-
1.
Radicals, Oxidative/Nitrosative Stress and Preeclampsia.
Taysi, S, Tascan, AS, Ugur, MG, Demir, M
Mini reviews in medicinal chemistry. 2019;(3):178-193
Abstract
Preeclampsia (PE) has a profound effect in increasing both maternal and fetal morbidity and mortality especially in third World. Disturbances of extravillous trophoblast migration toward uterine spiral arteries is characteristic feature of PE, which, in turn, leads to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Underlying pathogenesis appeared to be an altered bioavailability of nitric oxide (NO•) and tissue damage caused by increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The increase in ROS and RNS production or the decrease in antioxidant mechanisms generates a condition called oxidative and nitrosative stress, respectively, defined as the imbalance between pro- and antioxidants in favor of the oxidants. Additionally, ROS might trigger platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. As a consequence of these disorders could result in deficiencies in oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the one hand, enzymatic and nonenzymatic antioxidants scavenge ROS and protect tissues against oxidative damage. More specifically, placental antioxidant enzymes including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) protect the vasculature from ROS, maintaining the vascular function. On the other hand, ischemia in placenta in PE reduces the antioxidant activity. Collectively, the extent of oxidative stress would increase and therefore leads to the development of the pathological findings of PE including hypertension and proteinuria. Our goal in this article is to review current literature about researches demonstrating the interplay between oxidative, nitrosative stresses and PE, about their roles in the pathophysiology of PE and also about the outcomes of current clinical trials aiming to prevent PE with antioxidant supplementation.
-
2.
Pulse Radiolysis Studies for Mechanism in Biochemical Redox Reactions.
Kobayashi, K
Chemical reviews. 2019;(6):4413-4462
Abstract
Pulse radiolysis is a powerful method for generating highly reduced or oxidized species and free radicals. Combined with fast time-resolved spectroscopic measurement, we can monitor the reactions of intermediate species on time scales ranging from picoseconds to seconds. The application of pulse radiolysis to water generates hydrated electrons (eaq-) and specific radicals, rendering this technique useful for investigating a number of biological redox processes. The first pulse radiolysis redox investigations explored in this review involved intramolecular electron transfer processes in protein with multiple electron-accepting sites. Pulse radiolysis enabled direct monitoring of the internal electron transfer rates and the distribution of electrons within proteins. Structural information from X-ray data has allowed analysis of the rate constants and their activation parameters in relation to the mechanisms with current theoretical treatments. The second set of pulse radiolysis redox investigations explored here concerned the intermediates of enzyme reactions after redox reactions. Pulse radiolysis allowed the extremely rapid donation of electrons to a redox center in a protein. It makes it possible to observe the unstable intermediates after the reduction and the following subsequent steps. For example, the intermediates generated through the one-electron reduction of oxygenated hemoproteins, such as cytochrome P450 and nitric oxide synthase, were characterized. Interestingly, ligand exchange can occur upon the reduction of heme iron, in which different amino acid residues bind to heme in the ferrous and ferric states, respectively. We directly observed the ligand-switching intermediates of bacterial CooA, a CO sensor, and bacterial iron response regulator protein. These ligand exchange processes are physiologically important for regulating the electrode potential and effective formation of superoxide anion or HO•. The third set of pulse radiolysis redox investigations explored in this review concerns free-radical processes in biological systems. Free radicals are produced in cells and organisms in a variety of processes. The cell has developed special and very effective machinery for controlling and detoxifying reactive radicals. Radiation-generated radicals allow studies of the reactions between specific radicals and solutes, often revealing the mechanisms underlying the initial and subsequent reactions. The crucial contribution was made using pulse radiolysis techniques and knowledge of the identities, properties, and reactions of radicals. These radicals include superoxide (O2•-), nitric monoxide (NO•), ascorbate, urate, and protein radicals. This review focuses on the reactions of these radicals and their physiological functions.
-
3.
Evolutionary adaptations that enable enzymes to tolerate oxidative stress.
