Free radical-mediated damage

Lindsay, T.F., Romaschin, A.D. and Walker, P.M. (1990). Free radical mediated damage in skeletal muscle. Microsurg. Endothel. Lymphatics 5, 157-170. 

Iron-Stimulated Free Radical-Mediated Damaging Processes... 

Mechanisms of Mitochondria Protection from Free Radical-Mediated Damage... 

Inhibition of Free Radical-Mediated Damage in Cells... 

This mode of superoxide-dependent free radical-mediated damaging activity remains an important one although the nature of the generated reactive species (free hydroxyl radicals or perferryl, or ferryl ions) is still obscure. However, after the discovery of the fact that many cells produce nitric oxide in relatively large amounts (see below), it became clear that there is another and possibly a more portent mechanism of superoxide-induced free radical damage, namely, the formation of highly reactive peroxynitrite. 

Reaction of nitric oxide with superoxide is undoubtedly the most important reaction of nitric oxide, resulting in the formation of peroxynitrite, one of the main reactive species in free radical-mediated damaging processes. This reaction is a diffusion-controlled one, with the rate constant (which has been measured by many workers, see, for example, Ref. [41]), of about 2 x 109 1 mol-1 s-1. Goldstein and Czapski [41] also measured the rate constant for Reaction (11) ... 

There are numerous in vitro and in vivo studies, in which the damaging free radical-mediated effects of iron have been demonstrated. Many such examples are cited in the following chapters. However, recent studies [170,171] showed that not only iron excess but also iron deficiency may induce free radical-mediated damage. It has been shown that iron deficiency causes the uncoupling of mitochondria that can be the origin of an increase in mitochondria superoxide release. Furthermore, a decrease in iron apparently results in the reduction of the activity of iron-containing enzymes. Thus, any disturbance in iron metabolism may lead to the initiation of free radical overproduction. 

MECHANISMS OF MITOCHONDRIA PROTECTION FROM FREE RADICAL-MEDIATED DAMAGE... 

The efficiency of vitamin E in the suppression of free radical-mediated damage induced by iron overload has been studied in animals and humans. Galleano and Puntarulo [46] showed that iron overload increased lipid and protein peroxidation in rat liver. Vitamin E supplementation successfully suppressed these effects and led to an increase in a-tocopherol, ubiquinone-9, and ubiquinone-10 contents in liver. Important results were obtained by Roob et al. [47] who found that vitamin E supplementation attenuated lipid peroxidation (measured as plasma MDA and plasma lipid peroxides) in patients on hemodialysis after receiving iron hydroxide sucrose complex intravenously during hemodialysis session. These findings support the proposal that iron overload enhances free radical-mediated damage in humans. 

There are contradictory data on the effects of dietary ascorbic acid on free radical-mediated damage in animals. Barja et al. [65] found that the administration of 660mg/kg vitamin C to guinea pigs for 5 weeks significantly decreased the levels of protein carbonyls and lipid peroxidation products. On the other hand, the administration of 500mg/kg vitamin C to... 

Contemporary interest in ubiquinones is explained by their potential antioxidant activity and the possibility of using these nontoxic natural compounds as pharmaceutical agents. But it should be noted that ubiquinones are not vitamins and that they are synthesized in humans. Taking into account a high level of ubiquinones in mitochondria, the effective supplementation of ubiquinones to fight against free radical-mediated damage seems to be a hard task. 

Chelators of transition metals, mainly iron and copper, are usually considered as antioxidants because of their ability to inhibit free radical-mediated damaging processes. Actually, the so-called chelating therapy has been in the use probably even earlier than antioxidant therapy because it is an obvious pathway to treat the development of pathologies depending on metal overload (such as calcium overload in atherosclerosis or iron overload in thalassemia) with compounds capable of removing metals from an organism. Understanding of chelators as antioxidants came later when much attention was drawn to the possibility of in vivo hydroxyl radical formation via the Fenton reaction ... 

In 1986, the antioxidant effects of thioredoxin reductase were studied by Schallreuter et al. [81]. It has been shown that thioredoxin reductase was contained in the plasma membrane surface of human keratinocytes where it provided skin protection against free radical mediated damage. Later on, the reductive activity of Trx/thioredoxin reductase system has been shown for the reduction of ascorbyl radical to ascorbate [82], the redox regulation of NFkB factor [83], and in the regulation of nitric oxide-nitric oxide synthase activities [84,85],... 

In agreement with the above consideration of the role of oxidative stress in cancer development, it was found that tumor cells (thymocytes) are more sensitive to oxidative stress than normal thymocytes [178], There are apparently the other free radical-mediated damaging processes, which can be more intensive in tumors. For example, it has been found that metHb formation was significantly elevated in cancer patients [179]. 

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