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19 pages, 4172 KiB

Open AccessArticle

Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

by Maria Borja-Gonzalez, Jose C. Casas-Martinez, Brian McDonagh and Katarzyna Goljanek-Whysall

Antioxidants 2020, 9(4), 345; https://doi.org/10.3390/antiox9040345 - 23 Apr 2020

Cited by 25 | Viewed by 4238

Abstract

Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential [...] Read more.

Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and IL6, as well as H₂O₂, increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or IL6 treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating IL6R, PTEN and FOXO3 signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and IL6, within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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23 pages, 6320 KiB

Open AccessArticle

Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch

by Lukas Bergerhausen, Julius Grosche, Juliane Meißner, Christina Hecker, Michele F. Caliandro, Christoph Westerhausen, Andrej Kamenac, Maryam Rezaei, Matthias Mörgelin, Gereon Poschmann, Dietmar Vestweber, Eva-Maria Hanschmann and Johannes A. Eble

Antioxidants 2020, 9(3), 227; https://doi.org/10.3390/antiox9030227 - 10 Mar 2020

Cited by 12 | Viewed by 3115

Abstract

While adhering to extracellular matrix (ECM) proteins, such as laminin-111, cells temporarily produce hydrogen peroxide at adhesion sites. To study the redox regulation of α7β1 integrin-mediated cell adhesion to laminin-111, a conserved cysteine pair within the α-subunit hinge region was replaced for alanines. [...] Read more.

While adhering to extracellular matrix (ECM) proteins, such as laminin-111, cells temporarily produce hydrogen peroxide at adhesion sites. To study the redox regulation of α7β1 integrin-mediated cell adhesion to laminin-111, a conserved cysteine pair within the α-subunit hinge region was replaced for alanines. The molecular and cellular effects were analyzed by electron and atomic force microscopy, impedance-based migration assays, flow cytometry and live cell imaging. This cysteine pair constitutes a thiol-switch, which redox-dependently governs the equilibrium between an extended and a bent integrin conformation with high and low ligand binding activity, respectively. Hydrogen peroxide oxidizes the cysteines to a disulfide bond, increases ligand binding and promotes cell migration toward laminin-111. Inversely, extracellular thioredoxin-1 reduces the disulfide, thereby decreasing laminin binding. Mutation of this cysteine pair into the non-oxidizable hinge-mutant shows molecular and cellular effects similar to the reduced wild-type integrin, but lacks redox regulation. This proves the existence of a dominant thiol-switch within the α subunit hinge of α7β1 integrin, which is sufficient to implement activity regulation by extracellular redox agents in a redox-regulatory circuit. Our data reveal a novel and physiologically relevant thiol-based regulatory mechanism of integrin-mediated cell-ECM interactions, which employs short-lived hydrogen peroxide and extracellular thioredoxin-1 as signaling mediators. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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10 pages, 1465 KiB

Open AccessArticle

NoxO1 Knockout Promotes Longevity in Mice

by Tim Schader, Christina Reschke, Manuela Spaeth, Susanne Wienstroer, Szeka Wong and Katrin Schröder

Antioxidants 2020, 9(3), 226; https://doi.org/10.3390/antiox9030226 - 10 Mar 2020

Cited by 5 | Viewed by 3710

Abstract

According to the free radical theory of aging, reactive oxygen species (ROS) have been proposed to be a major cause of aging for a long time. Meanwhile, it became clear that ROS have diverse functions in a healthy organism. They act as second [...] Read more.