Imlay, JA, Sethu, R, Rohaun, SK
Free radical biology & medicine. 2019;:4-13
-
-
Free full text
-
Abstract
Biochemical mechanisms emerged and were integrated into the metabolic plan of cellular life long before molecular oxygen accumulated in the biosphere. When oxygen levels finaly rose, they threatened specific types of enzymes: those that use organic radicals as catalysts, and those that depend upon iron centers. Nature has found ways to ensure that such enzymes are still used by contemporary organisms. In some cases they are restricted to microbes that reside in anoxic habitats, but in others they manage to function inside aerobic cells. In the latter case, it is frequently true that the ancestral enzyme has been modified to fend off poisoning. In this review we survey a range of protein adaptations that permit radical-based and low-potential iron chemistry to succeed in oxic environments. In many cases, accessory domains shield the vulnerable radical or metal center from oxygen. In others, the structures of iron cofactors evolved to less oxidizable forms, or alternative metals replaced iron altogether. The overarching view is that some classes of biochemical mechanism are intrinsically incompatible with the presence of oxygen. The structural modification of target enzymes is an under-recognized response to this problem.
-
4.
The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela.
Cardone, RA, Alfarouk, KO, Elliott, RL, Alqahtani, SS, Ahmed, SBM, Aljarbou, AN, Greco, MR, Cannone, S, Reshkin, SJ
International journal of molecular sciences. 2019;(15)
Abstract
Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs' cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism.
-
5.
The Free Radical Diseases of Prematurity: From Cellular Mechanisms to Bedside.
Perrone, S, Santacroce, A, Longini, M, Proietti, F, Bazzini, F, Buonocore, G
Oxidative medicine and cellular longevity. 2018;:7483062
Abstract
During the perinatal period, free radicals (FRs) are involved in several physiological roles such as the cellular responses to noxia, the defense against infectious agents, the regulation of cellular signaling function, and the induction of a mitogenic response. However, the overproduction of FRs and the insufficiency of an antioxidant mechanism result in oxidative stress (OS) which represents a deleterious process and an important mediator of damage to the placenta and the developing fetus. After birth, OS can be magnified by other predisposing conditions such as hypoxia, hyperoxia, ischemia, hypoxia ischemia-reperfusion, inflammation, and high levels of nonprotein-bound iron. Newborns are particularly susceptible to OS and oxidative damage due to the increased generation of FRs and the lack of adequate antioxidant protection. This impairment of the oxidative balance has been thought to be the common factor of the so-called "free radical related diseases of prematurity," including retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, kidney damage, and oxidative hemolysis. In this review, we provide an update focused on the factors influencing these diseases refining the knowledge about the role of OS in their pathogenesis and the current evidences of such relationship. Mechanisms governing FR formation and subsequent OS may represent targets for counteracting tissue damage.
-
6.
Sources of free radicals and oxidative stress in the oral cavity.
Żukowski, P, Maciejczyk, M, Waszkiel, D
Archives of oral biology. 2018;:8-17
Abstract
OBJECTIVE An oral cavity is a place especially susceptible to oxidative damage. It is subjected to many environmental pro-oxidative factors or factors that have the ability to generate reactive oxygen species (ROS). The aim of this article is to present the main sources of ROS and oxidative stress in the oral environment. DESIGN A literature search was performed using the PubMed and Google Scholar databases. RESULTS One of the most important ROS sources in the oral cavity is periodontal inflammation. Other sources of ROS include: xenobiotics (ethanol, cigarette smoke, drugs), food (high-fat diet, high-protein diet, acrolein), dental treatment (ozone, ultrasound, non-thermal plasma, laser light, ultraviolet light), and dental materials (fluorides, dental composites, fixed orthodontic appliances, and titanium fixations). It has been shown that excessive production of ROS in the oral cavity may cause oxidative stress and oxidative damage to cellular DNA, lipids, and proteins, thus predisposing to many oral and systemic diseases. CONCLUSIONS Recognition of the exogenous sources of ROS and limitation of exposure to the ROS generating factors can be one of the prophylactic measures preventing oral and systemic diseases. It is suggested that antioxidant supplementation may be helpful in people exposed to excessive production of ROS in the oral cavity system.
-
7.
Selenoproteins are involved in antioxidant defense systems in thalassemia.
