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      Genistein and Ascorbic Acid Reduce Oxidative Stress-Derived DNA Damage Induced by the Antileishmanial Meglumine Antimoniate

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          ABSTRACT

          Meglumine antimoniate (Glucantime) is a pentavalent antimonial used to treat leishmaniasis, despite its acknowledged toxic effects, such as its ability to cause oxidative damage to lipids and proteins. Recently, our group demonstrated that meglumine antimoniate causes oxidative stress-derived DNA damage. Knowing that antioxidants modulate reactive oxygen species, we evaluated the capacity of genistein and ascorbic acid for preventing genotoxicity caused by meglumine antimoniate. For that, mice ( n= 5/group) received genistein (via gavage) in doses of 5, 10, and 20 mg/kg for three consecutive days. After this period, they were treated with 810 mg/kg meglumine antimoniate via intraperitoneal (i.p.) route. Furthermore, mice ( n= 5/group) simultaneously received ascorbic acid (i.p.) in doses of 30, 60, and 120 mg/kg and 810 mg/kg meglumine antimoniate. We also conducted post- and pretreatment assays, in which animals received ascorbic acid (60 mg/kg) 24 h prior to or after receiving meglumine antimoniate. Genomic instability and mutagenicity were analyzed through conventional comet assay and enzymatic assay using formamide pyrimidine DNA glycosylase (Fpg) enzyme, as well as the micronucleus test, respectively. Meglumine antimoniate induced an increase in the DNA damage after digestion with Fpg, reinforcing its mutagenic potential by oxidizing DNA bases, which was prevented by genistein. Similarly, ascorbic acid was capable of reducing mutagenic effects in simultaneous treatment as well as in posttreatment. Therefore, our results demonstrate that both compounds are efficient in preventing mutations in mammalian cells treated with meglumine antimoniate.

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          The role of antioxidants in the chemistry of oxidative stress: A review.

          This Review Article is focused on the action of the reactive oxygenated species in inducing oxidative injury of the lipid membrane components, as well as on the ability of antioxidants (of different structures and sources, and following different mechanisms of action) in fighting against oxidative stress. Oxidative stress is defined as an excessive production of reactive oxygenated species that cannot be counteracted by the action of antioxidants, but also as a perturbation of cell redox balance. Reactive oxygenated/nitrogenated species are represented by superoxide anion radical, hydroxyl, alkoxyl and lipid peroxyl radicals, nitric oxide and peroxynitrite. Oxidative stress determines structure modifications and function modulation in nucleic acids, lipids and proteins. Oxidative degradation of lipids yields malondialdehyde and 4-hydroxynonenal, but also isoprostanes, from unsaturated fatty acids. Protein damage may occur with thiol oxidation, carbonylation, side-chain oxidation, fragmentation, unfolding and misfolding, resulting activity loss. 8-hydroxydeoxyguanosine is an index of DNA damage. The involvement of the reactive oxygenated/nitrogenated species in disease occurrence is described. The unbalance between the oxidant species and the antioxidant defense system may trigger specific factors responsible for oxidative damage in the cell: over-expression of oncogene genes, generation of mutagen compounds, promotion of atherogenic activity, senile plaque occurrence or inflammation. This leads to cancer, neurodegeneration, cardiovascular diseases, diabetes, kidney diseases. The concept of antioxidant is defined, along with a discussion of the existent classification criteria: enzymatic and non-enzymatic, preventative or repair-systems, endogenous and exogenous, primary and secondary, hydrosoluble and liposoluble, natural or synthetic. Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors or UV radiation absorbers. The specific mechanism of action of the most important representatives of each antioxidant class (endogenous and exogenous) in preventing or inhibiting particular factors leading to oxidative injury in the cell, is then reviewed. Mutual influences, including synergistic effects are presented and discussed. Prooxidative influences likely to occur, as for instance in the presence of transition metal ions, are also reminded.
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            Oxidative Stress, Prooxidants, and Antioxidants: The Interplay

            Oxidative stress is a normal phenomenon in the body. Under normal conditions, the physiologically important intracellular levels of reactive oxygen species (ROS) are maintained at low levels by various enzyme systems participating in the in vivo redox homeostasis. Therefore, oxidative stress can also be viewed as an imbalance between the prooxidants and antioxidants in the body. For the last two decades, oxidative stress has been one of the most burning topics among the biological researchers all over the world. Several reasons can be assigned to justify its importance: knowledge about reactive oxygen and nitrogen species production and metabolism; identification of biomarkers for oxidative damage; evidence relating manifestation of chronic and some acute health problems to oxidative stress; identification of various dietary antioxidants present in plant foods as bioactive molecules; and so on. This review discusses the importance of oxidative stress in the body growth and development as well as proteomic and genomic evidences of its relationship with disease development, incidence of malignancies and autoimmune disorders, increased susceptibility to bacterial, viral, and parasitic diseases, and an interplay with prooxidants and antioxidants for maintaining a sound health, which would be helpful in enhancing the knowledge of any biochemist, pathophysiologist, or medical personnel regarding this important issue.
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              Direct enzymic detection of endogenous oxidative base damage in human lymphocyte DNA.

              The endogenous production of oxidative damage in DNA by free radicals released as a by-product of respiration is a likely cause of mutations which, if they occur in appropriate genes, may lead to cancer. Using an endonuclease specific for oxidized pyrimidines, in conjunction with the highly sensitive method of single cell gel electrophoresis, we have detected significant oxidative damage in untreated, freshly isolated lymphocytes from normal, healthy individuals.
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                Author and article information

                Journal
                Antimicrobial Agents and Chemotherapy
                Antimicrob Agents Chemother
                American Society for Microbiology
                0066-4804
                1098-6596
                September 2018
                August 27 2018
                June 25 2018
                : 62
                : 9
                Article
                10.1128/AAC.00456-18
                6125564
                29941649
                © 2018
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