According to the free radical theory of aging, reactive oxygen species (ROS) have been proposed to be a major cause of aging for a long time. Meanwhile, it became clear that ROS have diverse functions in a healthy organism. They act as second messengers, and as transient inhibitors of phosphatases and others. In fact, their detrimental role is highly dependent on the context of their production. NADPH oxidases (Nox) have been discovered as a controllable source of ROS. NoxO1 enables constitutive ROS formation by Nox1 by acting as a constitutively active cytosolic subunit of the complex. We previously found that both Nox1 and NoxO1 were highly expressed in the colon, and that NoxO1-/- deficiency reduces colon health. We hypothesized that a healthy colon potentially contributes to longevity and NoxO1 deficiency would reduce lifetime, at least in mouse. In contrast, here we provide evidence that the knockout of NoxO1 results in an elongated life expectancy of mice. No better endothelial function, nor an improved expression of genes related to longevity, such as Sirt1, were found, and therefore may not serve as an explanation for a longer life in NoxO1 deficiency. Rather minor systemic differences, such as lower body weight occur. As a potential reason for longer life, we suggest better DNA repair capacity in NoxO1 deficient mice. Although final fatal DNA damage appears similar between wildtype and NoxO1 knockout animals, we identified less intermediate DNA damage in colon cells of NoxO1-/- mice, while the number of cells with intact DNA is elevated in NoxO1-/- colons. We conclude that NoxO1 deficiency prolongs lifetime of mice, which correlates with less intermediate and potentially fixable DNA damage at least in colon cells. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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14 pages, 1939 KiB

Open AccessArticle

Reversible Thiol Oxidation Inhibits the Mitochondrial ATP Synthase in Xenopus laevis Oocytes

by James Cobley, Anna Noble, Rachel Bessell, Matthew Guille and Holger Husi

Antioxidants 2020, 9(3), 215; https://doi.org/10.3390/antiox9030215 - 05 Mar 2020

Cited by 10 | Viewed by 3505

Abstract

Oocytes are postulated to repress the proton pumps (e.g., complex IV) and ATP synthase to safeguard mitochondrial DNA homoplasmy by curtailing superoxide production. Whether the ATP synthase is inhibited is, however, unknown. Here we show that: oligomycin sensitive ATP synthase activity is significantly [...] Read more.

Oocytes are postulated to repress the proton pumps (e.g., complex IV) and ATP synthase to safeguard mitochondrial DNA homoplasmy by curtailing superoxide production. Whether the ATP synthase is inhibited is, however, unknown. Here we show that: oligomycin sensitive ATP synthase activity is significantly greater (~170 vs. 20 nmol/min⁻¹/mg⁻¹) in testes compared to oocytes in Xenopus laevis (X. laevis). Since ATP synthase activity is redox regulated, we explored a regulatory role for reversible thiol oxidation. If a protein thiol inhibits the ATP synthase, then constituent subunits must be reversibly oxidised. Catalyst-free trans-cyclooctene 6-methyltetrazine (TCO-Tz) immunocapture coupled to redox affinity blotting reveals several subunits in F₁ (e.g., ATP-α-F₁) and F_o (e.g., subunit c) are reversibly oxidised. Catalyst-free TCO-Tz Click PEGylation reveals significant (~60%) reversible ATP-α-F₁ oxidation at two evolutionary conserved cysteine residues (C²⁴⁴ and C²⁹⁴) in oocytes. TCO-Tz Click PEGylation reveals ~20% of the total thiols in the ATP synthase are substantially oxidised. Chemically reversing thiol oxidation significantly increased oligomycin sensitive ATP synthase activity from ~12 to 100 nmol/min⁻¹/mg⁻¹ in oocytes. We conclude that reversible thiol oxidation inhibits the mitochondrial ATP synthase in X. laevis oocytes. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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19 pages, 2587 KiB

Open AccessArticle

Cross-talk between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment

by Erin Clapper, Sicong Wang, Prahlad V. Raninga, Giovanna Di Trapani and Kathryn F. Tonissen

Antioxidants 2020, 9(3), 207; https://doi.org/10.3390/antiox9030207 - 03 Mar 2020

Cited by 14 | Viewed by 3076

Abstract

Chronic myeloid leukaemia (CML) is currently treated with inhibitors of the CML specific oncoprotein, bcr-abl. While this strategy is initially successful, drug resistance can become a problem. Therefore, new targets need to be identified to ensure the disease can be appropriately managed. The [...] Read more.

