Editorial

3 pages, 177 KiB

Open AccessEditorial

by Brandon J. Reeder

Antioxidants 2023, 12(5), 1077; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12051077 - 11 May 2023

Cited by 1 | Viewed by 871

Globins have been studied for their “pseudo-peroxidase” activity for over 70 years, being an ideal model of other kinetically more rapid metalloenzymes [...] Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

Research

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19 pages, 2933 KiB

Open AccessArticle

Identification of Heme Oxygenase-1 as a Putative DNA-Binding Protein

by Alejandro Scaffa, George A. Tollefson, Hongwei Yao, Salu Rizal, Joselynn Wallace, Nathalie Oulhen, Jennifer F. Carr, Katy Hegarty, Alper Uzun and Phyllis A. Dennery

Antioxidants 2022, 11(11), 2135; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11112135 - 28 Oct 2022

Cited by 2 | Viewed by 1718

Abstract

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in degrading heme into biliverdin and iron. HO-1 can also enter the nucleus and regulate gene transcription independent of its enzymatic activity. Whether HO-1 can alter gene expression through direct binding to target DNA remains unclear. [...] Read more.

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in degrading heme into biliverdin and iron. HO-1 can also enter the nucleus and regulate gene transcription independent of its enzymatic activity. Whether HO-1 can alter gene expression through direct binding to target DNA remains unclear. Here, we performed HO-1 CHIP-seq and then employed 3D structural modeling to reveal putative HO-1 DNA binding domains. We identified three probable DNA binding domains on HO-1. Using the Proteinarium, we identified several genes as the most highly connected nodes in the interactome among the HO-1 gene binding targets. We further demonstrated that HO-1 modulates the expression of these key genes using Hmox1 deficient cells. Finally, mutation of four conserved amino acids (E215, I211, E201, and Q27) within HO-1 DNA binding domain 1 significantly increased expression of Gtpbp3 and Eif1 genes that were identified within the top 10 binding hits normalized by gene length predicted to bind this domain. Based on these data, we conclude that HO-1 protein is a putative DNA binding protein, and regulates targeted gene expression. This provides the foundation for developing specific inhibitors or activators targeting HO-1 DNA binding domains to modulate targeted gene expression and corresponding cellular function. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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20 pages, 4090 KiB

Open AccessArticle

Antiglycation and Antioxidant Effect of Nitroxyl towards Hemoglobin

by Olga V. Kosmachevskaya, Elvira I. Nasybullina, Igor S. Pugachenko, Natalia N. Novikova and Alexey F. Topunov

Antioxidants 2022, 11(10), 2007; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11102007 - 11 Oct 2022

Cited by 4 | Viewed by 2058

Abstract

Donors of nitroxyl and nitroxyl anion (HNO/NO⁻) are considered to be promising pharmacological treatments with a wide range of applications. Remarkable chemical properties allow nitroxyl to function as a classic antioxidant. We assume that HNO/NO⁻ can level down the non-enzymatic [...] Read more.

Donors of nitroxyl and nitroxyl anion (HNO/NO⁻) are considered to be promising pharmacological treatments with a wide range of applications. Remarkable chemical properties allow nitroxyl to function as a classic antioxidant. We assume that HNO/NO⁻ can level down the non-enzymatic glycation of biomolecules. Since erythrocyte hemoglobin (Hb) is highly susceptible to non-enzymatic glycation, we studied the effect of a nitroxyl donor, Angeli’s salt, on Hb modification with methylglyoxal (MG) and organic peroxide―tert-butyl hydroperoxide (t-BOOH). Nitroxyl dose-dependently decreased the amount of protein carbonyls and advanced glycation end products (AGEs) that were formed in the case of Hb incubation with MG. Likewise, nitroxyl effectively protected Hb against oxidative modification with t-BOOH. It slowed down the destruction of heme, formation of carbonyl derivatives and inter-subunit cross-linking. The protective effect of nitroxyl on Hb in this system is primarily associated with nitrosylation of oxidized Hb and reduction of its ferryl form, which lowers the yield of free radical products. We suppose that the dual (antioxidant and antiglycation) effect of nitroxyl makes its application possible as part of an additional treatment strategy for oxidative and carbonyl stress-associated diseases. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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14 pages, 2500 KiB

