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Special Issue "Biology of Reactive Oxygen and Nitrogen Species: Redox Signaling, Metabolic Effects, Cellular Functions and Oxidative Damage"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (31 July 2018)

Special Issue Editors

Guest Editor
Assoc. Prof. Dr. Andrey V. Kozlov

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Austrian Cluster for Tissue Regeneration, A-1200 Vienna, Austria
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Interests: mitochondria; reactive oxygen and nitrogen species; endoplasmic reticulum (-stress); iron metabolism; organ failure; inflammation; hypoxia; critical care diseases
Guest Editor
Assoc. Prof. Dr. Sergey Dikalov

Vanderbilt University, Clinical Pharmacology Department, 2200 Pierce Ave, 558 PRB, Nashville, TN 37232, USA
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Special Issue Information

Dear Colleagues,

For a long time, reactive oxygen and nitrogen species (RONS) were considered as deleterious chemically-active molecules causing oxidative damage to nearly all types of biomolecules. More recently, RONS have been discovered as regulators of diverse intracellular processes, such as redox signalling, metabolic processes, and cellular functions. Thus, the biological impact of RONS is a sum of diverse and possibly even opposite effects, which can modulate physiological processes and also contribute to the development of a disease.

Consideration of possible mechanism switching between beneficial and deleterious effects of RONS led to a rather common assumption, that low levels of ROS activate signalling pathways while oxidative stress denotes high levels of ROS. However, numerous reports on the chemistry of RONS show, that molecules jointly named RONS indeed have quite different chemical properties and consequently must have different biological effects. Some of these species are more suitable for physiological reactions, while the others exert predominantly damaging capacity. Thus, the identification of specific RONS occurring in biological systems is as important as the determination of total amount of RONS formed.

This Special Issue will focus on two aspects of RONS biology indicated above. The first one, which considers the links between RONS and diverse cellular/organ functions as well as impact of RONS on clinical outcomes. The second aspect is related to the identification of specific type of RONS involved in the regulation of diverse cellular/organ functions, particular those relevant for development of diseases. Papers addressing both aspects simultaneously will be greatly favored.

Assoc. Prof. Dr. Andrey V. Kozlov
Assoc. Prof. Dr. Sergey Dikalov
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • superoxide radical
  • hydrogen peroxide
  • peroxynitrite
  • mitochondria
  • peroxisome
  • NADPH-oxidase
  • hypoxia
  • inflammation
  • redox signaling
  • gene expression
  • metabolism
  • cellular functions

Published Papers (7 papers)

