Protein thiyl radical reactions and product formation: a kinetic simulation

Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and β-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention. © 2013.

We use published Gibbs energies of formation and equilibrium constants to determine electrode potentials for the partially reduced intermediates along the pathway of reduction of dioxygen to water, as well as of ozone and singlet dioxygen. The results are summarized in an oxidation state (Frost) diagram. Our review of the literature on electrode potentials leads us to revise values for the O(2)/O(2)(*-) couple to E degrees (O(2g)/O(2)(*-))=-0.35+/-0.02V and E degrees (O(2aq)/O(2)(*-))=-0.18+/-0.02V from -0.33 and -0.16V, respectively. Other electrode potentials (pH 7) for the radical species covered are E degrees '(O(3g)/O(3)(*-))=+0.91V, E degrees '(HO(2)(*), H(+)/H(2)O(2))=+1.05V, E degrees '(H(2)O(2), H(+)/HO(*), H(2)O)=+0.39V, and E degrees '(HO(*), H(+)/H(2)O)=+2.31V. Copyright 2010 Elsevier Inc. All rights reserved.

Cellular DNA damage under prooxidant conditions has been shown to be mediated by iron. In fact, iron is an important element in the establishment of a prooxidant status in the cell. It is discussed that there exists a mutual dependence between iron metabolism and oxidative stress. Changes in the former by means of genetic manipulation bring about modification in the redox status as judge by oxidative damage in DNA. On the other hand, the induction of a cellular prooxidative condition activates the protein IRP (iron regulatory protein) in a way that renders the cell more able to take up iron. The possible implications of these results is discussed in the light of recent findings reported in the literature on hydrogen peroxide as a signaling species for cell proliferation. The question of DNA strand break formation under prooxidant conditions is reviewed from the viewpoint of which agent is more important: an oxidant generated by Fenton type reaction or Ca2+-activated nucleases. The presence of iron in the nucleus is reviewed. Results have been produced indicating that the larger concentration of this metal in the nucleus, as compared to the cytosol, seems to be explained by an iron-type P-ATPase. There is no explanation, presently, for iron presence in the nucleus, but it certainly imposes a prooxidant trend that needs to be counterbalanced in some way, and evidence is reviewed that nuclear metallothionein plays a role in this regard.