Open AccessArticle

The Balancing of Peroxynitrite Detoxification between Ferric Heme-Proteins and CO₂: The Case of Zebrafish Nitrobindin

by Giovanna De Simone, Andrea Coletta, Alessandra di Masi, Massimo Coletta and Paolo Ascenzi

Antioxidants 2022, 11(10), 1932; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11101932 - 28 Sep 2022

Cited by 4 | Viewed by 1250

Abstract

Nitrobindins (Nbs) are all-β-barrel heme proteins and are present in prokaryotes and eukaryotes. Although their function(s) is still obscure, Nbs trap NO and inactivate peroxynitrite. Here, the kinetics of peroxynitrite scavenging by ferric Danio rerio Nb (Dr-Nb(III)) in the absence and [...] Read more.

Nitrobindins (Nbs) are all-β-barrel heme proteins and are present in prokaryotes and eukaryotes. Although their function(s) is still obscure, Nbs trap NO and inactivate peroxynitrite. Here, the kinetics of peroxynitrite scavenging by ferric Danio rerio Nb (Dr-Nb(III)) in the absence and presence of CO₂ is reported. The Dr-Nb(III)-catalyzed scavenging of peroxynitrite is facilitated by a low pH, indicating that the heme protein interacts preferentially with peroxynitrous acid, leading to the formation of nitrate (~91%) and nitrite (~9%). The physiological levels of CO₂ dramatically facilitate the spontaneous decay of peroxynitrite, overwhelming the scavenging activity of Dr-Nb(III). The effect of Dr-Nb(III) on the peroxynitrite-induced nitration of L-tyrosine was also investigated. Dr-Nb(III) inhibits the peroxynitrite-mediated nitration of free L-tyrosine, while, in the presence of CO₂, Dr-Nb(III) does not impair nitro-L-tyrosine formation. The comparative analysis of the present results with data reported in the literature indicates that, to act as efficient peroxynitrite scavengers in vivo, i.e., in the presence of physiological levels of CO₂, the ferric heme protein concentration must be higher than 10⁻⁴ M. Thus, only the circulating ferric hemoglobin levels appear to be high enough to efficiently compete with CO₂/HCO₃⁻ in peroxynitrite inactivation. The present results are of the utmost importance for tissues, like the eye retina in fish, where blood circulation is critical for adaptation to diving conditions. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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13 pages, 2401 KiB

Open AccessArticle

Modulating Nitric Oxide Dioxygenase and Nitrite Reductase of Cytoglobin through Point Mutations

by John Ukeri, Michael T. Wilson and Brandon J. Reeder

Antioxidants 2022, 11(9), 1816; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11091816 - 15 Sep 2022

Cited by 3 | Viewed by 1391

Abstract

Cytoglobin is a hexacoordinate hemoglobin with physiological roles that are not clearly understood. Previously proposed physiological functions include nitric oxide regulation, oxygen sensing, or/and protection against oxidative stress under hypoxic/ischemic conditions. Like many globins, cytoglobin rapidly consumes nitric oxide under normoxic conditions. Under [...] Read more.

Cytoglobin is a hexacoordinate hemoglobin with physiological roles that are not clearly understood. Previously proposed physiological functions include nitric oxide regulation, oxygen sensing, or/and protection against oxidative stress under hypoxic/ischemic conditions. Like many globins, cytoglobin rapidly consumes nitric oxide under normoxic conditions. Under hypoxia, cytoglobin generates nitric oxide, which is strongly modulated by the oxidation state of the cysteines. This gives a plausible role for this biochemistry in controlling nitric oxide homeostasis. Mutations to control specific properties of hemoglobin and myoglobin, including nitric oxide binding/scavenging and the nitrite reductase activity of various globins, have been reported. We have mapped these key mutations onto cytoglobin, which represents the E7 distal ligand, B2/E9 disulfide, and B10 heme pocket residues, and examined the nitric oxide binding, nitric oxide dioxygenase activity, and nitrite reductase activity. The Leu46Trp mutation decreases the nitric oxide dioxygenase activity > 10,000-fold over wild type, an effect 1000 times greater than similar mutations with other globins. By understanding how particular mutations can affect specific reactivities, these mutations may be used to target specific cytoglobin activities in cell or animal models to help understand the precise role(s) of cytoglobin under physiological and pathophysiological conditions. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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15 pages, 1722 KiB