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Research

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Open AccessArticle The H2S Donor GYY4137 Stimulates Reactive Oxygen Species Generation in BV2 Cells While Suppressing the Secretion of TNF and Nitric Oxide
Molecules 2018, 23(11), 2966; https://doi.org/10.3390/molecules23112966
Received: 1 October 2018 / Revised: 7 November 2018 / Accepted: 7 November 2018 / Published: 14 November 2018
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Abstract
GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including
[...] Read more.
GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 μM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H2S donor, Na2S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted. Full article
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Open AccessArticle Organ-Specific Oxidative Events under Restrictive Versus Full Reperfusion Following Hemorrhagic Traumatic Shock in Rats
Molecules 2018, 23(9), 2195; https://doi.org/10.3390/molecules23092195
Received: 25 July 2018 / Revised: 17 August 2018 / Accepted: 28 August 2018 / Published: 30 August 2018
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Abstract
Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with complications that are partly ascribed to the formation of reactive oxygen species (ROS). The aim of our study was to compare the effects of restrictive reperfusion (RR) to rapid full reperfusion
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Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with complications that are partly ascribed to the formation of reactive oxygen species (ROS). The aim of our study was to compare the effects of restrictive reperfusion (RR) to rapid full reperfusion (FR) on ROS formation and/or oxidative events. Materials and methods: Anesthetized male rats were randomly subjected to HTS followed by FR (75 mL/kg/h) or RR (30 mL/kg/h for 40 min, followed by 75 mL/kg/h) with Ringer’s solution (n = 8/group). Compartment-specific ROS formation was determined by infusion of ROS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) during resuscitation, followed by electron paramagnetic resonance spectroscopy. Sham-operated animals (n = 8) served as controls. The experiment was terminated 100 min post-shock. Results: Mean arterial pressure was significantly higher in the FR compared to the RR group during early reperfusion. Only RR animals, not FR animals, showed significantly higher ROS concentrations in erythrocytes (1951 ± 420 vs. 724 ± 75 AU) and in liver (474 ± 57 vs. 261 ± 21 AU) compared to sham controls. This was accompanied by elevated alanine aminotransferase and creatinine levels in RR animals compared to both shams and FR animals, while lipid peroxidation products (thiobarbituric acid reactive substances) were significantly increased only in the kidney in the FR group (p < 0.05). RR animals showed significantly higher plasma peroxiredoxin-4 values when compared to the FR group (20 ± 2 vs. 14 ± 0.5 RLU). Conclusion: Restrictive reperfusion after HTS is associated with increased ROS formation in erythrocytes and liver compared to sham controls. Moreover, the restrictive reperfusion is associated with a more pronounced injury to the liver and kidney, which is likely mediated by other than lipid peroxidation process and/or oxidative stress reactions. Full article
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Open AccessArticle Activation of Anthracene Endoperoxides in Leishmania and Impairment of Mitochondrial Functions
Molecules 2018, 23(7), 1680; https://doi.org/10.3390/molecules23071680
Received: 14 June 2018 / Revised: 2 July 2018 / Accepted: 7 July 2018 / Published: 10 July 2018
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Abstract
Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs)
[...] Read more.
Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs’ reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon-centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action. Full article
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Open AccessArticle Computational Modeling of In Vitro Swelling of Mitochondria: A Biophysical Approach
Molecules 2018, 23(4), 783; https://doi.org/10.3390/molecules23040783
Received: 22 February 2018 / Revised: 12 March 2018 / Accepted: 27 March 2018 / Published: 28 March 2018
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Abstract
Swelling of mitochondria plays an important role in the pathogenesis of human diseases by stimulating mitochondria-mediated cell death through apoptosis, necrosis, and autophagy. Changes in the permeability of the inner mitochondrial membrane (IMM) of ions and other substances induce an increase in the
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Swelling of mitochondria plays an important role in the pathogenesis of human diseases by stimulating mitochondria-mediated cell death through apoptosis, necrosis, and autophagy. Changes in the permeability of the inner mitochondrial membrane (IMM) of ions and other substances induce an increase in the colloid osmotic pressure, leading to matrix swelling. Modeling of mitochondrial swelling is important for simulation and prediction of in vivo events in the cell during oxidative and energy stress. In the present study, we developed a computational model that describes the mechanism of mitochondrial swelling based on osmosis, the rigidity of the IMM, and dynamics of ionic/neutral species. The model describes a new biophysical approach to swelling dynamics, where osmotic pressure created in the matrix is compensated for by the rigidity of the IMM, i.e., osmotic pressure induces membrane deformation, which compensates for the osmotic pressure effect. Thus, the effect is linear and reversible at small membrane deformations, allowing the membrane to restore its normal form. On the other hand, the membrane rigidity drops to zero at large deformations, and the swelling becomes irreversible. As a result, an increased number of dysfunctional mitochondria can activate mitophagy and initiate cell death. Numerical modeling analysis produced results that reasonably describe the experimental data reported earlier. Full article
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Open AccessArticle Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery
Molecules 2018, 23(3), 687; https://doi.org/10.3390/molecules23030687
Received: 22 February 2018 / Revised: 13 March 2018 / Accepted: 17 March 2018 / Published: 19 March 2018
Cited by 4 | PDF Full-text (5097 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A recently discovered key role of reactive oxygen species (ROS) in mitochondrial traffic has opened a wide alley for studying the interactions between cells, including stem cells. Since its discovery in 2006, intercellular mitochondria transport has been intensively studied in different cellular models
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A recently discovered key role of reactive oxygen species (ROS) in mitochondrial traffic has opened a wide alley for studying the interactions between cells, including stem cells. Since its discovery in 2006, intercellular mitochondria transport has been intensively studied in different cellular models as a basis for cell therapy, since the potential of replacing malfunctioning organelles appears to be very promising. In this study, we explored the transfer of mitochondria from multipotent mesenchymal stem cells (MMSC) to neural cells and analyzed its efficacy under normal conditions and upon induction of mitochondrial damage. We found that mitochondria were transferred from the MMSC to astrocytes in a more efficient manner when the astrocytes were exposed to ischemic damage associated with elevated ROS levels. Such transport of mitochondria restored the bioenergetics of the recipient cells and stimulated their proliferation. The introduction of MMSC with overexpressed Miro1 in animals that had undergone an experimental stroke led to significantly improved recovery of neurological functions. Our data suggest that mitochondrial impairment in differentiated cells can be compensated by receiving healthy mitochondria from MMSC. We demonstrate a key role of Miro1, which promotes the mitochondrial transfer from MMSC and suggest that the genetic modification of stem cells can improve the therapies for the injured brain. Full article
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Review