Chronic myeloid leukaemia (CML) is currently treated with inhibitors of the CML specific oncoprotein, bcr-abl. While this strategy is initially successful, drug resistance can become a problem. Therefore, new targets need to be identified to ensure the disease can be appropriately managed. The thioredoxin (Trx) system, comprised of Trx, thioredoxin reductase (TrxR), and NADPH, is an antioxidant system previously identified as a target for therapies aimed at overcoming drug resistance in other cancers. We assessed the effectiveness of TrxR inhibitors on drug resistant CML cells and examined links between TrxR and the bcr-abl cell-signalling pathway. Two TrxR inhibitors, auranofin and [Au(d2pype)₂]Cl, increased intracellular ROS levels and elicited apoptosis in both sensitive and imatinib resistant CML cells. Inhibition of TrxR activity by these pharmacological inhibitors, or by specific siRNA, also resulted in decreased bcr-abl mRNA and protein levels, and lower bcr-abl downstream signalling activity, potentially enhancing the effectiveness of TrxR inhibitors as CML therapies. In addition, imatinib resistant CML cell lines showed upregulated expression of the Trx system. Furthermore, analysis of datasets showed that CML patients who did not respond to imatinib had higher Trx mRNA levels than patients who responded to treatment. Our study demonstrates a link between the Trx system and the bcr-abl protein and highlights the therapeutic potential of targeting the Trx system to improve CML patients’ outcomes. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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19 pages, 2153 KiB

Open AccessArticle

Manganese Porphyrin-Based SOD Mimetics Produce Polysulfides from Hydrogen Sulfide

by Kenneth R. Olson, Yan Gao, Faihaan Arif, Shivali Patel, Xiaotong Yuan, Varun Mannam, Scott Howard, Ines Batinic-Haberle, Jon Fukuto, Magdalena Minnion, Martin Feelisch and Karl D. Straub

Antioxidants 2019, 8(12), 639; https://doi.org/10.3390/antiox8120639 - 12 Dec 2019

Cited by 17 | Viewed by 4468

Abstract

Manganese-centered porphyrins (MnPs), MnTE-2-PyP⁵⁺ (MnTE), MnTnHex-2-PyP⁵⁺ (MnTnHex), and MnTnBuOE-2-PyP⁵⁺ (MnTnBuOE) have received considerable attention because of their ability to serve as superoxide dismutase (SOD) mimetics thereby producing hydrogen peroxide (H₂O₂), and oxidants of ascorbate and simple [...] Read more.

Manganese-centered porphyrins (MnPs), MnTE-2-PyP⁵⁺ (MnTE), MnTnHex-2-PyP⁵⁺ (MnTnHex), and MnTnBuOE-2-PyP⁵⁺ (MnTnBuOE) have received considerable attention because of their ability to serve as superoxide dismutase (SOD) mimetics thereby producing hydrogen peroxide (H₂O₂), and oxidants of ascorbate and simple aminothiols or protein thiols. MnTE-2-PyP⁵⁺ and MnTnBuOE-2-PyP⁵⁺ are now in five Phase II clinical trials warranting further exploration of their rich redox-based biology. Previously, we reported that SOD is also a sulfide oxidase catalyzing the oxidation of hydrogen sulfide (H₂S) to hydrogen persulfide (H₂S₂) and longer-chain polysulfides (H₂S_n, n = 3–7). We hypothesized that MnPs may have similar actions on sulfide metabolism. H₂S and polysulfides were monitored in fluorimetric assays with 7-azido-4-methylcoumarin (AzMC) and 3′,6′-di(O-thiosalicyl)fluorescein (SSP4), respectively, and specific polysulfides were further identified by mass spectrometry. MnPs concentration-dependently consumed H₂S and produced H₂S₂ and subsequently longer-chain polysulfides. This reaction appeared to be O₂-dependent. MnP absorbance spectra exhibited wavelength shifts in the Soret and Q bands characteristic of sulfide-mediated reduction of Mn. Taken together, our results suggest that MnPs can become efficacious activators of a variety of cytoprotective processes by acting as sulfide oxidation catalysts generating per/polysulfides. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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20 pages, 3020 KiB

Open AccessArticle

Fibroblasts to Keratinocytes Redox Signaling: The Possible Role of ROS in Psoriatic Plaque Formation

by Victoria Barygina, Matteo Becatti, Francesca Prignano, Torello Lotti, Niccolò Taddei and Claudia Fiorillo

Antioxidants 2019, 8(11), 566; https://doi.org/10.3390/antiox8110566 - 18 Nov 2019

Cited by 17 | Viewed by 4523

Abstract

Although the role of reactive oxygen species-mediated (ROS-mediated) signalling in physiologic and pathologic skin conditions has been proven, no data exist on the skin cells ROS-mediated communication. Primary fibroblasts were obtained from lesional and non-lesional skin of psoriatic patients. ROS, superoxide anion, calcium [...] Read more.