Open AccessArticle

Oxidative Implications of Substituting a Conserved Cysteine Residue in Sugar Beet Phytoglobin BvPgb 1.2

by Simon Christensen, Leonard Groth, Nélida Leiva-Eriksson, Maria Nyblom and Leif Bülow

Antioxidants 2022, 11(8), 1615; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11081615 - 20 Aug 2022

Cited by 4 | Viewed by 1494

Abstract

Phytoglobins (Pgbs) are plant-originating heme proteins of the globin superfamily with varying degrees of hexacoordination. Pgbs have a conserved cysteine residue, the role of which is poorly understood. In this paper, we investigated the functional and structural role of cysteine in BvPgb1.2, a [...] Read more.

Phytoglobins (Pgbs) are plant-originating heme proteins of the globin superfamily with varying degrees of hexacoordination. Pgbs have a conserved cysteine residue, the role of which is poorly understood. In this paper, we investigated the functional and structural role of cysteine in BvPgb1.2, a Class 1 Pgb from sugar beet (Beta vulgaris), by constructing an alanine-substituted mutant (Cys86Ala). The substitution had little impact on structure, dimerization, and heme loss as determined by X-ray crystallography, size-exclusion chromatography, and an apomyoglobin-based heme-loss assay, respectively. The substitution significantly affected other important biochemical properties. The autoxidation rate increased 16.7- and 14.4-fold for the mutant versus the native protein at 25 °C and 37 °C, respectively. Thermal stability similarly increased for the mutant by ~2.5 °C as measured by nano-differential scanning fluorimetry. Monitoring peroxidase activity over 7 days showed a 60% activity decrease in the native protein, from 33.7 to 20.2 U/mg protein. When comparing the two proteins, the mutant displayed a remarkable enzymatic stability as activity remained relatively constant throughout, albeit at a lower level, ~12 U/mg protein. This suggests that cysteine plays an important role in BvPgb1.2 function and stability, despite having seemingly little effect on its tertiary and quaternary structure. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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20 pages, 9174 KiB

Open AccessArticle

Cytoglobin Silencing Promotes Melanoma Malignancy but Sensitizes for Ferroptosis and Pyroptosis Therapy Response

by Joey De Backer, Darko Maric, Karim Zuhra, Annemie Bogaerts, Csaba Szabo, Wim Vanden Berghe and David Hoogewijs

Antioxidants 2022, 11(8), 1548; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11081548 - 10 Aug 2022

Cited by 8 | Viewed by 2346

Abstract

Despite recent advances in melanoma treatment, there are still patients that either do not respond or develop resistance. This unresponsiveness and/or acquired resistance to therapy could be explained by the fact that some melanoma cells reside in a dedifferentiated state. Interestingly, this dedifferentiated [...] Read more.

Despite recent advances in melanoma treatment, there are still patients that either do not respond or develop resistance. This unresponsiveness and/or acquired resistance to therapy could be explained by the fact that some melanoma cells reside in a dedifferentiated state. Interestingly, this dedifferentiated state is associated with greater sensitivity to ferroptosis, a lipid peroxidation-reliant, iron-dependent form of cell death. Cytoglobin (CYGB) is an iron hexacoordinated globin that is highly enriched in melanocytes and frequently downregulated during melanomagenesis. In this study, we investigated the potential effect of CYGB on the cellular sensitivity towards (1S, 3R)-RAS-selective lethal small molecule (RSL3)-mediated ferroptosis in the G361 melanoma cells with abundant endogenous expression. Our findings show that an increased basal ROS level and higher degree of lipid peroxidation upon RSL3 treatment contribute to the increased sensitivity of CYGB knockdown G361 cells to ferroptosis. Furthermore, transcriptome analysis demonstrates the enrichment of multiple cancer malignancy pathways upon CYGB knockdown, supporting a tumor-suppressive role for CYGB. Remarkably, CYGB knockdown also triggers activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and subsequent induction of pyroptosis target genes. Altogether, we show that silencing of CYGB expression modulates cancer therapy sensitivity via regulation of ferroptosis and pyroptosis cell death signaling pathways. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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Review