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Open AccessFeature PaperReview Peroxidase Activity of Human Hemoproteins: Keeping the Fire under Control
Molecules 2018, 23(10), 2561; https://doi.org/10.3390/molecules23102561
Received: 28 August 2018 / Revised: 28 September 2018 / Accepted: 1 October 2018 / Published: 8 October 2018
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Abstract
The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to
[...] Read more.
The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to generate free radicals in the peroxidase cycle and (pseudo)hypohalous acids in the halogenation cycle. The major true peroxidases are myeloperoxidase, eosinophil peroxidase and lactoperoxidase. (2) Pseudo-peroxidases perform various important functions in the body, but under the influence of external conditions they can display peroxidase-like activity. As oxidative intermediates, these peroxidases produce not only active heme compounds, but also protein-based tyrosyl radicals. Hemoglobin, myoglobin, cytochrome c/cardiolipin complexes and cytoglobin are considered as pseudo-peroxidases. Рeroxidases play an important role in innate immunity and in a number of physiologically important processes like apoptosis and cell signaling. Unfavorable excessive peroxidase activity is implicated in oxidative damage of cells and tissues, thereby initiating the variety of human diseases. Hence, regulation of peroxidase activity is of considerable importance. Since peroxidases differ in structure, properties and location, the mechanisms controlling peroxidase activity and the biological effects of peroxidase products are specific for each hemoprotein. This review summarizes the knowledge about the properties, activities, regulations and biological effects of true and pseudo-peroxidases in order to better understand the mechanisms underlying beneficial and adverse effects of this class of enzymes. Full article
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Open AccessReview Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity
Molecules 2018, 23(6), 1483; https://doi.org/10.3390/molecules23061483
Received: 14 May 2018 / Revised: 13 June 2018 / Accepted: 15 June 2018 / Published: 19 June 2018
Cited by 1 | PDF Full-text (1919 KB) | HTML Full-text | XML Full-text
Abstract
Fatty acid (FA)-stimulated insulin secretion (FASIS) is reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, all converging into insulin resistance. Focusing on pancreatic islet β-cells, we compare the physiological FA roles with
[...] Read more.
Fatty acid (FA)-stimulated insulin secretion (FASIS) is reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, all converging into insulin resistance. Focusing on pancreatic islet β-cells, we compare the physiological FA roles with the pathological ones. Considering FAs not as mere amplifiers of glucose-stimulated insulin secretion (GSIS), but as parallel insulin granule exocytosis inductors, partly independent of the KATP channel closure, we describe the FA initiating roles in the prediabetic state that is induced by retardations in the glycerol-3-phosphate (glucose)-promoted glycerol/FA cycle and by the impaired GPR40/FFA1 (free FA1) receptor pathway, specifically in its amplification by the redox-activated mitochondrial phospholipase, iPLA2γ. Also, excessive dietary FAs stimulate intestine enterocyte incretin secretion, further elevating GSIS, even at low glucose levels, thus contributing to diabetic hyperinsulinemia. With overnutrition and obesity, the FA overload causes impaired GSIS by metabolic dysbalance, paralleled by oxidative and metabolic stress, endoplasmic reticulum stress and numerous pro-apoptotic signaling, all leading to decreased β-cell survival. Lipotoxicity is exerted by saturated FAs, whereas ω-3 polyunsaturated FAs frequently exert antilipotoxic effects. FA-facilitated inflammation upon the recruitment of excess M1 macrophages into islets (over resolving M2 type), amplified by cytokine and chemokine secretion by β-cells, leads to an inevitable failure of pancreatic β-cells. Full article
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