Genc, GE, Ozturk, Z, Gumuslu, S
Metallomics : integrated biometal science. 2017;(9):1241-1250
Abstract
Thalassemia major (TM) is a hereditary blood disease that affects the production of hemoglobin, resulting in severe anemia. Iron overload because of repeated blood transfusion and increased intestinal iron absorption and hemolysis are the major causes of increased oxidative stress in these patients. Growth and maturational delay, cardiomyopathy, endocrinopathies, and osteoporosis are the complications of thalassemia, secondary to anemia and iron overload. The human body has endogenous defense mechanisms to help protect against free radical-induced cell damage. Selenoproteins are important enzymes involved in these antioxidant defense mechanisms. In thalassemia patients, selenoproteins are essential because of their potential defense against oxidative damage due to iron overload and hemolysis. The aim of this review is to provide an overview of data regarding selenoproteins including glutathione peroxidase, thioredoxin reductase and iodothyronine deiodinases in TM patients. We also underline some complications of thalassemia that may be associated with selenoproteins.
-
8.
[Molecular effects of mitochondrial mutations in cytochrome b of complex III and their impact on the levels of free radical production].
Borek, A, Ekiert, R, Osyczka, A
Postepy biochemii. 2016;(2):162-172
Abstract
Cytochrome bc1 (mitochondrial complex III) is a common element of several bioenergetic systems. This enzyme catalyses electron transfer from ubiquinol to cytochrome c coupled to translocation of protons across the membrane, which contributes to generation of protonmotive force utilized for ATP production. Cytochrome b, together with cytochrome c1 and iron-sulfur protein (ISP), forms the evolutionarily conserved catalytic core. Transfer of electrons within this enzyme, is facilitated by the movement of ISP domain that allows communication between cytochrome b and cytochrome c1. Mutations in the subunits of catalytic core may cause mitochondrial diseases, however elucidation of their molecular effects in human cells is difficult. For that reason yeast or bacterial systems are used. It was found that some mutations in cytochrome b influence the movement of ISP and, in consequence, the levels of superoxide generation. By exploring the effects of mitochondrial mutations in model systems one can not only learn about molecular basis of diseases but also gain insights about catalytic and side reactions in cytochrome bc1.
-
9.
Regulation of exercise blood flow: Role of free radicals.
Trinity, JD, Broxterman, RM, Richardson, RS
Free radical biology & medicine. 2016;:90-102
-
-
Free full text
-
Abstract
During exercise, oxygen and nutrient rich blood must be delivered to the active skeletal muscle, heart, skin, and brain through the complex and highly regulated integration of central and peripheral hemodynamic factors. Indeed, even minor alterations in blood flow to these organs have profound consequences on exercise capacity by modifying the development of fatigue. Therefore, the fine-tuning of blood flow is critical for optimal physical performance. At the level of the peripheral circulation, blood flow is regulated by a balance between the mechanisms responsible for vasodilation and vasoconstriction. Once thought of as toxic by-products of in vivo chemistry, free radicals are now recognized as important signaling molecules that exert potent vasoactive responses that are dependent upon the underlying balance between oxidation-reduction reactions or redox balance. Under normal healthy conditions with low levels of oxidative stress, free radicals promote vasodilation, which is attenuated with exogenous antioxidant administration. Conversely, with advancing age and disease where background oxidative stress is elevated, an exercise-induced increase in free radicals can further shift the redox balance to a pro-oxidant state, impairing vasodilation and attenuating blood flow. Under these conditions, exogenous antioxidants improve vasodilatory capacity and augment blood flow by restoring an "optimal" redox balance. Interestingly, while the active skeletal muscle, heart, skin, and brain all have unique functions during exercise, the mechanisms by which free radicals contribute to the regulation of blood flow is remarkably preserved across each of these varied target organs.
-
10.
Spore photoproduct lyase: the known, the controversial, and the unknown.
Yang, L, Li, L
The Journal of biological chemistry. 2015;(7):4003-9
Abstract
Spore photoproduct lyase (SPL) repairs 5-thyminyl-5,6-dihydrothymine, a thymine dimer that is also called the spore photoproduct (SP), in germinating endospores. SPL is a radical S-adenosylmethionine (SAM) enzyme, utilizing the 5'-deoxyadenosyl radical generated by SAM reductive cleavage reaction to revert SP to two thymine residues. Here we review the current progress in SPL mechanistic studies. Protein radicals are known to be involved in SPL catalysis; however, how these radicals are quenched to close the catalytic cycle is under debate.