It is increasingly proposed that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a key role in human cancer development [1–6], especially as evidence is growing that antioxidants may prevent or delay the onset of some types of cancer (reviewed in [7,8]). ROS is a collective term often used by biologists to include oxygen radicals [superoxide (O # J−), hydroxyl (OHJ), peroxyl (RO # J) and alkoxyl (ROJ)] and certain nonradicals that are either oxidizing agents and}or are easily converted into radicals, such as HOCl, ozone (O $ ), peroxynitrite (ONOO−), singlet oxygen ("O # ) and H # O # . RNS is a similar collective term that includes nitric oxide radical (NOJ), ONOO−, nitrogen dioxide radical (NO # J), other oxides of nitrogen and products arising when NOJ reacts with O # J−, ROJ and RO # J. ‘Reactive ’ is not always an appropriate term; H # O # , NOJ and O # J− react quickly with very few molecules, whereas OHJ reacts quickly with almost anything. RO # J, ROJ, HOCl, NO # J, ONOO− and O $ have intermediate reactivities. ROS and RNS have been shown to possess many characteristics of carcinogens [4] (Figure 1). Mutagenesis by ROS}RNS could contribute to the initiation of cancer, in addition to being important in the promotion and progression phases. For example, ROS}RNS can have the following effects. (1) Cause structural alterations in DNA, e.g. base pair mutations, rearrangements, deletions, insertions and sequence amplification. OHJ is especially damaging, but "O # , RO # J, ROJ, HNO # , O $ , ONOO− and the decomposition products of ONOO− are also effective [9–13]. ROS can produce gross chromosomal alterations in addition to point mutations and thus could be involved in the inactivation or loss of the second wild-type allele of a mutated proto-oncogene or tumour-suppressor gene that can occur during tumour promotion and progression, allowing expression of the mutated phenotype [4]. (2) Affect cytoplasmic and nuclear signal transduction pathways [14,15]. For example, H # O # (which crosses cell and organelle membranes easily) can lead to displacement of the inhibitory subunit from the cytoplasmic transcription factor nuclear factor κB, allowing the activated factor to migrate to the nucleus [14]. Nitration of tyrosine residues by ONOO− may block phosphorylation. (3) Modulate the activity of the proteins and genes that respond to stress and which act to regulate the genes that are related to cell proliferation, differentiation and apoptosis [4,14–17]. For example, H # O # can stimulate transcription of c-jun

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Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer.

Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. The free radicals, both the reactive oxygen species (ROS) and reactive nitrogen species (RNS), are derived from both endogenous sources (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells etc.) and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, certain drugs like halothane, paracetamol, and radiation). Free radicals can adversely affect various important classes of biological molecules such as nucleic acids, lipids, and proteins, thereby altering the normal redox status leading to increased oxidative stress. The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Parkinson’s disease-PD, Alzheimer’s disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers). This review deals with chemistry, formation and sources, and molecular targets of free radicals and it provides a brief overview on the pathogenesis of various diseased conditions caused by ROS/RNS.

/pdf/free-radicals-properties-sources-targets-and-their-4af1hv9bf7.pdf

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock, and ischemia/reperfusion injury. The aim of this review is to describe recent developments in the field of oxidative stress research. The first part of the review focuses on the roles of reactive oxygen species (ROS) in shock, inflammation, and ischemia/reperfusion injury. The second part of the review deals with the novel findings using recently identified pharmacological tools (e.g., peroxynitrite decomposition catalysts and selective superoxide dismutase mimetics (SODm) in shock, ischemia/reperfusion, and inflammation. 1) The role of ROS consists of immunohistochemical and biochemical evidence that demonstrates the production of ROS in shock, inflammation, and ischemia/reperfusion injury. ROS can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation, and ischemia/reperfusion. 2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm, which selectively mimic the catalytic activity of the human superoxide dismutase enzymes, have been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure associated with shock, inflammation, and ischemia/reperfusion injury. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical, and hydrogen peroxide) are all potential reactants capable of initiating DNA single-strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase, leading to eventual severe energy depletion of the cells and necrotic-type cell death. Antioxidant treatment inhibits the activation of poly(ADP-ribose) synthetase and prevents the organ injury associated with shock, inflammation, and ischemia/reperfusion.

Antioxidant Therapy: A New Pharmacological Approach in Shock, Inflammation, and Ischemia/Reperfusion Injury

ion from the Sugar Moiety Wendy Knapp Pogozelski† and Thomas D. Tullius*,‡ Department of Chemistry, State University of New York at Geneseo, Geneseo, New York 14454, and Department of Chemistry, Boston University, Boston, Massachusetts 02215 Received August 27, 1997 (Revised Manuscript Received February 26, 1998)

Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the Sugar Moiety.

