there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.
Hydroxyl radicals cause oxidative damage to cells because they unspecifically attack biomolecules [22] located less than a few nanometres from its site of generation and are involved in cellular disorders such as neurodegeneration [23, 24], cardiovascular disease [25], and cancer [26, 27].
It is generally assumed that in biological systems is formed through redox cycling by Fenton reaction, where free iron (Fe2+) reacts with hydrogen peroxide (H2O2) and the Haber-Weiss reaction that results in the production of Fe2+ when superoxide reacts with ferric iron (Fe3+)
other transition-metal including Cu, Ni, Co, and V can be responsible for formation in living cells
The hydroperoxyl radical () plays an important role in the chemistry of lipid peroxidation
The is a much stronger oxidant than superoxide anion-radical
Lipid peroxidation can be described generally as a process under which oxidants such as free radicals or nonradical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) that involve hydrogen abstraction from a carbon, with oxygen insertion resulting in lipid peroxyl radicals and hydroperoxides as described previously
under medium or high lipid peroxidation rates (toxic conditions) the extent of oxidative damage overwhelms repair capacity, and the cells induce apoptosis or necrosis programmed cell death
The overall process of lipid peroxidation consists of three steps: initiation, propagation, and termination
Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced.
The main primary products of lipid peroxidation are lipid hydroperoxides (LOOH)
Among the many different aldehydes which can be formed as secondary products during lipid peroxidation, malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) have been extensively studied
MDA has been widely used for many years as a convenient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its facile reaction with thiobarbituric acid (TBA)
MDA is one of the most popular and reliable markers that determine oxidative stress in clinical situations [53], and due to MDA’s high reactivity and toxicity underlying the fact that this molecule is very relevant to biomedical research community
4-HNE is considered as “second toxic messengers of free radicals,” and also as “one of the most physiologically active lipid peroxides,” “one of major generators of oxidative stress,” “a chemotactic aldehydic end-product of lipid peroxidation,” and a “major lipid peroxidation product”
MDA is an end-product generated by decomposition of arachidonic acid and larger PUFAs
Identifying in vivo MDA production and its role in biology is important as indicated by the extensive literature on the compound (over 15 800 articles in the PubMed database using the keyword “malondialdehyde lipid peroxidation” in December 2013)
MDA reactivity is pH-dependent
When pH decreases MDA exists as beta-hydroxyacrolein and its reactivity increases
MAA adducts are shown to be highly immunogenic [177–181]. MDA adducts are biologically important because they can participate in secondary deleterious reactions (e.g., crosslinking) by promoting intramolecular or intermolecular protein/DNA crosslinking that may induce profound alteration in the biochemical properties of biomolecules and accumulate during aging and in chronic diseases
MDA is an important contributor to DNA damage and mutation
This MDA-induced DNA alteration may contribute significantly to cancer and other genetic diseases.
Dietary intake of certain antioxidants such as vitamins was associated with reduced levels of markers of DNA oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells of healthy subjects, which could contribute to the protective role of vitamins on cancer risk