran Sulfate; Diet; Male; Mice; Oxidative Stress; Peroxidase; Random Allocation; Tumor Necrosis Factor-alpha; Zinc Acetate

The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Anticarcinogenic Agents; Azoxymethane; Carcinogens; Chemoprevention; Colitis; Colonic Neoplasms; Coumaric Acids; Deoxyguanosine; Dextran Sulfate; Dipeptides; Disease Models, Animal; Heme Oxygenase (Decyclizing); Intestinal Mucosa; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Prodrugs

Many plants contain significant amounts of 4-coumaric acid (4CA), a compound with antioxidant properties in vitro and in vivo. The aim of this study was to assess the effects of 4CA pretreatment on DNA oxidative stress induced by intestinal inflammation in rodents.. 4CA (50 mg/kg) was administered to rats for 14 days mixed in the diet. Colitis was induced on days 13 and 14 by administering 6% (w/v) dextran sodium sulphate (DSS) in the drinking water.. In the colon mucosa, DSS treatment increased myeloperoxidase activity (P < 0.05), oxidative DNA damage (P < 0.01), and cyclooxygenase-2 (COX-2) expression (P < 0.01) and reduced superoxide dismutase-2 (SOD-2) expression (P < 0.05). It was found that treatment with 4CA prior to DSS-induced inflammation reduced oxidative DNA damage (P < 0.01), COX-2 over-expression (P < 0.01) and restored SOD-2 gene expression to control levels. Similar effects were observed with nimesulide administered p.o. (5 mg/kg, 1 day before and during DSS treatment). PGE levels in plasma and colon mucosa were increased by DSS treatment and this effect was inhibited by pretreatment with 4-CA (P < 0.01).. Mild acute intestinal inflammation induced by DSS can be inhibited by 4-CA and this action is associated with the suppression of COX-2 expression and activity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Colitis; Coumaric Acids; Cyclooxygenase 2; Deoxyguanosine; Dextran Sulfate; Dinoprostone; DNA Damage; Glutathione; Intestinal Mucosa; Male; Oxidative Stress; Peroxidase; Plant Extracts; Propionates; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Superoxide Dismutase; Xanthine Oxidase

The goal of this study was to evaluate for evidence of oxidative stress in colonic inflammation in a novel model of inflammatory bowel disease, nonsteroidal anti-inflammatory drug- (NSAID-) treated interleukin-10-deficient (IL10(-/-)) mice. IL10(-/-) and wild-type (wt) mice were treated with a nonselective NSAID (piroxicam, 200 ppm in the diet) for 2 weeks to induce colitis, and parameters for oxidative stress in the colonic tissues were evaluated. Mean chemiluminescence enhanced with lucigenin in the colons from IL10(-/-) mice treated with piroxicam was more than 5-fold higher than that of the control wt group. Chemiluminescence was inhibited with diphenylethylene iodinium, but not allopurinol, indomethacin, or N-omega-nitro-L-arginine, indicating that flavin-containing enzymes were the source of the reactive oxygen species. Colonic aconitase activity in NSAID-treated IL10(-/-) mice decreased to 50% of the activity of control mice. There was no difference in the total glutathione levels in the colonic mucosa among the groups; however, glutathione disulfide levels were approximately 2-fold greater in the colon of NSAID-treated IL10(-/-) mice as compared with control groups. Immunohistochemistry studies of colons from NSAID-treated IL10(-/-) mice demonstrated intense staining with two antibodies that recognize advanced glycation endproducts formed through glycation and oxidation: anticarboxymethylysine and antipentosidine. The epithelial cells and lamina propria cells in the colons of NSAID-treated IL10(-/-) mice showed immunostaining with antinitrotyrosine, indicating the presence of reactive nitrogen species. Colonic epithelium of IL10(-/-) mice with colitis showed moderate immunostaining for 8-hydroxy-2'-deoxyguanosine in the nuclei. NSAID-treated IL10(-/-) mice treated with diphenylene idodonium chloride (DPI), an irreversible inhibitor of flavoprotein enzymes, experienced significantly reduced inflammation. Taken together, these results strongly indicate the presence of oxidative stress in the inflammatory bowel disease in NSAID-treated IL10(-/-) mice and suggests a role for oxidative stress in the pathophysiology of this model of inflammatory bowel disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aconitate Hydratase; Acridines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chlorides; Colitis; Colon; Gene Deletion; Glutathione; Glycation End Products, Advanced; Guanine; Immunohistochemistry; Interleukin-10; Intestinal Mucosa; Luminescent Measurements; Mice; Mice, Knockout; Oxidative Stress; Piroxicam; Reactive Nitrogen Species

As we have shown previously [Tardieu,D., Jaeg,J.P., Cadet,J., Embvani,E., Corpet,D.E. and Petit,C. (1998) Cancer Lett, 134, 1-5], a 48-h treatment of 6% dextran sodium sulphate (DSS) in drinking water led to a reproducible 2-fold increase of the mutagenic oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in colonic mucosa DNA of rats in vivo. The aim of this study was to test the effect of nimesulide, a preferential COX-2 inhibitor, on the DSS-induced 8-oxodGuo increase. We show that nimesulide when administered orally, simultaneously with DSS at 5 mg/kg/day, not only totally prevents 8-oxodGuo formation but also suppresses the 5-fold increase of superoxide induced by DSS in the colonic mucosa. This was measured by in vivo formazan blue precipitation (P < 0.01 in the Wilcoxon test). Moreover, nimesulide enhances apoptosis by approximately 30% as compared with the already high level induced by DSS treatment (P < 0.01). It is suggested that the significant increase in mutagenic oxidative DNA damage, produced by mild acute colonic inflammation, could be important in the initiation of colon cancer in both animals and man. These effects may explain at least partly the well-documented protective action towards colon cancer by preferential COX-2 inhibitors, either xenobiotics such as nimesulide or natural nutrients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Colitis; Cyclooxygenase Inhibitors; Deoxyguanosine; Female; Intestinal Mucosa; Oxidative Stress; Peroxidase; Rats; Rats, Inbred F344; Sulfonamides; Superoxides