DNA is one of the prime molecules, and its stability is of utmost importance for proper functioning and existence of all living systems. Genotoxic chemicals and radiations exert adverse effects on genome stability. Ultraviolet radiation (UVR) (mainly UV-B: 280–315 nm) is one of the powerful agents that can alter the normal state of life by inducing a variety of mutagenic and cytotoxic DNA lesions such as cyclobutane-pyrimidine dimers (CPDs), 6-4 photoproducts (6-4PPs), and their Dewar valence isomers as well as DNA strand breaks by interfering the genome integrity. To counteract these lesions, organisms have developed a number of highly conserved repair mechanisms such as photoreactivation, base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Additionally, double-strand break repair (by homologous recombination and nonhomologous end joining), SOS response, cell-cycle checkpoints, and programmed cell death (apoptosis) are also operative in various organisms with the expense of specific gene products. This review deals with UV-induced alterations in DNA and its maintenance by various repair mechanisms.

https://downloads.hindawi.com/journals/jna/2010/592980.pdf

Molecular Mechanisms of Ultraviolet Radiation-Induced DNA Damage and Repair

Box, H. C., Patrzyc, H. B., Dawidzik, J. B., Wallace, J. C., Freund, H. G., Iijima, H. and Budzinski, E. E. Double Base Lesions in DNA X-Irradiated in the Presence or Absence of Oxygen. Previously, double lesions in which two adjacent bases are modified were identified in DNA oligomers exposed in solution to ionizing radiation. However, the formation of such lesions in polymer DNA had not been demonstrated. Using reference oligomer containing a specific double lesion and employing liquid chromatography-mass spectrometry (LC-MS), it was possible to show directly that double lesions are formed in irradiated calf thymus DNA. The double lesion in which a pyrimidine base is degraded to a formamido remnant and an adjacent guanine base is oxidized to 8-oxoguanine was detected in DNA X-irradiated in oxygenated aqueous solution. The double lesion in which the methyl carbon atom of a thymine base is covalently linked to carbon at the 8-position of an adjacent guanine base was detected in DNA irradiated in ...

https://bioone.org/journals/radiation-research/volume-153/issue-4/0033-7587(2000)153[0442:DBLIDX]2.0.CO;2/Double-Base-Lesions-in-DNA-X-Irradiated-in-the-Presence/10.1667/0033-7587(2000)153[0442:DBLIDX]2.0.CO;2.pdf

Double base lesions in DNA X-irradiated in the presence or absence of oxygen.

Two additional carbohydrates are reported whose crystal structures trap electrons intermolecularly in single crystals x irradiated at low temperature, namely sucrose and rhamnose. Five carbohydrate and polyhydroxy compounds are now known which exhibit this phenomenon. The following characteristics of the phenomenon were investigated: (1) the hyperfine couplings of the electron with protons of the polarized hydroxy groups forming the trap; (2) the distances between these protons and the trapped electron; (3) the spin density of the electron at the protons and (4) the relative stabilities of the electron trapped in various crystal structures.

Characteristics of trapped electrons and electron traps in single crystals

The intermolecular trapping of electrons has been observed in single crystals of dulcitol and L(+) arabinose x‐irradiated at 4.2 °K. Attribution of a major component of the ESR absorption to trapped electrons is based upon the character of the hyperfine pattern, which arises from multiple anisotropic hyperfine interactions with exchangeable protons, and on the g value of the absorption, which is always less than the free spin value. The removal of the trapped electron absorption upon irradiation with visible light has also been demonstrated. In these experiments all of the electrons are trapped in identical sites. This circumstance provides some important advantages in the study of the factors affecting the stabilization of charge in an environment of polarizable molecules.

Trapped electrons in irradiated single crystals of polyhydroxy compounds

Irradiation of the dinucleoside monophosphate d(GpT) in an oxygenated solution gives products characterized by damage on one or both guanine and thymine bases, the yields of which were proportional to radiation dose.

Vicinal lesions in X-irradiated DNA?

Anions formed by the addition of an electron to the uracil base were observed in single crystals of the barium salt of uridine 5′ phosphate x‐irradiated at 4.2 °K. The hyperfine coupling tensor for the C6–H proton was deduced from ENDOR measurements; the principal values are −59.12, −32.92, and −16.24 MHz. Similar measurements were made on single crystals of cytidine 3′ phosphate. The principal values for the C6–H proton hyperfine coupling in the anion formed on the cytosine base are −59.26, −33.98, and −14.68 MHz.

Edwin E. Budzinski

Papers

Double base lesions in DNA X-irradiated in the presence or absence of oxygen.

Characteristics of trapped electrons and electron traps in single crystals

Trapped electrons in irradiated single crystals of polyhydroxy compounds

Vicinal lesions in X-irradiated DNA?

The reduction of nucleotides by ionizing radiation: Uridine 5′ phosphate and cytidine 3′ phosphate