Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and oxysterols in the development of neurodegenerative diseases and inflammation-related cancer. Our recent studies identifying and characterizing carbonylated proteins reveal oxidative damage to heat shock proteins in neurodegenerative disease models and inflammation-related cancer, suggesting dysfunction in their antioxidative properties. In neurodegenerative diseases, DNA damage may not only play a role in the induction of apoptosis, but also may inhibit cellular division via telomere shortening. Immunohistochemical analyses showed co-localization of oxidative/nitrative DNA lesions and stemness markers in the cells of inflammation-related cancers. Here, we review oxidative stress and its significant roles in neurodegenerative diseases and cancer.

Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.

Infection and chronic inflammation have been recognized as important factors for carcinogenesis. Under inflammatory conditions, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from inflammatory and epithelial cells and result in oxidative and nitrative DNA damage, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-nitroguanine. The DNA damage can cause mutations and has been implicated in the initiation and/or promotion of inflammation-mediated carcinogenesis. It has been estimated that various infectious agents are carcinogenic to humans (IARC group 1), including parasites (Schistosoma haematobium(SH) andOpisthorchis viverrini(OV)), viruses (hepatitis C virus (HCV), human papillomavirus (HPV), and Epstein-Barr virus (EBV)), and bacteriumHelicobacter pylori(HP). SH, OV, HCV, HPV, EBV, and HP are important risk factors for bladder cancer, cholangiocarcinoma, hepatocellular carcinoma, cervical cancer, nasopharyngeal carcinoma, and gastric cancer, respectively. We demonstrated that 8-nitroguanine was strongly formed via inducible nitric oxide synthase (iNOS) expression at these cancer sites of patients. Moreover, 8-nitroguanine was formed in Oct3/4-positive stem cells in SH-associated bladder cancer tissues and in Oct3/4- and CD133-positive stem cells in OV-associated cholangiocarcinoma tissues. Therefore, it is considered that oxidative and nitrative DNA damage in stem cells may play a key role in inflammation-related carcinogenesis.

Chronic inflammation induced by repeated infection with Opisthorchis viverrini has been postulated to be a risk factor for cholangiocarcinoma. To clarify the mechanism of carcinogenesis induced by repeated O.viverrini infection, we investigated the timecourse of 8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) formation, inducible nitric oxide synthase (iNOS) expression, nitric oxide production and pathological features in hamsters with two (2-IF) or three (3-IF) O.viverrini infections. Inflammatory cell infiltration triggered by repeated infection (3-IF > 2-IF > 1-IF) was earlier than by single infection (1-IF). HPLC coupled with an electrochemical detector revealed that 8-oxodG level in the liver was the highest on day 3 in 3-IF and day 7 in 2-IF, earlier than that on day 21 in 1-IF. Notably, a double immunofluorescence study revealed that formation of 8-nitroguanine and 8-oxodG appeared to increase in the epithelium of bile ducts in the order 3-IF > 2-IF > 1-IF after the decrease in inflammatory cells. This may be explained by the fact that repeated infection increased iNOS expression in the epithelium of bile ducts in the order 3-IF > 2-IF > 1-IF on day 90. Proliferating cell nuclear antigen accumulated in the epithelium of bile ducts on day 90 after repeated O.viverrini infection, supporting the hypothesis that cell proliferation was promoted by inflammation-mediated DNA damage. In conclusion, more frequent O.viverrini infection can induce the expression of iNOS not only in inflammatory cells but also in the epithelium of bile ducts and subsequently cause nitrosative and oxidative damage to nucleic acids, which may participate in the initiation and/or promotion steps of cholangiocarcinoma development.