scholarly journals JNK signalling regulates antioxidant responses in neurons

2020 ◽  
Author(s):  
Chris Ugbode ◽  
Nathan Garnham ◽  
Laura Fort-Aznar ◽  
Gareth Evans ◽  
Sangeeta Chawla ◽  
...  
Keyword(s):  
Antioxidant Defense ◽  
Redox Homeostasis ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Wild Type ◽  
Antioxidant Responses ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Adaptive Role

AbstractReactive oxygen species (ROS) are generated during physiological bouts of synaptic activity and as a consequence of pathological conditions in the central nervous system. How neurons respond to and distinguish between ROS in these different contexts is currently unknown. In Drosophila mutants with enhanced JNK activity, lower levels of ROS are observed and these animals are resistant to both changes in ROS and changes in synapse morphology induced by oxidative stress. In wild type flies, disrupting JNK-AP-1 signalling perturbs redox homeostasis suggesting JNK activity positively regulates neuronal antioxidant defense. We validated this hypothesis in mammalian neurons, finding that JNK activity regulates the expression of the antioxidant gene Srxn-1, in a c-Jun dependent manner. We describe a conserved ‘adaptive’ role for neuronal JNK in the maintenance of redox homeostasis that is relevant to several neurodegenerative diseases.

scholarly journals The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
V. Helfinger ◽  
K. Palfi ◽  
A. Weigert ◽  
K. Schröder
Keyword(s):  
Ex Vivo ◽  
Macrophage Polarization ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Superoxide Anions ◽  
Wild Type ◽  
Macrophage Population ◽  
The Family ◽  
High Level

The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.

scholarly journals Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

2021 ◽  
Vol 8 ◽  
Author(s):  
Maite R. Zavala ◽  
Romina G. Díaz ◽  
María C. Villa-Abrille ◽  
Néstor G. Pérez
Keyword(s):  
Antioxidant Defense ◽  
Calcium Transient ◽  
Ros Production ◽  
Oxygen Species ◽  
Force Response ◽  
Wild Type ◽  
Myocardial Stretch ◽  
Thioredoxin 1 ◽  
Two Phases ◽  
Antioxidant Molecule

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.

Photoprotection during iron deficiency is mediated by the bHLH transcription factors PYE and ILR3

2021 ◽  
Vol 118 (40) ◽  
pp. e2024918118
Author(s):  
Garo Z. Akmakjian ◽  
Nabila Riaz ◽  
Mary Lou Guerinot
Keyword(s):  
Singlet Oxygen ◽  
Fe Deficiency ◽  
Bhlh Transcription Factor ◽  
Dependent Manner ◽  
Ros Production ◽  
Oxygen Species ◽  
Wild Type ◽  
Gene Encoding ◽  
Photosynthetic Machinery ◽  
Bhlh Transcription Factors

Iron (Fe) is an essential micronutrient whose availability is limiting in many soils. During Fe deficiency, plants alter the expression of many genes to increase Fe uptake, distribution, and utilization. In a genetic screen for suppressors of Fe sensitivity in the E3 ligase mutant bts-3, we isolated an allele of the bHLH transcription factor (TF) ILR3, ilr3-4. We identified a striking leaf bleaching phenotype in ilr3 mutants that was suppressed by limiting light intensity, indicating that ILR3 is required for phototolerance during Fe deficiency. Among its paralogs that are thought to be partially redundant, only ILR3 was required for phototolerance as well as repression of genes under Fe deficiency. A mutation in the gene-encoding PYE, a known transcriptional repressor under Fe deficiency, also caused leaf bleaching. We identified singlet oxygen as the accumulating reactive oxygen species (ROS) in ilr3-4 and pye, suggesting photosensitivity is due to a PSII defect resulting in ROS production. During Fe deficiency, ilr3-4 and pye chloroplasts retain normal ultrastructure and, unlike wild type (WT), contain stacked grana similar to Fe-sufficient plants. Additionally, we found that the D1 subunit of PSII is destabilized in WT during Fe deficiency but not in ilr3-4 and pye, suggesting that PSII repair is accelerated during Fe deficiency in an ILR3- and PYE-dependent manner. Collectively, our results indicate that ILR3 and PYE confer photoprotection during Fe deficiency to prevent the accumulation of singlet oxygen, potentially by promoting reduction of grana stacking to limit excitation and facilitate repair of the photosynthetic machinery.

scholarly journals Overexpression of catalase in mitochondria mitigates changes in hippocampal cytokine expression following simulated microgravity and isolation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Linda Rubinstein ◽  
Ann-Sofie Schreurs ◽  
Samantha M. Torres ◽  
Sonette Steczina ◽  
Moniece G. Lowe ◽  
...  
Keyword(s):  
Simulated Microgravity ◽  
Cytokine Expression ◽  
Hindlimb Unloading ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Wild Type ◽  
Mitochondrial Ros ◽  
Cytokine Milieu ◽  
The Central Nervous System ◽  
Induced Changes