Although the role of reactive oxygen species-mediated (ROS-mediated) signalling in physiologic and pathologic skin conditions has been proven, no data exist on the skin cells ROS-mediated communication. Primary fibroblasts were obtained from lesional and non-lesional skin of psoriatic patients. ROS, superoxide anion, calcium and nitric oxide levels and lipoperoxidation markers and total antioxidant content were measured in fibroblasts. NADPH oxidase activity and NOX1, 2 and 4 expressions were assayed and NOX4 silencing was performed. Fibroblasts and healthy keratinocytes co-culture was performed. MAPK pathways activation was studied in fibroblasts and in co-cultured healthy keratinocytes. Increased intracellular calcium, •NO and ROS levels as well as an enhanced NADPH oxidase 4 (NOX4)–mediated extracellular ROS release was shown in lesional psoriatic vs. control fibroblasts. Upon co-culture with lesional fibroblasts, keratinocytes showed p38 and ERK MAPKs pathways activation, ROS, Ca²⁺ and •NO increase and cell cycle acceleration. Notably, NOX4 knockdown significantly reduced the observed effects of lesional fibroblasts on keratinocyte cell cycle progression. Co-culture with non-lesional psoriatic and control fibroblasts induced slight cell cycle acceleration, but notable intracellular ROS accumulation and ERK MAPK activation in keratinocytes. Collectively, our data demonstrate that NOX4 expressed in dermal fibroblasts is essential for the redox paracrine regulation of epidermal keratinocytes proliferation. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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Review

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17 pages, 1665 KiB

Open AccessReview

Role of Selenoproteins in Redox Regulation of Signaling and the Antioxidant System: A Review

by Ying Zhang, Yeon Jin Roh, Seong-Jeong Han, Iha Park, Hae Min Lee, Yong Sik Ok, Byung Cheon Lee and Seung-Rock Lee

Antioxidants 2020, 9(5), 383; https://doi.org/10.3390/antiox9050383 - 05 May 2020

Cited by 113 | Viewed by 8075

Abstract

Selenium is a vital trace element present as selenocysteine (Sec) in proteins that are, thus, known as selenoproteins. Humans have 25 selenoproteins, most of which are functionally characterized as oxidoreductases, where the Sec residue plays a catalytic role in redox regulation and antioxidant [...] Read more.

Selenium is a vital trace element present as selenocysteine (Sec) in proteins that are, thus, known as selenoproteins. Humans have 25 selenoproteins, most of which are functionally characterized as oxidoreductases, where the Sec residue plays a catalytic role in redox regulation and antioxidant activity. Glutathione peroxidase plays a pivotal role in scavenging and inactivating hydrogen and lipid peroxides, whereas thioredoxin reductase reduces oxidized thioredoxins as well as non-disulfide substrates, such as lipid hydroperoxides and hydrogen peroxide. Selenoprotein R protects the cell against oxidative damage by reducing methionine-R-sulfoxide back to methionine. Selenoprotein O regulates redox homeostasis with catalytic activity of protein AMPylation. Moreover, endoplasmic reticulum (ER) membrane selenoproteins (SelI, K, N, S, and Sel15) are involved in ER membrane stress regulation. Selenoproteins containing the CXXU motif (SelH, M, T, V, and W) are putative oxidoreductases that participate in various cellular processes depending on redox regulation. Herein, we review the recent studies on the role of selenoproteins in redox regulation and their physiological functions in humans, as well as their role in various diseases. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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17 pages, 1179 KiB

Open AccessReview

Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

by Elena Tibaldi, Enrica Federti, Alessandro Matte, Iana Iatcenko, Anand B. Wilson, Veronica Riccardi, Mario Angelo Pagano and Lucia De Franceschi

Antioxidants 2020, 9(4), 353; https://doi.org/10.3390/antiox9040353 - 24 Apr 2020

Cited by 6 | Viewed by 3685

Abstract

The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of [...] Read more.

