Superoxide is a primary oxygen radical that is produced when an oxygen molecule receives one electron. Superoxide dismutase (SOD) plays a primary role in the cellular defense against an oxidative insult by ROS. However, the resulting hydrogen peroxide is still reactive and, in the presence of free ferrous iron, may produce hydroxyl radicals and exacerbate diseases. Polyunsaturated fatty acids are the preferred target of hydroxyl radicals. Ferroptosis, a type of necrotic cell death induced by lipid peroxides in the presence of free iron, has attracted considerable interest because of its role in the pathogenesis of many diseases. Radical electrons, namely those released from mitochondrial electron transfer complexes, and those produced by enzymatic reactions, such as lipoxygenases, appear to cause lipid peroxidation. While GPX4 is the most potent anti-ferroptotic enzyme that is known to reduce lipid peroxides to alcohols, other antioxidative enzymes are also indirectly involved in protection against ferroptosis. Moreover, several low molecular weight compounds that include α-tocopherol, ascorbate, and nitric oxide also efficiently neutralize radical electrons, thereby suppressing ferroptosis. The removal of radical electrons in the early stages is of primary importance in protecting against ferroptosis and other diseases that are related to oxidative stress.

Controlled oxidation, such as disulfide bond formation in sperm nuclei and during ovulation, plays a fundamental role in mammalian reproduction. Excess oxidation, however, causes oxidative stress, resulting in the dysfunction of the reproductive process. Antioxidation reactions that reduce the levels of reactive oxygen species are of prime importance in reproductive systems in maintaining the quality of gametes and support reproduction. While anti-oxidative enzymes, such as superoxide dismutase and peroxidase, play a central role in eliminating oxidative stress, reduction-oxidation (redox) systems, comprised of mainly glutathione and thioredoxin, function to reduce the levels of oxidized molecules. Aldo-keto reductase, using NADPH as an electron donor, detoxifies carbonyl compounds resulting from the oxidation of lipids and proteins. Thus, many antioxidative and redox enzyme genes are expressed and aggressively protect gametes and embryos in reproductive systems.

Since skin is the first barrier separating the body from the external environment, impaired wound healing can be life threatening to living organisms. Delayed healing processes are observed in animals under certain circumstances, such as advanced age, diabetes, and immunosuppression, but the underlying mechanisms of the abnormality remain elusive. Redox homeostasis is defined as the balance between the levels of reactive oxygen species (ROS) and antioxidants in which antioxidative enzymes play central roles in scavenging ROS. In addition to deleterious effects, ROS also exert beneficial functions on some cellular processes such as transducing phosphorylation signaling, but excessive antioxidants may impede the healing process. Hence, strict control over the amounts of antioxidants is desirable when applied for therapeutic purposes. Here we overview recent findings regarding the relationships between antioxidative enzymes and wound healing. Unveiling the role of antioxidative enzymes is expected to contribute to our understanding of the wound healing processes.

Reactive oxygen species are involved in the aging process and diseases. Despite the important role of Cu/Zn SOD (superoxide dismutase) encoded by SOD1, SOD1^−/− mice appear to grow normally under conventional breeding conditions. In the present paper we report on a novel finding showing a distinct connection between oxidative stress in erythrocytes and the production of autoantibodies against erythrocytes in SOD1^−/− mice. Evidence is presented to show that SOD1 is primarily required for maintaining erythrocyte lifespan by suppressing oxidative stress. A SOD1 deficiency led to an increased erythrocyte vulnerability by the oxidative modification of proteins and lipids, resulting in anaemia and compensatory activation of erythropoiesis. The continuous destruction of oxidized erythrocytes appears to induce the formation of autoantibodies against certain erythrocyte components, e.g. carbonic anhydrase II, and the immune complex is deposited in the glomeruli. The administration of an antioxidant, N-acetylcysteine, suppressed erythrocyte oxidation, ameliorated the anaemia, and inhibited the production of autoantibodies. These data imply that a high level of oxidative stress in erythrocytes increases the production of autoantibodies, possibly leading to an autoimmune response, and that the intake of antioxidants would prevent certain autoimmune responses by maintaining an appropriate redox balance in erythrocytes.

Limited amounts of reactive oxygen species are necessary for cell survival and signaling, but their excess causes oxidative stress. H ₂ O ₂ and other reactive oxygen species are formed as byproducts of several metabolic pathways, possibly including oxidative protein folding in the endoplasmic reticulum. B- to plasma-cell differentiation is characterized by a massive expansion of the endoplasmic reticulum, finalized to sustain abundant immunoglobulin (Ig) synthesis and secretion. The increased production of disulfide-rich Ig might cause oxidative stress that could serve signaling roles in the differentiation and lifespan control of antibody-secreting cells. Here we show that terminal B-cell differentiation entails redox stress, NF-E2-related factor-2 (Nrf2) activation, and reshaping of the antioxidant responses. However, plasma-cell differentiation was not dramatically impaired in peroxiredoxin (Prx)1-, 2-, 3-, and 4-, glutathione peroxidase 1-, and Nrf2-knockout splenocytes, suggesting redundancy and robustness in antioxidant systems. Endoplasmic reticulum (ER)-resident Prx4 increases dramatically during differentiation. In its absence, IgM secretion was not significantly affected, but more high-molecular-weight covalent complexes accumulated intracellularly. Our results suggest that the early intracellular production of H ₂ O ₂ facilitates B-cell proliferation and reveal a role for the Nrf2 pathway in the differentiation and function of IgM-secreting cells. Antioxid. Redox Signal. 13, 1133–1144.

For normal spermatogenesis, the temperature of the scrotum is lower than that of the body. The mechanism by which mammalian testes undergoes cell death as the result of exposure to heat continues to be a matter of debate. Since generation of reactive oxygen species (ROS) during heat stress and involvement in spermatogenic cell damage are postulated, we induced experimental cryptorchidism in the testes of SOD1-knockout mice and examined effects of the gene deficiency. The cleavage of DNA in testicular cells, as judged by TUNEL staining, were elevated in SOD1-knockout mice at an earlier stage than in the wild-type mice. To confirm responsiveness of SOD1 for this high susceptibility to heat stress, spermatogenic cells were isolated from SOD1-knockout and wild-type mice and cultured at 32.5 and 37°C. The cells isolated from SOD1-knockout were more vulnerable at both temperatures than those from wild-type mice. The exposure of cultured rat spermatogenic cells to ROS induced the release of cytochrome c from mitochondria, while Sertoli cells were more resistant under the same conditions. Tiron, a superoxide scavenger, suppressed the heat-induced release of cytochrome c from mitochondria. Collectively, these data suggest that ROS are generated during heat stress and cause spermatogenic cell death. Alternatively, since even a short exposure triggers harmful damage to spermatogenic cells, generated ROS may function as a type of signal for cell death rather than directly causing oxidative damage to cells.