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18 pages, 2337 KiB

Open AccessReview

Keap1-Nrf2 Heterodimer: A Therapeutic Target to Ameliorate Sickle Cell Disease

by Waseem Chauhan and Rahima Zennadi

Antioxidants 2023, 12(3), 740; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12030740 - 17 Mar 2023

Cited by 4 | Viewed by 2276

Abstract

Sickle cell disease (SCD) is a monogenic inheritable disease characterized by severe anemia, increased hemolysis, and recurrent, painful vaso-occlusive crises due to the polymerization of hemoglobin S (HbS)-generated oxidative stress. Up until now, only four drugs are approved for SCD in the US. [...] Read more.

Sickle cell disease (SCD) is a monogenic inheritable disease characterized by severe anemia, increased hemolysis, and recurrent, painful vaso-occlusive crises due to the polymerization of hemoglobin S (HbS)-generated oxidative stress. Up until now, only four drugs are approved for SCD in the US. However, each of these drugs affects only a limited array of SCD pathologies. Importantly, curative therapies, such as gene therapy, or hematopoietic stem cell transplantation are not available for every patient because of their high costs, availability of donor matching, and their serious adverse effects. Therefore, there is an unmet medical need for novel therapeutic strategies that target broader SCD sequelae. SCD phenotypic severity can be alleviated by increasing fetal hemoglobin (HbF) expression. This results in the inhibition of HbS polymerization and thus sickling, and a reduction in oxidative stress. The efficacy of HbF is due to its ability to dilute HbS levels below the threshold required for polymerization and to influence HbS polymer stability in RBCs. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)-complex signaling is one of the most important cytoprotective signaling controlling oxidative stress. Nrf2 is present in most organs and, after dissociation from Keap1, it accumulates in the cytoplasm, then translocates to the nucleus where it binds to the antioxidant response element (ARE) sequences and increases the expression of various cytoprotective antioxidant genes. Keeping this in mind, various researchers have proposed a role of multiple agents, more importantly tert-Butylhydroquinone (tBHQ), curcumin, etc., (having electrophilic properties) in inhibiting keap1 activity, so that Nrf2 can translocate to the nucleus to activate the gamma globin gene, thus maintaining alpha-hemoglobin-stabilizing protein (AHSP) and HbF levels. This leads to reduced oxidative stress, consequently minimizing SCD-associated complications. In this review, we will discuss the role of the Keap-1–Nrf2 complex in hemoglobinopathies, especially in SCD, and how this complex might represent a better target for more effective treatment options. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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7 pages, 501 KiB

Open AccessPerspective

Hemoglobin Oxidation Reactions in Stored Blood

by Abdu I. Alayash

Antioxidants 2022, 11(4), 747; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040747 - 08 Apr 2022

Cited by 10 | Viewed by 3888

Abstract

Hemoglobin (Hb) inside and outside the red blood cells (RBCs) undergoes constant transformation to an oxidized form in a process known as autoxidation. The ferrous heme iron (Fe²⁺) of the prosthetic group is spontaneously transformed into an oxidized ferric (Fe³⁺ [...] Read more.

Hemoglobin (Hb) inside and outside the red blood cells (RBCs) undergoes constant transformation to an oxidized form in a process known as autoxidation. The ferrous heme iron (Fe²⁺) of the prosthetic group is spontaneously transformed into an oxidized ferric (Fe³⁺) form, but under oxidative stress conditions a higher oxidation ferryl heme (Fe⁴⁺) is also formed. Although Fe³⁺ is a non-functional form of Hb, the Fe⁴⁺ is also extremely reactive towards other biological molecules due to its high redox potential. The RBC contains an effective reductive machinery that maintains Hb in the functional form with little oxidation during its life span. The redox transformation of Hb occurs to a lesser extent in young RBCs; it may, however, have detrimental effects on the integrity of these cells during ex vivo storage or when RBCs are subjected to pathogen reduction processes. In this review, Hb oxidation reactions (“oxidative lesion”) will be described, including details of how these reactions might impact the clinical use of stored or processed blood for therapeutic purposes. Full article

(This article belongs to the Special Issue Globin Associated Oxidative Stress)

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