The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s). Translational studies have revealed the important link between oxidation and signal transduction pathways in hematological disorders. The intricate nature of intracellular signal transduction mechanisms, based on the generation of complex networks of different types of signaling proteins, revealed the novel and important role of phosphatases together with kinases in disease mechanisms. Thus, therapeutic approaches to abnormal signal transduction pathways should consider either inhibition of overactivated/accumulated kinases or homeostatic signaling resetting through the activation of phosphatases. This review discusses the progress in the knowledge of the interplay between oxidation and cell signaling, involving phosphatase/kinase systems in models of globally distributed hematological disorders. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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20 pages, 1220 KiB

Open AccessReview

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

by Moran Benhar

Antioxidants 2020, 9(4), 309; https://doi.org/10.3390/antiox9040309 - 11 Apr 2020

Cited by 66 | Viewed by 7128

Abstract

It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, [...] Read more.

It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, nitrosative stress and dysregulated cell death are implicated in a wide variety of pathological conditions, including cancer, cardiovascular and neurological diseases. Therefore, much effort is devoted to elucidate the molecular mechanisms linking oxidant/antioxidant systems and cell death pathways. This review is focused on thiol redox modifications as a major mechanism by which oxidants and antioxidants influence specific regulated cell death pathways in mammalian cells. Growing evidence indicates that redox modifications of cysteine residues in proteins are involved in the regulation of multiple cell death modalities, including apoptosis, necroptosis and pyroptosis. In addition, recent research suggests that thiol redox switches play a role in the crosstalk between apoptotic and necrotic forms of regulated cell death. Thus, thiol-based redox circuits provide an additional layer of control that determines when and how cells die. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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15 pages, 1099 KiB

Open AccessReview

Role of Cytosolic 2-Cys Prx1 and Prx2 in Redox Signaling

by Yosup Kim and Ho Hee Jang

Antioxidants 2019, 8(6), 169; https://doi.org/10.3390/antiox8060169 - 10 Jun 2019

Cited by 42 | Viewed by 6493

Abstract

Peroxiredoxins (Prxs), a family of peroxidases, are reactive oxygen species scavengers that hydrolyze H₂O₂ through catalytic cysteine. Mammalian Prxs comprise six isoforms (typical 2-Cys Prxs; Prx1–4, atypical 2-Cys Prx; Prx5, and 1-Cys Prx; Prx6) that are distributed over various cellular [...] Read more.

Peroxiredoxins (Prxs), a family of peroxidases, are reactive oxygen species scavengers that hydrolyze H₂O₂ through catalytic cysteine. Mammalian Prxs comprise six isoforms (typical 2-Cys Prxs; Prx1–4, atypical 2-Cys Prx; Prx5, and 1-Cys Prx; Prx6) that are distributed over various cellular compartments as they are classified according to the position and number of conserved cysteine. 2-Cys Prx1 and Prx2 are abundant proteins that are ubiquitously expressed mainly in the cytosol, and over 90% of their amino acid sequences are homologous. Prx1 and Prx2 protect cells from ROS-mediated oxidative stress through the elimination of H₂O₂ and regulate cellular signaling through redox-dependent mechanism. In addition, Prx1 and Prx2 are able to bind to a diversity of interaction partners to regulate other various cellular processes in cancer (i.e., regulation of the protein redox status, cell growth, apoptosis, and tumorigenesis). Thus, Prx1 and Prx2 can be potential therapeutic targets and it is particularly important to control their level or activity. This review focuses on cytosolic 2-Cys Prx1 and Prx2 and their role in the regulation of redox signaling based on protein-protein interaction. Full article

(This article belongs to the Special Issue Redox Regulation of Cell Signalling)

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