Superoxide dismutases enhance H2O2-induced DNA damage and alter its site specificity

AbstractSuperoxide dismutases (SODs) are involved in the protection of cells from oxygen toxicity. However, several papers have reported that the overexpression of CuZn-SOD causes oxidative damage to cells. We investigated a mechanism by which an excess of SODs accelerates oxidative stress. The presence of CuZn-SOD, Mn-SOD or Mn(II) enhanced the frequency of DNA damage induced by hydrogen peroxide (H2O2) and Cu(II), and altered the site specificity of the latter: H2O2 induced Cu(II)-dependent DNA damage with high frequency at the 5′-guanine of poly G sequences; when SODs were added, the frequency of cleavages at thymine and cytosine residues increased. SODs also enhanced the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine by H2O2 and Cu(II). We conclude that SODs may increase carcinogenic risks, e.g. of tumors in Down syndrome

Role of Nitrative and Oxidative DNA Damage in Inflammation-Related Carcinogenesis

Chronic inflammation induced by biological, chemical, and physical factors has been found to be associated with the increased risk of cancer in various organs. We revealed that infectious agents including liver fluke, Helicobacter pylori, and human papilloma virus and noninfectious agents such as asbestos fiber induced iNOS-dependent formation of 8-nitroguanine and 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG) in cancer tissues and precancerous regions. Our results with the colocalization of phosphorylated ATM and γ-H2AX with 8-oxodG and 8-nitroguanine in inflammation-related cancer tissues suggest that DNA base damage leads to double-stranded breaks. It is interesting from the aspect of genetic instability. We also demonstrated IL-6-modulated iNOS expression via STAT3 and EGFR in Epstein-Barr-virus-associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes. Such epigenetic alteration may occur by controlling the DNA methylation through IL-6-mediated JAK/STAT3 pathways. Collectively, 8-nitroguanine would be a useful biomarker for predicting the risk of inflammation-related cancers

Protection effect of taurine on nitrosative stress in the mice brain with chronic exposure to arsenic

<p>Abstract</p> <p>Background</p> <p>Arsenic exposure induces overproduction of reactive nitrogen species (RNS) in brain tissue and results in nucleic acid damage to the nerve cells. The 8-nitroguanine is one of the major products formed by the reaction of guanine, and ONOO^-, and has been used as a popular biomarker of nucleic acid damage due to RNS attacking. In the present study, we examined whether the administration of taurine can protect against nucleic acid damage of brain neurons by arsenic-induced RNS.</p> <p>Materials and methods</p> <p>Sixty mice (30 male and 30 female) weighing 19.5 ± 1.5 g were divided into 3 groups: (1) control group, (2) experimental group that received arsenic (As₂O₃), and (3) antagonistic group that received taurine with arsenic. Arsenic was administered for 60 days. 8-Nitroguanine expressions in brain neurons of mice were examined by the immunohistochemical method. Histopathological changes in brain tissues of mice were observed under light microscope and the immunohistochemistry method was used to investigate 8-nitroguanine expressions in cerebrum and cerebellum of mice.</p> <p>Results</p> <p>In the control group, no abnormal histopathological changes were observed in brain tissue of the mice. In brain tissue of the mice exposed to arsenic, histopathological results showed swells, evident vacuolar degeneration in cytoplasm, karyorrhexis and karyolysis. Relatively light pathological changes were observed in brain of the mice co-administered arsenic and taurine. Little or no expression of 8-nitroguanine in brain tissue was observed in controls. However, intensive expression of 8-nitroguanine was found in brain tissue of mice exposed to arsenic and it was mainly distributed in nucleus neighbouring the nuclear membrane, but a little in cytoplasm. A weak expression of 8-nitroguanine was observed in brain cells of mice co-administered arsenic and taurine.</p> <p>Conclusions</p> <p>The brain neurons may be the major target cells of arsenic neurotoxicity. Co-administration of arsenic and taurine can alleviate DNA damage of brain neurons caused by arsenic through the RNS signal pathway.</p

Nuclear Localization of COX-2 in relation to the Expression of Stemness Markers in Urinary Bladder Cancer

Inflammation may activate stem cells via prostaglandin E2 (PGE2) production mediated by cyclooxygenase-2 (COX-2) expression. We performed an immunohistochemical analysis of the expression of stemness markers (Oct3/4 and CD44v6) and COX-2 in urinary bladder tissues obtained from cystitis and cancer patients with and without Schistosoma haematobium infections. Immunoreactivity to Oct3/4 was significantly higher in S. haematobium-associated cystitis and cancer tissues than in normal tissues. CD44v6 expression was significantly higher in bladder cancer without S. haematobium than in normal tissues. COX-2 was located in the cytoplasmic membrane, cytoplasm, and nucleus of the cancer cells. Interestingly, the nuclear localization of COX-2, which was reported to function as a transcription factor, was significantly associated with the upregulation of Oct3/4 and CD44v6 in bladder cancer tissues with and without S. haematobium infection, respectively. COX-2 activation may be involved in inflammation-mediated stem cell proliferation/differentiation in urinary bladder carcinogenesis

チオ - ベータ - ジケトンキンゾクキレートノセイシツニタイスルイオウハイイノコウカ

京都大学0048新制・課程博士薬学博士甲第1398号薬博第107号新制||薬||60(附属図書館)3974UT51-48-J36京都大学大学院薬学研究科製薬化学専攻(主査)教授 田中 久, 教授 宇野 豊三, 教授 大崎 健次学位規則第5条第1項該当Kyoto UniversityDA