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Introduction to Oxidative (Eu)stress in Exercise Physiology
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, James N. Cobley
Arguably the most important free radicals in biological systems are radical derivatives from oxygen, and although oxygen is necessary for survival, it has the potential to become toxic when supplied at concentrations higher than normally encountered (i.e., the toxicity of molecular oxygen is primarily due to the production of ROS). Ground state molecular oxygen is, in fact, a di-radical, with two unpaired electrons located in a different antibonding orbital with the same directional spin. Consequently, oxygen can only react with non-radicals by accepting a pair of electrons that spin in an anti-parallel manner (McCord, 1979).
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The calicheamicins bind in the DNA minor groove where they undergo a Bergman-type cyclization, generating a diradical species (i.e., 1,4-didehydrobenzene) that abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA resulting in strand scission and cell death. Calicheamicin was the first payload to be attached to a CD33-targeted antibody in an approved ADC (i.e., gemtuzumab ozogamicin; MylotargTM), and is also utilized as a payload in another approved ADC (e.g., inotuzumab ozogamicin; Besponsa™).
Free Radical Damage and Lipid Peroxidation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Richard O. Recknagel, Eric A. Glende, Robert S. Britton
Carbon-centered radicals can initiate the process, e.g., the trichloromethyl free radical (·CCl3), as in carbon tetrachloride hepatotoxicity. Initiation of lipid peroxidation is also associated with generation of oxygen-centered radicals. With the important exception of its participation in radical reactions, molecular O2 is relatively unreactive. All kinds of flammable and burnable materials, including gun powder, gasoline, paper, matches, cloth, wood, paint, sugars, fats, and proteins, are in continuous contact with O2 yet no combustion takes place. Combustion will take place when the temperature is elevated. Molecular O2 is a diradical; it has two unpaired electrons. The unpaired electrons have parallel spins and for reaction (other than radical reactions) to take place there has to be a spin inversion, which requires energy input. This takes place when the temperature is raised. Despite the fact that O2 is relatively inert, it is the major terminal oxidant for biological oxidations, as a result of enzymic catalysis. A large fraction of the O2 consumed in normal respiration, of the order of 90% or more, undergoes tetravalent reduction in the mitochondrial cytochrome-cytochrome oxidase chain to form H2O. The remaining 10% is consumed by reactions in the ER, in the cytoplasm, in other parts of the cell, and in mitochondrial O2 consumption not involving cytochrome oxidase. The overall reaction catalyzed by the mitochondrial respiratory chain is
Magnetic fields and apoptosis: a possible mechanism
Published in Electromagnetic Biology and Medicine, 2022
The spin state plays a pivotal role in all the redox reactions that are at the core of our metabolic machinery. Redox reactions involve the transfer of electrons from one reactant to another. These kinds of reactions are so important that our life depends on them. The synthesis of many complex molecules often requires the oxidation of their precursors, via the use of molecular oxygen. The reason why oxygen is so important in biology is its atomic structure, characterized by the presence of two uncoupled electron spins despite its even atomic number. According to Pauli’s principle, a fundamental principle in quantum physics, oxygen can be considered as an “electron lover,” due to the need of additional electrons to match the coupled spins, in search for stability, thus finally acting as an oxidant. The utilization of molecular oxygen is vital in many biological pathways and the ability of aerobic organisms to harness the power of molecular oxygen as a terminal electron acceptor in their respiratory cycles has revolutionized the evolution of life (Falkowski and Godfrey 2008). The presence of two uncoupled electrons in the oxygen atomic structure makes oxygen a di-radical, since when an electron is uncoupled we are usually dealing with an uncoupled spin or free radical.
Pesticides induced oxidative stress and female infertility: a review
Published in Toxin Reviews, 2020
Jitender Kumar Bhardwaj, Meenu Mittal, Priyanka Saraf, Priya Kumari
ROS are unstable and highly reactive molecules as their unpaired electrons tend to acquire stability by acquiring other electrons from nucleic acids, proteins, carbohydrates, lipids, or any nearby molecule, that leads to cascade of chain reactions resulting in cellular damage and diseases. It includes chemically reactive molecules that contains oxygen radical like superoxide (O2•−), hydrogen peroxide (H2O2), and hydroxyl ion (OH•) (Grigorov 2012). O2 is a diradical so it readily reacts with other radicals and is found in abundance in biological system. Interactions between the superoxide (SO) anion and hydrogen peroxide (H2O2) generates more toxic radicals through Fenton’s reaction, which uses a metal ion catalyst in order to produce OH* (Kehrer 2000)
Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent
Published in International Journal of Hyperthermia, 2022
Joy Garrett, Erin Metzger, Mark W. Dewhirst, Karen E. Pollok, John J. Turchi, Isabelle C. Le Poole, Kira Couch, Logan Lew, Anthony Sinn, Jeffrey M. Zaleski, Joseph R. Dynlacht
Bergman cyclization from thermal activation of metalloenediynes results in diradical generation, and cyclization reactivity has been correlated with efficiency of degradation of supercoiled DNA in vitro [29]. In contrast, minimal degradation of DNA is observed in the presence of the cyclized analogs. Using the γ-H2AX assay, we previously have shown that hyperthermia enhances production of DSBs or results in the inhibition of DSB repair in cultured U-1 melanoma cells treated with FeSO4-PyED; thus, potentiation by hyperthermia of cell death induced by FeSO4-PyED is likely mediated via the creation of more initial DSBs or through alteration of the DNA damage repair response [32]. However, the association between Bergman cyclization and enhancement of cytotoxicity when cells are treated with metalloendiynes during hyperthermia treatment compared to treatment at 37 °C has been less clear. We hypothesized that enhancement of cytotoxicity after treatment at an elevated temperature is mediated through Bergman cyclization. Testing for a differential effect of the non-reactive cyclized analog, FeSO4-PyBD, on cell survival at physiological vs. supraphysiological temperatures could directly address this issue. A comparison of survival curves generated for U-1 cells with either FeSO4-PyED or FeSO4-PyBD, at 37 °C or 42.5 °C, revealed no difference in clonogenic survival for cells treated with either compound at 37 °C (Figure 2). However, heating at 42.5 °C during FeSO4-PyED treatment significantly enhanced cytotoxicity compared to treatment at 37 °C, whereas heating at 42.5 °C with FeSO4-PyBD did not. These data indicate that Bergman cyclization and formation of the diradical is wholly responsible for heat-induced enhancement of metalloenediyne cytotoxicity.