Novel therapeutic approaches in limiting oxidative stress and inflammation.

The interaction between reactive oxygen species (ROS) and inflammation plays an important role in the pathogenesis of endothelial dysfunction and cardiovascular disease, cancer and other diseases. Thus, antioxidant strategies may be important in immune regulation and in limiting inflammation. Surprisingly, large clinical trials have shown that ROS scavenging by antioxidant vitamins is ineffective or even harmful in spite of the fact that reactive oxygen species themselves are pro-inflammatory, regulate immune system and enhance atherosclerosis. Therefore, there is a need of novel, more specific antioxidant and anti-inflammatory approaches aimed on prevention of ROS formation, by targeting specific molecular pathways involved in ROS generation and their activation of pro-inflammatory cascades. Potential targets include the NADPH oxidases (Nox enzymes), xanthine oxidase, endothelial nitric oxide synthase and mitochondrial oxidases. Nox enzymes play central role, as they can stimulate other enzymatic sources of ROS. The interplay between inflammation and oxidative stress is discussed in the context of adipose tissue, perivascular inflammation and role of the central nervous system in immune regulation. All of the above participate in "brain-vessel axis" critical in the pathogenesis of numerous pathologies. Role of cytokines such as TNF-alpha, IL-17 or IL-6 and their links to superoxide and hydrogen peroxide production are discussed. Statins, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, block upstream signaling of Nox activation, including MAP kinase signaling or G protein activation, which contribute to their clinical effectiveness. Here, we discuss novel possibilities that drugs directly inhibiting Nox activation could successfully inhibit oxidative stress and inflammation related to cardiovascular disease. Moreover, we describe potential gene therapy approaches in limiting oxidative stress in the vasculature. These approaches can become also useful in cancer immunomodulation.