AbstractIsolation on Earth can alter physiology and signaling of organs systems, including the central nervous system. Although not in complete solitude, astronauts operate in an isolated environment during spaceflight. In this study, we determined the effects of isolation and simulated microgravity solely or combined, on the inflammatory cytokine milieu of the hippocampus. Adult female wild-type mice underwent simulated microgravity by hindlimb unloading for 30 days in single or social (paired) housing. In hippocampus, simulated microgravity and isolation each regulate a discrete repertoire of cytokines associated with inflammation. Their combined effects are not additive. A model for mitochondrial reactive oxygen species (ROS) quenching via targeted overexpression of the human catalase gene to the mitochondria (MCAT mice), are protected from isolation- and/or simulated microgravity-induced changes in cytokine expression. These findings suggest a key role for mitochondrial ROS signaling in neuroinflammatory responses to spaceflight and prolonged bedrest, isolation, and confinement on Earth.

Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders

2020 ◽  
Vol 20 (13) ◽  
pp. 1142-1153 ◽  
Author(s):  
Sreyashi Chandra ◽  
Md. Tanjim Alam ◽  
Jhilik Dey ◽  
Baby C. Pulikkaparambil Sasidharan ◽  
Upasana Ray ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodegenerative Disorders ◽  
The Body ◽  
Therapeutic Approaches ◽  
Cns Disorders ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Present Understanding ◽  
Lateral Sclerosis

Background: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington’s disease (HD). Objective: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. Methods: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. Results: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. Conclusion: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

scholarly journals Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 986
Author(s):  
Nada S. Aboelella ◽  
Caitlin Brandle ◽  
Timothy Kim ◽  
Zhi-Chun Ding ◽  
Gang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Rejection ◽  
Oxygen Species ◽  
Antitumor Effects ◽  
Key Drivers ◽  
Cancer Immunotherapies ◽  
The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

Mitochondria-Targeted Ratiometric Fluorescent Imaging of Cysteine

The Analyst ◽  
2021 ◽  
Author(s):  
Ya-Nan Wei ◽  
Bo Lin ◽  
Yang Shu ◽  
Jian-Hua Wang
Keyword(s):  
Reactive Oxygen Species ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Fluorescent Imaging ◽  
Oxygen Species ◽  
Cellular Redox ◽  
Critical Part ◽  
Physiological Processes

As an indispensable biothiol, cysteine (Cys) plays a critical part in cellular redox homeostasis, pathological and physiological processes. One of the main sources of reactive oxygen species (ROS) in human...

scholarly journals Unique Cellular and Biochemical Features of Human Mitochondrial Peroxiredoxin 3 Establish the Molecular Basis for Its Specific Reaction with Thiostrepton

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 150
Author(s):  
Kimberly J. Nelson ◽  
Terri Messier ◽  
Stephanie Milczarek ◽  
Alexis Saaman ◽  
Stacie Beuschel ◽  
...  
Keyword(s):  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Wild Type ◽  
Cellular Models ◽  
Chemotherapeutic Approach ◽  
Promising Target ◽  
Redox Responsive ◽  
Catalytic Cysteine ◽  
Increased Sensitivity ◽  
Peroxiredoxin 3

A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial peroxiredoxin 3 (PRX3) plays a significant role in detoxifying hydrogen peroxide (H2O2). PRX3 is a molecular target of thiostrepton (TS), a natural product and FDA-approved antibiotic. TS inactivates PRX3 by covalently adducting its two catalytic cysteine residues and crosslinking the homodimer. Using cellular models of malignant mesothelioma, we show here that PRX3 expression and mROS levels in cells correlate with sensitivity to TS and that TS reacts selectively with PRX3 relative to other PRX isoforms. Using recombinant PRXs 1–5, we demonstrate that TS preferentially reacts with a reduced thiolate in the PRX3 dimer at mitochondrial pH. We also show that partially oxidized PRX3 fully dissociates to dimers, while partially oxidized PRX1 and PRX2 remain largely decameric. The ability of TS to react with engineered dimers of PRX1 and PRX2 at mitochondrial pH, but inefficiently with wild-type decameric protein at cytoplasmic pH, supports a novel mechanism of action and explains the specificity of TS for PRX3. Thus, the unique structure and propensity of PRX3 to form dimers contribute to its increased sensitivity to TS-mediated inactivation, making PRX3 a promising target for prooxidant cancer therapy.

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