Biological Markers of Oxidative Stress in Cardiovascular Diseases: After so Many Studies, What do We Know?

Numerous conditions, including cancer, diabetes, aging, and atherosclerosis, are thought to be associated with oxidative stress. Oxidative stress is defined as a persistent imbalance between oxidation and antioxidation, resulting in the damage of cellular macromolecules and is often considered to be involved in wide variety of human diseases. However, the current literature is very heterogeneous making it rather difficult to draw general conclusions. Often, different biomarkers have been used in different health problems. In addition, individual biomarkers are often measured using nonspecific methods. The development of informative and highly reliable markers is very important. The conflicting results of numerous studies, including clinical trials, make it clear that despite the explosion of studies performed in the last decades, leading to nutritional guidelines recommending consumption of food-related antioxidants, direct proof is still lacking.

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production.

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10-2-10-1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.